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1st EAU-ICUDInternational Consultation on Kidney Cancer Barcelona-2010

EDITORSZ. KIRKALI AND P. MULDERS

KIDNEY CANCER

Edition 2011

ICUD

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fo r i n f o r m a t i o n a n d o r d e r s :

D i s t r i b u t o r : eD IT Ions 2 15 B ou leva rd F landrin - 7 5 0 16 Paris - F R AN C EF ax: + 33 1 4 5 0 4 7 2 8 9 E- mail : editions21@ w anadoo.f r

© ICuD - eA u 2 0 1 1A l l r i ght s r e s e r ve d. N o pa r t of t hi s publ i c a t i on m a y be r e pr oduc e d, s t or e d i n a r e t r i e va l s ys t e m , or t r a ns m i t t e d i na n y f or m or by a ny m e a ns , e l e c t r oni c , m e c ha ni c a l , pho t oc opyi ng, r e c o r di ng, or ot he r w i s e , w i t hout pr i or pe r m i s --s i o n of t he publ i s he r .

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T he gr e a t t r a ge dy of s c i e nc e :T he s l a yi ng of a be a ut i f ul hypot he s i s by a n ugl y f a c t

T hom a s H uxl e y ( 1 8 25 - 1 895)

IsB n : 0-9546956- 9- 0

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ConT enT s

- C ontents 3

- Pref ace 4

- F acu lty 6

- Classificatin of Kidney Cancer 9

- Evidence Based Medicine Overview 10

C ommittee 1 : Etiology and Epidemiology 15B . lj u n g b e r g , S. C. Campbell , H. Choi, D. Jacqmin, L.A. Kiemeney, J. Lee, S. Weikert

C ommittee 2 : Basic Research in Kidney Cancer 31e. oo s t e r w i j k , A. Belldegrun, A. R. Brannon, D. S. Finley, K. Junker, F. Pouliot, W. K. Rathmell, H. Uemura,

C ommittee 3 : Pathology 4 7f. A l g a b a , H. Akaza, A. López-Beltrán, G. Martignoni, H. Moch, R. Montironi, V. Reuter.

C ommittee 4 : Prognostic Factors of Renal Cell Carcinoma: A Contemporary Review 7 3P . I. K a r a k i e w i c z, C. Cheng, V. Ficarra, M. Murai, S. Oudard, A. J. Pantuck, S. F. Shariat, R. Zigeuner

C ommittee 5 : Treatment of Localized Renal Cell Carcinoma 9 9H . Va n P o p p e l , F. Becker, J. Caddedu, I. Gill, G. Janetschek, M. Jewett, P. Laguna, M. Marberger, F. Montorsi, T. Polascik, O. Ukimura, G. Zhu

C ommittee 6 : Locally Advanced Disease 15 3C. G . W o o d , T. W. Chong, Y. Hirao, S. Joniau, M. Kuczyk, B. Leibovich, V. Margulis, V. Master, S. Rawal, M. Wirth

C ommittee 7 : Treatment of Metastatic Disease 16 7J .- J . P a t a r d , J . B e l l m u n t , A. Bex, R. Bukowski, T. Choueiri, T. Eisen, B. Escudier, R. Motzer, B. Rini, J. Roigas, C. Sternberg

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Preface to IcUD-eaU InternatIonal

consUltatIon on KIDney cancer 2010

Kidney cancer remains to be an important item in the agenda of medicine. Better understanding of the mechanisms of renal cancer development, advances in surgery, utilization of alternative therapies and development of effective targeted therapies make kidney cancer a hot topic. The International Consultation on Urological Diseases (ICUD) and European Association of Urology (EAU) with the support of European Organisation for Research and Treatment of Cancer (EORTC) Genitourinary Group organized the 2010 International Consultation on Kidney Cancer. Experts from all around the world gathered in Barcelona during the EAU Annu al M eeting on April 16 , 20 10 . Actu ally this w as not a momentou s eve nt b u t a more than a year of planning and hard work of many people. Thanks to the hard work of everyone involved, only 11 months after the event, you are able to hold this excellent book and CD in yo u r hand.

New developments on this disease makes it timely to have a presentation at the and a subsequent consensus report that finally will be presented as a booklet/CD-rom at the 2011 EAU meeting in Vienna.

Usually, when there are many developments in a field during a relatively short period of time, it is not easy to come to a consensus. In this respect, the chairmen of the 7 committees did a tremendou s j ob to set the scene, to create the f oru m f or discu ssing the releva nt evi dence and to finalize the elements of the consensus in their respective committees. While the committees w ent throu g h a consensu s process, they f ollow ed the O xf ord g rading syst em leve ls of evi dence and u sed the f ou r g rades f rom the O xf ord syst em f or recommendations. T his w as done b y a search f or papers throu g h the maj or datab ases cove ring the last ye ars as M edline, Pu b med, Emb ase and C ochrane L ib rary . T hey searched in releva nt j ou rnals and ev alu ated all the papers.

Z. Kirkali P. M u lders

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The first committee chaired by Dr.Ljungberg (Umea, Sweden) inve stig ated the ‘ E ti o l o g y a n d ep i d emi o l o g y ” of renal cell carcinoma (RCC). By describing the risk factors and incidence trends, they ob tained the 20 10 vi ew point and stated consensu s. T he second committee was on “Basic research in kidney cancer” and chaired by Dr Oosterwijk from Nijmegen were relevant research results were summarized. The following committee was dealing with “ P a th o l o g y ” and chaired b y D r.Alg ab a f rom B arcelona, Spain. An ext ensive description w as given on morphology images and cytopathological entities with the latest classification issues describ ed. C ommittee 4 g ave one of most ext ensive ove rvi ew s of “ P r o g n o st i c f a ct o r s” in renal cell carcinoma. Dr.Karakiewicz (Montreal, Canada) and his committee presented a literature-based overview reaching meta-analysis status. In committee 5, Dr.Van Poppel from Leuven, B elg iu m and the g rou p g ave one of the most detailed ove rvi ew s of the cu rrent literatu re on “ T r ea tmen t o f l o ca l i ze d R C C ”. With the use of many illustrations it became one of the best pu b lications on this su b j ect so f ar. “ T r ea tmen t o f Lo ca l l y a d va n ce d R C C ’ : w as inve stig ated b y committee 6 under the chairmanship of Dr.Wood (Houston, USA). This subject was dealt with in a detailed manner and g ave a va lu ab le state- of - the- art on this ve ry timely issu e. F inally the “ T r ea tmen t o f M eta st a ti c d i se a se ” w as handled b y committee 7 co- chaired b y D r.B ellmu nt (Barcelona, Spain) and Dr. Patard (Rennes, France). In a time of rapid changes in the systemic manag ement of R C C , they w ere ab le to implement the latest resu lts in their consensu s.

The ICUD/EAU 2010 International Consultation on Kidney Cancer is the first-time ever consensus meeting on one of the most hot topics in urologic oncology, Kidney Cancer. The chairmen and the exp erts in their respective committees have done a w onderf u l j ob to produ ce this state-of-the-art, evidence based knowledge and recommendations. We are grateful to the executive committees of ICUD and EAU respectively represented by Dr.Paul Abrams from Bristol, UK and Dr.Manfred Wirth from Dresden, Germany. Ms.Evelyn White and her team at EAU Central Office were extremely instrumental in logistics. Last but not least, this book could not be realized without the tireless work of Dr.Saad Khoury and his team.

We hope that you will enjoy reading this timely, up-to-date, evidence-based book and find the recommendations of the world-renown experts in kidney cancer useful in your practice.

Z I Y A K I R K AL I & PET ER M U L D ER S

E d i to r s

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fA CulT Y

C ommittee 1

Etiolog y and Epidemiolog yB . L j ungberg D ep a r tmen t o f S u r g i ca l a n d P er i o p er a ti ve S ci en ce sU meå U n i ve r si tyU meåS w ed en

s. C. Ca m p b e l lS ect i o n o f U r o l o g i c O n co l o g yG l i ckm a n U r o l o g i ca l a n d K i d n ey I n st i tu te a t C l eve l a n d C l i n i cD ep a r tmen t o f U r o l o g yC l eve l a n d , O h i oU . S . A .

H . Y . Ch o iD ep a r tmen t o f U r o l o g yS u n g kyu n kw a n U n i ve r si ty , S ch o o l o f M ed i ci n eS a msu n g M ed i ca l C en terS eo u l K o r ea

D . J a c q m i nU n i ve r si ty o f S tr a sb o u r gD ep a r tmen t o f U r o l o g y S u r g er y D ep a r tmen tS tr a sb o u r gF r a n ce

l.A . K i e m e n e yD ep a r tmen t o f U r o l o g yR a d b o u d U n i ve r si ty N i j meg en M ed i ca l C en tr eN i j meg en T h e N eth er l a n d s

J . e. le eD ep a r tmen t o f F o o d a n d N u tr i ti o nS o o km yu n g W o men ’ s U n i ve r si ty5 2 Hyo ch a n g w o n - g i l , Y o n g sa n - g uS eo u lK o r ea

s. W e i k e r tD ep a r tmen t o f U r o l o g yC h a r i té – U n i ve r si ty M ed i ci n eB er l i nG er ma n y

C ommittee 2

Basic Research in Kidney C ancer

E . O osterw ij k ,D ep a r tmen t o f U r o l o g yR a d b o u d U n i ve r si ty N i j meg en M ed i ca l C en ter N i j meg enT h e N eth er l a n d s

A . B e l l d e g r u n , D ep a r tmen t o f U r o l o g yU n i ve r si ty o f C a l i f o r n i a , S ch o o l o f M ed i ci n eLo s A n g el es, C a l i f o r n i aU . S . A .

A .R. B r a n n o n ,Li n eb er g er C o mp r eh en si ve C a n ce r C en terU n i ve r si ty o f N o r th C a r o l i n aC h a p el Hi l l , N o r th C a r o l i n aU . S . A .

D . s. fi n l e y ,D ep a r tmen t o f U r o l o g yU n i ve r si ty o f C a l i f o r n i a , S ch o o l o f M ed i ci n eLo s A n g el es, C a l i f o r n i aU . S . A .

K . J u n k e r ,D ep a r tmen t o f U r o l o g yU n i ve r si ty Ho sp i ta l s Je n aJe n aG er ma n y

f. P o u l i o t ,D ep a r tmen t o f U r o l o g yU n i ve r si ty o f C a l i f o r n i a , S ch o o l o f M ed i ci n eLo s A n g el es, C a l i f o r n i aU . S . A .

T he Chairs

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W . K . Ra t h m e l l ,Li n eb er g er C o mp r eh en si ve C a n ce r C en terU n i ve r si ty o f N o r th C a r o l i n a C h a p el Hi l l , N o r th C a r o l i n aU . S . A .

H . ue m u r a , D ep a r tmen t o f U r o l o g yK i n ki U n i ve r si ty , S ch o o l o f M ed i ci n eO sa ka - S a ya ma , O sa kaJa p a n

C ommittee 3

PAT H O L O G YF. A l gabaS ect i o n o f P a th o l o g y F u n d a ci ó P u i g ve r tU n i ve r si ta t A u tó n o ma d e B a r ce l o n aB a r ce l o n aS p a i n

H . A k a zaD ep a r tmen t o f U r o l o g y U n i ve r si ty o f T su ku b aT s u ku b a - ci ty , I b a r a kiJa p a n

A . ló p e z- B e l t r á n ,D ep a r tmen t o f S u r g er y a n d P a th o l o g y C o r d o b a U n i ve r si ty , F a cu l ty o f M ed i ci n eC o r d o b aS p a i n

G . M a r t i g n o n iD ep a r tmen t o f P a th o l o g y U n i ve r si ty o f Ver o n aVer o n aI ta l y

H . M o c hD ep a r tmen t P a th o l o g yI n st i tu te o f S u r g i ca l P a th o l o g yU n i ve r si ty Ho sp i ta l o f Z u r i chZ u r i chS w i tze r l a n d

R. M o n t i r o n iD ep a r tmen t o f P a th o l o g yU n i ve r si ty o f A n co n aT o r ette, A n co n aI ta l y

V. Re u t e rP a th o l o g y D ep a r tmen t M emo r i a l S l o a n K etter i n g C a n ce r C en terN ew Y o r k , N ew Y o r kU . S . A .

C ommittee 4

Prog nostic F actors of R enal C ell C arcinoma:A contemporary R evi ew

P . I . K arak iew icz,C a n ce r P r o g n o st i cs a n d Hea l th O u tco me U n i tU n i ve r si ty o f M o n tr ea l Hea l th C en tr eM o n tr ea lC a n a d a

C. Ch e n g , D ep a r tmen t o f U r o l o g yS i n g a p o r e G en er a l Ho sp i ta l S i n g a p o r e

V. fi c a r r a ,D ep a r tmen t o f O n co l o g i ca l a n d S u r g i ca l S ci en ce sU n i ve r si ty o f P a d u aP a d u aI ta l y

M . M u r a i ,D ep a r tmen t o f U r o l o g yK ei o U n i v er si ty , S ch o o l o f M ed i ci n eS h i n j u ku - ku , T o kyoJa p a n

s. ou d a r d ,D ep a r tmen t o f M ed i ca l O n co l o g yG eo r g es P o mp i d o u E u r o p ea n Ho sp i ta lP a r i sF r a n ce

A . J . P a n t u c k ,D ep a r tmen t o f U r o l o g y P a th o l o g yU n i ve r si ty o f C a l i f o r n i a - Lo s A n g el esLo s A n g el es, C a l i f o r n i aU . S . A .

s. f. sh a r i a t ,D ep a r tmen t o f U r o l o g y W ei l l M ed i ca l C o l l eg e o f C o r n el l U n i ve r si ty N ew Y o r k, N ew Y o r kU . S . A .

M . su nC a n ce r P r o g n o st i cs a n d Hea l th O u tco me U n i tU n i ve r si ty o f M o n tr ea l Hea l th C en tr eM o n tr ea lC a n a d a

R. Z i g e u n e r ,D ep a r tmen t o f U r o l o g yU n i ve r si ty Ho sp i ta lK a r l F r a n ze n U n i ve r si ty o f G r a zG r a zA u st r i a

C ommittee 5

T reatment of L ocalize d R enal C ell C arcinoma

H . V an P oppelU r o l o g y D ep a r tmen tU n i ve r si ty Ho sp i ta l Leu ve nLeu ve nB el g i u m

f. B e c k e rU r o l o g y C l i n i cU n i ve r si ty C l i n i c o f S a a r l a n dN eu kr i ch enG er ma n y

J . Ca d d e d uD ep a r tmen t o f U r o l o g yS o u th W est er n M ed i ca l C en terD a l l a sU . S . A .

I. G i l lG l i ckm a n U r o l o g i ca l a n d K i d n ey I n st i tu teC l eve l a n d C l i n i c C l eve l a n d , O h i oU . S . A .

G . J a n e t s c h e kD ep a r tmen t o f U r o l o g yU n i ve r si ty o f S a l zb u r gS a l zb u r gA u st r i a

M . J e w e t tD i vi si o n o f U r o l o g yU n i ve r si ty o f T o r o n toT o r o n toC a n a d a

P . la g u n aD ep a r tmen t o f U r o l o g y A ca d emi c M ed i ca l C en tr eA mst er d a mT h e N eth er l a n d s

M . M a r b e r g e rD ep a r tmen t o f U r o l o g yM ed i ca l U n i ve r si ty Vi en n aVi en n aA u st r i a

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T . P o l a s c i kD u ke U n i ve r si ty M ed i ca l C en terB o x 2 8 0 5 D U M C ,D u r h a m, N C 2 7 7 0 8U . S . A .U k i mu r a O sa mu .U S C I n st i tu te o f U r o l o g yK eck S ch o o l o f M ed i ci n eU n i ve r si ty o f S o u th er n C a l i f o r n i aLo s A n g el es, C a l i f o r n i aU . S . A

G . Z h uD ep a r tmen t o f U r o l o g yB ei j i n g Ho sp i ta lB ei j i n gP eo p l es R ep u b l i c o f C h i n a

C ommittee 6

L ocally Adva nced D isease

C. G . W oodD ep a r tmen t o f U r o l o g y a n d C a n ce r B i o l o g yT h e U n i ve r si ty o f T exa s M . D . A n d er so n C a n ce r C en terHo u st o n , T exa sU . S . A .

T . W . Ch o n gD ep a r tmen t o f U r o l o g yS i n g a p o r e G en er a l Ho sp i ta lS i n g a p o r e

Y . H i r a oD ep a r tmen t o f U r o l o g yN a r a M ed i ca l U n i ve r si ty N a r aJa p a n

s. J o n i a uD ep a r tmen t o f U r o l o g yU n i ve r si ty Ho sp i ta l G a st h u i sb er gLeu ve n B el g i u m

M . K u c zy kD ep a r tmen t o f U r o l o g yE b er h a r d - K a r l s- U n i ve r si tyT ü b i n g en G er ma n y

B . le i b o v i c hD ep a r tmen t o f U r o l o g yM a yo M ed i ca l S ch o o l a n d M a yo C l i n i cR o ch est er , M i n n eso taU . S . A .

V. M a r g u l i sD ep a r tmen t o f U r o l o g yT h e U n i ve r si ty o f T exa s S o u th w est er n M ed i ca l C en ter a t D a l l a sD a l l a s, T exa s U . S . A .

V . M asterD ep a r tmen t o f U r o l o g yE mo r y U n i ve r si tyA tl a n ta , G eo r g i aU . S . A .

S. Raw alD ep a r tmen t o f U r o l o g yR a j i v G a n d h i C a n ce r Ho sp i ta lN ew D el h i I n d i a

M . W irthD ep a r tmen t o f U r o l o g yT ech n i ca l U n i ve r si ty o f D r esd enU n i ve r si ty C a r l G u st a v C a r u sD r esd enG er ma n y

C ommittee 7

T reatment of M etastatic D isease

J . J . P atardD ep a r tmen t o f U r o l o g yC en tr e Ho sp i ta l i er B i cê tr eLe K r eml i n B i cê tr eF r a n ce

J . B el l muntM ed i ca l O n co l o g y S er vi ceHo sp i ta l D el M a rB a r ce l o n aS p a i n

A . B e xD ep a r tmen t o f U r o l o g yN eth er l a n d s C a n ce r I n st i tu teA mst er d a mT h e N eth er l a n d s

R. B u k o w s k iD ep a r tmen t o f U r o l o g y C l eve l a n d C l i n i c F o u n d a ti o nC l eve l a n d , O h i oU . S . A .

T . Ch o u e i r iD ep a r tmen t o f O n co l o g yC l eve l a n d C l i n i c F o u n d a ti o nC l eve l a n d , O h i oU . S . A .

T . ei s e nD ep a r tmen t o f M ed i ca l O n co l o g yU n i ve r si ty o f C a mb r i d g eA d d en b r o o ke ’ s Ho sp i ta lC a mb r i d g eU n i ted K i n g d o m

B . es c u d i e rD ep a r tmen t o f U r o l o g yI n st i tu t G u st a ve R o u ssy Vi l l ej u i fF r a n ce

R. M o t ze rD ep a r tmen t o f U r o l o g yM emo r i a l S l o a n K etter i n g C a n ce r C en terN ew Y o r k , N ew Y o r kU . S . A .

B . Ri n iD ep a r tmen t o f U r o l o g yC l eve l a n d C l i n i cC l eve l a n d , O h i oU . S . A .

J . Ro i g a sD ep a r tmen t o f U r o l o g yVi va n tes K l i n i ku m a m U r b a nB er l i n G er ma n y

C. st e r n b e r gF o n d a zi o n e Vi n ce n so P a n sa d o r oR o meI ta l y

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ClA ssIfICA T Ion of K ID neY CA nCeR

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InT RoD uCT IonThe International Consultation on Urological Diseases (ICUD) is a non-governmental organization registered with the World Health Organisation (WHO). In the last ten years Consultations have been organised on BPH, Prostate Cancer, Urinary Stone Disease, Nosocomial Infections, Erectile Dysfunction and Urinary Incontinence. These consultations have looked at pu b lished ev idence and produ ced recommendations at f ou r lev els; hig hly recommended, recommended, optional and not recommended. This method has been useful but the ICUD b eliev es that there shou ld b e more ex plicit statements of the lev els of ev idence that g enerate the su b sequ ent g rades of recommendations.T he Ag ency f or H ealth C are Policy and R esearch (AHCPR) have used specified evidence levels to justify recommendations f or the inv estig ation and treatment of a v ariety of conditions. T he O x f ord C entre f or Ev idence B ased M edicine hav e produ ced a w idely accepted adaptation of the work of AHCPR. (June 5th 2001 http://minerva.minervation. com/cebm/docs/levels.html). The ICUD has examined the O x f ord g u idelines and discu ssed w ith the O x f ord g rou p their applicability to the Consultations organised by ICUD. It is hig hly desirab le that the recommendations made b y the C onsu ltations f ollow an accepted g rading sy stem su pported b y ex plicit lev els of ev idence.The ICUD proposes that future consultations should use a modified version of the Oxford system which can be directly ‘ mapped’ onto the O x f ord sy stem.1 . 1 s t Step: Define the specific questions or statements

t h a t t h e r e c o m m e n d a t i o n s a r e s u p p o s e d t o a d d r e s s .2 . 2 n d st e p : A n a l y s e a n d r a t e ( l e v e l o f e v i d e n c e ) t h e

r e l e v a n t p a p e r s p u b l i s h e d i n t h e l i t e r a t u r e . T he analy sis of the literatu re is an important step in preparing recommendations and their g u arantee of qu ality .2 . 1 W hat papers shoul d be incl uded in the anal ysis?• Papers pu b lished, or accepted f or pu b lication in the peer

rev iew ed issu es of j ou rnals.• T he committee shou ld do its b est to search f or papers

accepted f or pu b lication b y the peer rev iew ed j ou rnals in the relevant field but not yet published.

• Ab stracts pu b lished in peer rev iew j ou rnals shou ld b e identified. If of sufficient interest the author(s) should be asked for full details of methodology and results. The relev ant committee memb ers can then ‘ peer rev iew ’ the data, and if the data confirms the details in the abstract, then that ab stract may b e inclu ded, w ith an ex planatory f ootnote. T his is a complex issu e – it may actu ally increase pu b lication b ias as “ u ninteresting ” ab stracts commonly do not prog ress to f u ll pu b lication.

• Papers pu b lished in non peer rev iew ed su pplements w ill not b e inclu ded.

An ex hau stiv e list shou ld b e ob tained throu g h:I. the m a j o r d a t a b a s e s covering the last ten years (e.g.

M edline, Emb ase, C ochrane L ib rary , B iosis, Science Citation Index)

II. the t a b l e o f c o n t e n t s of the maj or j ou rnals of u rolog y and other relevant journals, for the last three months, to take into accou nt the possib le delay in the index ation of the pu b lished papers in the datab ases.

It is expected that the highly experienced and expert committee memb ers prov ide additional assu rance that no important stu dy w ou ld b e missed u sing this rev iew process.

2 . 2 H ow papers are anal ysed?Papers pu b lished in peer rev iew ed j ou rnals hav e dif f ering qu ality and lev el of ev idence.Each committee w ill rate the inclu ded papers according to levels of evidence (see below).The level (strength) of evidence provided by an individual stu dy depends on the ab ility of the stu dy desig n to minimise the possib ility of b ias and to max imise attrib u tion.is inuenced by:• t h e t y p e o f s t u d yT he hierarchy of stu dy ty pes are:- Sy stematic rev iew s and meta- analy sis of randomisedcontrolled trials- R andomised controlled trials- N on- randomised cohort stu dies- C ase control stu dies- C ase series- Ex pert opinion• h o w w e l l t h e s t u d y w a s d e s i g n e d a n d c a r r i e d o u tFailure to give due attention to key aspects of study methodology increase the risk of bias or confounding factors, and thu s redu ces the stu dy ’ s reliab ility .T he u se of s t a n d a r d c h e c k l i s t s is recommended to insu re that all relev ant aspects are considered and that a consistent approach is u sed in the methodolog ical assessment of the ev idence.The objective of the check list is to give a quality rating for indiv idu al stu dies.• h o w w e l l t h e s t u d y w a s r e p o r t e dThe ICUD has adopted the CONSORT statement and its widely accepted check list. The CONSORT statement and the checklist are available athttp: //www.consort-statement.org2 . 3 H ow papers are rated?Papers are rated f ollow ing a « le v e l o f ev i d e n c e s c a l e » .ICUD has modified the Oxford Center for Evidence-Based M edicine lev els of ev idence.T he lev els of ev idence scales v ary b etw een ty pes of stu dies (ie therapy, diagnosis, differential diagnosis/symptom prevalence study).the Oxford Center for Evidence-Based Medicine Website: http://minerva.minervation.com/cebm/docs/ levels.html3 . 3 rd Step: Synthesis of the ev idenceAf ter the selection of the papers and the rating of the lev el of ev idence of each stu dy , the nex t step is to compile a su mmary of the indiv idu al stu dies and the ov erall direction of the ev idence in an ev i d e n c e T a b l e .4 . 4 th Step: Considered j udgment ( integration of

indiv idual cl inical ex pertise)H av ing completed a rig orou s and ob j ectiv e sy nthesis of the evidence base, the committee must then make a judgement as to the g rade of the recommendation on the b asis of this ev idence. T his requ ires the ex ercise of j u dg ement b ased on clinical experience as well as knowledge of the evidence and the methods u sed to g enerate it. Ev idence b ased medicine requ ires the integ ration of indiv idu al clinical ex pertise w ith b est

eV IDence – B aseD M eDIcIne oV erV IeW of tH e M aIn stePs forDeV eloPInG anD G raDInG G UIDelIne recoM M enDatIons.

1 1

av ailab le ex ternal clinical ev idence f rom sy stematic research. Without the former, practice quickly becomes tyrannised b y ev idence, f or ev en ex cellent ex ternal ev idence may b e inapplicab le to, or inappropriate f or, an indiv idu al patient: without current bestevidence, practice quickly becomes ou t of date. Althou g h it is not practical to lay ou r “ ru les” f or ex ercising j u dg ement, g u ideline dev elopment g rou ps are asked to consider theevidence in terms of quantity, quality, and consistency ; applicab ility ; g eneralisab ility ; and clinical impact.

5 . 5 t h st e p : fi n a l G r a d i n gThe grading of the recommendation is intended to strike an appropriate b alance b etw een incorporating the complex ity of ty pe and qu ality of the ev idence and maintaining clarity f or g u ideline u sers.T he recommendations f or g rading f ollow the O x f ord C entre f or Ev idence- B ased M edicine.T he lev els of ev idence show n b elow hav e ag ain b een modified in the light of previous consultations. There are now 4 lev els of ev idence instead of 5 .T he g rades of recommendation hav e not b een redu ced and a “ no recommendation possib le” g rade has b een added.

6 . le v e l s o f ev i d e n c e a n d G r a d e s o f Re c o m m e n d a t i o n T h e r a p e u t i c In t e r v e n t i o n s

All interv entions shou ld b e j u dg ed b y the b ody of ev idence for their efficacy, tolerability, safety, clinical effectiveness and cost effectiveness. It is accepted that at present little data ex ists on cost ef f ectiv eness f or most interv entions.6 . 1 L ev el s of E v idenceF irstly , it shou ld b e stated that any lev el of ev idence may b e positive (the therapy works) or negative (the therapy doesn’t work). A level of evidence is given to each individual study.

• le v e l 1 evidence (incorporates Oxford 1a, 1b) usually involves meta-anaylsis of trials (RCTs) or a good quality randomised controlled trial, or ‘ all or none’ stu dies in w hich no treatment is not an option, f or ex ample in v esicov ag inal fistula.

• le v e l 2 evidence (incorporates Oxford 2a, 2b and 2c) includes “low” quality RCT (e.g. < 80% follow up) or metaanalysis (with homogeneity) of good quality prospective ‘ cohort stu dies’ . T hese may inclu de a sing le g rou p w hen indiv idu als w ho dev elop the condition are compared w ith others f rom w ithin the orig inal cohort g rou p. T here can b e parallel cohorts, where those with the condition in the first g rou p are compared w ith those in the second g rou p.

• le v e l 3 evidence (incorporates Oxford 3a, 3b and 4) inclu des:

g o o d q u a l i t y retrospectiv e ‘ case- control stu dies’ w here a g rou p of patients w ho hav e a condition are matched appropriately (e.g. for age, sex etc) with control individuals w ho do not hav e the condition.

g o o d q u a l i t y ‘ case series’ w here a complete g rou p of patients all, with the same condition/disease/therapeutic intervention, are describ ed, w ithou t a comparison control g rou p.

• le v e l 4 evidence (incorporates Oxford 4) includes expert opinion w ere the pinion is b ased not on ev idence b u t on ‘first principles’ (e.g. physiological or anatomical) or bench research. T he D elphi process can b e u sed to g iv e ‘ ex pert opinion’ greater authority. In the Delphi process a series of qu estions are posed to a panel; the answ ers are collected into a series of ‘options’; the options are serially ranked; if a 75% agreement is reached then a Delphi consensus statement can b e made.

6 . 2 G rades of RecommendationThe ICUD will use the four grades from the Oxford system. As w ith lev els of ev idence the g rades of ev idence may apply either positively (do the procedure) or negatively (don’t do the procedure). Where there is disparity of evidence, for example if there w ere three w ell condu cted R C T ’ s indicating that D ru g A w as su perior to placeb o, b u t one R C T w hose resu lts show no dif f erence, then there has to b e an indiv idu al j u dg ement as to the g rade of recommendation g iv en and the rationale ex plained.• G r a d e A recommendation u su ally depends on consistent

lev el 1 ev idence and of ten means that the recommenda--tion is ef f ectiv ely mandatory and placed w ithin a clinical care pathw ay . H ow ev er, there w ill b e occasions w here ex cellent evidence (level 1) does not lead to a Grade A recommenda--tion, f or ex ample, if the therapy is prohib itiv ely ex pensiv e, dangerous or unethical. Grade A recommendation can follow from Level 2 evidence. However, a Grade A recom--mendation needs a g reater b ody of ev idence if b ased on any thing ex cept L ev el 1 ev idence

• G r a d e B recommendation u su ally depends on consistent lev el 2 and or 3 stu dies, or ‘ maj ority ev idence’ f rom R C T ’ s.

• G r a d e C recommendation u su ally depends on lev el 4 stu d--ies or ‘majority evidence’ from level 2/3 studies or Dephi processed ex pert opinion.

• G r a d e D “ N o recommendation possib le” w ou ld b e u sed where the evidence is inadequate or conicting and when ex pert opinion is deliv ered w ithou t a f ormal analy tical pro--cess, su ch as b y D ephi.

7 . le v e l s o f ev i d e n c e a n d G r a d e s o f Re c o m m e n d a t i o n f o r M e t h o d s o f A s s e s s m e n t a n d In v e s t i g a t i o nF rom initial discu ssions w ith the O x f ord g rou p it is clear that application of levels of evidence/grades of recommendation f or diag nostic techniqu es is mu ch more complex than f or interv entions.The ICUD recommend, that, as a minimum, any test should b e su b j ected to three qu estions:1. does the test hav e g ood technical perf ormance, f or

ex ample, do three aliqu ots of the same u rine sample g iv e the same resu lt w hen su b j ected to ‘ stix ’ testing ?

2. D oes the test hav e g ood diag nostic perf ormance, ideally ag ainst a “ g old standard” measu re?

3. D oes the test hav e g ood therapeu tic perf ormance, that is, does the u se of the test alter clinical manag ement, does the u se of the test improv e ou tcome?

For the third component (therapeutic performance) the same approach can b e u sed as f or section 6 .8 . le v e l s o f ev i d e n c e a n d G r a d e s o f Re c o m m e n d a t i o n

f o r B a s i c sc i e n c e a n d ep i d e m i o l o g y st u d i e sThe proposed ICUD system does not easily fit into these areas of science. F u rther research needs to b e carried ou t, in order to dev elop ex plicit lev els of ev idence that can lead to recommendations as to the sou ndness of data in these important aspects of medicine.

ConClusIonT h e ICuD b e l i e v e s t h a t i t s c o n s u l t a t i o n s s h o u l d f o l l o w t h e ICuD s y s t e m o f l e v e l s o f e v i d e n c e a n d g r a d e s o f r e c o m m e n d a t i o n , w h e r e p o s s i b l e . T h i s s y s t e m c a n b e m a p p e d t o t h e ox f o r d s y s t e m .T h e r e a r e a s p e c t s t o t h e ICuD s y s t e m t h a t r e q u i r e f u r t h e r r e s e a r c h a n d d e v e l o p m e n t , p a r t i c u l a r l y d i a g n o s t i c p e r f o r m a n c e a n d c o s t e f f e c t i v e n e s s , a n d a l s o f a c t o r s s u c h a s p a t i e n t p r e f e r e n c e .

P . A b r a m s , s K h o u r y , A . G r a n t 1 9 / 1 / 0 4

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13

KIDney cancer

eD IT oRs

Z . K IRK A lI A nD P . M ulD eRs

14

15

Co m m i t t e e 1

et i o l o g y a n d ep i d e m i o l o g y

Ch a i r m a n :B . LJ U N G B E R G

M e m b e r s :S . C . C A M P B E LL

H. Y . C HO I

D . J A C Q M I N

L. A . K I E M E N E Y

J . E . LE E

S . W E I K E R T

Co r r e s p o n d e n c e B ö rj e L j u ng b erg M D , PhDProf essor of U rolog y C hairman D epartment of Su rg ical and perioperative sciencesU meå U nive rsity9 0 1 8 5 U meå Sw edentel + 4 6 9 0 7 8 5 1330 - f ax + 4 6 9 0 125 39 6

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T A B le of ConT enT s

I. InT RoD uCT Ion

II. InCID enCe of RCC

1 . InCID enCe In euRoP eA n CounT RIes2 . InCID enCe W oRlD W ID e

III. RCC M oRT A lIT Y RA T es

IV. eT IoloG ICA l fA CT oRs

1 . seX :2 . RA Ce:3 . A G e:4 . CIG A ReT T e sM oK InG :

5 . oVeRW eIG H T / oB esIT Y :6 . B looD P RessuRe, H Y P eRT ensIon

A nD use of A nT IH Y P eRT ensIVe M eD ICA T Ions:

7 . ConClusIons:8 . ReCoM M enD A T Ions:

V. G eneT IC fA CT oRs

1 . fA M IlIA l A nD H eReD IT A RY RenA l CA nCeR sY nD RoM es

2 . VH l sY nD RoM e3 . H eReD IT A RY P A P IllA RY RCC4 . fA M IlIA l leIoM Y oM A T osIs RCC5 . B IRT - H oG G - D uB É sY nD RoM e

VI. eT IoloG Y of oT H eR D IseA ses

1 . A CQ uIReD RenA l CY sT IC D IseA se2 . D IA B eT es3 . uRInA RY T RA CT InfeCT Ion4 . ConClusIons:5 . ReCoM M enD A T Ions:

VII. nuT RIT IonA l fA CT oRs, D IeT A nD RenA l Cell CA nCeR ( RCC)

1 . P RoT eIn A nD fA T2 . VIT A M Ins3 . oT H eR nuT RIenT s

VIII. oCCuP A T Ion

17

et i o l o g y a n d ep i d e m i o l o g y

B . LJ U N G B E R G

S . C . C A M P B E LL, H. Y . C HO I ,

D . J A C Q M I N , L. A . K I E M E N E Y , J . E . LE E ,

S . W E I K E R T

R enal cell carcinoma (R C C ) is the most common renal tu mou r and accou nts f or approxi mately 9 0 % of all renal malig nancies.[ 1] D espite adva nces in diag nosis arou nd 20 - 30 % of the patients still have metastatic R C C (mR C C ) at the time of diag nosis[ 2] . Arou nd 20 – 30 % of patients u nderg oing nephrectomy w ill exp erience relapse and deve lop metastasis.[ 1,3] F or these patients w ith mR C C , ou tcomes are g enerally poor and the incidence of R C C and mR C C imposes a seriou s w orldw ide epidemiolog ical b u rden (leve l of evi dence 2)[ 2] . T he g eneral increase in incidence seems to have peake d and decrease in incidence as w ell as in mortality has b een noticed in some cou ntries. L if estyl e f actors are the most important etiolog ical f actors.

II. InCID enCe of RCC

W orldw ide, ki dney cancer is the 14 th most common malig nancy w ith approxi mately 20 0 ,0 0 0 new cases diag nosed in 20 0 2.[ 4 ] Althou g h R C C is a g lob al prob lem, the incidence va ries g eog raphically[ 4 ] . R ates of R C C are hig h in Eu rope, N orth America, and Au stralia, w hereas rates are low in I ndia, Japan, Af rica, and C hina. U ntil the last ye ars, w orldw ide incidence has increased b y ab ou t 2% ye arly . (leve l of evi dence: 3).

1 . InCID enCe In euRoP eA n CounT RIes:

I n 20 0 6 , arou nd 6 4 ,0 0 0 new cases of ki dney cancer w ere estimated in the EU [ 5 ,6 ] (10 th most common cancer, fi g u r e 1 ) and 26 ,4 0 0 ki dney cancer- related deaths occu rred. I n the Eu ropean ob serv atory of cancer of 20 0 9 , estimated ag e- standardize d ki dney cancer incidence rates per 10 0 ,0 0 0 Eu ropeans w ere

14 .5 (N = 4 0 .39 5 ) f or males and 6 .9 (N = 24 .6 5 6 ) f or f emales. C ze ch R epu b lic, L ithu ania, Estonia and I celand have the hig hest R C C rates in Eu rope w hile in R omania, B u lg aria, and Sw itze rland the incidence w as ob serve d low est [ 4 ,6 ] . D if f erences in estimated ki dney cancer incidence and mortality f rom ki dney cancer among males in 27 Eu ropean cou ntries, are show n in t a b l e 1 . Althou g h the w orldw ide incidence of R C C has increased, data f rom a Eu ropean stu dy , analyzi ng ki dney cancer incidence b etw een19 8 0 and 20 0 4 , indicate a shif t tow ards stab iliza tion or eve n a decrease in b oth sexe s in some cou ntries in w estern and northern Eu rope, exce pt f or Eng land, Scotland and I reland, w hereas incidence in Eastern Eu rope has increased [ 7 ] . (leve l of evi dence: 3). ( fi g u r e 2 .)

2 . InCID enCe W oRlD W ID e :

I t is estimated that only in the U S there w ill b e ab ou t 5 4 ,0 0 0 new cases of ki dney cancer and 13,0 0 0 ki dney cancer- related deaths in 20 0 8 .[ 8 ] T he pattern of occu rrence as describ ed f or Eu rope is also ob serve d in the U .S. D ata f rom the Su rve illance, Epidemiolog y , and End R esu lts (SEER ) datab ase show a g reater incidence increase of R C C diag nosed b etw een 19 7 5 and 19 9 8 f or b lack patients ag ed 20 – 5 9 ye ars compared w ith w hite patients of the same ag e and disease stag e (4 .5 % vs 2.9 % , respective ly) [ 9 ,10 ] . Su rvi va l w as also low er among b lack compared w ith w hite patients w ith R C C [ 6 ] . A retrospective stu dy of clinical trial popu lations f rom 19 9 2 to 20 0 2, su pports the finding that race is a predictor of overall survival in patients w ith mR C C .[ 11] F rom the SEER data, it w as also ob serve d that Asian Americans had ab ou t half the risk of ki dney cancer than the other racial/ ethnic g rou ps, w hich is consistent w ith low er incidence rates of R C C in Asian cou ntries.[ 9 ] I n Japan also, ki dney cancer, is more f requ ent in males than in f emales, and show s an su b stantial g eog raphical dif f erence in total incidence w ithin the cou ntry [ 12,13]

I. InT RoD uCT Ion

18

III. RCC M oRT A lIT Y RA T es

K idney cancer accou nted f or 10 2,0 0 0 deaths and the rates w here ab ou t tw ice as hig h f or males as f or f emales. O ve rall mortality rates w ere hig hest in N orth America, Au stralia/ N ew Z ealand and W estern, Eastern and N orthern Eu rope (fi g u r e 3 ). Af rica and Asia reported the low est mortality rates [ 14 ] (leve l of ev idence: 1).

I n 20 0 6 in the Eu ropean U nion the estimated nu mb er of ki dney cancer death w as 27 .326 , arou nd 2,2 % of all cancer deaths (16 .7 9 8 males (rate 5 .8 ) and 10 .5 28 f emales (rate 2.6 ). T he ove rall mortality rates

f or ki dney cancer in EU cou ntries have increased u ntil the late 19 8 0 s/ early 19 9 0 s, thereaf ter rates have stab ilize d or declined.[ 7 ] ( fi g u r e 2 .) I n total the mortality rates declined f rom 4 .8 per 10 0 ,0 0 0 in 19 9 0 – 19 9 4 to 4 .1 in 20 0 0 – 20 0 4 in men, and declined f rom 2.1 to 1.8 per 10 0 ,0 0 0 in w omen.[ 4 ] (leve l of evi dence: 3). T he chang ing mortality rates in the EU va ry among the dif f erent cou ntries. I n Scandinavi a, a decrease in mortality is ob serve d since the 8 0 s, w hereas a decrease since the early 19 9 0 s is seen in F rance, G ermany , I taly , Au stria, and T he N etherlands. T he decreases w ere g enerally g reater in men than in w omen. Some Eu ropean cou ntries do not show decreased mortality rates and an increased rate has b een ob serve d in some of the eastern Eu ropean cou ntries [ 7 ] . T his f avo u rab le trend in mortality w ithin the EU , mig ht in part b e accou nted f or b y improve ments in diag nosis and treatment, and b y the rising incidence of small renal masses, b u t it can not b e f u lly exp lained.[ 15 ,16 ] (leve l of evi dence: 3).

I n the U S, ove rall mortality rates of patients w ith ki dney cancer have increased f rom 1.5 per 10 0 ,0 0 0 in 19 8 3 to 6 .5 per 10 0 ,0 0 0 in 20 0 2.[ 17 ] T his increase mig ht b e at least partly b e exp lained b y the f act that small tu mors are more su ccessf u lly treated and 5 - ye ar relative su rvi va l rates have improve d ove r time f or patients w ith R C C f rom 5 6 .4 % (diag nosed 19 8 3– 19 8 7 ) to 6 8 .9 % (diag nosed 19 9 8 – 20 0 2). [ 16 ] Af ter the b eg inning of 20 0 0 s the rates have b een leve ling of f and slig htly declined u ntil 20 0 6 , a similar trend as is present in Eu rope w here the rates have b een declining in most cou ntries.[ 7 ,18 ,19 ] (leve l of evi dence: 3).

ReCoM M enD A T Ions: N one

IV. eT IoloG ICA l fA CT oRs

1 . seX :

Ag e- standardize d incidence rates of R C C have g enerally b een reported to b e hig her among men than w omen [ 1] . T his pattern is consistently ob serve d throu g hou t the w orld w ith the exce ption of W estern Af rica w ere reported incidence rates seemed to b e hig her among w omen. I ncidence data, in particu lar f rom more deve loped reg ions of the w orld, su g g est that men are at an increased risk of deve loping R C C (leve l of evi dence: 3).

2 . RA Ce:

R eported ag e- standardize d incidence rates of R C C are hig hest in Eu rope and N orthern America [ 1] . T he incidence rates seem to b e su b stantially low er among Asians b oth in most Asian cou ntries and in the U S [ 1- 3] . T hese ob serva tions su g g est a hig her risk of R C C among w hites compared to Asians (leve l of evi dence: 3). T he low est incidence rates have b een reported f rom Af rican cou ntries [ 1] , b u t on

T abl e 1. E stimated incidence and mortal ity rates from k idney cancer in men in 2 7 E uropean countries in 2 0 0 6 ; age standardize d rate per 10 0 , 0 0 0 [ 6 ] .

Co u n t r y In c i d e n c e M o r t a l i t y

C ze ch R epu b lic 28 .9 14 .5 6L ithu ania 27 .0 9 9 .9 5Estonia 24 .26 11.25L atvi a 21.7 6 10 .8 4I celand 20 .7 4 10 .19Poland 20 .0 4 8 .7 3F rance 18 .8 5 .37H u ng ary 17 .7 9 7 .7 5Au stria 17 .7 8 5 .4 5I reland 17 .5 7 7 .0 2B elg iu m 16 .4 7 6 .7 4G ermany 16 .4 3 5 .6 3Slova ki a 15 .8 3 9 .0 3Slove nia 15 .5 6 7 .9 9L u xe mb ou rg 15 .4 5 9 .5 3Eu ropean U nion 14 .5 4 5 .8 3F inland 14 .16 6 .7 8I taly 14 .11 4 .6 6N orw ay 13.0 4 5 .2G reece 11.7 9 4 .33D enmark 10 .9 1 6 .4 2U nited K ing dom, 10 .8 4 5 .8 8T he N etherlands 10 .8 3 5 .9 4C yp ru s 10 .7 4 5 .6 6M alta 10 .0 6 7 .5 2Sw eden 9 .9 2 6 .12B u lg aria 9 .6 9 4 .12Spain 9 .29 4 .38Sw itze rland 8 .24 3.6Portu g al 6 .9 3.32R omania 5 .7 3 3.9 3

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Figure 2 . T rends in ov eral l age- adj usted incidence and mortal ity from RCC per 10 0 0 0 0 men in 11 E uropean countries betw een 19 8 0 and 2 0 0 4 . From L ev i F, et al . B J U I nt. 2 0 0 8 ; 10 1( 8 ) :9 4 9 - 5 8 .

Figure 1. E stimated number of cancer cases and deaths in 4 0 E uropean countries 2 0 0 8 . B ased on an il l ustration in Farl ey J et al , E U RO P E A N J O U RN A L O F CA N CE R 2 0 10 ; 4 6 , 7 6 5 – 7 8 1.

20

the contrary the incidence rates are hig hest among Af rican Americans in the U S [ 2, 3] . R acial disparities in incidence rates may b e attrib u tab le to dif f erences in f requ ency of diag nostic imag ing , access to health care, and preva lence of other risk f actors. At present, ev idence on an independent association b etw een race and R C C risk is inconclu sive .

3 . A G e:

D ata f rom the “ C ancer I ncidence in F ive C ontinents” datab ase at I AR C and the U .S. the Su rve illance, Epidemiolog y , and End R esu lts (SEER ) prog ram indicate that incidence rates in Eu rope and U SA increase consistently w ith ag e, w ith a plateau reached arou nd the ag e g rou p of 7 0 - 7 5 ye ars and ab ove [ 2, 4 ] . T he latter ef f ect may b e du e to less f requ ent diag nostic testing in this ag e g rou p.

4 . CIG A ReT T e sM oK InG :

C ig arette smoki ng has b een estab lished as a risk f actor f or R C C b y a larg e nu mb er of stu dies. A meta-analysi s [ 5 ] inclu ding 19 case- control and 5 cohort studies confirmed that ever smoking increases the risk of R C C compared to neve r smoki ng (leve l of evi dence: 2). T he increases in risk related to eve r smoki ng w ere estimated to b e 5 4 % f or men and 22% f or w omen. T he association b etw een smoki ng and R C C is relative ly w eak, b u t a clear dose- response relationship is evi dent w ith hig her risk estimates w ith heavi er smoki ng [ 5 ] (leve l of evi dence: 2).

T here is only limited evi dence to su g g est that smoki ng cessation may redu ce the risk of R C C in eve r smoki ng men af ter 10 ye ars or long er of non-smoki ng [ 5 - 7 ] (leve l of evi dence: 3). L imited data

Figure 3 . A ge- standardize d mortal ity rates for k idney cancer by gender in different continents ( G l obal Cancer Statistics, 2 0 0 2 [ 14 ] )

21

f rom f ew case- control stu dies su g g est a potential association b etw een passive smoki ng and R C C [ 7 -9 ] (leve l of evi dence: 3).

5 . oVeRW eIG H T / oB esIT Y :

Ex cess b ody w eig ht has b een estab lished as a risk f actor f or R C C in seve ral case- control and cohort stu dies. M ost stu dies inve stig ated b ody mass index (B M I ) u sing self - reported b ody w eig ht and heig ht. A meta- analysi s [ 10 ] of prospective stu dies provi ded ev idence f or an association b etw een B M I and risk of R C C w ith su mmary risk estimates (per 5 kg / m2 increase in B M I ) of 1.24 in men and 1.34 in w omen (leve l of evi dence: 2). T he resu lts su g g ested a somew hat strong er association in w omen than in men, b u t this dif f erence w as not rob u st and mainly drive n b y one larg e N orw eg ian cohort stu dy [ 11] . A qu antitative revi ew of earlier stu dies f ou nd equ ally strong associations among men and w omen. Overall, evidence on sex-specific differences in the association b etw een B M I and R C C risk is not conclu sive . Stu dies inve stig ating b ody f at distrib u tion su g g ested an increased risk of R C C w ith increasing w aist- to- hip ratio [ 12- 15 ] (leve l of evi dence: 3), b u t ev idence is too limited to conclu de that ab dominal ob esity is a risk f actor of R C C independently of B M I . L imited data su g g est an increased risk of R C C w ith weight gain or weight uctuations [12, 13, 16] (level of evi dence: 3).

6 . B looD P RessuRe, H Y P eRT ensIon A nD use of A nT IH Y P eRT ensIVe M eD ICA T Ions:

H y pertension or its treatment has b een associated w ith the risk of R C C in seve ral prospective cohort stu dies [ 14 ,16 - 24 ] (leve l of evi dence: 2). T hree cohort [ 16 , 23, 24 ] and one case- control stu dy [ 25 ] measu red b lood pressu re and ob serve d an increased risk of R C C w ith eleva ted b lood pressu re, w ith a clear dose- response relationship reported in tw o cohort stu dies [ 16 , 24 ] (leve l of evi dence: 2). T w o other prospective cohort stu dies ob serve d an increased risk of R C C mortality w ith eleva ted b lood pressu re in men (fi g u r e 4 . 26 , 27 ). T he independent contrib u tion of b lood pressu re leve l and antihyp ertensive medication u se have g enerally b een difficult to distinguish, as most studies are based on a diag nosis of hyp ertension that is inevi tab ly linke d to treatment w ith antihyp ertensive dru g s. D ata f rom one case- control stu dy and one adequ ately pow ered cohort stu dy indicate that hig h b lood pressu re, rather than the u se of antihyp ertensive medication increases R C C risk [ 24 , 25 ] (leve l of evi dence: 3). O ther stu dies did not consider b lood pressu re and medication u se independently of each other. D ata f rom tw o cohort stu dies su g g est that b etter control of b lood pressu re may low er R C C risk [ 16 , 24 ] (leve l of evi dence: 3), w hereas u se of antihyp ertensive medications inclu ding diu retics is prob ab ly not a cau sal risk f actor [ 17 , 19 , 24 , 25 ] (leve l of evi dence:

3). T he association ob serve d b etw een u se of diu retics and other antihyp ertensive dru g s may thu s b e du e to conf ou nding b y a history of hyp ertension, b u t data on this issu e remain inconclu sive .

7 . ConClusIons:

C ig arette smoki ng , exce ss b ody w eig ht according to increases in B M I , and hyp ertension are the most prevalent modifiable risk factors of RCC increasing the risk independently of each other in b oth sexe s.

L ong - term smoki ng cessation may redu ce R C C risk in men, while its inuence in women is unclear.

B ody f at distrib u tion may impact R C C risk independently of B M I , b u t f u rther stu dies are necessary .

Eleva ted b lood pressu re increases R C C risk, w hile u se of antihyp ertensive medications per se may not b e a risk f actor as long as b lood pressu re is ef f ective ly controlled.

8 . ReCoM M enD A T Ions:

R edu ctions in the preva lence of cig arette smoki ng , exce ss b ody w eig ht, and u ncontrolled b lood pressu re are recommended as preve ntive strateg ies f or R C C (G rade B recommendation). Smoki ng cessation can possib ly decrease R C C risk in ex- smoke rs af ter 10 ye ars or long er (G rade C recommendation). Ef f ective control of b lood pressu re may decrease R C C risk in indivi du als w ith hyp ertension (G rade C recommendation).

V. G eneT IC fA CT oRs

1 . fA M IlIA l A nD H eReD IT A RY RenA l CA nCeR sY nD RoM es

O ve rall, approxi mately 2- 3% of R C C are f amilial, i.e. primarily du e to inherited g enetic def ects (See tab le 2) [ 4 7 ,4 8 ] . Each of the common histolog ic su b typ es of R C C has a corresponding f amilial syn drome, and each of these is cau sed b y a distinct g enetic alteration [ 4 9 ] . All of these syn dromes are relative ly rare, su ch as V H L w hich appears to b e the most common, althou g h f ou nd in only 1/ 36 ,0 0 0 b irths. T hese syn dromes shou ld b e considered in patients w ith early onset and/ or mu ltif ocal/ b ilateral disease. Some are du e to mu tated or inactiva ted tu mor su ppressor g enes and others to activa ted oncog enes, ye t all are transmitted in an au tosomal dominant manner. G enetic cou nseling and g ene sequ encing shou ld b e considered, and appropriate screening f or the other manif estations of the syn dromes shou ld b e perf ormed [ 5 0 ] . F amily memb ers at risk shou ld also b e cou nseled to consider releva nt clinical and g enetic testing . M ost of these syn dromes can b e manag ed conserva tive ly; at least u ntil tu mor size

22

reaches 3.0 cm, b ecau se the risk of metastasis remains relative ly low u ntil this threshold is reached. N ephron- sparing approaches are pref erred in an ef f ort to delay or preclu de the need f or dialysi s [ 5 1] . O ne exce ptional syn drome is f amilial leiomyo matosis R C C in w hich the tu mors are of ten hig hly ag g ressive – a more proactiv e approach is of ten indicated in this sy ndrome.

2 . VH l sY nD RoM e

T he f amilial syn drome f or clear cell R C C is V H L in w hich patients can also deve lop hemang iob lastomas of the central nervo u s syn drome, retinal ang iomas, and pheochromocyt omas. B enig n tu mors in the inner ear, pancreas, and epididym is are also common [ 5 2] . Penetrance f or each of these manif estations is f ar f rom complete, e.g . R C C is only f ou nd in ab ou t 4 0 -5 0 % of patients. T he V H L g ene is located at 3p25 - 26 and produ ces a protein that normally targ ets hyp oxi a indu cib le f actors (H I F s) f or u b iqu itin- mediated deg radation. L oss of f u nction leads to accu mu lation of H I F s and su b sequ ent u preg u lation of V EG F and other f actors that promote ang iog enesis and tu mor g row th [ 5 3] . T u mors in this syn drome thu s tend to b e hig hly va scu lar contrib u ting to their potential morb idity . N ephron- sparing approaches are pref erred b u t V H L ki dney tu mors can b e lethal, and R C C is the most common cau se of death in this syn drome [ 5 0 ] .

ReCoM M enD A T Ion: Active screening f or R C C in patients w ith this syn drome can allow f or early detection and improve d clinical ou tcomes. (G rade C recommendation)

3 . H eReD IT A RY P A P IllA RY RCC

H ereditary papillary R C C is cau sed b y activa tion of the c- met proto- oncog ene on chromosome 7 q31, w hich encodes a g row th f actor receptor. M u tations

lead to constitu tive activa tion of the receptor, w hich promotes tu mor g row th. T yp e 1 papillary R C C is excl u sive ly ob serve d in this syn drome, w hich is u niqu e in that it does not present w ith manif estations in other org an syn dromes [ 4 8 ] .

4 . fA M IlIA l leIoM Y oM A T osIs RCC

F amilial leiomyo matosis R C C can present w ith cu taneou s leiomyo mas and w omen of ten have a history of hyst erectomy f or u terine leiomyo mas at an early ag e. T yp e I I papillary R C C w ith a tendency tow ards ag g ressive tu mor b iolog y is characteristic [ 4 8 , 5 3] . T he f u marate hyd ratase g ene on chromosome 1q4 2 has b een correlated w ith this syn drome, althou g h research to link this K reb s cycl e enzym e to malig nant transf ormation is still in prog ress.

5 . B IRT - H oG G - D uB É sY nD RoM e

B irt- H og g - D u b é (B H D ) syn drome, in w hich patients develop cutaneous fibrofolliculomas, lung cysts, spontaneou s pneu mothoraces, and a va riety of renal tu mors primarily derive d f rom the distal nephron, is the final familial RCC syndrome characterized as of 20 10 . R enal tu mors typ ically inclu de chromophob e R C C , oncocyt omas, and hyb rid or transitional tu mors that exh ib it f eatu res of b oth of these entities [ 4 9 ] . H ow eve r, other f orms of R C C , inclu ding clear cell R C C , have also b een ob serve d in this syn drome, w hich is u niqu e in the dive rsity of tu mor typ es that have b een reported. O ve rall penetrance f or renal tu mors is ab ou t 20 - 4 0 % . M ost renal tu mors in B H D have limited b iolog ical ag g ressive ness, althou g h metastatic b ehavi or and lethality have b een reported. T his syn drome has b een correlated to mu tations in the f ollicu lin tu mor su ppressor g ene on chromosome 17 p11.2 [ 5 0 ] .

Figure 4 . Rel ativ e risk functions of RCC according to systol ic ( A ) and diastol ic ( B ) bl ood pressure in a popul ation based prospectiv e cohort study ( E P I C) . From W eik ert et al , A m J E pidemiol 2 0 0 7 .

23

VI. eT IoloG Y of oT H eR D IseA ses

1 . A CQ uIReD RenA l CY sT IC D IseA se

Acqu ired renal cyst ic disease (AR C D ) consists of mu ltiple hyp erplastic renal cyst s on each ki dney . I t happens in patients w ith end stag e renal disease (ESR D ) and most of ten seen in patients on long -term hemodialysi s.[ 5 4 - 5 6 ] AR C D is also f requ ently associated w ith adenomas and can prog ress to R C C .[ 5 7 ] T he incidence of R C C in AR C D is mu ch hig her than g eneral popu lation Stu dies in the U S reported a

three to six time hig her incidence.[ 5 8 ,5 9 ] I n Japan, R C C dev elops seve ral to tw enty times hig her in dialysi s patients than in the g eneral popu lation.[ 6 0 ] Therefore ARCD is a definite high risk factor of RCC. (leve l of evi dence: 2b ). Also an association of R C C w ith a period of dialysi s w as inve stig ated. T he stu dy reported that patients w ho had 10 y ears of dialy sis dev eloped no sig ns of R C C ev en 15 y ears f orw ards.

I t is controve rsial that renal hyp erplastic cyst s and adenomas u nderg o malig nant transf ormation. B retan [ 6 2] et al insisted that there mig ht b e a prog ression f rom b enig n renal cyst to epithelial hyp erplasia and to RCC based on the findings of renal tumors occurring in hyp erplastic epitheliu m of some complicated cyst s. B u t no other stu dies va lidated the theory .

Syndrome G enetic E l ement M aj or Cl inical M anifestations

vo n H ippel– L indau VHL g ene C lear cell R C C

(chromosome 3p25 - 26 ) H emang iob lastomas

of the central nervo u s syst em

R etinal ang iomas

Pheochromocyt oma

H ereditary c- met proto- oncog ene T yp e 1 papillary R C C

papillary R C C (chromosome 7 q31)

F amilial leiomyo matosis and R C C

F u marate hyd ratase T yp e 2 papillary R C C

(chromosome 1q4 2) C u taneou s leiomyo mas

U terine leiomyo mas

B irt- H og g - D u b é F ollicu lin C hromophob e R C C

(chromosome 17 p11.2) O ncocyt oma

T ransitional tu mors*

O ccasional clear cell R C C

Cutaneous fibrofolliculomas

L u ng cyst s

Spontaneou s pneu mothorax

* A l so k now n as hybrid oncocytic tumors and containing features of both chromophobe RCC and oncocytoma.

A dapted from Campbel l SC, L ane B R: M al ignant Renal T umors. Campbel l - W al sh U rol ogy, 10 h edition. E dited by W ein A J , K av oussi L R, N ov ick A C, P artin A W , P eters CA , E l sev ier, P hil adel phia, P A , Chapter 4 9 , in press, A ugust, 2 0 0 9 .

T abl e 2 . Famil ial Renal Cel l Carcinoma Syndromes. [ 4 9 , 5 2 ] A dapted from Campbel l SC, L ane B R: M al ignant Renal T umors. Campbel l - W al sh U rol ogy, 10 h edition. E dited by W ein A J , K av oussi L R, N ov ick A C, P artin A W , P eters CA , E l sev ier, P hil adel phia, P A , Chapter 4 9 , in press, A ugust, 2 0 0 9 .

24

R C C occu rring in ESR D has a f ew characteristics dif f erent f rom classic R C C . T he ag e w hen R C C is diag nosed is yo u ng er in patients w ith ESR D than in the g eneral popu lation. T he incidence ratio of male to f emale is hig her in patients w ith ESR D than in the g eneral popu lation. (7 : 1 vs 2: 1, respective ly) [ 6 3]

Some inve stig ators reported that the cyst s in the patients w ith AR C D redu ce af ter renal transplantation.[ 6 4 ] H ow eve r, the risk of R C C af ter renal transplantation may not decrease. L evi ne[ 6 5 ] et al. and H einz[ 6 6 ] et al. reported R C C deve loping af ter transplantation.

2 . D IA B eT es

D iab etes mellitu s (D M ) is kn ow n to b e associated w ith an increased risk of seve ral cancers. H ow eve r, D M is a controve rsial risk f actor in R C C .[ 6 7 - 7 1] Two cohort studies reported significantly increased risks of R C C in patients w ith D M w ith relative risks of 1.3 in men and 1.7 in w omen,[ 6 8 ,6 9 ] b u t most of other stu dies f ailed to prove a relation b etw een D M and risk of R C C .[ 7 1- 7 3] T w o international renal-cell- cancer stu dies ob serve d b orderline or no direct association.[ 7 0 ,7 4 ]

A recent epidemiologic study did not find significant O R s b etw een D M and R C C . T he au thors conclu ded that ove rw eig ht and ob esity are w eakl y associated w ith R C C b u t attrib u ting D M as a risk f actor is controve rsial.[ 7 5 ] (leve l of evi dence: 3)

3 . uRInA RY T RA CT InfeCT Ion

C ohort stu dies reg arding U T I history as an independent risk f actor f or R C C are limited. C how et al.[ 7 6 ] inve stig ated the incidence and risk of U T I in a popu lation- b ased cohort of 6 1,14 4 patients hospitalize d f or u rinary stones in Sw eden f rom 19 6 5 to 19 8 3. Af ter 25 ye ars of f ollow - u p, C how et al. reported on no increase in the incidence of R C C f or the su b set of cohort patients w ho had a history of U T I .

I n 5 case control stu dies M cL au g hlin et al.[ 7 7 ] , H iatt et al.[ 7 8 ] , and Parke r et al.[ 7 9 ] reported an increased risk of R C C associated w ith a history of U T I w hile Schlehof er et al.[ 8 0 ] and M cC redie et al.[ 8 1] reported no association. These conicting results indicate that U T I is not an independent risk f actor f or R C C . (lev el of ev idence: 3)

4 . ConClusIons:

ARCD is definitely a risk factor of RCC and patients w ith ESR D shou ld b e reg u larly screened. I t is u nclear w hether transplantation redu ces the risk of R C C . D iab etes and u rinary tract inf ection are controve rsial as independent risk f actors of R C C .

5 . ReCoM M enD A T Ions:

I n AR C D , reg u lar screening of the ki dney (G rade B recommendation) is recommended f or early diag nosis f or R C C .

VII. nuT RIT IonA l fA CT oRs, D IeT A nD RenA l Cell CA nCeR ( RCC)

T here is more than a 10 - f old dif f erence in incidence of ki dney cancer b etw een hig h- income cou ntries and middle/ low - income cou ntries [ 8 2] . I ncidence has increased more than 9 0 % in less than 20 ye ars in Eastern Asia [ 8 3,8 4 ] , coinciding w ith dramatic chang es in f ood su pply and dietary patterns. T og ether these data su g g est that lif estyl e, inclu ding diet, plays a role in R C C deve lopment.

1 . nuT RIenT s

a) P rotein and Fat

An ecolog ic stu dy has reported that the per capita daily intake s of f at and protein are positive ly correlated w ith the incidence of ki dney cancer in b oth men and w omen [ 8 5 ] (leve l of evi dence: 3).

H ig h protein consu mption has b een hyp othesize d to increase R C C risk b ecau se of the potential u nf avo rab le ef f ect on the ki dney of nitrog en w aste produ cts. M ost case- control stu dies have reported non-significant or significant positive associations b etw een intake s of total or animal protein and the risk of R C C [ 8 6 - 8 8 ] (leve l of evi dence: 3). H ow eve r, prospective stu dies, w hich avo id selection and recall b ias b ecau se participants start to b e f ollow ed f rom the b eg inning of the stu dy , and dietary inf ormation is collected prior to diag nosis of R C C , have b een less su pportive . A pooled analysi s of 13 prospective cohort stu dies in the U S, C anada, and Eu rope [ 8 9 ] and a larg e Eu ropean collab orative stu dy [ 9 0 ] ob serve d no association b etw een total, animal, or plant protein and R C C risk (leve l of evi dence: 2).

R esu lts of case- control stu dies on total f at or va riou s typ es of f at intake (ve g etab le, animal, dairy , satu rated, monou nsatu rated, polyu nsatu rated, trans f at, and cholesterol) and R C C risk have b een inconsistent [ 8 7 ,8 8 ,9 0 - 9 2] , and no association w as f ou nd in a collab orative analysi s of 13 prospective cohort stu dies [ 8 9 ] (leve l of evi dence: 2).

b) V itamins

Prospective stu dies of mu ltivi tamin u se and risk of R C C have f ou nd no association [ 9 3,9 4 ] (leve l of evi dence: 2). O ther su pplemental u se or intake of vi tamins (f rom b oth f oods and su pplements), inclu ding f olate and vi tamins A, C , D , and E, have not show n consistent resu lts [ 8 7 ,9 3,9 5 - 10 1] . O ne recent larg e case- control stu dy that exa mined

25

g enetic polym orphisms of vi tamin D receptor g enes su g g ested that vi tamin D cou ld play a role in R C C [ 10 2] (leve l of evi dence: 3), b u t this possib ility needs f u rther stu dy .

c) O ther nutrients

Among stu dies that have exa mined associations b etw een R C C and nu trients ab u ndant in f ru its and vegetables, such as dietary fiber [87,90,91], indivi du al carotenoids [ 8 7 ,8 8 ,9 5 ,9 8 ,10 1,10 3] , and avonoids [97,104,105], many case-control studies and a pooled analysi s of cohort stu dies f ou nd an inve rse association f or some of these nu trients [ 9 5 ,10 3,10 6 ,10 7 ] (leve l of evi dence: 2). H ow eve r, this may b e partly exp lained b y the inve rse association f or intake of f ru its and ve g etab les noted in the same popu lations [ 9 5 ,10 3,10 6 ,10 7 ] . B ecau se stu dies on total carb ohyd rate [ 8 7 ,9 0 ,9 1] or minerals [ 8 7 ,9 6 ,10 7 ] are sparse, their findings cannot be considered conclu sive .

2 . fooD G RouP s

a) Fruits and v egetabl es

Althou g h the resu lts f or f ru its and v eg etab les f rom case- control stu dies of R C C have b een inconsistent [ 8 6 ,8 7 ,10 6 - 110 ] , the larg est su ch stu dies (each w ith more than 5 0 0 R C C cases) have show n more consistent inve rse associations f or total f ru it [ 8 7 ] , total ve g etab les [ 8 7 ,10 6 ,10 9 ] , and su b g rou ps of ve g etab les [ 8 7 ,9 5 ,10 7 ,10 9 ] (leve l of evi dence: 3).

I n a prospective stu dy , a pooled analysi s of 13 cohort stu dies f ou nd that f ru it and ve g etab le consu mption w as associated w ith a low er risk of R C C [ 22] (leve l of evi dence: 2) w hereas stu dies of a larg e Eu ropean [ 111] and a U S [ 112] cohort did not find an inverse association (leve l of evi dence: 2).

b) M eat and FishT he consu mption of red or processed meat w as associated w ith increased risk of R C C in a meta-analysi s of case- control stu dies [ 113] and in other case- control stu dies [ 10 9 ,110 ,114 ] (leve l of evi dence 2). H ow eve r, a pooled analysi s of cohort stu dies f ou nd no increase in risk f or either red meat or processed meat [ 8 9 ] (leve l of evi dence: 2). T he data on pou ltry intake w ere not consistent [ 8 9 ,10 9 ,110 ] .

Total fish intake was not associated with RCC risk in case- control stu dies [ 10 9 ,114 ] or in a pooled analysi s of 13 cohort stu dies [ 8 9 ] (leve l of evi dence: 2). Althou g h one Sw edish cohort stu dy su g g ested a lower risk of RCC among women with high fatty fish consu mption [ 115 ] (leve l of evi dence: 2), stu dies on specific type of fish consumption are few.

c) A l cohol , coffee, and other bev eragesT he main f u nctions of the ki dneys are to reg u late w ater and inorg anic- ion b alance and to excr ete

w aste produ cts and f oreig n chemicals [ 116 ] . B ecau se complicated chemical exch ang es take place in renal tissu es, the risk of R C C may b e af f ected b y the qu antity and typ e of b eve rag es consu med.

Stu dies on intake of alcohol or alcoholic b eve rag e show ed su g g estive inve rse or no associations [ 8 7 ,8 8 ,9 5 ,117 ] . H ow eve r, recent case- control [ 118 -120 ] and cohort stu dies [ 121- 123] show ed that moderate alcohol consumption was significantly inve rsely associated w ith risk of R C C (leve l of evidence: 2). Total uid intake was not associated with R C C risk [ 124 ] (leve l of evi dence: 2), su g g esting that the du ration that carcinog enic solu tes are in contact w ith R C C may b e u nrelated to the mechanism b y w hich alcohol preve nts R C C risk.

C of f ee intake w as not associated w ith R C C risk in most case- control stu dies [ 8 8 ,9 2,9 5 ,125 ,126 ] , b u t a pooled analysi s of cohort stu dies f ou nd a low er risk of R C C w ith cof f ee consu mption [ 127 ] (leve l of evi dence: 2).

F inding s on other b eve rag es inclu ding sof t drinks, j u ice, milk, and tea w ere inconsistent in prospective stu dies [ 127 ,128 ] and in case- control stu dies [ 8 6 -8 8 ,10 6 ,10 9 ,110 ,117 ,125 ,129 ,130 ] .

3 . oT H eR fooD G RouP s

R esu lts w ere inconsistent f or cereals, g rain produ cts, g lyce mic index/ g lyce mic load [ 8 7 ,8 8 ,10 7 ,110 ,131- 133] , and dairy produ cts other than milk, inclu ding eg g s, yo g u rt, ice cream, cheese [ 8 7 ,8 8 ,9 7 ,10 6 ,10 7 ,10 9 ] .

VIII. oCCuP A T Ion

W orldw ide, ki dney cancer occu rs ab ou t tw ice as f requ ent among males as among f emales. B ecau se of this male/ f emale ratio and the w idespread interest in health ef f ects related to occu pational exp osu res, seve ral stu dies inve stig ated associations b etw een occu pation and ki dney cancer.

Q u ite a f ew stu dies presented clearly increased risks of ki dney cancer related to seve ral occu pations, possib ly b ecau se of historical hig h exp osu re leve ls. A larg e international case- control stu dy f ou nd significant associations with employment in the blast-f u rnace or the coke - ove n indu stry (R R 1.7 ), the iron and steel indu stry (R R 1.6 ) and exp osu re to asb estos (R R 1.4 ), cadmiu m (R R 2.0 ), dry- cleaning solve nts (R R 1.4 ), g asoline (R R 1.6 ) and other petroleu m produ cts (R R 1.6 ) (leve l of evi dence: 3).[ 134 ] Similar associations w ere f ou nd in a mu lticenter stu dy f rom G ermany .[ 135 ] T hese stu dies w ere condu cted in the nineties w ith qu estionnaires ab ou t exp osu res in the decades b ef ore that. N ow adays, in g eneral, strong ly increased risks are not f ou nd anym ore, althou g h a recent stu dy condu cted in C entral and Eastern

26

Eu rope, the area w ith the hig hest rates of ki dney cancer w orldw ide, su g g ested an association b etw een ki dney cancer and ag ricu ltu ral w ork, particu larly among f emale w orke rs (leve l of evi dence: 3).[ 136 ]

A commonly reported toxi c mineral w ith su g g ested nephrocarcinog enicity is asb estos.[ 1] A more recent meta- analysi s of asb estos- exp osed cohort stu dies conclu ded, how eve r, that there is u nconvi ncing ev idence of an increased association, althou g h hig h asb estos exp osu re mig ht cau se a small increase in risk (leve l of evi dence: 2).[ 137 ]

W orke rs exp osed to hig h leve ls of polycycl ic aromatic hy drocarb ons, like coke and coal ove n w orke rs, w ere reported to have an increased risk of ki dney cancer (leve l of evi dence: 3).[ 134 1] T he resu lts of two cohort studies showed a highly significant ex cess of mortality among steelw orke rs as coke ov en w orke rs, b u t af ter a f ollow - u p of 30 ye ars no increased mortality risk w as f ou nd anym ore (leve l of ev idence: 2).[ 138 ] Also, a stu dy of Eu ropean asphalt w orke rs did not show an increased ki dney cancer risk. [ 139 ]

F inding s indicate that there is no association between oil refinery workers, who are highly exposed to g asoline, and risk of ki dney cancer. A popu lation-b ased case- control stu dy of occu pational exp osu re condu cted in the 19 8 0 s in C anada f ou nd an O R of 1.0 f or b oth g asoline and other exp osu re to lead and ki dney cancer.[ 14 0 ] T he same w as tru e in a stu dy f rom Sw eden w here occu pational diesel exp osu re w as not f ou nd to b e related to ki dney cancer (leve l of ev idence: 3).[ 14 1]

Perchloroethyl ene is a primary solv ent in the dry-cleaning indu stry w hich may b e carcinog enic to hu mans.[ 14 2] A revi ew of occu pational exp osu re to perchloroethyl ene and cancer did not su pport this su g g estion and reported that apart f rom limitations and inconsistencies in the pu b lished literatu re, a relationship b etw een PC E and ki dney cancer is u nlike ly (leve l of evi dence: 3).[ 14 3] T richloroethyl ene (T C E), a solve nt u sed as va por deg reaser f or the cleaning of metal parts, w as linke d to ki dney cancer b ecau se of evi dence of carcinog enicity in exp erimental animals, and some reg ions in G ermany have a hig h T C E exp osu re[ 14 4 ] B u t these findings are not supported by the results of other inve stig ations that conclu ded that the carcinog enicity of trichloroethyl ene in hu mans remains a matter of controve rsy (leve l of evi dence: 3).[ 14 5 ]

R ecently a case- control stu dy of pesticides exp osu re and kidney cancer showed a significantly increased risk[146], but more studies are needed to confirm these findings (level of evidence: 3).

ConClusIon: B ased on the literatu re, ove rall, ki dney cancer is not considered to b e a typ ical occu pation- related tu mor.[ 14 7 ]

ReCoM M enD A T Ion: I t is g enerally recommended to decrease or preve nt exp osu re to occu pational carcinog ens (e.g ., asb estos, polycycl ic aromatic hyd rocarb ons, dry- cleaning solvents, cadmium) by means of modifications of produ ction processes or protective interve ntions. Su ch policies may also low er the risk of renal cell cancer, b u t presu mab ly to a small ext ent only (G rade C R ecommendation).

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113. F aramaw i M F , Johnson E, F ry M W , Sall M , Y i Z . C onsu mption of dif f erent typ es of meat and the risk of renal cancer: meta- analysi s of case- control stu dies. C ancer C au ses C ontrol 20 0 7 ; 18 : 125 - 33.

114 . H u J, L a V ecchia C , D esM eu les M , N eg ri E, M ery L . M eat

and fish consumption and cancer in Canada. Nutr Cancer 20 0 8 ; 6 0 : 313- 24 .

115 . W olk A, L arsson SC , Johansson JE, Ekm an P. L ong - term fatty fish consumption and renal cell carcinoma incidence in w omen. JAM A 20 0 6 ; 29 6 : 137 1- 6 .

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121. Allen N E, B eral V , C asab onne D , et al. M oderate Alcohol I ntake and C ancer I ncidence in W omen. J N atl C ancer I nst 20 0 9 .

122. L ee JE, H u nter D J, Spieg elman D , et al. Alcohol intake and renal cell cancer in a pooled analysi s of 12 prospective stu dies. J N atl C ancer I nst 20 0 7 ; 9 9 : 8 0 1- 10 .

123. Setiaw an V W , Stram D O , N omu ra AM , K olonel L N , H enderson B E. R isk f actors f or renal cell cancer: the mu ltiethnic cohort. Am J Epidemiol 20 0 7 ; 16 6 : 9 32- 4 0 .

124 . L ee JE, G iova nnu cci E, Smith- W arner SA, Spieg elman D, Willett WC, Curhan GC. Total uid intake and use of indivi du al b eve rag es and risk of renal cell cancer in tw o larg e cohorts. C ancer Epidemiol B iomarke rs Prev 20 0 6 ; 15 : 120 4 - 11.

125 . B enhamou S, L enf ant M H , O ry- Paoletti C , F lamant R . R isk f actors f or renal- cell carcinoma in a F rench case-control stu dy . I nt J C ancer 19 9 3; 5 5 : 32- 6 .

126 . M ontella M , T ramacere I , T ava ni A, et al. C of f ee, decaf f einated cof f ee, tea intake , and risk of renal cell cancer. N u tr C ancer 20 0 9 ; 6 1: 7 6 - 8 0 .

127 . L ee JE, H u nter D J, Spieg elman D , et al. I ntake s of cof f ee, tea, milk, soda and j u ice and renal cell cancer in a pooled analysi s of 13 prospective stu dies. I nt J C ancer 20 0 7 ; 121: 224 6 - 5 3.

128 . W ashio M , M ori M , Saka u chi F , et al. R isk f actors f or kidney cancer in a Japanese population: findings from the JAC C Stu dy . J Epidemiol 20 0 5 ; 15 Su ppl 2: S20 3- 11.

129 . B ianchi G D , C erhan JR , Parke r AS, et al. T ea consu mption and risk of b ladder and ki dney cancers in a popu lation- b ased case- control stu dy . Am J Epidemiol 20 0 0 ; 15 1: 37 7 -8 3.

130 . Y u M C , M ack T M , H anisch R , C icioni C , H enderson B E. C ig arette smoki ng , ob esity , diu retic u se, and cof f ee consu mption as risk f actors f or renal cell carcinoma. J N atl C ancer I nst 19 8 6 ; 7 7 : 35 1- 6 .

131. B oeing H , Schlehof er B , W ahrendorf J. D iet, ob esity and risk f or renal cell carcinoma: resu lts f rom a case control-stu dy in G ermany . Z Ernahru ng sw iss 19 9 7 ; 36 : 3- 11.

132. G eorg e SM , M ayn e ST , L eitzm ann M F , et al. D ietary g lyce mic index, g lyce mic load, and risk of cancer: a prospective cohort stu dy . Am J Epidemiol 20 0 9 ; 16 9 : 4 6 2-7 2.

133. G aleone C , Pelu cchi C , M aso L D , et al. G lyce mic index, g lyce mic load and renal cell carcinoma risk. Ann O ncol 20 0 9 .

30

134 . M andel JS, M cL au g hlin JK , Schlehof er B et al. I nternational renal- cell cancer stu dy . I V . O ccu pation. I nt J C ancer. 19 9 5 ; 6 1(5 ): 6 0 1- 6 0 5 .

135 . Pesch B , H aerting J, R anf t U , K limpel A, O elschlag el B , Schill W . O ccu pational risk f actors f or renal cell carcinoma: agent-specific results from a case-control study in G ermany . M U R C Stu dy G rou p. M u lticenter u rothelial and renal cancer stu dy . I nt J Epidemiol. 20 0 0 ; 29 (6 ): 10 14 -10 24 .

136 . H eck JE, C harb otel B , M oore L E et al. O ccu pation and renal cell cancer in C entral and Eastern Eu rope. O ccu p Envi ron M ed. 20 0 9 .

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139 . B of f etta P, B u rstyn I , Partanen T et al. C ancer mortality among Eu ropean asphalt w orke rs: an international epidemiolog ical stu dy . I . R esu lts of the analysi s b ased on j ob titles. Am J I nd M ed. 20 0 3; 4 3(1): 18 - 27 .

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14 1. B of f etta P, D osemeci M , G ridley G , B ath H , M oradi T , Silve rman D . O ccu pational exp osu re to diesel eng ine emissions and risk of cancer in Sw edish men and w omen. C ancer C au ses C ontrol. 20 0 1; 12(4 ): 36 5 - 37 4 .

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14 4 . B ru ning T , Pesch B , W iesenhu tter B et al. R enal cell cancer risk and occu pational exp osu re to trichloroethyl ene: resu lts of a consecu tive case- control stu dy in Arnsb erg , G ermany . Am J I nd M ed. 20 0 3; 4 3(3): 27 4 - 28 5 .

14 5 . R aaschou - N ielsen O , H ansen J, M cL au g hlin JK et al. C ancer risk among w orke rs at D anish companies u sing trichloroethyl ene: a cohort stu dy . Am J Epidemiol. 20 0 3; 15 8 (12): 118 2- 119 2.

14 6 . K arami S, B of f etta P, R othman N et al. R enal cell carcinoma, occu pational pesticide exp osu re and modification by glutathione S-transferase polymorphisms. C arcinog enesis. 20 0 8 ; 29 (8 ): 15 6 7 - 15 7 1.

14 7 . Siemiatycki J, R ichardson L , Straif K et al. L isting occu pational carcinog ens. Envi ron H ealth Perspect. 20 0 4 ; 112(15 ): 14 4 7 - 14 5 9 .

31

Co m m i t t e e 2

B a s i c Re s e a r c h i n K i d n e y Ca n c e r

Ch a i r :

E . O O S T E R W I J K ,

M e m b e r s :A . B E LLD E G R U N A . R . B R A N N O N , D . S . F I N LE Y , K . J U N K E R ,F . P O U LI O T ,

W . K . R A T HM E LL,H. U E M U R A ,

Co r r e s p o n d e n c eEg b ert O osterw ij k26 7 Exp erimental U rolog yD epartment of U rolog yU nive rsity M edical C enter N ij meg en6 5 0 0 H B N ij meg enT he N etherlands

32

T A B le of ConT enT s

I. InT RoD uCT Ion

II. T H e M oleCulA R B A sIs of RenA l CA nCeR

III. T A RG eT eD T H eRA P Ies In RCC

IV. RCC A nD T H e IM M une sY sT eM

V. G eneT IC fA CT oRs A nD RCC

VI. ConClusIons

33

B a s i c Re s e a r c h i n K i d n e y Ca n c e r

E . O O S T E R W I J K ,

A . B E LLD E G R U N , A . R . B R A N N O N , D . S . F I N LE Y ,

K . J U N K E R , F . P O U LI O T , W . K . R A T HM E LL,

H. U E M U R A ,

C ancer of the ki dney is exp ected to af f ect almost 10 0 .0 0 0 patients in the U nited States and Eu ropean U nion in 20 10 [ 1; 2] . R enal cell carcinomas (R C C ) ref er to cortically derive d tu mors of the renal parenchym a and encompass a heterog eneou s g rou p of cancers [3]. Advances in basic research aimed at defining pivo tal molecu lar eve nts in the deve lopment of these dif f erent entities has show n that renal cancers can be subdivided based on genetic profiles. Moreover, kn ow ledg e of u nderlyi ng molecu lar characteristics identified the vascular endothelial growth factor (V EG F ) and the mammalian targ et of rapamyci n (mT O R ) pathw ay s as f u ndamental to the b iolog y of clear cell R C C . T his b iolog ic insig ht provi ded a rationale f or targ eting these g row th f actor sig naling pathw ays in R C C .

B asic science in R C C is a va st area theref ore w e w ill f ocu s on f ou r areas of research that w ere f elt most releva nt f or renal cancer and are not discu ssed in- depth in other chapters: the molecu lar b asis of renal cancer, targeted therapies, renal cancer and immunity, and genetic factors and RCC. Finally, it is important to note that g reat maj ority of b asic research in R C C is f ocu sed on clear cell R C C g ive n the hig h prevalence of this histological subtype. Additionally, w hile the va st maj ority of stu dies have b een performed on material from primary lesions, future stu dies shou ld consider exa mination of metastatic lesions as w ell.

II. T H e M oleCulA R B A sIs of RenA l CA nCeR

Historically, four main histological renal cancers were recognized in the Heidelberg classification: clear

cell Renal Cell Cancer (ccRCC, 60-80%), papillary RCC (10-15%), chromophobe RCC (~5%) and renal oncocytoma (~5%) [3;4] Recently, translocation linked[5;6], mucinous tubular and spindle type RCC [7] and tubulocystic carcinoma[8] (all comprising <1% of cases) have b een added to this list. I t is now clear that these morpholog ical su b typ es represent hig hly dissimilar diseases in b oth g enetics and clinical behavior, and thus may or may not be variants of a common cancer or common cell of orig in ( fi g u r e 1 ) .

T he b iolog y of the vo n H ippel- L indau (V H L ) g ene product, pVHL, and its regulation of the hypoxia indu cib le f actor (H I F ) f amily of hyp oxi a- reg u lated transcription factors, is tightly linked to ccRCC biology. The discovery of the VHL gene, and its association w ith the V H L syn drome of central nervo u s system hemangioblastomas, pheochromocytoma/ paraganglioma, and ccRCC, in 1993[9] quickly led to the discove ry that V H L mu tation is also tig htly associated with sporadic ccRCC, detected in up to 90% of tumors [10-13]. The loss of VHL leads to the loss of regulation of HIF family members HIF1α, HIF2α [14-18], and HIF3α [19], which is further composed of sev eral splice va riants. X enog raf t stu dies have demonstrated that restoration of pV H L expression or suppression of deregulated HIF2α impairs the g row th of these tu mors [ 20 ; 21] .

Papillary RCC, chromophobe RCC and renal oncocyt oma are less dominated b y mu tations in a sing le g ene. M u tations in c- met have b een associated with familial papillary type 1 RCC, but only in a subset of sporadic papillary RCC, and is thus less dominant than VHL is for ccRCC [22]. A more rare, but also hig hly ag g ressive typ e of papillary typ e I I renal cell carcinoma has b een associated w ith mu tations in the fumarate hydratase gene [23], although the releva nce of this mu tation in sporadic disease is u nkn ow n. H eterozyg ou s kn ock- ou t of the g ene

I. InT RoD uCT Ion

34

implicated in the B irt- H ig g - D u b é (B H D ) syn drome in mice leads to the deve lopment of renal cyst s and three different histological types of renal tumors, similar to hu man B H D w hich is closely associated with familial chromophobe RCC, but predisposes to other histologies as well [24].

I n spite of the tig ht correlation of ccR C C w ith inactivation of VHL, the effect on HIF deregulation is not u nif orm: va riant mu tations in V H L may contrib u te to imbalances of HIF1α and HIF2α deregulation, leading to distinct ef f ects on cell g row th [ 25 ; 26 ] . I n a strateg y to determine w hether tu mors cou ld b e defined based upon the most studied and understood pathway in RCC, gene expression profiles were linke d w ith V H L mu tation analysi s and exp ression characteristics of the HIFs [27]. In this study, 160 ccRCCs were classified as VHL mutant or wild ty pe and according to H I F protein exp ression. V H L mutant, HIF1 and HIF2 expressing tumors (H1H2) overexpressed the Akt/mTOR pathway, while VHL mu tant tu mors exp ressing solely H I F 2 (H 2 tu mors) replicated more rapidly, marked by overexpression of Ki-67, which other groups have identified as a poor-

risk marker [28]. ccRCC can thus be characterized as H1H2 or H2, with dramatically differing effects on tu mor cell prolif eration and C - myc reg u lation [ 27 ] . R ecent evi dence su g g ests that the H 2 tu mors may be derived from H1H2 tumors that lose HIF1α in a subset of tumors, suggesting a potentially selective pressure to lose the HIF1α gene during tumor progression [29]. These insights potentially narrow the key tumorigenic events within the VHL/HIF axis.

Besides VHL loss and HIF activation, major efforts have ye t to identif y a simple linear prog ression of g enetic lesions accou nting f or the g ains in aggressiveness in RCC [30-34]. Two recent ccRCC cyt og enetic stu dies lend clu es to u nderstanding this prog ression. O ne stu dy perf ormed b oth sing le nu cleotide polym orphism (SN P) analysi s and g ene ex pression analysi s on sporadic ccR C C and tu mors f rom patients w ith V H L disease [ 30 ] . Importantly, this study demonstrated that tumors f rom sporadic and V H L - disease ccR C C tu mors have overall similar profiles, but sporadic tumors are more heterog enou s and contain a hig her nu mb er of genetic events per tumor, but they cannot be

Figure 1: Schematic representation of the nephron and the different subtypes of RCC according to the ‘Heidelberg’ classification in relation to their positions within the nephron and collecting tubule. Genetic changes that are characteristic for the different RCC subtypes are indicated.

35

disting u ished u sing u nsu pervi sed analysi s of g ene expression data. In a prospective analysis of 282 ccRCC patients with up to 108 months of follow-up using traditional cytogenetic karyotyping techniques [ 32] chromosomal loss at 3p (the g enomic home of the VHL gene) was significantly associated with improved disease-specific survival, while losses of 4p, 9p and 14q were significantly associated with reduced disease-specific survival, but the specific g enes in these reg ions implicated in cau sing the poor prog nosis remain to b e characterize d.

The first whole sequencing study in ccRCC confirmed that considerab le g enetic heterog eneity exi sts in ccRCC [29] emphasizing that even though the vast maj ority of ccR C C contain mu tated V H L most like ly every tumor has a unique gene signature. This study also substantiated findings in multiple mouse knock-out studies and a zebrafish study which demonstrated that VHL mutations/knock out alone is insufficient to produ ce ccR C C and that additional g enetic eve nts are required [35;36].

Although unable to cause sporadic ccRCC alone, the presence and typ e of V H L mu tations in tu mors have b een consistently considered as possib le b iomarke rs. Cowey, et al, recently reviewed its potential in prog nosis and prediction [ 37 ] . F u rther research is still required to establish VHL’s efficacy as a biomarker, but given the frequency of its inactivation, more opportu nities to u nderstand the heterog eneity of this disease may lie in exp loration of dow nstream f actors. W hen V H L is inactiva ted and H I F exp ression constitutively stabilized, a host of other genes w hich make u p va riou s components of the hyp oxi a response are transcriptionally u preg u lated (revi ew ed in [38]). It remains to be determined which of these factors or pathways most significantly contributes to the formation or maintenance of ccRCC’s malignant phenotype. One HIF target, the vascular endothelial growth factor (VEGF), has been found to be significantly upregulated in kidney tumors compared to its eleva ted exp ression in many other cancers. As a prognostic biomarker, VEGF has not been proven to be valuable, but may be predictive of response to VEGF targeted therapy, as described below.

I n order to identif y more ef f ective b iomarke rs and further understand the underlying biology, several dif f erent g rou ps perf ormed g ene ex pression analyse s on ccR C C tu mor samples. T a b l e 1 g ive s an ove rvi ew of these studies. One of the initial expression profiling studies examined 29 ccRCC tumors, identifying 51 g enes that cou ld classif y tu mors b ased on 5 ye ar disease-specific survival [39]. This study verified the possibility that gene expression profiles could be used to predict outcome in ccRCC, but remains to be validated or defined by biological parameters that may accou nt f or this dif f erence in disease activi ty . One study of 51 tumor samples identified vascular cell adhesion molecule-1, VCAM-1, as a prognostic

biomarker [40], which has subsequently undergone retrospective validation [41;42]. Importantly, high exp ression of this molecu le predicted f or b etter ove rall su rvi va l in b oth clear cell and papillary tumors, suggesting that VCAM-1 expression may g enerally indicate tu mor cells w ith low er metastatic potential. T he f u rther implications f or sensitivi ty to antiang iog enic therapy are not ye t kn ow n.

Several gene signatures for RCC progression, for example three genes (caveolin 1, lysyl oxidase, and annexin A4) have been identified as associated with RCC aggression and/or survival [43] [44]. Similarly, su rvi vi n w as show n to independently predict clear cell progression and risk of death [45] [46]. Finally, the largest study, analyzing 177 clear cell tumors, identified 340 transcripts (including VCAM-1) significant in multivariate analysis with stage, grade and performance status [47] [48].

W hile the ab ove stu dies f ocu sed on clinical endpoints in their analyses, many started with an unsupervised analysi s to g et a g eneral u nderstanding of the data. The study that identified VCAM-1 as a prognostic b iomarke r saw the presence of potentially tw o subgroups within the stage IV tumors, with survival differences [40]. This suggests that molecular f eatu res b eyo nd clinical stag ing cou ld provi de inf ormative data in u nderstanding eve n metastatic tumor behavior. The group of Zhao, et al. examined their 177 tumors using 3,674 genes also observed two larger groups of ccRCC, with significant survival dif f erences as w ell as predicted b iolog ical pathw ay distinctions [47]. These studies helped to set the stag e f or f u rther delineation of su b g rou ps w ithin ccR C C .

T w o other stu dies stand ou t as b eing predominantly g eared tow ard identif yi ng the inherent su b g rou ps and u nderlyi ng b iolog ical dif f erences of ccR C C . One group first looked at 16 ccRCC tumors and saw that there seemed to be two types of clear cell, one that more hig hly ove rexp ressed metab olic g enes and the other extracellular matrix/cell adhesion genes[49]. Most recently, a bioinformatic technique called u nsu pervi sed consensu s clu stering w as u sed on 48 tumors to identify two subtypes of ccRCC, ccA and ccB, distinguished by fewer than 120 probes[50]. Validating these results in the Zhao, et al., data set of 177 tumors, patients with ccA tumors have a marke d su rvi va l adva ntag e ove r those w ith ccB tumors. Additionally, this dataset validates the characteristics that ccA tumors display a profile of altered metabolism, whereas ccB tumors display characteristics of w ou nd healing and epithelial to mesenchym al transition.

Finally, one study focused entirely on metastases [51], finding that late occurring metastases more highly expressed genes involved in angiogenesis, cell migration and adhesion. Additionally, genes

36

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38

related to cell divi sion and cell cycl e w ere ov erexp ressed in samples f rom patients w ith multiple metastases, indicating that the presence of more metastases mig ht b e cau sed b y an increased g row th potential.

All of the potential b iomarke rs emerg ing f rom the g ene expression studies require removal and processing of at least part of the tu mor. Plasma seru m proteins have traditionally been studied to find non-invasive diag nostic marke rs f or the presence of ccR C C as compared to normal or benign renal tissue. Currently, there are no circu lating tu mor marke rs ava ilab le f or clinical u se in manag ement of R C C . Seve ral molecu les have b een stu died as candidates f or diag nosis of R C C : I n clear cell R C C the resu lts w ith VEGF and VEGFR have been contradictory[52;53], and these marke rs mig ht b e more su itab le as predictive than as diag nostic marke rs. R ecent stu dies have show n eleva ted C AI X leve ls in ccR C C patients [54], with a significant association between C AI X seru m leve ls and occu rrence of metastases [55]. Furthermore, in patients with localized disease an eleva ted C AI X leve l predicts the recu rrence and is correlated with a shorter PFS. Again, there is not a complete concordance w ith tissu e resu lts. O ther markers related to tumor biology like MMP-7, CD95, bFGF, hepcidin-25, Il-10 or IL-6 showed promising results as possible biomarkers for RCC [56-60], b u t these marke rs need to b e va lidated in separate stu dies. B ecau se of the complexi ty of the tu mor deve lopment and progression, identification of complex protein sig natu res is more promising . H ig h throu g hpu t technolog ies like M AL D I (M atrix- assisted laser desorption/ionization) or SELDI (Surface Enhanced Laser Desorption/Ionisation) allow the analysis of the w hole proteome of many samples in a short time w ith hig h sensitivi ty . SEL D I - T O F - M S (T ime of F lig ht M ass Spectrometry) has especially b een u sed to define prognosis related profiles. Unique protein sig natu res of tu mor patients compared to normal controls with high sensitivity (70-87%) and specificity (89.9-92%) have been described [56-63]. One of the candidate proteins, SAA1, was identified by 3 groups[61;64;65]. In all published studies, elevated SAA1 concentration correlated with metastasis, poor prognosis and shorter survival [61;64-66], ev en thou g h dif f erent cu t- of f va lu es w ere u sed. I ndependent stu dies are needed to su b stantiate the va lu e of SAA1. Finally, an 831 tumor tissue microarray study analyzed 15 proteins that are associated w ith the pV H L and phosphatase and tensin homolog u e (PT EN ) pathways [67]. Surprisingly, while pVHL and phospho-mT O R staining correlated inve rsely w ith tu mor stag e and grade, neither protein correlated with survival. Within the intermediate stage tumors (pT2 and pT3), tu mors w ith p27 and C AI X exp ression associated w ith improve d ou tcome. T his stu dy su g g ests that

the dysr eg u lation of seve ral independent pathw ays are crucial for tumor progression, corroborating the sequencing study by Dalglish, et al. [29].

MicroRNA, 21-23 nucleotide segments of single-stranded non-coding RNA, have now been implicated in tumorigenesis of many cancers, even being identified as potential prognostic biomarkers in several of these (reviewed in [68]). The aberrant exp ression of these non- coding R N As can provi de a powerful method of epigenetic tumor regulation, as an indivi du al microR N A can alter the exp ression of many target genes. In RCC, various studies have identified various individual or panels of microRNAs that are dif f erentially exp ressed b etw een normal renal tissu e and tu mor or b etw een histolog ical subtypes [69-76]. The identification of relevant targ ets of these tu mor associated microR N As are just becoming realized [74]. MicroRNAs can be easily extracted from formalin fixation, paraffin embedded tissue, and blood. The ability to easily u se non- inva sive measu res to identif y a stab le targ et make s microR N As a ve ry attractive b iomarke r f or diagnostic, prognostic, and predictive purposes.

A larg e nu mb er of potential b iomarke rs have emerg ed f rom all these g ene exp ression stu dies. Encouragingly, trends are beginning to emerge b etw een stu dies. T he next important step w ill b e b ring ing these potential b iomarke rs and b iomarke r profiles to the clinical arena.

III. T A RG eT eD T H eRA P Ies In RCC

T he increased u nderstanding of the f u ndamental disease b iolog y of R C C has b een translated into the deve lopment of therapies w ith inhib itory activi ty against the implicated pathways, particularly the V EG F and mT O R pathw ays. A nu mb er of tyr osine ki nase inhib itors (T K I ) have now b een reg istered for treatment of metastatic RCC (mRCC) (sunitinib, sorafenib, pazopanib) and more TKI (e.g. axitinib, tivo za nib ) are b eing deve loped. T he rapid and simu ltaneou s emerg ence of seve ral active compou nds has f ar ou tpaced the ab ility to critically u nderstand precise mechanisms of response and resistance [ 7 7 ] ( fi g u r e 2 ) .

Surprisingly, the TKI were clinically implemented w ith ve ry f ew preceding pre- clinical stu dies. F or example, the cross-reactivity of TKI with non-target (non-VEGF-receptor) TK [78] was established after clinical implementation and preclinical stu dies in va riou s animal models demonstrated stab iliza tion or reg ression of xe nog raf ted tu mors (mostly in non- R C C models). T he rationale to stu dy this new categ ory of dru g s in R C C patients w as b ased on theoretical considerations that these T K I attacke d pathways essential in RCC biology and, therefore, mig ht b e appropriate new dru g s f or R C C therapy .

39

Indeed, the effects of TKI in RCC patients are impressive, with objective response rates as high as 45% (reviewed by e.g., Rini et al. [79]), but treatment is often accompanied by many side effects requiring dose redu ction or cessation of treatment.

T K I treatment of R C C patients leads to a massive destru ction of the tu mor va scu latu re w ith concomitant tu mor necrosis. W hether R C C cells themselve s are targeted remains uncertain [80]. At pharmacological releva nt doses no ef f ect on tu mor cells w as observed[80] and there is evidence that tumor co-option occurs, i.e., tumor growth along larger mature vessels, permitting tumors to escape TKI treatment. Additionally, resistance to existing VEGF blocking agents may include upregulation of HIF- and/or non-

HIF-mediated angiogenic proteins or inadequate targ et inhib ition. mT O R therapy resistance may invo lve a compensatory increase in u pstream elements leading to H I F produ ction [ 7 7 ] .

Obviously, predictive biomarkers for response to TKI in mRCC patients are urgently needed, and some have b een describ ed. Seru m f rom patients w ith clinical response or prog ression w as screened b y cyt oki ne arrays to discove r that T N F - alpha and MMP-9 levels remained low in responders [81]. Additionally, high levels of these proteins in the serum correlated w ith decreased ove rall su rvi va l. I n another study, low serum levels of sVEGFR-3 and VEGF-C corresponded w ith long er prog ression f ree su rvi va l (PF S) and ob j ective response rate in b eva cizu mab -

Figure 2: In conditions of normoxia and normal von Hippel Lindau (VHL) gene function, VHL protein is the substrate recognition component of an E3 ubiquitin ligase complex that targets hypoxia-inducible factor alpha (HIFα) for proteolysis. In cellular hypoxia or with an inactivated VHL gene, the VHL protein-HIF interaction is disrupted, leading to stabilization/accumulation of HIF transcription factors. HIF accumulation can also result from activation of mammalian target of rapamycin (mTOR) downstream of cellular stimuli and the PI3-K/Akt pathway. mTOR phosphorylates and activates p70S6K leading to enhanced translation of certain proteins including HIF. Activated HIF translocates into the nucleus and leads to transcription of a large repertoire of hypoxia-inducible genes including vascular endothelial growth factor (VEGF) and platelet derived growth factor (PDGF). These ligands bind to their cognate receptors present on the surface of endothelial cells, leading to cell migration, proliferation and permeability. Sites of action of targeted therapies are illustrated. Temsirolimus and everolimus bind to FK506-binding protein (FKBP), and the resultant protein–drug complex inhibits the kinase activity of the mTOR complex 1 (mTORC1). Bevacizumab is a VEGF ligand-binding antibody. Sunitinib, sorafenib, axitinib and pazopanib are small molecule inhibitors of multiple tyrosine kinase receptors including VEGF-R and PDGFR (Reprinted with permission. © 2008 American Society of Clinical Oncology. Rini BI: Metastatic renal cell carcinoma: many treatment options, one patient. J Clin Oncol 2009;27:3225-34.)

40

refractory mRCC [82]. A third study suggested that large changes in serum VEGF, sVEGFR-2 and sV EG F R - 3 leve ls corresponded w ith tu mor response [83], and a fourth study found a correlation between fold-increase of serum VEGF and clinical benefit [84]. All of these potential predictive biomarkers require external validation in larger sample sizes, b u t su g g est that seru m may prove to contain cog ent marke rs of su rvi va l and response.

IV. RCC A nD T H e IM M une sY sT eM

T here is increasing evi dence that T K I treatment leads to alterations of the immu ne statu s of R C C patients [85;86]. Sunitinib can reverse myeloid-derived suppressor cell induced immune suppression, but other stu dies indicate that Su nitinib can inhib it the prolif eration of primary hu man T cells f rom normal healthy vo lu nteers as w ell as f rom R C C patients [87]. Moreover, sunitinib treatment appears to reve rse T h1 su ppression and impairs N K f u nction. Similarly, sorafenib treatment impairs NK activity and cytotoxicity at pharmacological levels [85]. Also, sorafenib treatment leads to a decrease of T reg in primary lesions and T reg leve ls decrease to normal leve ls af ter soraf enib treatment. W hether the immu ne component is important and mig ht b e u sed to ou r adva ntag e in desig ning comb ination therapies is an uncharted field [86].

I t is important to realize that R C C tu mors deve lop in immu ne competent hosts and that these tu mors have escaped f rom immu ne su rve illance and immu ne editing leading to tu mor cells that are resistant to immu ne- syst em mediated destru ction ( fi g u r e 3 ) [88]. Nevertheless, to date, immunotherapy is the only treatment that can consistently indu ce du rab le complete clinical responses in mRCC [89].

Seve ral stu dies have demonstrated the ab ility of tumor infiltrating lymphocytes (TIL) to induce tumor response in mR C C w ith ob j ective response rates between 0 and 25 %, with concomitant infusion of IL-2 [90-95]. At UCLA, patients with largely advanced and metastatic disease received a combination of TIL/CD8+ and IL-2. Overall, 9.1 % of patients achieved CR while 25.5% had a PR showing the potential of TIL in mRCC [94]. Taken together these studies demonstrated the need of u sing hig hly selective and specific activation methods of effector cells in order to achieve a meaning f u l antitu mor immu ne response. Unlike melanoma, where specific T-cell clones against well-defined tumor epitopes can be frequently generated, T-cell clones that specifically recog nize ki dney cancer tu mor antig ens are hard to g enerate. T he proof of concept of isolating these clones and su ccessf u lly treat patients w ith mR C C has how eve r b een w ell estab lished. O n the other

hand, given the in vitro work needed to isolate TIL, this approach still needs to prove that it indu ces b etter clinical responses than H D - I L 2 alone.

Side stu dies of clinical trials w ith dendritic cells loaded with cell lysates, peptides, or RNA or Treg depletion have demonstrated the induction of specific T cell responses, but no clear correlation between clinical benefit and the occurrence of a immune reaction was found [96;97]. There is evidence that va riou s f actor hamper an anti- tu mor response: defective CD8 signaling, a Th2-bias, and elevated leve ls of g ang liosides f rom T cells are associated with T cell dysfunction[98;99]. Basic research aimed at u nderstanding the relation b etw een R C C and immu ne cells have reve aled an increasing ly complex pictu re w ith many playe rs. C ross- talk b etw een R C C and dendritic cells (DC), Treg, CD4+, CD8+, NK-cells, γδT cells, NK-like T cells, and Myeloid Derived Suppressor Cells, have been described[100]. T he plasticity of cells f rom the immu ne syst em is ext raordinary and the tu mor milieu plays a pivo tal role and can greatly inuence the outcome.

In recent studies, efforts were poised at gene-modified T-cells [101] and multimodality immune-based strategies [102]. Gene-modified T cells in melanoma has show n interesting resu lts w ith tw o CR [103]. For RCC, infusion of gene-modified T cells with CAIX specificity lead to liver toxicity, probably du e to destru ction of b ile epithelial cells that also exp ress C AI X [ 10 1] . Althou g h this demonstrated that the gene-modified did exert the desired specificity, the ob serve d toxi city also hig hlig hts the potential prob lems of this approach: ext raordinary tu mor specificity appears to be of utmost importance. I n the mu lti- modality immu ne- b ased strateg y the CA9 and GMCSF genes were inserted in an adenovi ru s g enome to inf ect D C w hich allow ed the expression of the GMCSF/CA9 fusion protein [102]. O ve rexp ression of the f u sion protein in D C throu g h adenoviral infection CA9 specific T cells could be generated with toxicity against RCC. Hence, this new strateg y comb ines many immu notherapy approaches: 1) the immu nostimu latory ef f ects of cyt oki nes; 2) the va ccine capab ilities of D C and; 3) the specific antitumor activity generated by tumor antigen gene delivery in APC. Indeed, the CA9-GMCSF/DC based vaccine is an example of the new mu ltimodality immu ne- b ased strateg ies that may enhance the w ell- estab lished potentials of immu notherapy in R C C .

T he ef f ective ness of tu mor va ccines has b een show n in many animal models. However, translation to the clinic has proven difficult, possibly because in these model syst ems natu rally occu rring tu mors have not been studied, thereby avoiding tumor surveillance and tumor editing. Thus, the concept is tested in immune competent hosts that are va ccinated w ith peptides or tu mor homog enates and challeng ed w ith vi ab le

41

tumor cells or, alternatively, vaccination strategies are tested in animals w ith estab lished tu mors. I nitial tu mor va ccines w ere b ased on total tu mor cell lys ates that w ere inj ected to the patients (au tolog ou s tumor cell vaccines). However, new strategies using genetically modified tumor cells, antigen presenting cells (APC) or tumor specific peptides have been developed to increase the specificity of the response. T w o phase- I I I clinical trials that have u sed au tolog ou s cell lysa te or peptides to preve nt recu rrence in hig h-risk RCC patients have been published [104;105]. Jocham et al. have reported a statistically significant increase in 5-year PFS (77.4 vs 67.8%, p=0.0204) f or the v accine g rou p in hig h- risk non- metastatic RCC patients. More recently, Wood et al. published a similar stu dy in hig h- risk non- metastatic patients u sing heat shock protein derive d peptide va ccines and did not ob serve a statistical dif f erence in PF S (p=0.51). However, secondary analysis did show an almost statistically significant PFS survival when only stage I and II patients where included (p=0.056).

Therefore, vaccine approaches show great promise in preve nting recu rrence af ter nephrectomy b u t the subgroups of patients that would beneficiate from su ch therapy still need to b e determined. Animal models in w hich the natu ral history of hu man R C C can b e replicated w ill b e of g reat va lu e to test this concept more rig orou sly .

V. G eneT IC fA CT oRs A nD RCC

Epidemiological studies have conclusively identified three risk f actors f or the deve lopment of R C C : hypertension, obesity and smoking [106-108]. Furthermore, there is evidence that genetic factors inuence susceptibility to RCC; for instance, the lif e- time risk increases approxi mately tw o- f old f or those with a first-degree relative with RCC [109]. Thus far, candidate gene studies have not yielded notab le candidate g enes. I n a recent g enome- w ide association stu dy (G W AS) of R C C three su sceptib ility

Figure 3: Extrinsic tumor suppression by the immune system. Transformed cells (in this example kidney cells with mutated VHL) escaping intrinsic control are subjected to extrinsic tumor suppressor mechanisms that detect and eliminate developing tumors before they become clinically apparent. This is known as the elimination phase of a broader process that has been termed cancer immunoediting. Cancer immunoediting is now considered a process composed of 3 phases: elimination, or cancer immune surveillance; equilibrium, a phase of tumor dormancy where tumor cells and immunity enter into a dynamic equilibrium that keeps tumor expansion in check; and escape, where tumor cells emerge that either display reduced immunogenicities or engage a large number of possible immunosuppressive mechanisms to attenuate antitumor immune responses leading to the appearance of progressively growing tumors (Figure adapted from Swann JB, Smyth MJ. Immune surveillance of tumors. J Clin Invest 2007;117:1137-46. Reprinted with permission).

42

loci on chromosomes 2p21 (EPAS1), 11q13.3 and 12q24.31 (SCARB1) were identified (Purdue et al, submitted). The findings from the GWAS provided further evidence that EPAS1 (HIF2α) is a key gene in RCC development, but additional studies are needed to identify the functionally relevant common variants associated with increased risk.

Up to now little attention has been paid to inter-ethnic variability or individual differences, whereas this is an important aspect in the current TKI era. Patients of afro-american descent have higher incidence rates and lower survival rates compared to all other races, also when diagnosed with localized disease. In contrast, Asian/Pacific Islander patients have lower incidence rates and higher survival rates than all the other ethnicities [110]. Furthermore, response to treatment and frequency of severe toxicity is related to ethnic origin, most likely due to different pharmacokinetics and not the genetic nature of the disease. Sunitinib, sorafenib and pazopanib have been associated with significant toxicity profiles which vary widely. Higher toxicities during cytotoxic chemotherapy have been reported in patients enrolled Japanese trials compared to patients in American or European trials [111]. Ethnic differences in hematological toxicity have been attributed to the varying activities of drug –metabolizing enzymes and transporters that are mainly associated with polymorphisms in the promoter and coding regions of these enzymes [111]. In a phase II study assessing the efficacy and safety of sunitinib in Japanese patients, the incidence of hematological adverse events was numerically higher than those previously reported in western trials, however the AUC values for sunitinib were similar in both groups [112].

In the only pharmacogenetic study published until now, 31 single nucleotide polymorphisms in 12 can--didate genes, together with several non-genetic vari--ants, were analyzed for a possible association with toxicity [113]. Encouragingly, particular haplotypes (most notably by polymorphisms in CYP1A1) could be correlated to sunitinib-related toxicity. Because race-related differences in the frequency distribution of four genetic polymorphisms in the CYP1A1 P450 enzyme genes have been identified between Japa--nese and Caucasian populations, this may partly ex--plain the inter-ethnic differences observed [114].

VI. ConClusIonsIn the last decade, great strides have been made in the understanding of molecular mechanisms underlying renal cell carcinoma patients. The state-of-the-art has clearly led this field to the enviable position of having a range of molecularly targeted therapies. Nevertheless, despite the clear improvement in the therapeutic options for mRCC patients, therapies targeting the tumor cells themselves are highly desirable. Better models,

closer resembling the natural course of renal cancer are needed. It is foreseen that through integration of various high-throughput platforms personalized cancer treatment for renal cell carcinoma patients is possible. There are further improvements expected on the horizon: recent effort have made progress toward using formalin-fixed paraffin-embedded tissues for molecular analyses (including DNA and RNA recovery), which will permit studies on enormous archives of existing specimens [115] including metastatic lesions, a hitherto understudied area; mature profiles of protein and nucleic acid biomarkers will help us to define the spectrum of tumors that lie under the umbrella of ccRCC; and a future unmapped territory of genetic mutations to explore that may provide more tools and answers to the questions we ask. There is great hope for the future of renal cell carcinoma treatment, and it will be exciting to see what new advances will be made in the decade to come.

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46

47

Co m m i t t e e 3

P a t h o l o g y

Ch a i r m a n :

F . A LG A B A ,

M e m b e r s :

H. A K A Z A ,

A . LÓ P E Z - B E LT R Á N ,

G . M A R T I G N O N I ,

H. M O C H,

R . M O N T I R O N I ,

V. R E U T E R .

Co r r e s p o n d e n c eF erran Alg ab aSection of Patholog y .F u ndació Pu ig ve rtU nive rsitat Au tó noma de B arcelona

48

T A B le of ConT enT s

I. H IsT oRICA l B A CK G RounD

II. fRoM T H e ClA ssICA l T o 2 0 0 4 W H o RCC ClA ssIfICA T Ion

III. H eReD IT A RY A nD fA M IlIA l RCC

IV. CleA R Cell RenA l Cell CA RCInoM A

V. P A P IllA RY RenA l Cell CA RCInoM A M oRP H oloG Y

CRIT eRIA foR P A T H oloG ICA l D IA G nosIs.

VI. CH RoM oP H oB e RenA l Cell CA RCInoM A

VII. ColleCT InG D uCT CA RCInoM A , RenA l M eD ullA RY

CA RCInoM A

VIII. M uCInous T uB ulA R A nD sP InD le Cell CA RCInoM A

IX . RenA l CA RCInoM A s A ssoCIA T eD W IT H X P 1 1 .2

T RA nsloCA T Ions/ T fe3 G ene fusIons

X . RenA l Cell CA RCInoM A unClA ssIfIeD

X I. non 2 0 0 4 W H o RCC suB T Y P es ConsID eReD

X II. CRIT ICA l ReVIeW of G RA D InG

X III. G uID elInes foR P A T H oloG ICA l sT A G InG

eVA luA T Ion

X IV. M oleCulA R B A sIs of RenA l CA nCeR T ReA T M enT

49

P a t h o l o g y

F . A LG A B A ,

H. A K A Z A , A . LÓ P E Z - B E LT R Á N ,

G . M A R T I G N O N I , H. M O C H, R . M O N T I R O N I ,

V. R E U T E R .

I. H IsT oRICA l B A CK G RounD

T he microscopic characterisation of R enal C ell C arcinoma (R C C ) started in the mid- 19 th centu ry w ith the controve rsy arou sed b y G raw itz’ s hyp othesis. I n 18 8 3 G raw itz stated that “ a l ve o l a r ” (clear cell) tu mou rs, previ ou sly considered lipomas, w ere orig inated in the neoplastic transf ormation of adrenal cortical residu es into renal cortical. O ne ye ar later he confirmed his theory when he found ectopic adrenal cortex in the renal cortex [ 1] , T his theory w as readily opposed b y Su dek, w ho considered the renal tu b u lar orig in [ 2] . T he controve rsy b etw een su pporters and detractors of the G raw itz theory w ent on f or decades. T he term Hyp er n ep h r o ma w as introdu ced in 19 0 9 , and made ref erence to its adrenal orig in [ 3] . Ev en thou g h the su pport to the su pposedly adrenal origin started to grow weaker, and finally Oberling et al.’ s u ltrastru ctu ral stu dies [ 4 ] pu t a f u ll stop to the arg u ment w hen they demonstrated the tu b u lar orig in of renal carcinoma.

At this moment the international classifications unified all histological types under the common denomination of renal adenocarcinoma; this cou ld b e a clear cell or a g ranu lar cell carcinoma, its architectu re cou ld b e tu b u lar, papillary or cyst ic, and its appearance w as rarely sarcomatoid [ 5 ] .

O ne of the maj or adva nces w as T hoenes et al.’ s description of the ch r o mo p h o b e r en a l ce l l ca r ci n o ma [ 6 ] , morpholog ically dif f erent f rom the clear cell carcinoma and prob ab ly orig inated in the intercalated cells of the distal nephron [ 7 ] . F rom this description (initially not accepted b y the international classifications), the possibility of determining dif f erent orig ins of the histolog ical su b typ es started to b e searched w ith monoclonal antib odies [ 8 ] ; u nf ortu nately , f or the ove rlapping of the marke rs it

w as not possib le to dif f erentiate g rou ps, so no ki nd of modification of the established classification was finally determined.

I t w as only w hen K ova cs’ initial chromosome stu dies [9], subsequently redefined by the Heidelberg classification [10], were introduced that the renal cancer microscopic su b typ es w ere take n into accou nt again, as a correspondence was confirmed between g enetic ab normalities and microscopic phenotyp e.

II. fRoM T H e ClA ssICA l T o 2 0 0 4 W H o RCC ClA ssIfICA T Ion

The classifications can be different depending on their ob j ective and the dif f erent w ays of thinki ng thou g ht the time. T he mechanical model of disease and the limited therapeu tic modalities (practically only surgery) gave for a long time a classification with a f ew histolog ical su b typ es. W ith the introdu ction of the new therapies and the stu dy of the f amilial R C C [ 11] some molecu lar pathw ays are incorporate to the R C C . F or all of these considerations emerg es the latest WHO’s 2004 classification [12] that combines the morpholog ical and g enetic characteristics and starts to recog nise some va riations w ith evi dences of dif f erent immu nophenotyp e or molecu lar chang es w ith clinical implications.

The WHO’s 2004 classification ( T a b l e 1 ) make s a clear distinction b etw een certain tu mou r su b typ es havi ng b etter prog nosis, and others that do not. T he dif f erences reg arding prog nosis of the most u su al forms is statistically significant at the univariant stu dies [ 13, 14 ] , b u t it has no independent statistical significance in some other studies [15]. In spite of this, some cell su b typ es do seem to b e related to dif f erent carcinog enesis [ 16 ] , and their response to f u tu re therapies may b e dif f erent too [ 17 ] .

50

III. H eReD IT A RY A nD fA M IlIA l RCCEach tu mou r typ e presents a special histolog ical spectru m of phenotyp es w hich is accompanied b y the exp ression of a certain spectru m of antig ens that can b e detected immu nohistolog ically (among others f or dif f erential diag nostic pu rposes).

N early each renal cell tu mou r typ e occu rs in a sporadic or in a hereditary f orm [ 18 ] . A su rprising nu mb er of hereditary syn dromes predisposes to the deve lopment of renal cell carcinoma. W ithin the last ye ars 7 renal cancer syn dromes have b een characterize d. F ive of the predisposing g enes have meanwhile been identified: VHL, MET, FH, BHD, and HRPT2 ( T a b l e 2 ) .

VHL disease is the most frequent familial renal cancer syn drome and is associated w ith clear cell renal carcinoma and mu lti- org an neoplasia, escorted by mutations in the VHL gene and loss of the wild-type VHL-allele. The von Hippel-Lindau syndrome is estimated to occur at rates of 1:36.000 to 1:45.500 population. The typical renal manifestation of VHL are kidney cysts and renal clear cell carcinomas. Multiple ki dney tu mors of other histolog ical typ es ru le ou t the diagnosis of VHL syndrome. Histological examination of macroscopical inconspicous renal tissue from VHL-patients may reve al seve ral hu ndred independent tu mors and cyst s. T he mean ag e of manif estation is 37 ye ars ve rsu s 6 1 ye ars f or sporadic clear cell renal carcinomas, w ith an onset ag e of 16 to 6 7 ye ars. Metastatic RCC is the leading cause of death from VHL. The median life expectancy of VHL-patients was 49 years. In order to detect VHL-associated tu mors in time, analysi s of g erm line mu tations of the VHL-gene have been recommended in every patient w ith retinal or C N S hemang iob lastoma, particu larly of those in yo u ng er ag e and w ith mu ltiple lesions. Germ line mutations of the VHL-gene are spread all over the 3 exons. Missense-mutations are most common, b u t nonsense- mu tations microdeletions/insertions, splice mu tations and larg e deletions also occu r. T he spectru m of clinical manif estations of VHL reects the type of germ line mutations. Phenotyp es are b ased on the ab sence (typ e 1) or presence (type 2) of pheochromocytoma. VHL type

2 is u su ally associated w ith missense- mu tations and su b divi ded on the presence (typ e 2a) or ab sence (2b ) of renal cell carcinoma. I n contrast to loss of functions variance in VHL type 1, mutations predisposing to pheochromocytoma (VHL type 1) are mainly of the missance typ e predicted to g ive rise to conformationally change of pVHL. In addition, VHL type 2c has been used for patients with only pheochromocyt oma; how eve r seve ral ye ars later some of these cases developed other VHL manif estations.

Patients w ith hereditary papillary renal carcinoma (HPRC) have a germline-activating mutation in the MET-proto-oncogene which can cause renal cancers w ith papillary typ e- 1 histolog y . Papillary typ e- 2 renal carcinomas and u terine smooth- mu scle tu mors are associated w ith hereditary leiomyo matosis and renal cell cancer syndromes (HLRCC), which is caused by g ermline loss- of - f u nction mu tations in the F u marate-Hydratase (FH) gene. The hyperparathyreoidism-jaw tumor (HPT-JT) syndrome is associated with parathyroid adenomas, fibro-myalgious tumors of the j aw and renal tu mors. T his syn drome is caused by germline mutations in the HRPT2. The Birt-Hogg-Dubé syndrome (BHD) is associated w ith an increased risk f or renal cancers of va riou s histolog ical typ es, su ch as chromophob e R C C and oncocyt ic hyb rid tu mors.

With respect to these findings the cytogenetic b ackg rou nd of renal carcinog enesis b ecame more important as qu estions of an adenoma / carcinoma sequ ence and initiation steps and tu mou r prog ression w ere analyze d. I t shou ld b e noted that this research is still g oing on and is completed b y new molecu lar g enetic resu lts.

B ased on the kn ow ledg e of these dif f erent cyt og enetic pathw ays there w as an intensive research f or molecu lar chang es that w ere associated w ith these chromosomal aberrations. This finally led to some important tu mou r su ppressor g enes like the vo n Hippel-Lindau gene in clear cell carcinoma etc and oncog enes that are invo lve d in cell cycl e reg u lation and dif f erentiation.

Between 24-45% of VHL patients develop clear cell renal cell carcinoma (ccR C C ). I nactiva ting germline mutations of the VHL gene represents the g enetic hallmark of this syn drome and have b een demonstrated in almost all VHL patients. Sporadic clear cell R C C (the most f requ ent su b typ e of sporadic renal cancer [ 18 ] is characterize d b y inactiva tion of the VHL gene by deletion, mutation or promoter hyp ermethyl ation in ab ou t 7 0 % of the tu mors.

The functions of the VHL protein (pVHL) have been extensively studied in the last 15 years. The VHL protein (pVHL) is implicated in cell-cycle control and g ene reg u lation, and requ ires transcription-dependent nuclear-cytoplasmic trafficking for its

T abl e 1: W H O H I ST O L O G I CA L CL A SSI FI CA T I O N O F RCCC lear cell renal cell carcinomaMultilocular clear cell renal cell carcinomaPapillary renal cell carcinomaC hromophob e renal cell carcinomaC arcinoma of the collecting du cts of B elliniR enal medu llary carcinomaX p11 translocation carcinomasC arcinoma associated w ith neu rob lastomaMucinous tubular and spindle cell carcinomaRenal cell carcinoma, unclassified

51

function. There are two biologically active VHL protein isoforms: pVHL[30] and pVHL[19]. The distribution of VHL protein isoforms varies in the nu clear and cyt oplasmic compartments of renal tumors and alteration of subcellular pVHL trafficking is of potential releva nce f or the b iolog ical b ehavi or of clear- cell R C C [ 19 , 20 ] .

The pVHL functions as a recognition subunit in a E3 u b iqu itin protein lig ase complex , targ eting the h y p o xi a - i n d u ci b l e tr a n scr i p ti o n f a ct o r a (HIF-a) for u b iqu itin mediated deg radation in the presence of

oxyg en [ 21] . U nder normoxi c conditions, hyp oxi a-inducible factor-1 (HIF-1) is hydroxylated (-OH) on tw o conserve d proline residu es b y a f amily of prolyl hyd roxyl ases at its oxyg en- dependent deg radation domain. T his hyd roxyl ation provi des a su b strate-recognition site for the von Hippel–Lindau (VHL) E3 u b iqu itin lig ase complex, w hich contains elong ins C and B, cullin-2 (CUL2) and RBX1. Polyubiquitylation of HIF1- by the VHL complex leads to its proteasomal degradation by the 26S proteasome. Hypoxic conditions block hydroxylation, allowing HIF-1

s y n d r o m e c h r . g e n e p r o t e i n t u m o u r t y p e e x t r a r e n a l m a n i f e s t a t i o n sD e r m i s ot h e r

o r g a n svon Hippel-Lindau

3p25 V H L pVHL mu ltiple, b ilateralclearcell R C C ,renal cys ts

-

hemang iob lastoma ofretina / cns;phaeochromocyt oma;pancreatic- / renal cyst s; neu roendocrine tu mou rs;epidyd imal / parametrial cyst s; tu mou rs of the inner ear

h e r e d i t a r y papillaryR C C

7 p31 c- M E T HGF-R mu ltiple, b ilateralpapillary R C C ( typ e 1 )

- -

HLRC 1q4 2 F H FH papillary R C C( non typ e 1 )

leiomyo ma u terine leiomyo ma /leiomyo sarcoma

f amilialpapillary thyr oid

carcinoma

1q21 ? ? papillary R C C ,oncocyt omas

-

papillary thyr oidcarcinoma

hyp erpara-thyroidism –j aw tu mou r

( HP-JT )

1q25 HR P T 2 epithelial-stromal mixe d tu mou rs, papillary R C C

-

tu mou rs of the parathyr oi--dea;fibro-osseous jaw tumours

Birt-Hogg-Dubé 17 p11 B HD F ollicu lin mu ltiple chromo-phob e R C C , onco-cyt ic adenoma,papillary R C C

Facial fibrofolli-cu loma

pu lmonal cyst s;spontaneou spneu mothorax

tu b erou s

sclerosis

9 q34

16 p13

T S C 1

T S C 2

HamartinT u b erin

mu ltiple, b ilateralang iomyo lipomas,lym phang ioleio-myo matosis;

rare clear cell R C C

ang io-fibroma;peau chag rin;su b u ng u alfibroma

cardiac rhab domyo ma;adenomatou s smallintestine polyp s;pu lmonal / renal cyst s;cortical tu b er; su b epen--dym al g iant cell astrocy --tomas

constitu -tionaltransloca - t ion chr. 3

3p13-14

? ? mu ltiple, b ilateralclear cell R C C -

-

T abl e 2 : H ereditary renal cel l tumours

52

su b u nits to accu mu late and activa te transcription of hyp oxi a- responsive g enes. VHL inactiva tion — as occu rs in renal cells f rom patients w ith a g ermline VHL mu tation and loss of the w ild- typ e allele — mimics the hyp oxi c response b y preve nting degradation of HIF-1 subunits. Loss of VHL function causes accumulation of HIF-1 subunits in the cy toplasm and their translocation to the nu cleu s. HIF-1 dimerizes with HIF-1 and is coactivated by CBP/p300. HIF binds to hypoxia response elements (HRE) in gene promotors, thereby activating transcription of g enes u preg u lated in clear- cell renal tu mou rs, inclu ding va scu lar endothelial g row th factor (VEGF), erythropoietin and platelet-derived g row th f actor. C lear cell R C C is characterize d b y rich neo- va scu lariza tion and an of ten prominent va scu lar netw ork arou nd tu mor cells, su g g esting the elab oration of tu mor ang iog enesis f actors b y neoplastic cells. I t has b een demonstrated that strong va scu lariza tion in ccR C C is correlated w ith VEGF expression, suggesting that this growth factor plays a role in the va scu lar b iolog y of ccR C C tu mors as a consequence of VHL inactivation [22]. VEGF stimu lates endothelial cell prolif eration i n vi tr o and has also an ang iog enic activi ty i n vi vo .

Recently, it was shown that loss of VHL function results in strongly enhanced transcription of HIF-a indu cib le g enes, especially in u p- reg u lation of C X C R 4 [ 23] . T heref ore, the vo n Hi p p el - Li n d a u (VHL) tumor suppressor gene product is one of the maj or reg u lators of C X C R 4 exp ression and increased C X C R 4 exp ression leve ls are most like ly a consequence of impaired VHL function in ccRCC. Strong C X C R 4 exp ression is associated w ith poor prog nosis of R C C . T hu s, b y exp ressing C X C R 4 , tu mors ob vi ou sly aqu ire properties, w hich enab le them to inva de tissu e b arriers, mig rate to secondary org ans, and f orm metastases. Althou g h C X C R 4 /CXCL12 expression patterns may explain selection of specific organs for the formation of metastasis, the exa ct molecu lar mechanisms b y w hich the CXCR4/CXCL12 axis promotes tumor invasion are still u nclear.

Other pVHL functions include fibronectin matrix assemb ly , p5 3 stab iliza tion and transactiva tion [24, 25]. In addition, pVHL has the ability to bind and stab ilize microtu b u les b y protecting them f rom depolym eriza tion, w hich is a prerequ isite f or ciliu m f ormation [ 26 ] . I n f act, tw o previ ou s i n vi tr o stu dies showed that by re-expressing pVHL in VHL null ccRCC cell lines pVHL regulates the formation of primary cilia [ 27 , 28 ] . T hese ob serva tions strong ly suggest that loss of VHL function in renal epithelial cells leads to deg eneration of primary cilia, w hich represents a critical step tow ards cyst f ormation and ccRCC development in VHL patients. Interestingly, renal cyst s are also present in ab ou t 6 0 % of individuals suffering from the von Hippel-Lindau (VHL) disease. One might hypothesize that cyst

formation is one of the first visible renal alterations in VHL-caused tumor formation.

The elucidation of the different pVHL functions is the b asis f or u nderstanding the nove l therapeu tic strategies for RCC patients [29]. Targeting the VHL pathw ay f or therapeu tic interve ntion can theoretically occur at many sites. VHL protein function could be replaced, restoring b inding to hyp oxi a- indu cib le factor-1 (HIF-1) and allowing its proteasomal degradation. Further, the activity of HIF-1 could be a targ et f or inhib ition. F inally , molecu les u preg u lated b y HIF-1 (e.g. CXCR4) also provide specific targets for potential downstream inhibition of the VHL pathway.

IV. CleA R Cell RenA l Cell CA RCInoM A

T u mou rs are u su ally sing le in the sporadic cases, w ith 4 % mu ltiplicity and 3% b ilaterality . T he tu mou r is w ell delimited by pseudocapsule of fibrous tissue that is the consequ ence of compression of the su rrou nding tissues. Due to cytoplasm lipids accumulation the section surface is yellow. Haemorrhagic areas are f requ ent f or the larg e va scu lar stroma. O ccasionally there are scar areas and some of them eve n inclu de calcification. Necrosis is associated with more ag g ressive neoplasias.

T he cyst ic appearance it sometimes adopts may b e du e to necrosis and liqu ef action (pseu do- cyst s) or b ecau se it is f ormed b y g enu ine neoplastic cyst s .

Among the cyst ic renal cell carcinomas there are cases of clear cell renal cell carcinomas w ith a w ide cyst ic transf ormation, as w ell as cases w ith complete cyst ic appearance that lack a solid tu moral component.

T he latter su b typ e has b een called m u l t i l o c u l a r c y s t i c r e n a l c e l l ca r c i n o m a [ 30 ] . T he cyst s’ w all exh ib it isolated malig nant cells ( fi g . 1 ) . Macroscopically their appearance may be similar to that of a mu ltilocu lar cyst (cyst ic nephroma). T he exce llent prog nosis in a recent mu lti- institu tional stu dy su g g ests the possib ility of considering it a low -malig nant- potential carcinoma [ 31] .

1 . M ICRosCoP Y

As su g g ested b y its name, this neoplasia consists of clear cyt oplasm cells; they are clear du e to their hig h content of g lyco g en and lipids that dissolve in the cou rse of the histolog ic processing . C ells w ith a hig her mitochondrial content may b e seen to acqu ire an eosinophilic or g ranu lar appearance ( fi g . 2 ) . T he predominance of this cell typ e is exce ptional. R ou nded or irreg u lar eosinophilic cyt oplasm inclu sions are rarely f ou nd. T he nu clei are rou nded and their characteristics depend u pon their deg ree of dif f erentiation. T he most f requ ent arrang ement f orms

53

a solid pattern. T u b u lar and occasionally microcyst ic patterns can also b e present. Papillary areas are ve ry rarely ob serv ed [ 32] . F ive percent of cases are of the spindle cell (sarcomatoid) typ e [ 33] .

2 . IM M unoP H enoT Y P e

T he cells exp ress more f requ ently low molecu lar weight cytokeratins (CAM 5.2 around 60%) than hig h molecu lar w eig ht cyt oke ratins (C K 14 in 3.7 % ) [34]. Vimentin is expressed in 82.6% [35], CD10 in 9 4 % ( fi g . 4 ) and R C C antib ody in 8 5 % [ 36 ] . Epithelial membrane antigen (EMA) (MUC-1) in 85% [ 37 ] . G lu tathione S- transf erase α (G ST - α) in 8 2% [ 38 ] . F rom adhesion molecu les there is only 5 % of E-cadherin [37] and Kidney-specific cadherin (Ksp-cadherin) is neg ative [ 39 ] . Parva lb u min is exp ressed in 26 % and β-Defensin-1 in 13% [35]. Other markers su ch as c- ki t, R O N proto- oncog ene and p5 0 4 S – alpha-methylacyl-CoA racemase (AMACR) are vi rtu ally neg ative [ 4 0 , 4 1, 4 2] .

3 . G eneT IC CH A nG es

3p deletion (LOH 3p) is the most typical genetic

ab normality of this carcinoma, present in 7 5 .8 % of cases [ 4 3] , b u t not excl u sive to it [ 4 4 ] . T hree g enes have b een located on the short arm of chromosome 3 that are prob ab ly invo lve d in renal carcinoma. T he su ppressor g ene in 3p25 - 26 (VHL) w hich coincides with von Hippel-Lindau disease but is expressed in 34 - 5 6 % of sporadic carcinomas [ 4 5 ] , and those located on 3p14 .2 (potential g ene F HI T ) and on 3p.12, w hose deletion is more f requ ent that of the f ormer. O ther pu tative tu mou r su ppressor g enes at 3p as R A S S F 1 A and N R C - 1 at 3p12 are reported [ 4 6 , 4 7 ] .

LOH 3p interferes with the hypoxia-inducible pathway that activates VEGF and PDGF, both of which play an essential role in ang iog enesis, g lu cose transport, glycolysis, pH control, epithelial proliferation, cell mig ration and apoptosis, and can help the hyp oxi c adaptation of the clear cell carcinoma [ 4 8 ] . T heref ore, a therapeu tic mu lti- targ eted approach that selective ly and simu ltaneou sly b locks these g row th f actors represents an attractive w ay of treatment [ 4 9 , 5 0 ] .

Fig. 1A . - Cystic neopl asms w ith cl ear cel l in the w al l

Fig. 1B . - Fibrous w al l w ith cl ear cel l s.

Fig. 2 A . - Cl ear cel l renal cel l carcinoma Fig. 2 B . - E osinophil ic cel l s ( high grade) in cl ear cel l renal cel l carcinoma

54

V. P A P IllA RY RenA l Cell CA RCInoM A M oRP H oloG Y

CRIT eRIA foR P A T H oloG ICA l D IA G nosIs.

T u mors w ith a diameter u p to 5 millimeters are considered adenomas [ 12] . T hey are of ten incidental findings and occur in up to 23% of autopsy patients. T he larg er tu mors are vi ew ed as carcinomas, comprises the 15 % of all of su rg ically remove d renal cell neoplasms and its male to f emale ratio is 2:1[12].

Papillary renal cell neoplasms are g rossly characterize d b y a spherical b ou ndary and a b eig e to w hite colou r. T hey can exh ib it central necrosis resu lting f rom a poor va scu lar su pply and f requ ent hemorrhag es. I n some cases this f eatu re can b e so ext ensive to mimic a cyst b oth radiolog ically and g rossly [ 5 1] .

Papillary renal cell neoplasms are characterize d b y papillary or tu b u lo- papillary architectu re. T he epithelial neoplastic cells line a delicate fibrovascular core in w hich ag g reg ates of f oamy macrophag es can b e f ou nd. T he core can b e exp anded b y edema. I n carcinomas cholesterol cryst als, necrosis and haemorrhag e are f requ ently seen and haemosiderin g ranu les may b e present in macrophag es, stroma and tu mou r cell cyt oplasm. Sarcomatoid dedif f erentiation is seen in approxi mately 5 % of papillary renal cell carcinomas [ 5 1]

1 . P A T H oloG ICA l suB T Y P es

T w o w ell recog nize d morpholog ical typ es of papillary renal cell carcinomas have been described [52]: T yp e 1 tu mou rs have papillae cove red b y small cells w ith scanty cyt oplasm, arrang ed in a sing le laye r on the papillary b asement memb rane w ith low nu clear g rade ( fi g . 3 ) ; T yp e 2 tu mou rs are composed b y cells w ith hig her nu clear g rade, eosinophilic cytoplasm and pseudostratified nuclei on papillary cores ( fi g . 4 ) . T yp e 1 tu mou rs are more f requ ently multifocal. Psammoma bodies are common. Longer su rvi va ls have b een describ ed f or typ e 1 papillary renal cell carcinoma w hen compared w ith typ e 2 [ 5 4 ] . Papillary renal cell carcinomas entirely composed b y oncocyt es has b een describ ed [ 5 4 , 5 5 , 5 6 , 5 7 , 5 8 ] . T his su b set of papillary tu mors show s clinico- patholog ic f eatu res dif f erent f rom typ e 1 and typ e 2 papillary renal cell carcinomas and has b een proposed to b e ref erred as a third g rou p, b eing the ou tcome intermediate b etw een typ e 1 and typ e 2 [ 5 4 , 5 5 , 5 6 , 5 7 , 5 8 ] .

T here are emerg ing g rou ps of papillary renal carcinoma show ing at a cyt olog ic leve l a w ider spectru m than that already recog nize d. O ncocyt ic papillary renal cell carcinoma are composed of

papillary structures with delicate fibrovascular stalks containing , occasionally , crow ded lipid- laden f oamy macrophag es T he papillae are lined b y sing le or, more rarely, pseudostratified layers of cells with granular, deeply typ ical eosinophilic cyt oplasm w ith distinctive cell b order. T he nu clei w ere rou nd w ith f requ ently prominent nu cleoli conf orming to a nu clear g rade 3. Solid areas w ith morpholog ical f eatu res ove rlapping typ ical renal oncocyt oma are of ten ob serve d [ 5 4 , 5 5 , 5 6 , 5 7 , 5 8 ] .

Papillary renal cell carcinoma w ith clear cell chang es is a neoplasm composed of papillary stru ctu res cove red b y mediu m- size d cells w ith clear cyt oplasm made u p 20 % to 9 0 % of the total neoplastic area T he tu mor cells show va riab le deg rees of cyt oplasmic clarity; of ten, the cyt oplasm has a microve sicu lar or finely granular appearance similar to the cytoplasm of f oamy macrophag es that w ere f requ ently present w ithin papillary cores and in spaces b etw een the papillae. U su ally , the nu clei are positioned centrally or b asally , and nu clear g rade is qu ite homog eneou s throu g hou t the neoplasms [ 32, 5 9 , 6 0 ] .

Spindle cell areas in papillary renal cell carcinoma g enerally sig nif y sarcomatoid chang e and are hig h g rade. I t has b een reported that low - g rade spindle cell f oci, closely mimicki ng mu cinou s tu b u lar spindle cell carcinoma can occu r. T hese tu mors are predominantly solid, f eatu ring compact areas of low -g rade spindle cells lining thin, ang u lated tu b u les. Mucinous stroma was not appreciated in any case [ 6 1] .

2 . IM M unoH IsT oCH eM ICA l feA T uRes

R eaction f or cyt ok eratin 7 w as strong or moderate in 4 8 of 6 1 T yp e 1 tu mors, and reaction w as nu ll in 24 of 30 T yp e 2 orig inally describ ed tu mors [ 5 2] .

T he neoplastic oncocyt ic cells of oncocyt ic papillary renal cell carcinoma in all cases describ ed, exh ib ited strong , dif f u se, and g ranu lar positivi ty f or antimitochondrial antigen reaction and for AMACR ( fi g . 5 ) . T u moral cells demonstrated va riab le positivi ty f or cyt oke ratins, AE1/ AE3, C K 8 - 18 , C K 7 , CK19, EMA and CD10 was positive in 10 cases. T here w as dif f u se positivi ty f or vi mentin and some cases w ere positive f or parva lb u min [ 5 4 ] .

Papillary renal cell carcinoma w ith clear cell chang es showed strong immunoreactivity for AMACR, of w hich a su b set also exp ress cyt oke ratin 7 su ch as all cases of spindle cell papillary renal cell carcinomas reported [ 5 9 ] .

3 . M oleCulA R/ G eneT IC feA T uRes

Papillary renal cell carcinoma is characterize d b y trisomy of chromosomes 3q, 7 , 8 , 12, 16 , 17 and 20 and loss of the Y chromosome [ 6 2] ; these most consistent g enetic ab normalities are present in b oth solitary and mu ltif ocal papillary renal cell

55

carcinomas and they occu r early in the evo lu tion of this neoplasm[ 6 2] Some au thors have su g g ested g enetic dif f erences b etw een typ e 1 and typ e 2; typ e 1 papillary renal cell carcinoma cases seem to have a significantly higher frequency of allelic imb alance on 17 q than typ e 2 cases and typ e 2 cases an hig her

f requ ency of allelic imb alance on 9 p than typ e 1 cases [63, 64]. The c-Met proto-oncogene mutation on chromosome 7 characterize s hereditary and a su b set of sporadic papillary renal cell carcinomas [ 6 5 ] . Patients w ith the hereditary leiomyo matosis and renal- cell cancer syn drome are at risk f or cu taneou s and u terine leiomyo mas and solitary papillary renal-cell carcinoma w ith typ e 2 histolog ic f eatu res [ 6 6 ] . F u marate hyd ratase g ene, the g ene that cau ses this au tosomal dominant syn drome, encodes f u marate hyd ratase, a K reb s- cycl e enzym e [ 6 7 ] .

Among oncocyt ic papillary R C C s, three or more signals were frequently observed in the tumor cells: chromosomes 7 (rang e, 3% - 7 4 % ; 30 % in 7 of 12) and 17 (rang e, 6 % - 6 9 % ; z3 0 % in 7 of 12). I n 5 cases, three or more sig nals f or b oth chromosomes w ere f ou nd. N o sig nal f or Y w as ob serve d in 8 0 % to 9 0 % of nu clei in 3 tu mors of the 10 males [ 5 4 ] .

Among 14 papillary renal cell carcinoma w ith clear cell chang es, most neoplasms exh ib ited g ains of chromosome 7 ; nine show ed g ains of chromosome 17 and 4 neoplasms f rom 6 male patients show ed loss of chromosome Y .10 C hromosome 3p deletion was detected in 4 cases. FISH analysis from areas of papillary renal cell carcinoma and f rom areas w ith clear cell morpholog y in the same tu mor show ed similar resu lts [ 5 9 ]

All spindle cell papillary renal carcinomas reported show ed trisomy of chromosome 7 , and 3 of 5 show ed trisomy of chromosome 17 [ 6 1] .

4 . D IffeRenT IA l D IA G nosIs

Papillary renal cell carcinoma is the tu mou r that most f requ ently may exh ib it ove rlapping characters w ith other su b typ es of renal cell carcinoma. C lear cell renal carcinoma, w hich is the most f requ ent renal cell neoplasms, may show pseu do- papillary stru ctu res; in this context the immunoprofiling characterized by the immunoreactivities for AMACR and cytokeratin 7 and the g ains of chromosomes 7 and 17 are u su ally mandatory to classif y the neoplasms as to b e papillary su b typ e. T he solid va riant of papillary renal cell carcinoma may show ove rlapping f eatu res w ith seve ral neoplasms in particu lar w ith the metanephric adenoma w hereas the oncocyt ic v ariant encou nters in the dif f erential diag nosis the renal oncocyt oma; ag ain the g ains of b oth chromosomes 7 and 17 are present in this papillary su b typ e.

T he g rou p of papillary renal cell carcinoma is ext remely heterog eneou s in particu lar in the su b set of neoplasms classifiable as type 2 probably inclu ding cases of clear cell renal cell carcinoma w ith pseu dopapillary tu b u lo- g landu lar architectu re and hig h nu clear g rade, cases of translocation carcinoma and B ellini du ct carcinoma.

Fig. 3 . - P apil l ary renal cel l carcinoma type I , basophil ic cel l s

Fig. 4 . - P apil l ary renal cel l carcinoma type I I , eosinophil ic cel l s w ith high grade

Fig. 5 . - A M A CR ex pression in papil l ary renal cel l carcinoma.

56

VI. CH RoM oP H oB e RenA l Cell CA RCInoM A

C romophob e renal cell carcinoma (C R C C ), a renal cell carcinoma of low malig nant potential characterize d b y hu g e pale cells w ith prominent cell memb ranes, w as initially describ e in nitrosamine-induced renal tumours in rats. The first cases of C R C C in hu mans w ere reported in 19 8 5 . C R C C accou nt f or approxi mately 5 per cent of su rg ically remove d renal epithelial tu mors [ 7 1] T he median/mean ag e of incidence is in the sixt h decade, w ith a rang e in ag e of 27 to 8 6 ye ars, and the nu mb er of men and women is roughly equal. Mortality is less than 10 % . Sporadic and hereditary f orms do exi st.1 . M A CRosCoP IC A P P eA RA nCeDepending on size, chromophobe renal cell tumors consist of one or more solid tu mor nodu les w ith a slightly lobulated surface. In unfixed conditions the cu t su rf ace appears homog eneou sly orang e turning beige or sandy after formalin fixation. The u nif orm pale cu t su rf ace interspersed w ith a f ew hemorrhag es is a ve ry ch a racteristic g ross f eatu re, w hile a slig ht b row n colored cu t su rf ace is u su ally seldom.2 . H IsT oP A T H oloG YT he b asic chromophob e cell typ e is characterize d b y larg e polyg onal cells w ith a transparent slig htly reticu lated cyt oplasm f or nu merou s sometimes inva -g inated ve sicles, 15 0 - 30 0 nm in diameter resem--b ling those of the intercalated cells typ e b of the cor--tical collecting du ct, w ith prominent cell memb rane leading to a plant cell like appearance ( fi g . 6 ) . T he periva scu lar cells are of ten enlarg ed. An eosinophilic va riant does exi st ( fi g . 7 ) , it is pu rely composed of intensive ly g ranu lar larg e and small cells w ith promi--nent cell memb ranes [ 7 0 ] . Sarcomatoid/ spindle cell transf ormation does occu r ( fi g . 8 ) [ 7 2] . Another di--ag nostic hallmark is the lack of cyt oplasmic coloring w ith rou tine dye s b u t a dif f u se cyt oplasmic staining reaction with Hale`s iron colloid stain ( fi g . 9 ) . C hro--mophob e cells u su ally show condensed and hyp er--chromatic sometimes b inu cleated nu clei. I n g eneral, the g row th pattern is solid/ compact, sometimes crib --riform associated with focal calcifications and broad fibrotic septae. The so called hybrid tumors share histopatholog ical characteristics of chromophob e carcinoma and oncocyt ic adenoma as b oth cell typ es are interming led. F u hramn g rading seems not to b e appropiated to g rade chromophob e R C C .3 . IM M unoP RofIleI mmu nohistolog y presents the f ollow ing antig en profile: Pan-Cytoceratin +, Vimentin -, EMA + (diffuse), lectins +, Parvalbumin +, RCC-antigen - / +, CD 10 –. CRCC presents significant hypodiploid cell clones with ow cytometry and quantitative image analysis of DNA ploidy.

4 . CY T oG eneT ICs A nD M oleCulA R A lT eRA T Ions

R enal cell carcinomas of the chromophob e typ e are cyt og enetically characterize d b y a massive loss of chromosomes, i.e. - 1,- Y ,- 2,- 10 ,- 6 ,- 21,- 13,and -17. These data are confirmed by FISH- and CGH analysi s [ 6 8 , 6 9 ] .

Fig. 6 . - Chromophobe renal cel l carcinoma, cl ear cel l type

Fig. 7 . - Chromophobe renal cel l carcinoma, eosinophil ic type.

Fig. 8 . - Chromophobe renal cel l carcinoma of high grade w ith sarcomatoid component.

57

C y tog enetic and molecu lar g enetic data on chromophob e renal cell carcinoma (R C C ) is limited, possib ly du e to their g eneral tendency to g row ve ry slow ly in vi tro compared to all other typ e of renal tumors. Karyotyping, uorescence in situ hy b ridiza tion, comparative g enomic hyb ridiza tion, and microsatellite analyse s have reve aled that mu ltiple and nonrandom chromosomal losses, i.e. monosomies of chro mosomes 1, 2, 6 , 10 , 13, 17 , 21, and the Y or X chromosome are pathog nomonic f or chromophob e R C C . Additional stru ctu ral chromosomal ab errations have b een describ ed, b u t no (partial) loss of the short arm of chromosome 3. T he massive chromosomal losses lead to a hyp odiploid DNA index (low modal number of chromosomes). Endoredu plication/ polyp loidiza tion of the hyp odiploid cells has b een ob serve d. T elomeric associations and telomere shortening hav e also b een ob serv ed. F u rthermore, molecu lar analy sis of this su b ty pe has rev ealed g ross alterations of the mitochondrial DNA. Nagy et al. found somatic mitochondrial DNA mu tations, althou g h there ex act role remains to b e elu cidated.At the molecu lar leve l, C ontractor et al. show ed an association b etw een loss of chromosome 17 and mu tation of T P 5 3 tu mor su ppressor g ene in 27 % of the chromophob e R C C s. Sü kö sd et al. demonstrated loss of heterozygosity (LOH) around the P T E N g ene at the 10q23.3 chromosomal region. However, deletional or mu tational inactiva tion of the P T E N /M M A C 1 g ene cou ld b e excl u ded.The finding of mito chon drial DNA changes and the loss of Y / X and chromosome 1 in b oth renal oncocyt oma and chromophob e carcinoma mig ht indicate prog ression f rom renal oncocyt oma to chromophob e renal cell carcinomas the malig nant cou nter part of renal oncocyt oma throu g h additional chromosome losses, also exp laining the occasionally malig nant b ehavi or of renal oncocyt omas. W ith respect to hereditary R C C , no f amilies have b een reported w ith memb ers af f ected w ith chromophob e renal carcinomas.

F amilial clu stering is u nkn ow n. T here is an inherited cancer syndrome called Bird-Hogg-Dube-Syndrom (BHD), which is an autosomal dominant disease characterize d b y trichof ollicu lomas, trichodisko mas and lung cysts. The BHD-gene is localized on the short arm of chromosome 17 .

B ru nelli et al stu died a larg e nu mb er of classic and eosinophilic chromophob e R C C s and show ed that the eosinophilic va riant of chromophob e renal cell carcinoma and classic chromophob e renal cell carcinoma have similar f requ ency of losses of chromosomes 1, 2, 6 , 10 , and 17 , consistent w ith the notion that these tu mors are simply morpholog ic va riants of the same neoplasm.

T he mechanisms of the ka ryo typ ic chang es du ring the deve lopment of chromophob e R C C is u nkn ow n, b u t the characteristic chromosomal losses are helpf u l in estab lishing an accu rate diag nosis.

5 . M A J oR D IffeRenT IA l D IA G nosIs

• R en a l o n co cyt o ma . C hromophob e renal cell carcinomas, especially the eosinophilic va riant, are frequently difficult to distinguish from renal oncocyt omas on hematoxyl in and eosin stained histolog ic sections. T he distinction is important, as chromophob e renal cell carcinoma is a malig nant tu mor w hile oncocyt oma is considered to b e a b enig n lesion. R eports of “ malig nant” or “ metastatic” oncocyt omas are postu lated to actu ally represent misdiag nosed chromophob e renal cell carcinomas. The Hale’s colloidal iron stain shows a diffuse and strong reticu lar pattern in almost 10 0 % of chromophob e R C C . C hromophob e renal cell carcinomas f requ ently show loss of chromosomes 1 (7 0 % of classic, 6 7 % of eosinophilic), 2 (9 0 % classic, 5 6 % eosinophilic), 6 (8 0 % classic, 5 6 % eosinophilic), 10 (6 0 % classic, 4 4 % eosinophilic), and 17 (9 0 % classic, 7 8 % eosinophilic). 4 4 % of eosinophilic chromophob e renal cell carcinomas exhibit loss of all five of these chromosomes. G enetic alterations of oncocyt oma have not ye t b een well characterized. However, renal oncocytomas have b een reported to b ear either rearrang ements or translocations invo lvi ng chromosome 11q13[ 8 6 ] or partial or complete losses of chromosomes 1, 14 , and/ or a sex chromosome (Y or X ). Seve ral g rou ps of inve stig ators have reported that chromosome 3p loss is not detectab le in oncocyt oma. B ecau se of the f requ ent association b etw een oncocyt omas and chromosome 1p alterations, the loss of a tu mor su ppressor g ene residing on chromosome 1p has b een proposed as the earliest g enetic eve nt associated w ith the deve lopment of renal oncocyt oma. O ncocyt omas have also b een show n to exh ib it microsatellite instab ilities. Alterations in mitochondrial DNA have also been implicated in the deve lopment of oncocyt omas. I t is notew orthy that there are no apparent ove rlapping g enetic alterations shared b y eosinophilic chromophob e

Fig. 9 . - H al e’ s iron staining in chromophobe renal cel l carcinoma.

58

renal cell carcinoma and oncocyt oma, despite their morpholog ical similarities. I t has b een postu lated that eosinophilic chromophob e R C C orig inates f rom renal oncocyt oma, and represents the malig nant f orm of this tu mor.

• R en a l o n co cyt o si s. R enal oncocyt osis is characterize d b y the presence of mu ltiple tu mors w ith oncocyt ic f eatu res, of ten associated w ith small clu sters of tu b u le- like stru ctu res w ith oncocyt ic chang e. C ossu - R occa et al stu died 11 tu mors f rom the ki dneys of one su ch patient. F lu orescence in situ hyb ridiza tion w as perf ormed w ith centromeric prob es f or chromosomes 1, 2, 6 , 10 , and 17 in each of the 11 tu mors. All 11 tu mors f rom this patient w ith renal oncocyt osis show ed no loss of any of the chromosomes 1, 2, 6 , 10 , or 17 , a pattern identical to that f ou nd in normal control tissu es. T heref ore the chromosomal profile may be the diagnostic procedu re of choice f or disting u ishing b etw een chromophob e R C C and renal oncocyt osis.

6 . P RoG nosIs

T he larg e maj ority of C C R C s are stag e T 1 and T 2 (8 6 % ) w hereas only 10 % show ext ension throu g h the renal capsu le into su rrou nding adipose tissu e, only 4 % show invo lve ment of the renal ve in (T 3b ). A f ew cases of w ell- docu mented distant metastasis (lu ng , live r and pancreas) have b een describ ed . N o lym ph node metastases have b een reported ye t. Spindle cell phenotyp e is associated w ith ag g ressive tu mou r g row th/ metastasis. G enetic predictive f actors are not kn ow n.

VII. ColleCT InG D uCT CA RCInoM A , RenA l M eD ullA RY

CA RCInoM A

R enal collecting du ct, or B ellini’ s du ct, carcinoma (CDC) is a relatively rare subtype of renal cell carcinoma (R C C ), accou nting f or 0 .4 % to 1.8 % [ 7 3, 74] of all RCCs in Western counties. In Japan, the Japanese Society of Renal Cancer reported that a Nationwide survey of CDC from 2001 to 2003 [75]. I n this su rve y that w as the larg est case series to consider ou tcome to date, 8 1 cases w ere cou nted from 281 institutions throughout Japan. The incidence of CDC in Japan was considered as less than 1.5 % , b ecau se each institu tion exp erienced more than 10 patients w ith R C C per ye ar. Seve ral stu dies have show n a male predominance and a tendency f or this disease to occu r more f requ ently in relatively younger adults. Japanese survey show ed that the median ag e w as 5 8 .2 ye ars and males comprised 7 1.6 % of the patient popu lation. According to Japanese survey, regional lymph node metastases w ere present in 4 4 % of the patients at diag nosis, w hereas distant metastases w ere seen in 32%. The 1-, 3-, and 10-year disease-specific

su rvi va ls w ere 6 9 % , 4 5 % , and 14 % , respective ly .Renal medullary carcinoma (RMC) is a relatively new su b typ e of R C C that is thou g ht to arise f rom the calyceal epithelium. It has been first seen and is still detected almost excl u sive ly in indivi du als w ith sickl e cell trait or anemia. T his tu mor shares many histologic features with CDC, and some consider it a subtype of CDC or at least a closely related tumor. Althou g h relationship b etw een these tw o entities still remains controversial, most recently RMC is considered to differentiate from CDC [74, 76].

1 . M oRP H oloG ICA l CRIT eRIA foR P A T H oloG ICA l D IA G nosIs

CDCs are derived from the medulla, but many are infiltrative and extension into the cortex is common. Typically CDCs are white to gray and have a firm consistency on sectioning. Histologically, CDC is characterize d b y a tu b u lopapillary architectu re, w hich consists of an admixt u re of dilated tu b u les and papillary stru ctu res typ ically lined b y a sing le laye r of cu b oidal cells, of ten creating a cob b lestone appearance and associating w ith desmoplastic stromal reaction ( fi g . 1 0 ) . O n the other hand, it has b een reported that most common histolog ic appearance of RMC is cribriforming glands surrounding by a desmoplastic reaction. Both CDC and RMC are considered to be somewhat similar to poorly dif f erentiated u rothelial carcinoma.

2 . M oleCulA R/ G eneT IC feA T uResIn CDCs, trisomy for chromosomes 4, 7, 8, 17 and 20 and loss of chromosomes 14 , 18 and 22 w ere reported [ 7 7 ] . Another analyse s show ed monosomy of chromosomes 1, 6, 14, 15 and 22 [78]. Loss of heterozyg osity of 8 p and 13q has b een reported in f u rther stu dies [ 7 9 ] . T he most constant chang e w ou ld b e 1q32 deletion 8 0 , 8 1). T he molecu lar pathogenesis of CDC is not known. Although loss of chromosome 3p, including VHL gene was not common in CDC [79], some literatures have described that activation of VEGF signaling, which

Fig. 10 . - Col l ecting duct carcinoma w ith desmopl astic reaction

59

is analog ou s to the clear cell R C C hyp oxi a pathw ay may be related to RMC carcinogenesis [76, 82].

3 . IM M unoH IsT oCH eM ICA l feA T uResO n immu nohistochemistry , the characteristics f eatu re is co- exp ression of low - and hig h- molecu lar w eig ht cy toke ratines (cyt oke ratin 34 b E12) and positive reaction to lectins su ch as U l ex eu r o p ea u s ag g lu tinin-1 (U EA- 1) [ 7 3, 7 7 , 8 3] . K ob aya shi N , et al. [ 8 4 ] . have described that CDC expresses E-cadherin, c-K I T in addition to U EA- 1 and cyt ok eraitnes. T here is a variable expression of Leu M1 and EMA, whereas marke rs of proxi mal renal tu b u les are almost alw ays negative. Some studies reported that RMC strongly ex presses ke ratin 19 and T opo I I alpha [ 8 5 ] .

4 . D IffeRenT IA l D IA G nosIs

CDC is frequently difficult to distinguish from RMC, pelvi c u rothelial carcinoma (U C ) w ith marke d renal parenchy mal inva sion and hig h- g rade papillary RCC. To differentiate CDC from RMC, immu nohistochemical and molecu lar approaches may be useful. The difference between CDC and RMA was found in expression pattern of UEA-1, hig h- molecu lar w eig ht cyt oke ratin, c- K I T , E-cadherin, VEGF, EMA, Her-2neu, and karyotype of chromosomes [ 7 4 ] . I mmu nohistochemical approach is u sef u l f or the dif f erential diag nosis of these renal tu mors. Sw artz, et al. [ 7 6 ] have reported ab ou t differential diagnosis between CDC and RMC that characteristic immunohistochemical profile for CDC is positivity for cytokeratin 34bE12 and UEA-1. T he cyt oke ratin 34 b E12 marke r w as neg ative in RMCs and UEA-1 was present only a minority of RMCs in a focal, patchy distribution. It has been also reported that U EA- 1, E- cadherin, and c- K I T are frequently positive in CDC in comparison with papillary R C C , w hich u su ally exp resses marke rs f or proximal renal tubules, such as CD10, RCC antigen and AMACR [74, 84]. Although invasive UC has similar immunohistochemical features with CDC, it has b een also show n that hig h- and low - molecu lar-w eig ht cy toke ratin are positive at a low f requ ency compared w ith inva sive U C [ 8 4 ] .

VIII. M uCInous T uB ulA R A nD

sP InD le Cell CA RCInoM A

1 . M oRP H oloG ICA l CRIT eRIA foR P A T H oloG ICA l D IA G nosIs

This entity, included by the first time in the current WHO classification, [12] is a low-grade carcinoma composed of tig htly packe d tu b u les separated b y pale mu cinou s stroma and a spindle cell component ( fi g . 1 1 a n d 1 2 ) [ 12, 6 1- 9 8 ] . I t seems to derive f rom the distal nephron b u t some au thors b elieve it cou ld b e a va riant of papillary R C C w ith proxi mal tu b u le

orig in[ 6 1, 8 6 , 8 7 ] T here is a f emale predominance and the mean ag e is 5 3 ye ars at diag nosis.[ 12, 6 1- 9 8 ] . I t presents as circu mscrib ed asym ptomatic mass on u ltrasou nd exa mination.[ 1] Some patients may deve lop metastases on f ollow - u p. R are cases show ing tru e, w ell docu mented, sarcomatoid chang e have b een recently reported. [ 8 8 ] . T w o of these cases occu rred in a 7 1- ye ar- old w oman and an 8 0 - ye ar-old man w ho b oth u nderw ent a radical nephrectomy procedu re. [ 8 8 ] . I n addition to the classic mu cinou s tubular and spindle cell carcinoma (MTSRCC) morpholog y , b oth cases had a sarcomatoid component characterize d b y predominantly hig h-g rade spindle cells, solid pleomorphic epithelioid cells, and malignant fibrous histiocytoma-like storif orm patterns [ 8 8 ] . Sarcomatoid chang e comprised 6 0 % and 20 % of the tu mors, respective ly; one patient died w ith w idespread metastasis.5 I t is currently considered a poorly defined entity.

2 . M oleCulA R/ G eneT IC feA T uRes

T his tu mor has va riab le g enetic f eatu res and show s a comb ination of losses invo lvi ng chromosomes 1, 4 , 6 , 8 , 13, 14 and 15 and g ains of chromosomes

Fig. 11. - M ucinous tubul ar and spindl e cel l carcinoma. T ubul ar and spindl e components.

Fig. 12 . - M ucinous tubul ar and spindl e cel l carcinoma. M ucinous component.

60

2, 5 , 7 , 9 , 10 , 11, 12, 16 , 17 , 19 , 20 , 22, and X [ 6 1, 8 6 - 9 8 ] C ossu - R occa et al [ 8 9 ] stu died 10 mu cinou s tubular and spindle cell carcinoma with FISH for chromosomes 7 , 17 and Y . T hey f ou nd that renal MTSRCC lacks the gains of chromosomes 7 and 17 and losses of chromosome Y that are typ ically f ou nd in papillary renal cell carcinoma. R ako zy et al [90] studied 6 tumors from five patients with CGH and f ou nd mu ltiple g enetic ab normalities inclu ded consistent losses of chromosomes 1, 4 , 6 , 8 , 9 , 13, 14, 15 and 22 in all cases. CGH study by Ferlicot et al [91] identified the loss of chromosomes 1, 4, 6, 8, 13, 14, 15 and 18 in a group of MTSRCC.

3 . IM M unoH IsT oCH eM ICA l feA T uRes

A recent immu nohistochemical analysi s f ou nd a significant immunophenotypic overlap with papillary R C C , and some au thors b elieve this is a va riant of papillary R C C w ith spindle cell dif f erentiation [ 8 6 , 9 2] Exp ression of alpha- methyl acyl - C oA racemase (89%), cytokeratin 7 (82%), Vimentin (80%), EMA (7 8 % ), 34 ß E12 (4 5 % ) and E- C adherin (28 % ), and negativity for CK 14, CD 10, Villin, RCC antigen, c-ki t and U l ex E u r o p a eu s ag g lu tinin are characteristic of MTSRCC [12, 61- 98]The proliferative rate in MTSRCC is low (<1%). Some cases of MTSRCC may exp ress neu roendocrine marke rs, su ch as N SE and CD57 [93].

4 . D IffeRenT IA l D IA G nosIsMajor histologic differential diagnosis is type I papillary R C C and papillary R C C w ith solid g row th. [ 12, 6 1- 9 8 ] . A prob lem f u rther compou nded w ith the description of papillary R C C w ith low - g rade spindle cell f oci as a mimic of mu cinou s tu b u lar and spindle cell carcinoma [ 6 1] All cases in this categ ory w ere dif f u sely immu noreactive f or cyt oke ratin 7 , and focally CD10 positive. [61] Also, all 5 cases show ed trisomy of chromosome 7 , and 3 of 5 show ed trisomy of chromosome 17 by FISH, supporting classification as papillary RCC [61]. Rare cases of MTSRCC may present true sarcomatoid change a finding of importance in terms of dif f erential diag nosis [ 8 8 ] . MTSRCC may be “mucin-poor” and show a marked predominance of either of its principal morpholog ic components, w hich cou pled w ith the presence of other u nu su al f eatu res su ch as clear cells, papillations, f oamy macrophag es, and necrosis, may mimic other f orms of renal cell carcinoma [ 9 4 ] . Patholog ists mu st b e aw are of the spectru m of histologic findings within MTSRCC to ensure their accurate diagnosis [94-98]. Mucinous tubular and spindle cell renal carcinomas are u ncommon neoplasms w ith distinctive morpholog ic f eatu res. Since MTSRCC shares several morphological characteristics w ith typ e I papillary renal cell carcinoma and its morpholog ic va riants, kn ow ledg e of their molecular and immunohistochemical profiles can b e important in disting u ishing b etw een them [ 12, 6 1- 9 8 ] .

IX . RenA l CA RCInoM A s A ssoCIA T eD W IT H X P 1 1 .2

T RA nsloCA T Ions/ T fe3 G ene fusIons

These carcinomas are defined by several different translocations invo lvi ng chromosome X p11.2, all resu lting in g ene f u sions invo lvi ng the T F E 3 gene. The first reported translocation was the t(X ; 1)(p11.2; q21), w hich resu lts in f u sion of the P R C C and T F E 3 g enes. Another chromosome translocation is the t(X ; 17 )(p11.2; q25 ), w hich resu lts in f u sion of the A S P L (a.k. a. R C C 1 7 or A S P S C R 1 ) and T F E 3 g enes. O f note, the identical A S P L-T F E 3 g ene f u sion is also characteristic of alve olar sof t part sarcoma (ASPS), w here it w as orig inally identified. Other reported translocations include a t(X ; 1)(p11.2; p34 ), resu lting in f u sion of the P S F and T F E 3 g enes, and an inv( X )(p11; q12), resu lting in f u sion of the N o n O (p 5 4 n r b ) and T F E 3 g enes. T hese carcinomas predominantly af f ect children and yo u ng adu lts, thou g h rare adu lt cases have b een reported. T he A S P L- T F E 3 carcinomas characteristically present at adva nced stag e; almost all cases have b een associated w ith lym ph node metastases at diag nosis, eve n w ith small primaries [ 9 9 - 10 6 ] .

1 . M A CRosCoP IC A P P eA RA nCe

R enal carcinomas associated w ith X p11.2 translocations resemb le conve ntional (clear cell) renal carcinomas on g ross exa mination, most commonly b eing tan- ye llow , and of ten necrotic and hemorrhag ic.

2 . H IsT oP A T H oloG YT he most distinctive histopatholog ical appearance is that of a papillary carcinoma comprised of clear cells; how eve r, these tu mors f requ ently have a more nested architectu re, and of ten f eatu re cells w ith g ranu lar eosinophilic cyt oplasm. T he morpholog ic appearance of carcinomas associated with specific chromosome translocation b reakp oints dif f ers. T he A S P L- T F E 3 renal carcinomas are characterize d b y cells w ith vo lu minou s clear to eosinophilic cyt oplasm, discrete cell b orders, ve sicu lar chromatin and prominent nu cleoli. Psammoma b odies are constant and sometimes ext ensive , of ten arising w ithin characteristic hya line nodu les. T he P R C C - T F E 3 renal carcinomas g enerally f eatu re less ab u ndant cyt oplasm, f ew er psammoma b odies, f ew er hya line nodu les, and a more nested, compact architectu re. T oo f ew P S F - T F E 3 and N o n O - T F E 3 renal tu mors have so f ar b een stu died to comment on their distinctive histopatholog ical f eatu res, if any .

3 . IM M unoP RofIle

O nly ab ou t 5 0 % of renal carcinomas w ith X p11.2-

61

associated translocations exp ress epithelial markers such as cytokeratin and EMA by immu nohistochemistry , and the lab eling is of ten focal. Vimentin immunoreactivity is also often focal, w hich contrasts w ith conve ntional renal carcinomas. S-100 protein, desmin, and HMB45 are consistently neg ative . T he tu mors consistently lab el f or the Renal Cell Carcinoma Marker antigen and CD10, similar to conve ntional renal carcinomas. T he most distinctive immu nohistochemical f eatu re of these tu mors is nu clear immu noreactivi ty f or T F E3 protein, w hich is a common f eatu re in all X p11.2- associated carcinomas and ASPS.

4 . eleCT RonM ICRosCoP Y

U ltrastru ctu rally , X p11.2- associated carcinomas most closely resemb le conve ntional renal carcinomas b ecau se they f eatu re cell j u nctions, microvi lli, intracytoplasmic fat and glycogen. However, a significant number of cases demonstrate distinctive ultrastructural features. Most of the A S P L- T F E 3 renal carcinomas demonstrate memb rane- b ou nd cy toplasmic g ranu les and a f ew contain memb rane-b ou nd rhomb oidal cryst als identical to those seen in sof t tissu e ASPS O ccasional P R C C - T F E 3 renal carcinomas have demonstrated distinctive intracisternal microtu b u les identical to those seen in ex traske letal myxo id chondrosarcoma.

5 . M A J oR D IffeRenT IA l D IA G nosIs

• P a p i l l a r y r en a l ce l l ca r ci n o ma . T ranslocation renal cell carcinomas sometimes of ten show w ell developed papillary structures. However, they lack the cyt og enetic ab normalities that are typ ical of classic papillary R C C - trisomy of 7 and 17 , and loss of chromosome Y .

• C l ea r ce l l R C C . Some translocation renal cell carcinomas exh ib it the presence of clear cells f orming nested architecture, and are difficult to distinguish f rom classic clear cell R C C ; how eve r, translocation renal cell carcinoma lacks the chromosome 3p deletion typ ical of clear cell R C C .

6 . CY T oG eneT ICs A nD M oleCulA R A lT eRA T Ions

As mentioned above, these tumors are defined by X p11.2 translocations and resu lting T F E 3 g ene f u sions. T F E3 is a memb er of the b asic- helix- loop-helix f amily of transcription f actors, w hile P S F and N o n O encode splicing f actors. P R C C and A S P L encode nove l proteins f or w hich a f u nction has not ye t b een discove red, b u t the f ormer may also b e involved in splicing. Both the PRCC-TFE3 and ASPL-TFE3 fusion proteins retain the TFE3 DNA binding domain, localize to the nu cleu s, and can act as ab errant transcription f actors. T hrou g h interactions w ith other proteins, PR C C - T F E3 may also interf ere w ith splicing and mitotic checkp oint control. T he ex pression leve ls of T F E3 f u sion proteins appear

ab errantly hig h compared to native T F E3, perhaps b ecau se the f u sion partners of T F E 3 are u b iqu itou sly exp ressed and contrib u te their promoters to the f u sion proteins. I n terms of stru ctu ral heterog eneity , tw o alternative typ es of A S P L- T F E 3 f u sion transcripts and f ou r typ es of P R C C - T F E 3 transcripts have b een describ ed, b u t there are no apparent morpholog ic or clinical correlates of this g enetic va riab ility . I nteresting ly , w hile b oth the t(X ; 17 ) renal carcinomas and the sof t tissu e ASPS contain identical A S P L-T F E 3 f u sion transcripts, the t(X ; 17 ) translocation is consistently b alanced (reciprocal) in the f ormer b u t u su ally u nb alanced in the latter (i.e. the deriva tive X chromosome is not seen in ASPS).

7 . P RoG nosIs

Very little is known about the clinical behavior of these carcinomas. W hile the A S P L- T F E 3 renal carcinomas u su ally present at adva nced stag e, their clinical cou rse thu s f ar appears to b e indolent. Seve ral P R C C - T F E 3 renal carcinomas have recu rred late, u p to 20 or 30 ye ars af ter initial diag nosis.

X . RenA l Cell CA RCInoM A unClA ssIfIeD

1 . M oRP H oloG ICA l CRIT eRIA foR P A T H oloG ICA l D IA G nosIs

I n su rg ical series, it represents 4 - 7 % of renal tu mors [ 12, 10 7 ] , and at presentation most are of hig h g rade and stag e at diag nosis w ith poor su rvi va l [ 12, 9 6 , 9 7 , 9 8 , 10 7 , 10 8 , 10 9 , 110 ,111, 112] T he proportion of unclassified RCC carcinoma did not change with increasing decade of lif e in one stu dy [ 10 8 ] F eatu res w hich mig ht place a carcinoma in this categ ory are defined by the current WHO classification of kidney cancer [12]. Limited reported data suggests that it is an ag g ressive f orm of R C C , mainly b ecau se most cases are at adva nced stag e at presentation [ 12, 10 7 - 110 ] R esu lts b ased on tw o relative ly larg e series su pport this su g g estion. Z isman et al [ 10 9 ] reported 31 patients with unclassified RCC and compared the prog nostic ou tcome w ith 317 matched patients w ith clear cell RCC. The incidence of unclassified RCC in his series w as 2.9 % [ 10 9 ] At initial diag nosis 29 patients (94%) with unclassified and 264 (83%) with clear cell R C C had metastatic disease (p = 0 .14 3). Compared with the clear cell variety unclassified disease w as associated w ith larg er tu mors (p = 0 .0 0 5 ), increased risk of adrenal g land invo lve ment (25 % of cases, p = 0 .0 0 0 1), direct inva sion to adj acent org ans (4 2% , p = 0 .0 0 0 0 1), b one (5 2% , p = 0 .0 22), reg ional (5 2% , p = 0 .0 0 4 2) and non-reg ional lym ph node (4 1% , p = 0 .0 3) metastases [109]. Unclassified histology was a significant indicator f or poor prog nosis on mu ltiva riate analysi s (p <0.0001) [109]. Median survival in patients with

62

unclassified renal cell carcinoma was 4.3 months [ 10 9 ] . Most recently, Karakiewicz et al [110] revi ew ed 85 cases of unclassified RCC to compare cancer-specific mortality in patients with unclassified R C C vs. clear cell R C C af ter nephrectomy . O f patients with unclassified RCC, 80% had Fuhrman grades III or IV vs. 37.8% for clear cell RCC [110]. Moreover, 36.5% of patients with unclassified RCC had pathologically confirmed nodal metastases vs. 8 .6 % w ith clear cell R C C . F inally , 5 4 .1% of patients with unclassified RCC had distant metastases at the time of nephrectomy vs. 16 .8 % w ith clear cell RCC. Despite these differences in the overall analyse s, af ter matching f or tu mor characteristics, the unclassified RCC -specific mortality rate was 1.6 times hig her (P = 0 .0 4 ) in matched analyse s and 1.7 times hig her (P = 0 .0 0 1) in mu ltiva riate analyse s.5

B oth, Z isman et al [ 10 9 ] and K araki ew icz et al [ 110 ] concluded that unclassified RCC is associated with distinct and hig hly ag g ressive b iolog ical b ehavi or, and poor clinical ou tcome.

2 . ReCoM M enD eD P A T H oloG ICA l G uID elInes In T H ese CA ses

According to the current WHO classification of kidney cancer [12, 96] the features to define unclassified RCC include: i) composites of recognized types, ii) pu re sarcomatoid morpholog y w ithou t recog niza b le epithelial elements, iii) mu cin produ ction, iv) rare mixt u res of epithelial and stromal elements, and v) u nrecog niza b le cell typ es.

Pathologic studies on unclassified RCC are very limited w ith most reporting on small cases series [ 12, 9 6 , 9 7 , 9 8 , 10 7 , 10 8 , 10 9 , 110 ,111, 112] . Reuter [107], following the WHO criteria suggests that unclassified RCC represents a histologically and clinically heterog eneou s categ ory of tu mors that does not fit neatly into any of the other well-defined categories. Bakshi et al [111] reported that RCC antigen is expressed by 85% of unclassified R C C in their series. B ru der et al [ 112] reported 13 cases of unclassified RCC in a series of 41 renal cell carcinomas of patients yo u ng er than 22 ye ars. T hese tumors could not be assigned to types specified by the current WHO classification; of these, 10 cases were grouped as unclassified not otherwise specified, including a unique renal cell carcinoma w ith prominently va cu olated cyt oplasm and W T 1 expression. Three additional unclassified RCC occu rred in comb ination w ith nephrob lastoma. T he stu dy b y B ru der et al [ 112] adds new morpholog ic features which together with the WHO criteria might place a carcinoma in the category of unclassified R C C . Patholog ists mu st b e aw are of the spectru m of histologic findings within unclassified RCC to ensure their accu rate diag nosis [ 12, 9 6 , 9 7 , 9 8 , 10 7 , 10 8 , 10 9 , 110 ,111, 112] .

X I. non 2 0 0 4 W H o RCC suB T Y P es ConsID eReD

1 . T uB uloCY sT IC CA RCInoM A

T hese tu mou rs are composed b y packe d tu b u les and cyst s lined b y cu b oidal or hob nail cells w ith ab u ndant eosinophilic cyt oplasm and larg e nu clei show ing prominent nu cleoli.

a) Cl inical featuresT u b u locyst ic carcinoma has b een in part describ ed as a su b set of the g rou p of the B ellini’ s tu mou r or as low - g rade collecting du ct carcinoma.[ 113] I t has b een reported most in adu lts and w ith a male/ f emale ratio 7:1. Radiologically, it has a broad radiological differential diagnosis and can be classified as a Bosniak type II, III and IV. The great majority of these tu mors b ehave in an indolent f ashion, b u t a f ew have metastatize d. [ 114 - 117 ] .

b) M acroscopyT his tu mou r is u su ally a solitary u nencapsu lated tu mor w ith a w hite or g ray spong y cu t su rf ace. T hey can b e va riab le in size , althou g h most of them are pT1 tumors . Multifocal cases have been reported and association w ith papillary neoplasms have b een provi ded.[ 114 - 117 ] .

c) H istopathol ogyI t is composed of packe d tu b u les and cyst s separated by bland fibrous stroma. The lining cells are cuboidal to colu mnar and hob nail cells are commonly seen. T he cells have an ab u ndant eosinophilic or amphophilic cyt oplasm and the nu clei are larg e and have prominent nu cleoli ( fi g . 1 3 ) . O ccasional cells w ith a low - g rade nu clear chang es may b e seen.[ 114 -117 ] .

T he dif f erential diag nosis inclu de a va riou s spectru m of tu mou rs namely , mu ltilocu lated clear cell renal cell carcinoma, cyst ic nephroma, mixe d epithelial and stromal tu mor and cyst ic oncocyt oma.

d) Immunoprofile

A w ide rang e of marke r positivi ty w ith cyt oke ratins (CK8, CK18, CK19) are consistently positive. CD10 and P5 0 4 S (racemase) are positive in g reater than 9 0 % of tu mors. C K 7 is va riab le exp ressed, althou g h that pattern may b e w eak and f ocal. Staining f or kidney-specific cadherin and Pax-2 may also be seen. High molecular weight cytokeratin (34BE12) is nearly alw ays neg ative .[ 114 - 117 ]

e) Somatic genetics

Gene expression profiling and uorescence in situ hyb ridiza tion stu dies indicate that tu b u locyst ic carcinoma has a molecu lar sig natu re consisting in g ains of chromosomes 7 and 17 .[ 114 - 117 ]

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f) D iscussionT he histog enesis of tu b u locyst ic carcinoma is u nclear. T he association w ith mu ltiple papillary neoplasms prompted the arg u e that tu b u locyst ic carcinoma may represent a su b set of papillary renal cell carcinoma su ch as mu ltilocu lated clear cell renal cell carcinoma is considered a va riant of clear cell renal cell carcinoma. Due to unique clinico-patholog ical and g enetic characters, this typ e of renal cell carcinoma merit a f ormal recog nition in a renewed future classification.

2 . T H Y RoID - lIK e ( follICulA R) RenA l CA RCInoM A

T his tu mou r is a renal carcinoma w ith a f ollicu lar architectu re resemb ling f ollicu lar carcinoma of the thyr oid and composed b y cells show ing low - g rade pleomorphism w ith amphophilic to eosinophilic cy toplasm.

a) Cl inical featuresT he seve n tu mors reported to date w ere f rom f ou r f emale patients and three male adu lt patients. All tumors were incidental findings and two patients had a past history of u nrelated malig nancies. T he tu mors w ere tan colored and show a va riab le size and low pT . F ollow - u p data w ere ava ilab le f or all seve n cases and all patients remained tumor free after 6–84 months.[ 118 , 119 ] .

b) M icroscopy

T he tu mors contain a pseu docapsu le and are composed of cells show ing low - g rade pleomorphism w ith amphophilic to eosinophilic cyt oplasm. T he cells ag g reg ate into micro and macrof ollicles. Colloid-like proteinaceous uid may be revealed. Pseu doinclu sions and nu clear g roove s may b e present. T he main dif f erential diag nosis f or these tu mors is metastases f rom either a primary thyr oid f ollicu lar carcinoma or thyr oid carcinoma arising in a teratoma. T he eva lu ation of T T F 1 exp ression shou ld alw ays

b e u ndertake n in tu mors show ing this morpholog y to excl u de metastatic disease.[ 118 , 119 ] .

c) ImmunoprofileVariable expression of cytokeratin 7 and CD10 have b een reported. Six of the cases w ere neg ative f or RCC, WT1, vimentin, Ksp-cadherin, Pax 2, AMACR, CD56 and CD57, whereas all cases were negative f or T T F 1.[ 118 , 119 ] .

d) Somatic geneticsO ne case show ed g ains of chromosome 8 q24 , 12 and 16 , and loss of 1p36 .3 and 9 q21.33,10 3 w hereas gene expression profiling showed widespread u nderexp ression or ove rexp ression, particu larly invo lvi ng chromosomes 1, 2, 3, 5 , 6 , 10 , 11, 16 and 17 .[ 118 , 119 ] .

e) D iscussionT his tu mor cannot b e considered an entity b ecau se of the f ew cases stu died and reported.

3 . A CQ uIReD CY sT IC D IseA se-A ssoCIA T eD RenA l Cell CA RCInoM A A nD CleA R Cell P A P IllA RY RCC

T hese tu mors are associated w ith end renal disease. T he f ormer are composed b y larg e eosinophilic cells w ith a rou nded nu cleu s and larg e nu cleolu s arrang ed in va riety of architectu ral patterns and characterize d b y the presence of oxa late cryst als; the second b y cells w ith clear cyt oplasm and low - g rade nu clear pleomorphism org anize d in solid, tu b u lar and microcyst ic areas and f requ ently w ith a pronou nced cyst ic component.

a) Cl inical featuresStu dies indicate an increased preva lence of carcinoma in patients w ith end stag e renal disease. Most of the cases present more than one tumor in a sing le ki dney . I n a detailed stu dy of 6 6 tu mor- b earing ki dneys f rom patients w ith end- stag e renal disease, a w ide spectru m of renal neoplasia w as noted.[ 120 , 121] .

Fig. 13 B . - T ubul o- cystic carcinoma. Fig. 13 A . - T ubul o- cystic carcinoma.

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Acqu ired cyst ic disease- associated renal cell carcinoma are present in 4 6 % of ki dneys w ith acqu ired cyst ic disease and clear cell papillary R C C is the second tu mou r describ ed. T he last can occu r in ki dneys b oth w ith or w ithou t acqu ired cyst ic disease.[ 120 , 121] .

O u tcome data f or acqu ired cyst ic disease- associated renal cell carcinoma are limited, w ith one death f rom metastatic disease 34 months f ollow ing diag nosis, b eing reported. I n tw o other cases reg ional lym ph node metastases w ere seen.[ 120 , 121] .

N o deaths f rom clear cell papillary renal cell carcinoma associated in patients w ith and w ithou t end- stag e renal disease have b een reported.[ 120 , 121] .

b) M acroscopy

Acqu ired cyst ic disease- associated renal cell carcinoma are u su ally w ell- circu mscrib ed, larg e w ith dystrophic calcification. Clear cell papillary RCC f requ ently contain a prominent pseu docapsu le and cy stic f eatu re.

c) M icroscopy

Acqu ired cyst ic disease- associated renal cell carcinoma displaye d a va riety of architectu ral patterns w ith solid, acinar, cys tic and papillary patterns b eing present. I rreg u lar lu mina may g ive the tumor a cribriform appearance. Most of reported cases the tu mor appeared to arise in a cyst . T he tu mor cells contain eosinophilic cyt oplasm w ith a rou nded nu cleu s and larg e nu cleolu s. O xa late cryst als are present in the maj ority of tu mors and also calciu m ag g reg ates.[ 122]

C lear cell papillary R C C show in 5 0 % of cases a pronou nced cyst ic component; solid, tu b u lar and microcyst ic areas are also present. T he tu mor cells show a clear cy toplasm and a low - g rade nu clear pleomorphism w ith nu clei situ ated tow ards the su rf ace of the papillary tu f ts.[ 120 , 121] .

d) Immunoprofile

Acqu ired cyst ic disease- R C C s are positive f or vi ncu lin and AMACR on immunohistochemical examination, and in a proportion of cases show va riab le f ocal staining f or cyt oke ratin 7 and parva lb u min, discordant positive immu noexp ression f or cyt ok eratin AE1/ AE3 and CD10, and variable expression for vimentin CAM 5.2. [123, 124].

C lear cell papillary R C C show positive staining f or cytokeratin 7 and are negative for AMACR and parva lb u min.[ 123] .

e) Somatic genetics

I n a ki dney show ing acqu ired cyst ic disease, g enetic analysi s show ed g ains of chromosomes 7 and 17. In acquired cystic disease-RCCs FISH and

CGH analyses showed multiple gains of numerous chromosomes inclu ding chromosomes1, 2 , 6 , 10 , 3, 7, 17 and Y. Mutations of the VHL gene have not yet been identified in these tumors. Clear cell papillary R C C did not show neither 3p nor trisomies of chromosomes 7 and 17 .[ 121, 124 ] .

f) D iscussionDiscrete clinico-pathological informations are present in reg ard to acqu ired cyst ic disease- R C C s w hereas more data are needed f or the clear cell papillary R C C and its possib le relationship w ith other.

4 . leIoM Y oM A T ous RenA l Cell CA RCInoM A s

T hey are tu mors composed of tu b u lar ag g reg ates of neoplastic clear cell intermixe d in a prominent leiomyo matou s prolif eration.

a) Cl inical featuresAmong 12 reported cases, eig ht f emale and f ou r male patients rang ed in adu lt ag es. T w o of the patients had co- exi sting cancer (b reast carcinoma and papillary renal cell carcinoma) and one patient had tuberous sclerosis. Most tumors were incidental findings, although three patients presented with hematu ria. O u tcome stu dies f or leiomyo matou s renal cell carcinoma are limited. N o evi dence of recu rrence or metastases w as seen in these and tw o other cases f ollow ed f rom 6 months to 5 ye ars (mean 3 ye ars). [ 7 4 , 125 , 126 ] .

b) M acroscopy

Grossly the tumors measured 1.8–14 cm (mean 4.6 cm) and w ere va riou sly describ ed as tan, b row n, ye llow or w hite w ith the f requ ent presence of a thick inve sting capsu le. O f cases f or w hich details are ava ilab le, f ou r w ere pT 1a and one pT 1b at diag nosis.

c) M icroscopy

T he tu mors are composed of nests, cords and sheets of epithelial cells f requ ently f orming solid areas, tu b u les or papillary stru ctu res. T here is slig ht nu clear pleomorphism w ith ab u ndant clear cyt oplasm. T he stroma is composed b y matu re smooth mu scle w hich is of ten more pronou nced at the periphery and in some cases appears to ext end into adj acent renal tissu e or into perirenal f at.T he dif f erential diag nosis f or these tu mors is clear cell renal cell carcinoma, ang iomyo lipoma and sarcomatoid renal cell carcinoma. [ 7 4 , 125 , 126 ] .

d) Immunoprofile

T he epithelial component of the tu mor show ed positive immu noexp ression of cyt ok eratins AE1/ AE and CAM 5.2, CD-10, S-100 protein (focal), EMA and vi mentin. T here w as va riab le exp ression of 34 b E12, whereas smooth muscle actin and HMB45 was

65

neg ative . T he stroma component w as positive f or a smooth mu scle actin, caldesmon, desmin, vi mentin and negative for HMB45, CD117, cytokeratins, EMA, ER and PR .[ 7 4 ] .

e) Somatic genetics

G enetic stu dies on these tu mors are contradictory . In three cases FISH showed loss of VHL and FHIT, w ith loss of chromosome 3 in one case and 3p in another. I n a separate stu dy there w as no evi dence of 3p deletion in the three cases exa mined.[ 7 4 ] .

T here is still a deb ate among the relationship b etw een the renal adematou s tu mou r (R AT ) recently describ ed [ 127 ] , clear cell papillary and leiomyo matou s renal cell carcinoma. Microscopically, examination reveals a leiomyo matou s stroma su rrou nding and encasing a distinctive and characteristic epithelial component. T his latter is represented b y adenomatou s stru ctu res composed of cells w ith small deeply b asophilic nu clei alienated along the b asal memb rane. Along these characters, clear cell papillary renal carcinoma may also show ove rlapping morpholog ical f eatu res.F inally all these neoplasms are constanly positive for CK7. Due to aforementioned morphological contrasting findings, a formal classification is early.

X II. CRIT ICA l ReVIeW of G RA D InG

At first the Fuhrman’s grade was applied only to the clear cell renal cell carcinomas. N ow adays the g rading of all cell su b typ es is recommended . B u t in non clear cell typ es some criticism appears in the u se of this syst em, f or this reason w e w ill consider the g rading in dif f erent histolog ical su b typ es.

1 . CleA R Cell RenA l Cell CA RCInoM A

Despite criticisms to the reproducibility of the F u hrman’ s nu clear g rade (b ased on the size and shape of the nu cleu s and also on the presence or ab sence of nu cleoli) [ 128 ] it is the most w idely method u sed internationally .

I t is a g ood prog nostic marke r w ith, a 5 - ye ar cancer specific survival rate of 89%, 65% and 46% for g rades 1, 2 and 3- 4 , respective ly [ 129 ] . T he present trend is to su b divi de the f ou r F u hrman’ s g rades into low g rade (g rade 1 and 2) and hig h g rade (g rade 3 and 4 ) [ 130 ] . W ith this approach the interob serve r and intraob serve r va riab ility is improve d w ithou t loss of ou tcome discrimination [ 131] .

T he w ider u se of u ltrasou nd f avo u rs the detection of asym ptomatic renal tu mou rs [ 132] w ith a hig her incidence of organ-confined carcinomas. In this situ ation the F u hrman’ s g rading can also b e of help. N u clear g rade g reater than 2 correlates w ith significantly shorter survival (p = 0.018) in Stage I tu mou rs [ 133] .

2 . P A P IllA RY RenA l Cell CA RCInoM A

T he stu dy of the dif f erent criteria of F u hrman’ s syst em only f ocal nu cleolar g rade w as associated w ith su rvi va l, on u niva riate and mu ltiva riate analysi s in papillary R C C [ 134 ] , T hat means that the nu cleolar size is, prob ab ly , most important that the su b typ e.

3 . CH RoM oP H oB e RCC

I rreg u lar nu clei and prominent nu cleoli are typ ically seen. T heref ore, F u hrman’ s g rade is of ten reported w orse eve n in patients w ith f avo u rab le ou tcomes. Some au thors propose an adaptation of the classification for this RCC subtype with redefinition of three grades for chromophobe RCC: Grade 1: cells with wide nuclear range without nuclear crowding or anaplasia. Grade2: presence of nu clear pleomorphism and nu clear crow ding . Grade 3: nuclear anaplasia including giant cells and sarcomatoid transf ormation. T his new syst em accepts the more pleomorphic nu clear aspect in low g rades that correlates b etter w ith the pT categ ory and predicts the clinical ou tcome independently [ 135 ] T his new approach shou ld how eve r b e va lidated b y other series b ef ore its introdu ction in clinical practice.

F inally , the M u ci n o u s tu b u l a r a n d sp i n d l e ce l l ca r ci n o ma , a new subtype in the WHO 2004 classification, is not graded. Likewise, the O n co cyt o ma , as a b enig n tu mor, is not g raded.

X III. G uID elInes foR P A T H oloG ICA l sT A G InG

eVA luA T IonT he qu ality of any patholog ical eva lu ation depends on a caref u l macroscopic exa mination of the su rg ical specimens [136]. Basic for an efficacious pathological study are: identification of the anatomical structures, preserva tion of the complete specimens (i.e. no cu ts), and appropriate handling b y u rolog ists.

T he specimens shou ld b e manipu lated w hen f resh. Avo id stripping the capsu le b ef ore sectioning the specimen, and identif y the renal ve in, the renal artery , and the u reter. C aref u l ext ernal inspection is b asic f or eva lu ating the radicality of the nephrectomy . T he areas w here su ch radicality is du b iou s shou ld b e inke d w ith I ndian ink b ef ore sectioning .T he specimen shou ld b e sectioned eve ry 10 mm inclu ding the perinephric f at tissu e. Eve ry tu moral nodu le and anatomical stru ctu re shou ld b e identified and the specimen should be fixed and left ove rnig ht.Samples f or microscopy stu dy shou ld b e selected and identified by means of identification labels, and they should include: i) One tumour section per every centimetre of tu mou r diameter. ii) Section of the tu mou r- f at tissu e interf ace. iii) Accu rate stu dy of the

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sinu s f at tissu e close to the tu mou r, w ith a sag ittal section of this area [ 137 ] i n va si o n o f th e si n u s f a t ti s su e seems to entail g reater ag g ressive ness (5 years specific survival 25.9%) than perinephric fat tissue invasion (5 years specific survival 50.9%) [ 138 ] , prob ab ly b ecau se it contains a nu mb er of larg e thin- w alled ve ins and lym phatics, and it is not separated from the renal cortex by a fibrous capsule [ 139 ] iv)

Section of the renal ve in, eve n if normal. v) T w o or three samples of normal ki dney , close to the tu mou r and also distal to it. O ne of the ob j ective s of this sampling is finding microvascular invasion. vi ) Adrenal g land section, eve n if the tu mou r is f ar f rom it. vi i) C omplete dissection inclu ding lym ph nodes. T he nu mb er of lym ph nodes to b e dissected depends on the patholog ist’ s motiva tion and the u rolog ists´ s ski lls. G enerally the lym ph nodes are rarely identifiable unless specifically dissected by the su rg eon. I n this case inclu sion of the complete hiliar f at tissu e is recommended [ 137 ]

Margins are of the utmost importance. Positive marg ins are ve ry rarely f ou nd in specimens f rom a radical procedu re. I f positive marg ins w ere f ou nd, their location and their ext ension shou ld b e reported.

T he marg ins of a nephron- sparing nephrectomy are the renal parenchym a marg in and the perinephric f at marg in. I t is advi sab le to ink the exci sion marg ins b ef ore dissection. T he u rinary tract w all shou ld b e considered a marg in if the tu mou r ext ends into the calyce al syst em [ 14 0 ] .

X IV. M oleCulA R B A sIs of RenA l CA nCeR T ReA T M enT

T he kn ow ledg e of the molecu lar b asis of R C C has been improved with the introduction of DNA ex pression analysi s. Array b ased exp ression profiling allows for a molecular classification of tumours. The first gene expression profiling study in R C C w as pu b lished in 20 0 1 b y Y ou ng et a l . [ 14 1] . T hey analyse d a total of seve n samples consisting of clear cell R C C , chromophob e R C C and oncocyt oma w ith matching normal renal tissu e and f ou nd distinct dif f erences in g enes exp ression b etw een these entities. C lear cell R C C cou ld b e disting u ished f rom chromophob e R C C / oncocyt oma b y exp ression of Vimentin, whereas galectin-3 expression was more preva lent in oncocyt oma/ chromophob e R C C . T aka hashi et a l . pu b lished a correlation of R C C expression profiles with clinical follow up data and defined a group of transcripts, which predicted patient risk of prog ression more accu rately than conve ntional tu mou r stag ing in a small tu mou r cohort (n= 29 )[ 14 2] . C andidate diag nostic marke rs were identified by the same group in a larger

study (n=70): glutathione S-transferase was highly expressed in clear cell RCC, α-methylacyl racemase (AMACR) was typical of papillary RCC and carbonic anhyd rase I I w as f ou nd in chromophob e R C C [ 14 3] . The studies of Vasselli et a l . (58 tumors) and Jones et a l . (4 9 R C C s) f ocu sed on a clu ster or sig natu re b ased prediction of patient prog nosis [ 14 4 , 14 5 ] . Our refined understanding of the molecular pathways invo lve d in renal carcinog enesis has provi ded a rationale for novel therapeutics which specifically targ et molecu les of ab errantly activa ted pathw ays. The Von Hippel-Lindau (VHL) tumour suppressor g ene is epig enetically silenced or mu tated in the maj ority of sporadic clear cell renal carcinoma (see above). The decreased pVHL expression leads to a stabilisation of the hypoxia induced factor (HIF)-α and consequently to the transcription of HIF-α targ et g enes, many of w hich are invo lve d in tu mou r promoting processes as prolif eration, ang iog enesis and cell motility [ 14 8 ] . T arg eting the transcription factor HIF directly is difficult, but a variety of agents have been identified that downregulate HIF-α levels indirectly , e.g ., inhib itors targ eting the mammalian target of rapamycin (mTOR) [149, 159] or Heat shock protein 90 (HSP90) [149, 150]. Another approach is to target HIF-α regulated genes directly. HIF-α responsive genes of major importance in tumour biology are VEGF, PDGF, TGFα, EGFR and C a I X . VeG f is ove rexp ressed in R C C and has prog nostic properties [ 15 1] . P D G f (Platelet- derive d g row th f actor) correlates to hig her F u hrman g rades and appears to b e a prog nostic marke r in R C C [ 15 2] . T G f ( T r a n s f o r m i n g g r o w t h f a c t o r ) . TGF-α is ove rexp ressed in R C C and is indu ced b y hyp oxi a [153]. TGF-β is overexpressed in various malignant tu mors inclu ding R C C [ 15 4 ] . eG fR ( ep i d e r m a l g r o w t h f a c t o r r e c e p t o r , er b B - 1 ) is ove rexp ressed in the maj ority of R C C [ 15 5 , 15 6 ] . CA IX ( Ca r b o n i c a n h y d r a s e IX ) is ove rexp ressed in > 9 0 % of clear cell R C C , b u t is u su ally not f ou nd in normal tu b u lu s epitheliu m. I nteresting ly , in R C C it has b een f ou nd as a neg ative marke r of prog nosis and is discu ssed as a predictive marker of IL-2 therapy response [ 15 7 , 15 8 ] . O ther targ et g enes not associated w ith HIF-α are KIT, COX-2 and Matrix Metalloproteinases (MMP). K IT is a typ e I I I tyr osine ki nase receptor that is ove rexp ressed in chromophob e R C C and oncocyt oma, b u t rarely in clear cell R C C [ 16 0 ] . CoX - 2 is u preg u lated in many malig nant tu mou rs inclu ding R C C . Possib ly , C O X - 2 is a predictive marke r f or therapy response to C O X - inhib itors in R C C [ 16 1] . M a t r i x M e t a l l o p r o t e i n a s e s ( M M P ) have b een associated w ith a poor prog nosis in R C C [ 16 2] . A su mmary of releva nt b iomarke rs in R C C has b een recently pu b lished b y Eichelb erg et al. (Eichelb erg C, Junker K, Ljungberg B, Moch H. Diagnostic and prog nostic molecu lar marke rs f or renal cell carcinoma: a critical appraisal of the current state of research and clinical applicab ility . [ 16 4 ] .

67

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10 0 . Arg ani P, O lg ac S, T icko o S, et al. X p11 translocation renal cell carcinoma in adults: expanded clinical, pathologic, and genetic spectrum. Am J Surg Pathol 2007;31:1149-60.

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129. Tsui KH, Shvarts O, Smith RB, Figlin RA, deKernion JB, Belldegrun A.: Prognostic indicators for renal cell carcinoma: a multivariate analysis of 643 patients using the revised 1997 TNM staging criteria. J. Urol. 2000; 163: 10 9 0 - 10 9 5 .

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131. Al-Aynati M, Chen V, Salama S, Shuhaibar H, Treleaven D, Vincic L.: Interobserver and intraobserver variability using the F u hrman g rading syst em f or renal cell carcinoma. Arch Pathol Lab Med. 2003;127 : 593-596.

132. Bos SD, Mellema CT, Mensink HJ. :Increase in incidental renal cell carcinoma in the northern part of the N etherlands. Eur Urol. 2000;37:267-270.

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133. Gelb AB, Shibuya RB, Weiss LM, Medeiros LJ. : Stage I renal cell carcinoma. A clinicopatholog ic stu dy of 8 2 cases. Am. .J Surg. Pathol. 1993;17 : 275-286.

134. Sika-Paotonu D, Bethwaite PB, McCredie MR, William Jordan T, Delahunt B.Nucleolar grade but not Fuhrman grade is applicable to papillary renal cell carcinoma. Am J Surg Pathol. 2006; 30:1091-1096

135. Delahunt B, Sika-Paotonu D, Bethwaite PB, McCredie MR, Martignoni G, Eble JN,Jordan TW. Fuhrman grading is not appropriate for chromophobe renal cell carcinoma. Am J Surg Pathol. 2007 ;31:957-960.

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138. Bonsib SM.: The renal sinus is the principal invasive pathway: a prospective study of 100 renal cell carcinomas. Am J Surg Pathol. 2004;28:1594-1600.

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140. Algaba F, Arce Y, Lopez-Beltran A, Montironi R, Mikuz G, Bono AV; European Society of Uropathology; Uropathology Working Group.: Intraoperative frozen section diagnosis in urological oncology. Eur Urol. 2005;47 :129-136.

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142. Takahashi M, Rhodes DR, Furge KA, Kanayama H, Kaga--wa S, Haab BB, Teh BT. Gene expression profiling of clear cell renal cell carcinoma: gene identification and prognos--tic classification. Proc Natl Acad Sci U S A 2001;98:9754-9 .

143. Takahashi M, Yang XJ, Sugimura J, Backdahl J, Tretiakova M, Qian CN, Gray SG, Knapp R, Anema J, Kahnoski R, Nicol D, Vogelzang NJ, Furge KA, Kanayama H, Kagawa S, Teh BT. Molecular subclassification of kidney tumors and the discove ry of new diag nostic marke rs. O ncog ene 2003;22:6810-8.

144. Vasselli JR, Shih JH, Iyengar SR, Maranchie J, Riss J, Worrell R, Torres-Cabala C, Tabios R, Mariotti A, Stearman R, Merino M, Walther MM, Simon R, Klausner RD, Linehan WM. Predicting survival in patients with metastatic kidney cancer by gene-expression profiling in the primary tumor. Proc Natl Acad Sci U S A 2003;100:6958-63.

145. Jones J, Otu H, Spentzos D, Kolia S, Inan M, Beecken WD, Fellbaum C, Gu X, Joseph M, Pantuck AJ, Jonas D, Libermann TA. Gene signatures of progression and metastasis in renal cell cancer. C lin C ancer R es 2005;11:5730-9.

146. Tsui KH, Shvarts O, Smith RB, Figlin RA, deKernion JB, Belldegrun A. Prognostic indicators for renal cell carcinoma: a multivariate analysis of 643 patients using the revised 1997 TNM staging criteria. J Urol 2000;163:1090-5 ; qu iz 29 5 .

147. McDermott DF, Regan MM, Clark JI, Flaherty LE, Weiss GR, Logan TF, Kirkwood JM, Gordon MS, Sosman JA, Ernstoff MS, Tretter CP, Urba WJ, Smith JW, Margolin KA, Mier JW, Gollob JA, Dutcher JP, Atkins MB. Randomized phase I I I trial of hig h- dose interleu ki n- 2 ve rsu s su b cu tane--ou s interleu ki n- 2 and interf eron in patients w ith metastatic renal cell carcinoma. J Clin Oncol 2005;23:133-41.

148. Kaelin WG, Jr. Molecular basis of the VHL hereditary cancer syndrome. Nat Rev Cancer 2002;2:673-82.

149. Hudson CC, Liu M, Chiang GG, Otterness DM, Loomis DC, Kaper F, Giaccia AJ, Abraham RT. Regulation of hyp oxi a- indu cib le f actor 1alpha exp ression and f u nction by the mammalian target of rapamycin. Mol Cell Biol 2002;22:7004-14.

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151. Yildiz E, Gokce G, Kilicarslan H, Ayan S, Goze OF, Gultekin EY. Prognostic value of the expression of Ki-67, CD44 and va scu lar endothelial g row th f actor, and microve ssel invasion, in renal cell carcinoma. BJU Int 2004;93:1087-9 3.

152. Sulzbacher I, Birner P, Traxler M, Marberger M, Haitel A. Exp ression of platelet- derive d g row th f actor- alpha alpha receptor is associated w ith tu mor prog ression in clear cell renal cell carcinoma. Am J Clin Pathol 2003;120:107-12.

153. de Paulsen N, Brychzy A, Fournier MC, Klausner RD, Gnarra JR, Pause A, Lee S. Role of transforming growth factor-alpha in von Hippel--Lindau (VHL)(-/-) clear cell renal carcinoma cell proliferation: a possible mechanism coupling VHL tumor suppressor inactivation and tumorigenesis. Proc Natl Acad Sci U S A 2001;98:1387-9 2.

154. Mitropoulos D, Kiroudi A, Christelli E, Serafetinidis E, Zervas A, Anastasiou I, Dimopoulos C. Expression of transf orming g row th f actor b eta in renal cell carcinoma and matched non-involved renal tissue. Urol Res 2004;32:317-22.

155. Merseburger AS, Hennenlotter J, Simon P, Kruck S, Koch E, Horstmann M, Kuehs U, Kufer R, Stenzl A, Kuczyk MA. Membranous expression and prognostic implications of epidermal g row th f actor receptor protein in hu man renal cell cancer. Anticancer Res 2005;25:1901-7.

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Co m m i t t e e 4

P r o g n o s t i c fa c t o r s o f Re n a l Ce l l Ca r c i n o m a :

A c o n t e m p o r a r y Re v i e w

Ch a i r :

P . I . K A R A K I E W I C Z ,

M e m b e r s :

C . C HE N G ,V. F I C A R R A ,M . M U R A I ,

S . O U D A R D ,A . J. P A N T U C K ,S . F . S HA R I A T ,R . Z I G E U N E R ,

Co r r e s p o n d e n c ePierre I . K araki ew icz, C ancer Prog nostics and H ealth O u tcomes U nitU nive rsity of M ontreal H ealth C entre (C H U M )10 5 8 , ru e St- D enis, M ontreal, Q u eb ec, C AN AD A, H 2X 3J4 T el: 5 14 - 8 9 0 - 8 0 0 0 ext : 35 336 F ax: 5 14 - 227 - 5 10 3Email: pierre.ka raki ew icz@ u montreal.ca

Shahrokh F . ShariatD epartment of U rolog y ,W eill C ornell M edical C enter,N ew Y ork, N Y , U SA

74

T A B le of ConT enT s

I. InT RoD uCT Ion

II. H IsT oRY of P RoG nosT ICs In RCC

III. RCC B IoM A RK eRs

1 . T Issue- B A seD B IoM A RK eRs

2 . B looD - B A seD B IoM A RK eRs

IV. use of B IoM A RK eRs In P RoG nosT IC M oD els

V. ConClusIons

75

P r o g n o s t i c fa c t o r s o f Re n a l Ce l l Ca r c i n o m a :

A c o n t e m p o r a r y Re v i e w

M . S U N , S . F . S HA R I A T ,

C . C HE N G , V. F I C A R R A , M . M U R A I ,S . O U D A R D , A . J. P A N T U C K ,

R . Z I G E U N E R , P . I . K A R A K I E W I C Z ,

T he natu ral history of renal cell carcinoma (R C C ) may b e u npredictab le. F or exa mple, b etw een 4 .2 and 7 .1% of patients w ith tu mors < 4 centimeters that are u su ally indolent in natu re, harb or metastatic disease at presentation and are at an eleva ted risk of disease-specific mortality. [1] Conversely, as many as 4 0 % of patients w ith lym ph node metastases diagnosed at nephrectomy are alive at five years after surgery. [2] Several approaches have been proposed to help predicting the natu ral history of treated R C C and to disting u ish b etw een poor and f avo rab le risk patients. I n the cu rrent manu script, we will briey address the history of prognostics. We w ill revi ew the exi sting prog nostic f actors, as w ell as f actors predicting response to targ eted therapy and complete the revi ew w ith estab lished prog nostic models.

II. H IsT oRY of P RoG nosT ICs In RCC

I n 19 8 8 , Elson et al. pioneered the approach to multivariable modeling in prediction of cancer-specific mortality ( T a b l e 1 ) . [3] In 1999, Motzer et al. (n=670) identified five predictors (Karnofsky Performance Statu s) (K PS), lactate dehyd rog enase, hemog lob in, corrected calciu m, and presence/ ab sence of nephrectomy) of metastatic RCC mortality. [4] The developed Motzer score stratified patients between f avo rab le (0 risk f actors), intermediate (1- 2 risk f actors), and poor risk (> 3 risk factors). [4] In 2002, an update of the Motzer score (n=463) replaced nephrectomy statu s w ith time f rom diag nosis to start of interferon. [5] In 2004, a second update (n=251) reduced the score to three predictors (KPS, hemoglobin, and corrected calcium). [6]

In 2005, Mekhail et al. suggested several modifi--cations to the 20 0 2 M otze r score va riab les (K PS, lactate dehyd rog enase, hemog lob in, corrected calci--um, and time from diagnosis to start of interferon) [5] su ch as addition of previ ou s exp osu re to radiother--apy and va riab les indicating the presence of nodal, hepatic, and/or lung metastases (n=353; T a b l e 1 ). [7] I n 20 0 7 , Escu dier et al. also su g g ested the replace--ment of K PS w ith the nu mb er of metastatic sites. [8]Unfortunately, none of the original Motzer models w ere f ormally va lidated. I n consequ ence, their ac--cu racy , perf ormance characteristics and impact on clinical decision- maki ng remain u nkn ow n.

A report f rom the G r o u p e F r a n ça i s d ’ I mmu n o th é r a p i e su g g ested a dif f erent prog nostic model, w hich identified four variables that were statistically significantly associated with progression in patients receivi ng immu notherapy ( T a b l e 1 ) . T hese consisted of time f rom R C C diag nosis to metastases, nu mb er of metastatic sites, presence of hepatic metastases, and of theneutrophil count. [9] Recently, Heng et al. [10] devised and internally validated a model that replicates the M otze r methodolog y and relies on four of five Motzer criteria (hemoglobin, corrected calciu m, K PS and time f rom diag nosis to treatment), in addition to neu trophil and platelet cou nts. O f all models, the Heng et al.[10] model was the only one su b j ected to internal (b ootstrap) va lidation, w hich show ed 7 3% accu racy in predictionof mortality af ter therapy w ith va scu lar endothelial g row th f actor (V EG F ) therapy . I t aw aits its ext ernal va lidation.

T he M otze r, M ikh ail, G r o u p e F r a n ça i s d ’ I mmu -n o th é r a p i e and H eng models excl u sive ly apply to patients w ith metastatic R C C . O ther models have b een deve loped f or patients w ith all stag es or non-metastatic R C C . F or exa mple, inve stig ators f rom U nive rsity of C alif ornia L os Ang eles (U C L A) devi sed an integ rated stag ing syst em (U I SS) f or prediction of su rvi va l in patients w ith all stag es of R C C

I. InT RoD uCT Ion

76

T abl e 1. P rediction of ov eral l surv iv al and/ or progression- free surv iv al in metastatic renal cel l carcinoma

M o d e l sa m p l es i ze

T a r g e t p o p u l a t i o n P r e d i c t o r s c - i n d e x

Elson et al. [3] 6 10 mR C C - EC O G - PS - time f rom initial diag nosis - N u mb er of metastatic sites - prior cyt oxi c chemotherapy - w eig ht loss

n.r.

Motzer et al. [4] 6 7 0 mR C C treated w ith N T - lactate dehyd rog enase > U L N - hemog lob in > U L N - K PS - corrected seru m calciu m > U L N - ab sence of N T

n.r.

Motzer et al. [5] 4 6 3 mR C C treated w ith N T / I N F - K PS - lactate dehyd rog enase < U L N - hemog lob in > U L N - corrected seru m calciu m > U L N - time f rom diag nosis to I F N

n.r.

Motzer et al. [6] 25 1 mR C C treated w ith N T / I N F - K PS - hemog lob in > U L N - corrected seru m calciu m > U L N

n.r.

Negrier et al. [147] 7 8 2 mR C C treated w ith cyt oki ne - presence of b iolog ical sig ns of inammation - short time interva l f rom renal tu mor to mR C C - eleva ted neu trophil cou nt - live r metastases - b one metastases - perf ormance statu s - nu mb er of metastatic sites - alka line phosphotase - hemog lob in

n.r. (O S)

Negrier et al. [147] 7 8 2 mR C C treated w ith cyt oki ne - presence of hepatic metastases - short interva l f rom renal tu mor to metastases - > 1 metastatic site - eleva ted neu trophil cou nt

n.r. (PF S)

L eib ovi ch et al. [152]

17 3 mR C C treated w ith N T / I L - 2 - N classification - constitu tional sym ptoms - location of metastatic sites - histolog ical su b typ e - sarcomatoid f eatu res - thyr oid stimu lating hormone leve ls

n.r.

L eib ovi ch et al. [126]

7 27 metastatic clear cell R C C treated w ith N T

- ag e - g ender - sym ptoms at N T - time f rom N T to mR C C - location/ su rg ical treatment of metastases - presence/ leve l of tu mor thromb u s - histolog ical su b typ e - T N M (20 0 2) - tu mor size - perinephritic f at inva sion - lym ph node inva sion - nu clear g rade - tu mor necrosis - sarcomatoid dif f erentiation

6 7 .0 %

77

Negrier et al. [9] 7 8 2 mR C C patients treated w ith cyt oki ne

- > 1 metastatic site - havi ng receive d comb ination of therapies

n.r. (efficacy)

Mekhail et al. [7] 35 3 mR C C - mu ltif ocality - time f rom diag nosis to stu dy entry - lactate dehyd rog enase > U L N - corrected seru m calciu m > U L N - previ ou s radiotherapy - presence of hepatic/ pu lmonary/ retroperitoneal/ lym ph node metastases

n.r.

D onsko v et al. [184]

120 mR C C patients treated w ith I L - 2

- lactate dehyd rog enase - lym ph node metastases - hemog lob in - K PS - b one metastases - hig h b lood neu trophil cou nt - presence of intratu moral neu trophils - low intratu moral C D 5 7 + natu ral ki ller cell cou nt

n.r.

C hou eiri et al. [183]

120 mR C C patients treated w ith V EG F ag ents

- corrected seru m calciu m > U L N - neu trophil cou nt > U L N - platelet cou nt > U L N - EC O G - PS - time f rom diag nosis to stu dy start

n.r.

Escudier et al. [8] 30 0 mR C C patients w ho f ailed immu notherapy

- alka line phosphatase > U L N - corrected seru m calciu m > U L N - lactate dehyd rog enase > U L N - nu mb er of metastatic sites - time f rom diag nosis to metastatic diag nosis

n.r.

Motzer et al. [185] 37 5 mR C C patients treated w ith su nitinib

- corrected seru m calciu m - nu mb er of metastatic sites - hemog lob in > U L N - prior N T - lu ng metastases - live r metastases - EC O G - PS - thromb ocyt osis - time f rom diag nosis to treatment - alka line phosphotase - lactate dehyd rog enase

6 3.0 %

Heng et al. [10] 6 4 5 mR C C patients treated w ith V EG F ag ents

- K PS - time f rom diag nosis to treatment - hemog lob in > U L N - corrected seru m calciu m > U L N - neu trophil > U L N - platelet > U L N

7 3.0 %

T abl e 1. P rediction of ov eral l surv iv al and/ or progression- free surv iv al in metastatic renal cel l carcinoma ( continued)

L egend: mR C C : meta st a ti c r en a l ce l l ca r ci n o ma ; E C O G - P S : E a st er n C o o p er a ti ve O n co l o g y G r o u p P er f o r ma n ce S ta tu s; N T : n ep h r ect o my; U LN : u p p er l i mi t n o r ma l ; K P S : K a r n o f sky p er f o r ma n ce st a tu s; I N F : i n ter f er o n ; O S : o ve r a l l su r vi va l ; P F S : p r o g r essi o n - f r ee su r vi va l ; I L2- : i n ter l eu ki n 2- ; VE G F : va scu l a r en d o th el i a l g r o w th f a ct o r ; n . r . : n o t r ep o r ted

78

( T a b l e 2 ) . [11, 12] This model relies on the TNM stage, F u hrman g rade, and EC O G - PS and has b een w idely tested and validated (c-indices: 58-86%). [13-19] A mu lti- institu tional collab orative g rou p of Eu ropean and N orth American inve stig ators deve loped tw o prognostic models that address RCC-specific mortality b ased on va riab les that can b e ob tained either prior ( T a b l e 3 ) to or af ter nephrectomy ( T a b l e 4 ) . T hese tw o models can predict the natu ral history of R C C af ter nephrectomy . H ow eve r, they are not desig ned to accou nt f or the ef f ect of targ eted therapies in patients with metastatic RCC. [20, 21]

T he accu racy of the pre- nephrectomy model f or prediction of cancer-specific mortality at 5 yearsis 8 6 .7 % vs. 8 6 .8 % f or the post- nephrectomy model ( T a b l e 2 ) . Similar models w ere deve loped b y other inve stig ators and allow estimation of recu rrence-free survival [22, 23] or metastatic progression after nephrectomy,[24] with accuracy rates between 6 5 and 8 0 % . M u ltiva riab le models su ch as the UISS[11], the Kattan postoperative nomogram[25], BioScore[26], and SSIGN score (tumor stage, size, grade, necrosis) [27] have better prognostic ability than anatomical stag ing alone ( T a b l e 4 ) . D espite their

Table 2. Postoperative assessment of cancer-specific mortality

M o d e l sa m p l es i ze

T a r g e t p o p u l a t i o n P r e d i c t o r s c - i n d e x

Zisman et al. [11] 6 6 1 R C C of all stag es - AJC C - F u hrman g rade - EC O G - PS

8 2.0 - 8 6 .0 %

Zisman et al. [12] 8 14 R C C of all stag es - T N M (19 9 7 ) + EC O G - PS

7 3.0 % 7 9 .0 - 8 6 .0 %

Frank et al. [27] 18 0 1 L ocalize d clear cell R C C - T N M (19 9 7 ) - tu mor size - nu clear g rade - tu mor necrosis

8 5 .0 % (int.) 8 1.0 - 8 2.0 % (va l.)

Kim et al. [97] 318 R C C of all stag es - M stag e - metastatic C AI X - p5 3 - vi mentin - g elsolin

7 9 .0 %

Kim et al. [182] 15 0 M etastatic clear cell R C C - T stag e - EC O G - PS - C AI X - vi mentin - p5 3 - PT EN

6 8 .0 %

T hompson et al. [187]

15 6 0 L ocalize d clear cell R C C - T N M (19 9 7 ) - tu mor size - nu clear g rade - tu mor necrosis

n.r.

K araki ew icz et al. [20]

25 30 (dev .) 14 22 (va l.)

C lear cell, papillary , chromophob e R C C

- pT stag e - pN stag e - M stag e - tu mor size - F u hrman g rade - Symptoms classification

8 7 .8 - 8 9 .2% (va l.)

K araki ew icz et al. [188]

25 30 (dev .) 35 6 0 (va l.)

R C C of all stag es - pT stag e - pN stag e - M stag e - tu mor size - F u hrman g rade - Symptoms classification

8 7 .0 - 9 1.0 % (va l.)

Parker et al. [26] 8 18 C lear cell R C C - B 7 - H 1 - su rvi vi n - K i- 6 7

7 3.3%

L egend: R C C : r en a l ce l l ca r ci n o ma ; E C O G - P S : E a st er n C o o p er a ti ve O n co l o g y G r o u p P er f o r ma n ce S ta tu s; i n t. : i n ter n a l ; va l . : va l i d a ti o n ; d ev . : d eve l o p men t

79

T abl e 3 . P reoperativ e assessment of prognosis

M o d e l sa m p l e s i ze ou t c o m e c - i n d e x

Yaycioglu et al. [23] 29 6 R ecu rrence af ter nephrectomy 6 5 .1%

Cindolo et al. [22] 6 6 0 R ecu rrence af ter nephrectomy 6 7 .2%

Raj et al. [187] 29 0 (dev .) 9 4 (va l.) C lear cell R C C 8 2% (dev .) 7 6 % (v al.)

Lane et al. [188] 8 5 1 B enig n vs. malig nant I ndolent vs. ag g ressive

6 4 .4 % 5 5 .7 %

Hollingsworth et al. [189] 26 6 18 C SM and O S n.r.

Hutterer et al. [190] 25 22 (dev .) 2136 (v al.) L ym ph node metastases at nephrectomy

7 8 .4 %

Raj et al. [24] 25 17 M etastatic recu rrence af ter nephrectomy

8 0 .0 %

Karakiewicz et al. [21] 24 7 4 (dev .) 19 7 2 (v al.) C SM 8 4 - 8 8 %

Hutterer et al. [191] 26 6 0 (dev .) 27 16 (v al.) D istant metastases at nephrectomy 8 5 .0 %

Kutikov et al. [192] 30 8 0 1 C SM , O C M , N C M n.r.

L egend: dev.: development; val.: validation; n.r.: not reported; CSM: cancer-specific mortality; OCM: other-cancer mo r ta l i ty; N C M : n o n - ca n ce r r el a ted mo r ta l i ty; O S : o ve r a l l su r vi va l ; R C C : r en a l ce l l ca r ci n o ma

T abl e 4 . P ostoperativ e assessment of recurrence

M o d e l sa m p l e s i ze

T a r g e t p o p u l a t i o n P r e d i c t o r s c - i n d e x

Kattan et al. [25] 6 0 1 L ocalize d R C C - symptom classification - histolog ical su b typ e - tu mor size - pT stag e

7 4 .0 % (ove rall rec.)

Frank et al. [193] 18 6 4 L ocalize d clear cell R C C - ag e - g ender - symptom classification - T N M (19 9 7 ) - nu clear g rade - tu mor necrosis - sarcomatoid f eatu re - cyst ic architectu re - mu ltif ocality - su rg ical marg in statu s - nephrectomy typ e

8 0 .5 % (ab dominal rec.) 8 2.6 % (thoracic rec.) 8 0 .0 % (b one rec.)

Sorbellini et al. [194] 7 0 1 L ocalize d clear cell R C C - symptom classification - tu mor size - pT stag e - F u hrman g rade - tu mor necrosis - va scu lar inva sion

8 2.0 % (ove rall rec.)

Lam et al. [195] 5 5 9 L ocalize d/ locally adva nced R C C

- T N M (19 9 7 ) - nu clear g rade - EC O G - PS

n.r. (solitary rec., chest rec., ab dominal rec., b one rec., b rain rec.)

L egend: R C C : r en a l ce l l ca r ci n o ma ; r ec. : r ecu r r en ce ; E C O G - P S : E a st er n C o o p er a ti ve O n co l o g y G r o u p P er f o r ma n ce S ta tu s; n . r . : n o t r ep o r ted

80

adequ ate prog nostic ab ility , none of these models is 10 0 % accu rate. I n consequ ence, the search f or more accu rate marke rs continu es.M olecu lar ev ents that can u nve il the b iolog ical heterog eneity u nderlyi ng the va ried clinical b ehavi or of R C C may help in improvi ng indivi du alize d prog nostication and risk-stratified clinical decision-making. The hope and interest lies in the identification of accurate markers that w ill predict the responses to the exi sting ef f ective but toxic systemic therapies[28-32].

O ve r the past tw o decades, the molecu lar dissection of cancer has increased ou r u nderstanding of the pathw ays that are altered in neoplastic cells.W hile some b iomarke rs w ere show n to b e associated w ith other estab lished clinical and/ or patholog ical characteristics of R C C ( T a b l e 5 ) , others demonstrated a meaning f u l ef f ect w ith prog ression- f ree su rvi va l, overall survival, cancer-specific mortality, prognosis, and eve n added va lu e w hen incorporated w ith ex isting prog nostic models ( T a b l e 6 ) . T he f ollow ing parag raphs w ill ou tline the exi sting b iomarke rs, w hich demonstrated a potential f or improvi ng the predictive and/ or prog nostic ab ility of clinical and patholog ic va riab les.

III. RCC B IoM A RK eRs

1 . T Issue- B A seD B IoM A RK eRs

a) V on- H ippel L indau ( V H L ) gene

T he V H L g ene w as orig inally describ ed, isolated, and identified as a tumor suppressor gene on chromosome 3p resulting in deficient protein isof orms pV H L 19 and pV H L 30 ( fi g . 1 ) . I ts ab sence in the V H L f amilial tu mor syn drome predisposes to retinal ang iomas, central nervo u s sy stem hemang iob lastomas, pancreatic tu mors, pheochromocyt omas and mu ltiple b ilateral clear cell RCC lesions. [33] VHL is inactivated in almost all patients w ith V H L syn drome and approxi mately 7 0 % of sporadic clear cell RCC. [34] Alteration in the VHL proteins resu lts in impaired deg radation of hyp oxi a induced factor 1-alpha (HIF-1α), which accumulates ev en u nder normal (non- hyp oxi c) conditions. O ther V H L g ene ef f ects inclu de reg u lation of the cell- cycl e arrest vi a p5 3 and deposition of ext racellu lar matrix.

Presence of V H L alterations (mu tation or hy permethyl ation) predicts long er prog ression- f ree su rvi va l and low er mortality f or stag e I - I I I clear cell RCC (p=0.024 and 0.023, respectively). [34] However, the su rvi va l rate of patients w ith V H L mu tations w as not dif f erent f rom patients w ithou t V H L mu tations in other analyses. [35] The investigators postulated that reg u lation of ang iog enesis and prolif eration of R C C is not directly inuenced by VHL mutations, but that “loss-of-function” VHL mutations directly inuence the prog ression of R C C .

R ini et al. show ed that 6 0 % of metastatic R C C patients had V H L mu tations and that 4 8 % of those patients achieve d an ob j ective response to targ eted therapy vs. 35 % f or patients w ith no V H L mu tation or methylation. [36]The independent prognostic ef f ect of V H L mu tation w as also reported eve n af ter adj u sting f or EC O G - PS, hemog lob in, corrected calciu m, lactate dehyd rog enase, radiation exp osu re, previous therapy and number of metastatic sites. [37] In pazopanib-treated patients, a 76% clinical benefit rate (partial response+ stab le disease) w as achieve d in patients w ith V H L g ene va riation vs. 6 3% in those without. [38]Similar findings were recorded, where loss- of - f u nction V H L mu tation conf erred a 5 2% response rate (partial response+ complete response) to targ eted therapies vs. 31% f or w ild- typ e V H L (p=0.04). [39] Additional studies are clearly needed to b etter elu cidate the role of V H L mu tations in sporadic R C C , especially in the context of targ eted therapies. However, added data quantifying the added benefit and ext ernally va lidated accu racy resu lts of models that integ rate V H L are not ye t ava ilab le.

b) Hypoxia Inducible Factor (HIF-α)

HIF-α accumulates either in hypoxic cell conditions or when pVHL is deficient ( fi g . 1 ) . I ncreased expression of HIF-α was recorded in 75% (24/32) of clear cell R C C and only 38 % (3/ 8 ) of non- clear cell RCC cases. [40] None of the HIF-1α-negative clear cell R C C patients show ed a mu tation of the VHL gene. The level of HIF-α appeared to correlate w ith the presence of V H L mu tation. L idg ren et al. showed that clear cell RCC variant had significantly higher HIF-1α expression compared to papillary or chromophobe RCC variants. [41]Prognostic significance of HIF-α levels was recorded only in patients with clear cell RCC (p=0.02; Fig. 2A), but not in patients with papillary RCC (p=0.2). [41]

T he same au thors reported no su rvi va l dif f erence between patients with high and low HIF-1α expression in either clear cell or papillary R C C va riants (all p> 0 .1). [42] Conversely, Klatte et al. showed worse survival (13.5 vs. 24.4 months, p=0.005) with elevated HIF-1α tumor tissue levels ( fi g . 2 B ) . M ethodolog ical and analyt ical dif f erences may accou nt f or the dif f erent findings. [43]

I n patients exp osed to su nitinib , hig h leve ls of H I F -1α (p=0.003) or of HIF-2α (p=0.001) confer more favorable response (defined as complete or partial response) to therapy. [44] Clearly, standardized methodolog y and more stu dies are needed to b etter u nderstand the prog nostic and predictive role of HIF-α. Added value and external validity data are aw aited.

Va s c u l a r e n d o t h e l i a l g r o w t h f a c t o r ( VeG f)

V EG F , a dimeric g lyco protein and a memb er of the platelet- derive d g row th f actor, af f ects tu mor

81

T abl e 5 . M ol ecul ar mark er and its association w ith other establ ished cl inical and/ or pathol ogical characteristics of renal cel l carcinoma ( RCC) .

M a r k e r H i s t o l o g y T u m o r s t a g e

T u m o r s i ze

T u m o r n e c r o s i s

T u m o r g r a d e

M e t a s t a t i cd i s e a s e /

p r o g r e s s i o n

ot h e r

N eu trophil

C - reactive protein

+

V H L +

HIF-α + (clear cell)

T issue- based

V EG F + / ns (papillary) + + + + Predictor of microve ssel

inva sion

C AI X ns ns +

mT O R

pS6 +

PT EN +

pAkt + +

O ther

C ave olin- 1 + (clear cell)

p5 3 + (papillary) +

K i- 6 7

Su rvi vi n + (all H S) + Predictor of ag g ressive disease

B 7 - H 1 +

V imentin + (clear cell/papillary)

F ascin + (sarcomatoid) + + +

M M P + (non clear cell) + Predictor of ag g ressive disease

I M P3 + (sarcomatoid) + + + Predictor of lym ph node invo lve ment

B l ood- based

V EG F

C AI X + (clear cell) + / ns + ns

N G AL

SAA +

I G F - I

N M P- 22 Predictor of R C C diag nosis

L egend: +: associated with; ns: not significant

82

Table 6. Molecular marker and its association with progression-free survival (PFS), overall survival (OS), cancer-specific mortality (CSM), prognosis, treatment efficacy and its added value in established risk stratification for renal cell carcinoma (RCC).

M a r k e r P r o g n o s i s P fs os CsM T r e a t m e n t efficacy

A d d e d v a l u e i n

p r o g n o s t i c m o d e l s

N eu trophil + + (in I L - 2 patients) + ns (low response rate in I L - 2 patients)

+ (L eib ovi ch)

C - reactive protein

+ +

V H L + / ns + / ns + + (predicts response to targ eted therapy)

+

HIF-α + + (predicts response to su nitinib )

T issue- basedV EG F + +C AI X + +mT O RpS6 + + (predicts response to

temsirolimu s)PT EN + + (predicts response

to mT O R inhib itors)/ns (low response in

temsirolimu s)pAkt + (f or

localize d and metastatic

R C C )

+ + (predicts response to temsirolimu s)

O therC ave olin- 1 + / ns (coexp ression

w ith Akt / mT O R )p5 3 nsK i- 6 7 + + +

(coexp ression w ith C AI X )

Su rvi vi n + +B 7 - H 1 + +V imentin +F ascinM M P +I M P3 + + + (SSI G N )B l ood- basedV EG F + / ns + / ns (in metastatic

R C C )/ + (in soraf enib patients)

+ (predicts response rate in su nitinib )/ ns (does not predict response rate in

soraf enib )C AI X + +N G AL +SAA +I G F - I +N M P- 22

L egend: + : association; ns: not significant

83

ang iog enesis in b oth normal and patholog ic conditions ( fi g . 1 ) . I n tu mors, ang iog enesis is indu ced b y V EG F . I n clear cell R C C , the u preg u lation of V EG F mR N A is exp ected du e to the dysr eg u lation of H I F -1α as a result of the loss of VHL protein in addition to the hyp oxi c envi ronment. L arg er tu mors have inadequ ate b lood su pply and exa cerb ate hyp oxi a cau sing f u rther u preg u lation of V EG F exp ression. Enhanced V EG F concentration correlates w ith VHL gene inactivation. [45, 46] Increased VEGF produ ction occu rs in R C C patients w ith V H L g ene alterations (p< 0 .0 0 1) and adva nced g rade (p< 0 .0 0 1). [47] Elevated VEGF expression was reported in 29% of patients w ith clear cell R C C and u nexp ectedly in 67% of patients with papillary RCC (p=0.02) [48], but could not be confirmed in other studies [49]. In clear cell R C C , V EG F exp ression correlates w ith tu mor size (p=0.05) [48], Fuhrman grade (p=0.002), tumor necrosis (p=0.001), tumor stage (p=0.006)[50], microvessel invasion (p=0.01)[51], RCC progression rate (p=0.01)[50], and RCC-specific survival ( fi g . 3 ) . [48-50] Further confirmatory studies are needed to assess V EG F pathw ay w ith dow nstream molecu les su ch as phospho- ext racelu llar sig nal- reg u lated ki nase (pER K ) possib ly servi ng as b iomarke r f or therapy response. D espite its promising characteristics, VEGF awaits confirmation of its added va lu e and ext ernal va lidity .

c) Carbonic Anhydrase IX (CAIX)

CAIX is a HIF-1α regulated transmembrane protein associated w ith neoplastic g row th, ag g ressive tu mor phenotyp e, and poor prog nosis in a larg e spectru m of hu man tu mors ( fi g . 1 ) . [52-55] CAIX is thought to assist in reg u lating intra- cellu lar and ext racellu lar pH leve ls in response to tu moral hyp oxi a and su b sequ ent anaerob ic metab olism. I n R C C , especially clear cell R C C , C AI X can estab lish the diag nosis as it is exp ressed in ove r 8 0 % of R C C samples and 9 0 % of clear cell R C C specimens. I nteresting ly , hig h C AI X exp ression is associated w ith b etter prog nosis in localized RCC and metastatic RCC. [56-60]

F or exa mple, C AI X staining leve ls have b een show n to b e inve rsely related to metastatic spread (p=0.036) and high CAIX expression predicted b etter su rvi va l ( fi g . 4 ) , eve n af ter adj u sting f or the ef f ects of T stag e, F u hrman g rade, nodal statu s, and perf ormance statu s (all p< 0.005). [57] Moreover, low C AI X staining (< 8 5 % ) predicted w orse ou tcome in patients with metastatic RCC (HR: 3.10, p<0.001) [57] and eve n af ter adj u stment f or the ef f ects of clinical and patholog ic characteristics (H R : 4 .7 6 , p< 0 .0 0 1) [56]. Similar findings were reported in patients who received interleukin-2 therapy (p=0.04). [60] H ow eve r, low C AI X exp ression w as not associated

Figure 1. Biological pathways and markers in renal cell carcinoma.

EGFPDGF

ERK

mTOR

pS6

RASPI3K

AKT/PKBPTEN

vimentin

survi

vin

apoptosis

VEGF

fascin

MMP2-9

p53 (17p)

hypoxia

pVHL 19/30

mRNA translation

HIF

transcriptionalactivation of HIF

target genes

Cyclin D1m-Myc

Cell growth and survival

MEK

RAF

GF

GFR

normoxia

HIF

HIF HIFHIF

CAIX/G250

G250

mAB

Endothelial cell

PDGF-

PDGFR

VEGF

VEGFR

accumulation

Caspase 9

?metastatic

disease

stimulation

inhibition/downregulation

Tumor cell

VHL(3p25)

VHL inactivated VHLtumor

suppressorgene

84

w ith R C C death af ter adj u sting f or the ef f ect of tu mor grade (p=0.3) or coagulative tumor necrosis (p=0.1). [61] Data from ongoing trials will hopefully provide better insight in this highly promising marker. [62, 63] Besides prognostic value, the tumor-specific and hig h prev alence of C AI X in R C C make s it a g reat targ et f or imag ing and therapy u sing monoclonal antib odies su ch as G 25 0 .

d) Mammalian target of rapamycin (mTOR)

T he mT O R pathw ay reg u lates cell g row th and its u p- reg u lation in tu mors contrib u tes to many critical

cellu lar f u nctions su ch as protein deg radation and ang iog enesis ( fi g . 1 ) . [64] The prognostic role of mT O R as a b iomarke r is sparse and non- conclu sive . However, mTOR inhibitors (temsirolimus[31], everolimus[32]) have come to represent agents of choice f or metastatic R C C . T he prog nostic and predictive releva nce of mT O R and its u pstream (i.e., PT EN ) and dow nstream (i.e., phosphoryl ated S6 rib osomal protein- see b elow ) molecu les are b eing critically eva lu ated to identif y responders to these ag ents.

Figure 2. Kaplan-Meier survival curves stratified according to high vs. low HIF-1α levels in patients with clear cell renal cell carcinoma [41, 43]

Figure 3. Kaplan-Meier survival curves stratified according to VEGF negative vs. VEGF positive tumors (A) [48] and prognostic factors associated with survival in multivariable analyses (B) [48]

85

e) Ribosomal protein S6R ib osomal protein S6 (pS6 ), a dow nstream mTOR target, has S6 kinase activity [65] and the phosphoryl ated S6 (pS6 ) protein af f ects its dow nstream targ ets, altering mR N A translation ( fi g . 1 ) .[66]pS6 is differentially overexpressed in metastatic clear cell R C C and appears to b e associated w ith activa tion of the mT O R pathw ay . [67]pS6 is a predictor of survival in both localized (HR: 3.14, p=0.002) and metastatic RCC (HR: 1.55, p=0.04). [67] Indeed high expression of S6 kinase (p=0.02) predicted response to temsirolimus in 20 patients [68]and may prove to be useful in predicting optimal b iolog ic doses of mT O R inhib itors (i.e. everolimus) [69].

f) Protein Kinase B (pAkt)

pAkt , also called protein ki nase B , reg u lates b oth g row th and su rvi va l mechanisms b y phophoryl ating a w ide spectru m of su b strates in the cyt oplasm and the nu cleu s ( fi g . 1 ) . [70] In univariable, b u t not mu ltiva riab le, analyse s, eleva ted pAkt immu nostaining w as associated w ith hig her g rade (p=0.04), higher rate of metastatic disease (p=0.004) and poorer RCC-specific survival (p=0.01). [71] O thers reported a f avo rab le prog nosis in localize d RCC with high pAkt expression (HR: 0.66, p=0.3, Fig. 5A). [67] Conversely, poor prognosis was reported w ith hig h cyt oplasmic pAkt exp ression in metastatic RCC (HR: 1.31, p=0.2, Fig. 5B). [67] It is noteworthy that nu clear pAkt exp ression w as hig her in localize d RCC tissue than in metastatic RCC tissue. [67] As su ch, the localiza tion of pAkt may b e releva nt f or determination of its ef f ect on tu mor b ehavi or and resu lting prog nostic va lu e. Tumor samples from a subset of patients (n=19) w ithin a randomize d phase I I trial of temsirolimu s in metastatic RCC were studied. [68]High pAkt ex pression may predict response to temsirolimu s treated patients with advanced RCC (p=0.07).

O b j ective tu mor response w as ob serve d only in patients with high expression of pAkt. Confirmation of these findings is necessary before conclusions can b e made.g) PTEN

PT EN is a tu mor su ppressor protein that is encoded b y the tu mor su ppressor g ene P T E N ( fi g . 1 ) . U pstream to mT O R , the phosphatase PT EN reg u lates the mT O R pathw ay b y inhib iting Akt phosphryl ation through PI3K. [72, 73] While PTEN mutation may be a rare eve nt, P T E N loss occu rs du ring carcinog enesis and is associated w ith adve rse prog nosis in R C C . [72, 73] PTEN expression is higher in tumors with low er T stag e, non- clear cell R C C , and localize d stag e. H ig h PT EN exp ression improve s su rvi va l (HR: 0.74, p=0.3). [67]mTOR inhibitors may be most beneficial in patients with low PTEN expression. H ow eve r, recently no correlation b etw een b aseline PTEN and temsirolimus efficacy was found in poor-risk metastatic R C C patients ( fi g . 6 ). [74]

h) A l ternativ e biomark ers

su r v i v i n

D ereg u lation of apoptosis is a hallmark in hu man carcinog enesis, f acilitating the acqu isition of deleteriou s cancer traits, inclu ding loss of tu mor su ppressor g enes, ang iog enic chang es and immortaliza tion ( fi g . 1 ) . Su rvi vi n is a memb er of the inhib itor of apoptosis (I AP) g ene f amily that has b een f ou nd to control mitotic prog ression and indu ces chang es in g ene exp ression that are associated w ith tu mor cell inva sive ness. Su rvi vi n mR N A is selective ly exp ressed du ring emb ryo nic and f etal deve lopment, b ecomes u ndetectab le or exp ressed at low leve ls in most dif f erentiated normal adu lt tissu es, and is ove r-expressed in humans cancers, [75-79] including RCC [80]. Survivin is expressed in all RCC variants. [81]High survivin expression ( fi g . 7 ) is associated w ith poor dif f erentiation, more ag g ressive b ehavi or

Figure 4. Kaplan-Meier survival curves stratified according to high levels of CAIX vs. low levels of CAIX in patients with clear cell renal cell carcinoma (A) [56] and survival curves stratified according to CAIX expression and metastatic status (B) [57]

86

(all p<0.05) [81], and lower survival in clear cell RCC (eve n af ter adj u sting f or the ef f ects of EC O G - PS, TNM and grade(HR: 2.4, p<0.001) [82]. In localized R C C , hig h su rvi vi n exp ression predicted disease progression (HR: 1.9, p=0.02). [82]

B 7 - H 1

B 7 - H 1 is a cell- su rf ace g lyco protein w ithin the B 7 family of T-cell costimulatory molecules. [83] B7-H1 expression inhibits tumor-specific T-cell-mediated immu nity throu g h indu ction of T - cell apoptosis, impairs cyt oki ne produ ction, and diminishes the cytotoxicity of activated T cells. [84-88] High B7-H 1 exp ression w as associated w ith hig her R C C -specific (HR: 3.92, p<0.001) and all-cause mortality (H R : 2.37 , p< 0 .0 0 1) in 30 6 patients treated w ith nephrectomy for clear cell RCC. [89-91] In localized disease, tu mors w ith hig h B 7 - H 1 exp ression w ere more like ly to metastasize (H R : 4 .13, p< 0 .0 0 1) eve n af ter adj u sting f or the ef f ects of T stag e, g rade, and performance status (HR: 1.78, p=0.04). [89] In localized clear cell RCC (HR: 3.32, p=0.002), as well as in all R C C stag es (H R : 3.25 , p< 0 .0 0 1), hig h B 7 - H 1 ex pression in comb ination w ith su rv ivi n exp ression

predicted hig her mortality af ter adj u sting f or the ef f ects of T N M stag e, tu mor g rade, and EC O G - PS (n=298, fi g . 8 ). [92]

p 5 3

p5 3 protein is a D N A b inding molecu le invo lve d in the reg u lation of transcription ( fi g . 1 ) . [93] p53 has an important role in reg u lating cell g row th and prolif eration b y stopping cell cycl e and indu cting apoptosis w hen DNA damage occurs. [94] p53 mutations allow detection throu g h immu nohistochemical staining due to its extended half-life. [95] p53 overexpression in papillary , chromophob e and clear cell R C C w as recorded in 7 0 , 27 , and 12% of tu mors,respective ly . [96] p53 overexpression was an independent predictor of metastasis- f ree su rvi va l in patients w ith localized clear cell RCC (p=0.01). [96] The prognostic role of p5 3 in R C C remains controve rsial w ith stu dies f ailing to show any independent prog nostic va lu e f or survival (HR: 1.75, p=0.07). [97] In other studies, its prognostic significance was limited to patients with localized disease only (p=0.002). [98]

Figure 6. Correlation between baseline PTEN and temsirolimus efficacy in patients with poor-risk metastatic renal cell carcinoma [74]

Figure 5. Kaplan-Meier survival curves stratified according to protein expression of cytoplasmic pAkt in metastatic renal cell carcinoma (A) [67] and stratified according to protein expression of nuclear pAkt in localized renal cell carcinoma (B) [67]

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Figure 8. Illustration of proposed survivin and B7-H1 interaction [92]

Figure 7. Kaplan-Meier survival curves stratified according to low expression (score 1) vs. high expression (score 2–4) of survivin of patients with clear cell renal cell carcinoma [81]

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M a t r i x m e t a l l o p r o t e i n a s e s

T he matrix metalloproteinase (M M P) f amily of enzym es is comprised of critically important ex tracellu lar matrix remodeling proteases w hose activi ty has b een implicated in a nu mb er of ke y normal and patholog ic processes ( fi g . 1 ) . T he latter inclu de tu mor g row th, prog ression, and metastasis as w ell as the dysr eg u lated ang iog enesis that is associated w ith these eve nts. As a resu lt, these proteases have come to represent important therapeu tic and diag nostic targ ets f or the treatment and detection of hu man cancers. I n R C C , M M P2 and M M P9 w ere f ou nd to b e ove rexp ressed in 6 7 –76% and 43% of tumors, respectively. [99-101] In addition, ove rexp ression of M M P2 and M M P9 w as more common in non- clear cell R C C tu mors.M M P2 and M M P9 ove rexp ression w ere associated w ith aggressive behavior, tumor grade, and survival.[99-101] These associations are important, as there are seve ral syn thetic (i.e. b atimastat, marimastat) and natu ral (i.e. b ryo statins) matrix metalloproteinase inhib itors that cou ld help preve nt and/ or treat M M P overexpressing cancers.[102]

In s u l i n - l i k e g r o w t h f a c t o r II m RnA - b i n d i n g p r o t e i n 3 ( IM P 3 )

I M P3 is an oncof etal R N A- b inding protein that reg u lates transcription of insu lin- like g row th f actor I I mR N A. I M P3 is exp ressed in deve loping epitheliu m, mu scle, and placenta du ring early stag es of hu man and mou se emb ryo g enesis, b u t it is exp ressed at low or u ndetectab le leve ls in adu lt tissu es. I M P3 exp ression has b een associated w ith cell prolif eration and inva sion in va riou s cancers. I n R C C , I M P3 is associated w ith hig her R C C stag e, g rade, sarcomatoid dif f erentiation and cancer-specific mortality. In a cohort of 371 patients with localize d clear cell, papillary , chromophob e, and unclassified RCC, Jiang et al. reported that tumor cell IMP3 expression was significantly associated w ith prog ression to distant metastases and death, ev en af ter mu ltiva riab le adj u stment f or the ef f ects of patient ag e, sex, tu mor size , stag e, g rade, and histolog ical su b typ e ( fi g . 9 ) .[103] The prognostic va lu e of I M P3 w as ext ernally va lidated in 7 16 clear cell R C C tu mors show ing that I M P3 exp ression w as significantly associated with advanced T stage and g rade, increased reg ional lym ph node invo lve ment, and distant metastases, as w ell as an increased lik elihood f or coexi stent coag u lative tu mor necrosis and sarcomatoid differentiation.[104]In addition, ev en af ter mu ltiv ariab le adj u stment f or prog nostic f eatu res comprising the SSI G N score, positive I M P3 exp ression w as independently associated w ith an increased risk of death f rom R C C . I n a recent article, Jiang et al. have show n that addition of I M P3 ex pression to tu mor stag e improve s its prediction of metastasis.[105]IMP3 expression is a predictor of metastatic prog ression and death f rom R C C and

assessment of I M P3 exp ression may prove u sef u l to identify at risk patients who might benefit from ag g ressive adj u nctive therapy af ter primary tu mor resection. U ltimately , I M P3 and the I G F pathw ay may provi de u sef u l targ ets to improve clear cell R C C therapy; however, further studies will be warranted before any definitive conclusions can be made.

K i - 6 7

Ki-67 is a cell proliferation marker [106] that is associated w ith an ag g ressive phenotyp e in clear cell RCC. [107-110] High Ki-67 expression predicts higher recurrence rates (HR: 1.05, p=0.02) [111] and worse survival (HR: 1.95, p<0.001) [26, 112-114]. Interestingly, the combination of Ki-67 and C AI X (H R : 1.7 6 , p< 0 .0 0 1) su rpassed the prog nostic ability of nuclear grade in cancer-specific mortality analyses. [110]

Ca v e o l i n - 1

C ave olin- 1 is a stru ctu ral component of ca ve o l a e. T hese are plasma memb rane microdomains invo lve d in the intracellu lar sig naling pathw ays that reg u late cell adhesion, growth and survival. [115] Increased cave olin- 1 exp ression has b een associated w ith a poor clinical ou tcome in seve ral cancers su ch as prostate, lu ng , and esophag eal malig nancies. [116-123] Membranous caveolin-1 is expressed in 8 6 .4 % of clear cell R C C s and less than 5 % of each chromophob e or papillary R C C s. C ave olin- 1 co-exp ression w ith Akt / mT O R pathw ay components portended worse survival (HR: 2.13, p<0.001). [124] Others could, however, not confirm these findings (HR: 1.35, p=0.9). [125]

T u m o r n e c r o s i sC ontrove rsy exi sts reg arding the importance of tu mor necrosis in R C C prog nostics. T u mor necrosis represents one of the components of the L eib ovi ch scoring algorithm. [126] Previous evaluation of tumor necrosis as a potential marke r f or R C C mortality and recu rrence reve aled that it conf ers no added va lu e w hen standard clinical and/ or patholog ic tu mor characteristics w ere considered ( fi g . 1 0 A ). [107, 127-129] Tumor necrosis improved prediction of survival in patients with localized RCC (p=0.03) but not in patients with metastatic RCC (p=0.4). [107] To improve its prog nostic ab ility , K latte et al. su g g ested qu antif yi ng the ex tent of tu mor necrosis, instead of dichotomizi ng b etw een its presence vs. its ab sence ( fi g . 1 0 B - C) . [129] Added value and external accu racy remain to b e prove n.

C- r e a c t i v e p r o t e i nSeve ral inve stig ators exa mined the prog nostic significance of C-reactive protein. For example, C-reactive protein w as a strong predictor of metastasis (p< 0 .0 0 1) and ove rall mortality (p< 0 .0 0 1) af ter

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Figure 9. Kaplan-Meier metastasis-free survival (A) and overall survival (B) curves stratified according to IMP3 status [103]

Figure 10. Predictive accuracy estimates of the Karakiewicz nomogram and the SSIGN score with and without integration of tumor necrosis (A) [127] Kaplan-Meier survival curves stratified according to presence and absence of tumor necrosis (B) [129] and according to the extent of tumor necrosis (≤20 vs. >20%) (C) [129]

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nephrectomy f or localize d R C C in 130 patients. [130] C-reactive protein increased the predictive accu racy of seve ral estab lished clinical and pathologic predictors by 3.7% (p<0.001). [131]A g ain of 10 % (7 6 .6 vs. 8 6 .5 % ) w as reported b y Iimura et al. in a different cohort (n=539) within an ex ternal v alidation ( fi g . 1 1 ) . [132] In consequence, this inexp ensive and w idely ava ilab le b iomarke r is hig hly promising . I ts capab ility to predict response to targ eted therapy as a predictive marke rs remains to b e prove n.

Vi m e n t i nVimentin a cytoplasmic intermediate filament, is not u su ally exp ressed in epithelial cells ( fi g . 1 ) . V imentin exp ression is common in clear cell (26 -51%) and papillary RCC (61%). [133-137] Others f ou nd low f requ ency of vi mentin staining in clear cell RCC. [138] Vimentin overexpression (30 to 53%) predicted poor prog nosis (p< 0 .0 0 7 ), independent of the effect of T stage and grade. [137]

fa s c i nF ascin is a g lob u lar actin cross- linki ng protein invo lve d in cell adhesion and motility ( fi g . 1 ) . H ig h f ascin exp ression (p< 0 .0 0 1) correlated w ith sarcomatoid transf ormation, hig h tu mor stag e (p=0.008), high tumor grade (p=0.002), and larger tumor size (p<0.001). [139] Moreover, fascin ex pression predicted metastatic prog ression (H R : 7.2, p<0.001). Other investigators confirmed these findings.[140]

2 . B looD - B A seD B IoM A RK eRs

a) Thrombocytosis

T he prog nostic potential of thromb ocyt osis w as reported in five studies. [141-145] However, the qu estion of w hether a b iomarke r can improve the ab ility of estab lished predictors of cancer ou tcome requ ires more than the conve ntional u niva riab le and mu ltiva riab le analyse s, w ith associated haza rd rates and p- va lu es. I n order f or a b iomarke r to b e clinically u sef u l, it mu st add u niqu e predictive inf ormation, thu s improvi ng the perf ormance of a predictive model constru cted w ithou t the new b iomarke r b y a

significant margin. Thrombocytosis did not add any meaning f u l va lu e (+ 0 .3% ) to a model that comprised T N M stag e, ag e, tu mor size , F u hrman g rade, histolog ical su b typ e, and preoperative hemog lob in (n=1828). [141] In consequence, the prognostic va lu e of thromb ocyt osis remains to b e prove n.

b) Neutrophils

Seve ral inve stig ators demonstrated independent predictor statu s f or peripheral b lood and intratu moral neu trophils, w hen mortality w as considered as an endpoint. [146-150] In a phase II study, Donskov et al. eva lu ated 6 3 metastatic R C C patients treated w ith interleukin-2 or interleukin-2+histamine. [148] High peripheral b lood neu trophil cou nts predicted ve ry poor su rvi va l and lack of response to interleu ki n- 2 alone or interleu ki n- 2+ histamine. Seru m neu trophils w ere also inclu ded among six most inf ormative predictors in the Heng et al.[10] survival model. In addition, the presence of intratu moral neu trophils also independently predicted shorter recu rrence-free survival (hazard ratio [HR]: 3.0, p<0.001), higher R C C mortality (H R : 3.5 , p< 0 .0 0 1), and poor ove rall su rvi va l (H R : 3.1, p< 0 .0 0 1) in 121 patients w ith localized RCC. [151] Finally, intratumoral neutrophil cou nts improve d the predictive accu racy of the Leibovich scoring algorithm [152] from 74 to 80%. Despite those promising results, the confirmation of added va lu e w hen intratu moral neu trophils w as considered was not confirmed. This variable awaits its ext ernal va lidation.

c) VEGF

Plasma V EG F lev els correlate strong ly w ith tissu e VEGF expression (p=0.01). [50] Similarly, serum leve ls of V EG F correlate w ith clinical stag e and tumor grade of RCC, [50, 153, 154] vascular invasion (p=0.03), tumor size (p=0.01), [154] and survival. [153-155] For example, in 302 metastatic RCC patients, b aseline seru m V EG F leve ls predicted prog ression-f ree su rvi va l (H R : 1.19 , p< 0 .0 0 1) and ove rall su rvi va l (HR: 1.39, p<0.001) after treatment. [155] However, seru m V EG F f ailed to achieve independent predictor status in other studies. [153-157]This may be due to analyt ical prob lems in some of the stu dies. I t has

Figure 11. Predictive accuracy estimates of two models with and without integration of CRP [131, 132]

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b een previ ou sly f ou nd that V EG F leve ls are hig her w hen measu red in seru m than w hen measu red in plasma.[158] Since VEGF is present in platelet g ranu les and is released u pon platelet activa tion, the hig her leve ls of V EG F in seru m w ere like ly du e, at least in part, to those released f rom damag ed platelets, making the quantification of non-platelet derive d V EG F less accu rate. Af ter su nitinib exp osu re, low er V EG F plasma leve ls predicted response to therapy (p<0.05) [159] and decreased risk of disease progression (HR: 1.96, 95% confidence interval: 1.47 – 2.45) [160]. Low baseline soluble VEGF leve ls also predicted response to su nitinib af ter bevacizumab failure. [161] Conversely, VEGF levels f ailed to predict response to soraf enib according to RECIST criteria (p=0.6), but was associated with overall survival in these patients (p=0.01). [162]The va lidation of V EG F leve ls as a prog nostic f actor in targ eted therapies is cu rrently b eing eva lu ated in tw o separate trials (N C T 0 0 5 38 7 7 2, N C T 0 0 9 30 34 5 ).

d) Serum amyloid A

H u man seru m Amyl oid A (SAA) is an H D L -associated lipoprotein kn ow n to play a maj or role as a modulator of inammation and in the metabolism and transport of cholesterol. SAA is a potentially u sef u l b iomarke r to monitor patients harb oring hu man tu mors su ch as g astric, nasopharyn g eal, and lu ng cancer. I n R C C , SAA concentrations w ere hig her in metastatic patients and SAA leve ls w ere an independent predictor of all-cause survival.[163]A protein pattern, including SAA identified by surface enhanced laser desorption/ionization time-of-ight mass spectrometry (SEL D I - T O F - M S) analysi s of seru m samples of 5 0 clear cell R C C patients and 5 0 v olu nteers w as ab le to discriminate the tw o groups with a sensitivity of 70–78% and a specificity of 82–92%, respectively.[164] One major problem w ith the u se of SAA, an acu te phase reactant, as a potential seru m marke r in hu man cancer patients, is the f act that its eleva tion in the seru m of patients is su g g ested to b e of live r orig in rather than a tu mor- cell produ ct. I ndeed, SAA leve l in the b lood may eleva te u p to 10 0 0 - f old in response of the b ody to va riou s injuries including trauma and various inammations in addition to neoplasia.

e) CAIX

R ecently , an assay f or detecting low leve ls of C AI X in blood was developed. [165] Higher serum CAIX leve ls correlated w ith clear cell R C C va riant (8 6 % , p=0.001), but not with tumor stage or grade. [166] O thers f ou nd a correlation of hig her seru m C AI X levels with tumor size and disease stage (p=0.004), [167, 168] as well as disease recurrence (p=0.001) [168] and mortality (p=0.048) [169]. An ongoing trial w ill determine the prog nostic va lu e of seru m C AI X as a va lid b iolog ical marke r of treatment response to immu notherapy and/ or targ eted therapy in patients w ith metastatic R C C (N C T 0 0 9 4 20 5 8 ).

f) Neutrophil gelatinase-associatedlipocalin (NGAL)

N G AL is a protein u preg u lated in ‘ distressed’ cells, su ch as the case w hen in the presence of a tu mor. [170] It demonstrated high correlation with matrix metalloproteinase- 9 , a protein invo lve d in the deg radation of the ext racellu lar matrix, w hich relates to tumor invasion and metastases. [171] NGAL has a protective effect against acute ischemic injury [172], and is high in several human cancers. [173] Above-threshold leve l of N G AL resu lted in decreased prog ression- f ree su rvi va l relative to those w ith b elow - threshold leve l of N G AL in patients treated with sunitinib (3.4 vs. 8.2 months, p=0.03). [174]

g) Insulin-like growth factor-1

W hile there are many va ried roles of insu lin- like g row th f actor I (I G F - I ), and it exi sts in dif f erent b io-compartments, there is abundant scientific evidence demonstrating that I G F - I is an important metab olic b iomarke r associated w ith a va riety of health- and exe rcise- related ou tcomes. I n most cases (mu scle, b one, tendon, b ody composition, and cog nitive f u nction), eleva ted I G F - I concentrations are considered beneficial; however, cancer remains a notab le exce ption. I n a series of 25 6 R C C patients, seru m I G F - 1 leve ls w ere associated w ith all- cau se su rvi va l af ter adj u sting f or the ef f ects of tu mor stag e. [175] While interesting, the prognostic role of IGF axi s in R C C is only in its inf ancy .

3 . uRIne M A RK eRs

T he u rinary nu clear matrix protein 22 (N M P- 22) is a F ederal D ru g Administration (F D A) approve d b iomarke r f or b ladder cancer screening and monitoring. [176-178] It has also been examined as a diag nostic marke r f or R C C . T hree stu dies have show n that u rinary N M P- 22 leve ls w ere hig her in R C C patients compared to those in control su b j ects (all p< 0.005).[179-181] Well-done, large-scale stu dies are needed to estab lish the u tility of N M P- 22 in R C C diag nosis and potentially prog nosis.

IV. use of B IoM A RK eRs In P RoG nosT IC M oD els

A prog nostic model f or prediction of su rvi va l in R C C u sing primarily molecu lar marke rs as predictors (p5 3, C AI X , g elsolin, vi mentin, and metastatic status) was 79% accurate (n=318; T a b l e 2 , fi g . 1 2 ) . [97] Subsequently, the same group of authors eva lu ated a slig htly dif f erent model of molecu lar marke rs (C AI X , PT EN , vi mentin, p5 3) and w as 6 4 % accurate(n=150). Adding ECOG-PS and tumor stage increased predictive accu racy b y 4 % . Predictive accu racy relyi ng on clinical and molecu lar marke rs

92

(68%) was statistically significantly higher (p=0.003) than that of the UISS system alone (62%). [182] The integration of the BioScore[26] (tumor expression leve ls of B 7 - H 1, su rvi vi n, ki - 6 7 ) in clear cell R C C patients (n=634) to the UISS and the SSIGN models g ained respective ly 4 .5 and 1.6 % accu racy ( T a b l e 4 ) .

O thers eva lu ated the prog nostic va lu e of b iomarke rs w ith clinical and/ or patholog ical characteristics in patients w ith adva nced R C C treated w ith V EG F - or mTOR-targeted therapies or immunotherapy. [8, 146, 183-185] Recently, factors associated with longer ov erall su rvi va l w ithin su nitinib - treated patients inclu ded time f rom diag nosis to treatment of more than a ye ar, EC O G - PS, corrected calciu m, ab sence of b one metastases, low L D H , and hig h hemog lob in. [186] Factors associated with longer overall survival w ithin interf eron- alpha treated patients inclu ded: male g ender, ab sence of b one or lym ph node metastases, low er L D H , hig her hemog lob in, corrected calciu m, hig her neu trophil cou nt, and interva l f rom diag nosis to treatment of more than a year. [186]

I n anti- V EG F therapy- naï ve metastatic R C C , hemog lob in (p< 0 .0 0 1), corrected calciu m (p< 0 .0 0 1), K PS (p< 0 .0 0 1), time f rom diag nosis to treatment (p=0.01), neutrophils (p<0.001) and platelets (p=0.01) were adverse prognostic factors for overall survival (accuracy: 73%, n=645). [10]

V. ConClusIonsT he search f or predictive and prog nostic marke rs stems f rom the u npredictab le natu re of R C C in its localize d, locally adva nced and metastatic stag es. A

nu mb er of su ch marke rs emerg ed. O f those, many show promise b y vi rtu e of stratif yi ng the su rvi va l cu rve s or discriminating b etw een stag e distrib u tions (eg . C AI X , V EG F ). O ther marke rs achieve d independent predictor statu s (e.g . ki - 6 7 , seru m C AI X ) w hen their contrib u tion to the prediction of the endpoint of interest w as exa mined. F inally , the most va lu ab le ones (C - reactive protein, B ioScore (su rvi vi n, B 7 - H 1, ki - 6 7 )) demonstrated an added va lu e w hen combined accuracy was quantified without and with their contribution. Independent confirmation of their va lu e, w ithin ext ernal va lidation stu dies and u sing standardize d measu rements, represents an u nconditional requ irement prior to their integ ration into rou tine clinical practice. V alidation of inf ormative marke rs of response to targ eted ag ents represents a priority consideration.

T he va lu e of nove l marke rs is requ ired w ithin the f ramew ork of exi sting marke rs and models. F or exa mple, a recent model that relies on clinical and radiolog ical inf ormation can predict the prob ab ility of mortality from one to ten years after nephrectomy.[21] I t relies on clinical and radiolog ical va riab les and resu lts in 8 4 - 8 8 % accu racy . A similar model that integ rated patholog ical characteristics resu lted in 8 8 - 8 9 % accu racy f or predictions of mortality f rom one to ten years after nephrectomy.[20] Neither of the models relied on b iomarke r data. T he hig hly accu rate natu re of these models raises the b ar f or novel biomarkers, as it is relatively difficult to improve accu racy b eyo nd the 9 0 % mark. C onve rsely , the dearth of models capab le of accu rately predicting the prob ab ility of response to targ eted therapies represents an important unmet need in the field of R C C prog nostics.

Figure 12. Prognostic model for prediction of 2- and 40-year overall survival relying on metastatic status, metastatic CAIX, p53, vimentin and gelsolin in the format of a nomogram [97]

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123. K aram J, L otan Y , R oehrb orn C , et al. C ave olin- 1 ove rexp ression is associated w ith ag g ressive prostate cancer recurrence. Prostate. 2007;67(6):614-22.

124. Campbell L, Jasani B, Edwards K, Gumbleton M, Griffiths D F R . C omb ined exp ression of cave olin- 1 and an activa ted AK T / mT O R pathw ay predicts redu ced disease- f ree survival in clinically confined renal cell carcinoma. Br J Cancer. 2008 Mar 11;98(5):931-40.

125 . Joo H J, O h D K , K im Y S, L ee K B , K im SJ. I ncreased exp ression of cave olin- 1 and microve ssel density correlates w ith metastasis and poor prog nosis in clear cell renal cell carcinoma. B JU I nternational. 20 0 4 F eb 1;93(3):291-6.

126 . L eib ovi ch B C , C hevi lle JC , L ohse C M , et al. A scoring alg orithm to predict su rvi va l f or patients w ith metastatic clear cell renal cell carcinoma: a stratification tool for prospective clinical trials. J Urol. 2005 Nov 1;174(5):1759-63; discussion 63.

127 . I sb arn H , Patard J, L u g hezza ni G , et al. L imited Prog nostic V alu e of T u mor N ecrosis in Patients W ith R enal C ell C arcinoma. U rolog y . 20 0 9 Sep 23.

128 . K atz M D , Serrano M F , G ru b b R L , et al. Percent M icroscopic T u mor N ecrosis and Su rvi va l Af ter C u rative Su rg ery f or Renal Cell Carcinoma. J Urol. 2010 Mar 1;183(3):909-14.

129 . K latte T , Said JW , de M artino M , et al. Presence of tu mor necrosis is not a significant predictor of survival in clear cell renal cell carcinoma: hig her prog nostic accu racy of extent based rather than presence/absence classification. J Urol. 2009 Apr 1;181(4):1558-64; discussion 63-4.

130 . Johnson T V , Ab b asi A, O w en- Smith A, et al. Ab solu te Preoperative C - R eactive Protein Predicts M etastasis and M ortality in the F irst Y ear F ollow ing Potentially C u rative N ephrectomy f or C lear C ell R enal C ell C arcinoma. J U rol. 20 0 9 D ec 12.

131. K araki ew icz PI , H u tterer G C , T rinh Q - D , et al. C - reactive protein is an inf ormative predictor of renal cell carcinoma-specific mortality: a European study of 313 patients. Cancer. 2007 Sep 15;110(6):1241-7.

132. I imu ra Y , Saito K , F u j ii Y , et al. D eve lopment and ext ernal va lidation of a new ou tcome prediction model f or patients w ith clear cell renal cell carcinoma treated w ith nephrectomy b ased on preoperative seru m C - reactive protein and TNM classification: the TNM-C score. J Urol. 2009 Mar 1;181(3):1004-12; discussion 12.

133. L iu L , Q ian J, Sing h H , et al. I mmu nohistochemical analysi s of chromophob e renal cell carcinoma, renal oncocyt oma, and clear cell carcinoma: an optimal and practical panel f or dif f erential diag nosis. Arch Pathol L ab M ed. 20 0 7 Au g 1;131(8):1290-7.

134 . K hou ry JD , Ab rahams N A, L evi n H S, M acL ennan G T . T he u tility of epithelial memb rane antig en and vi mentin in the diag nosis of chromophob e renal cell carcinoma. Ann Diagn Pathol. 2002 Jun 1;6(3):154-8.

135 . Ave ry AK , B eckst ead J, R enshaw AA, C orless C L . U se of antib odies to R C C and C D 10 in the dif f erential diag nosis of renal neoplasms. Am J Surg Pathol. 2000 Feb 1;24(2):203-10 .

136 . Y ou ng AN , Amin M B , M oreno C S, et al. Exp ression profiling of renal epithelial neoplasms: a method for tumor classification and discovery of diagnostic molecular markers. Am J Pathol. 2001 May 1;158(5):1639-51.

137 . M och H , Schraml P, B u b endorf L , et al. H ig h- throu g hpu t tissu e microarray analysi s to eva lu ate g enes u ncove red

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b y cD N A microarray screening in renal cell carcinoma. Am J Pathol. 1999 Apr 1;154(4):981-6.

138 . W illiams AA, H ig g ins JPT , Z hao H , L j u nb erg B , B rooks JD . C D 9 and vi mentin disting u ish clear cell f rom chromophob e renal cell carcinoma. BMC Clin Pathol. 2009 Jan 1;9:9.

139 . Z ig eu ner R , D roschl N , T au b er V , R ehak P, L ang ner C . Biologic significance of fascin expression in clear cell renal cell carcinoma: syst ematic analy sis of primary and metastatic tu mor tissu es u sing a tissu e microarray technique. Urology. 2006 Sep 1;68(3):518-22.

14 0 . Jin J, Y U C , Su n G , et al. I ncreasing exp ression of f ascin in renal cell carcinoma associated w ith clinicopatholog ical parameters of ag g ressive ness. H istopatholog y . 2006;21(12):1287-93.

14 1. K araki ew icz PI , T rinh Q - D , L am JS, et al. Platelet cou nt and preoperative haemoglobin do not significantly increase the perf ormance of estab lished predictors of renal cell carcinoma-specific mortality. Eur Urol. 2007 Nov 1;52(5):1428-36.

14 2. Sym b as N , T ow nsend M , El- G alley R , et al. Poor prog nosis associated w ith thromb ocyt osis in patients w ith renal cell carcinoma. BJU Int. 2000;86(3):203-7.

14 3. Su ppiah R , Shaheen PE, Elson P, et al. T hromb ocyt osis as a prog nostic f actor f or su rvi va l in patients w ith metastatic renal cell carcinoma. Cancer. 2006 Oct 15;107(8):1793-8 0 0 .

14 4 . O ’ K eef e S, M arshall F , I ssa M , H armonn M , Petros J. Thrombocytosis is associated with a significant increase in the cancer specific death rate after radical nephrectomy. The Journal of Urology. 2002;168(4):1378-80.

14 5 . B ensalah K , L eray E, F erg elot P, et al. Prog nostic va lu e of thromb ocyt osis in renal cell carcinoma. T he Jou rnal of Urology. 2006 Mar 1;175(3 Pt 1):859-63.

14 6 . Atzp odien J, R oyst on P, W andert T , R eitz M , G rou p D - -G C R C C - I T . M etastatic renal carcinoma comprehensive prognostic system. Br J Cancer. 2003 Feb 10;88(3):348-5 3.

14 7 . N é g rier S, Escu dier B , G omez F , et al. Prog nostic f actors of su rvi va l and rapid prog ression in 7 8 2 patients w ith metastatic renal carcinomas treated b y cyt oki nes: a report f rom the G rou pe F rança is d’ I mmu nothé rapie. Ann O ncol. 2002 Sep 1;13(9):1460-8.

14 8 . D onsko v F , H okl and M , M arcu ssen N , T orp M adsen H H , vo n der M aase H . M onocyt es and neu trophils as ‘ b ad g u ys’ f or the ou tcome of interleu ki n- 2 w ith and w ithou t histamine in metastatic renal cell carcinoma- - resu lts f rom a randomised phase I I trial. B r J C ancer. 20 0 6 Jan 30;94(2):218-26.

14 9 . Atzp odien J, R eitz M . Peripheral b lood neu trophils as independent immu nolog ic predictor of response and long -term su rvi va l u pon immu notherapy in metastatic renal- cell carcinoma. C ancer b iotherapy & radiopharmaceu ticals. 2008;23(1):129-34.

15 0 . Atzp odien J, R oyst on P, Stoerke l S, R eitz M . F ractional polyn omials in a new metastatic renal carcinoma continu ou s prog nostic index invo lvi ng histolog y , lab oratory , and clinical predictors. C ancer b iotherapy & radiopharmaceuticals. 2007;22(6):812-8.

15 1. Jensen H K , D onsko v F , M arcu ssen N , et al. Presence of intratu moral neu trophils is an independent prog nostic f actor in localize d renal cell carcinoma. J C lin O ncol. 20 0 9 Oct 1;27(28):4709-17.

15 2. L eib ovi ch B C , H an K - R , B u i M H T , et al. Scoring alg orithm to predict su rvi va l af ter nephrectomy and immu notherapy in patients w ith metastatic renal cell carcinoma: a stratification tool for prospective clinical trials. Cancer. 2003 Dec 15;98(12):2566-75.

15 3. Jacob sen J, R asmu son T , G rankv ist K , L j u ng b erg B . V ascu lar endothelial g row th f actor as prog nostic f actor in renal cell carcinoma. J Urol. 2000 Jan 1;163(1):343-7.

15 4 . K latte T , B ö hm M , N eliu s T , et al. Eva lu ation of peri-operative peripheral and renal ve nou s leve ls of pro- and anti- ang iog enic f actors and their releva nce in patients w ith renal cell carcinoma. B JU I nternational. 20 0 7 Ju l 1;100(1):209-14.

15 5 . N eg rier S, Perol D , M enetrier- C au x C , et al. I nterleu ki n-6 , interleu ki n- 10 , and va scu lar endothelial g row th f actor in metastatic renal cell carcinoma: prog nostic va lu e of interleu ki n- 6 - - f rom the G rou pe F rancais d’ I mmu notherapie. J Clin Oncol. 2004 Jun 15;22(12):2371-8.

15 6 . Alamdari F I , R asmu son T , G rankvi st K , L j u ng b erg B . Ang iog enesis and other marke rs f or prediction of su rvi va l in metastatic renal cell carcinoma. Scandinavi an j ou rnal of urology and nephrology. 2007 Jan 1;41(1):5-9.

15 7 . Schips L , D alpiaz O , L ipsky K , et al. Seru m leve ls of va scu lar endothelial g row th f actor (V EG F ) and endostatin in renal cell carcinoma patients compared to a control group. Eur Urol. 2007 Jan 1;51(1):168-73; discussion 74.

15 8 . Shariat S, Anw u ri V , L amb D , et al. Association of preoperative plasma leve ls of va scu lar endothelial g row th f actor and solu b le va scu lar cell adhesion molecu le- 1 w ith lym ph node statu s and b iochemical prog ression af ter radical prostatectomy. J Clin Oncol. 2004;22(9):1655-63.

15 9 . D eprimo SE, B ello C L , Smerag lia J, et al. C ircu lating protein b iomarke rs of pharmacodyn amic activi ty of su nitinib in patients w ith metastatic renal cell carcinoma: modu lation of V EG F and V EG F - related proteins. J T ransl Med. 2007 Jan 1;5:32.

16 0 . Porta C , B ellmu nt J, Eisen T , Szczyl ik C , M u lders P. T reating the indivi du al: T he need f or a patient- f ocu sed approach to the manag ement of renal cell carcinoma. C ancer T reat R ev . 20 0 9 O ct 8 .

16 1. R ini B I , M ichaelson M D , R osenb erg JE, et al. Antitu mor activi ty and b iomarke r analysi s of su nitinib in patients w ith b eva cizu mab - ref ractory metastatic renal cell carcinoma. J Clin Oncol. 2008 Aug 1;26(22):3743-8.

16 2. Escu dier B , Eisen T , Stadler W M , et al. Soraf enib f or treatment of renal cell carcinoma: Final efficacy and saf ety resu lts of the phase I I I treatment approaches in renal cancer g lob al eva lu ation trial. J C lin O ncol. 20 0 9 Ju l 10;27(20):3312-8.

16 3. R amanku lov J, L ein M , Johannsen M , et al. Seru m amyl oid A as indicator of distant metastases b u t not as early tu mor marke r in patients w ith renal cell carcinoma. C ancer L ett. 2008;269(1):85-92.

16 4 . Ju nke r K , vo n Eg g eling F , M u ller J, Steiner T , Schu b ert J. Identification of biomarkers and therapeutic targets for renal cell cancer u sing ProteinC hip technolog y . U rolog e A. 2006;45(3):305-6, 8, 210-12.

16 5 . Z á va da J, Z á va dová Z , Z at’ ovi cová M , H yr sl L , K aw aciu k I . Solu b le f orm of carb onic anhyd rase I X (C A I X ) in the seru m and u rine of renal carcinoma patients. B r J C ancer. 2003 Sep 15;89(6):1067-71.

16 6 . M cK iernan JM , B u ttya n R , B ander N H , et al. T he detection of renal carcinoma cells in the peripheral b lood w ith an enhanced reve rse transcriptase- polym erase chain reaction assay for MN/CA9. Cancer. 1999 Aug 1;86(3):492-7.

16 7 . Z hou G X , I reland J, R aym an P, F ink e J, Z hou M . Quantification of carbonic anhydrase IX expression in seru m and tissu e of renal cell carcinoma patients u sing enzym e- linke d immu nosorb ent assay: prog nostic and diagnostic potentials. Urology. 2010 Feb 1;75(2):257-61.

16 8 . L i G , F eng G , G entil- Perret A, G enin C , T ostain J. Seru m carb onic anhyd rase 9 leve l is associated w ith postoperative

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recu rrence of conv entional renal cell cancer. J U rol. 20 0 8 Aug 1;180(2):510-3; discussion 3-4.

16 9 . G ilb ert SM , W hitson JM , M ansu kh ani M , et al. D etection of carb onic anhyd rase- 9 g ene exp ression in peripheral b lood cells predicts risk of disease recu rrence in patients w ith renal cortical tumors. Urology. 2006 May 1;67(5):942-5.

17 0 . K j eldsen L , Johnsen A, Seng elov H , B orreg aard N . I solation and primary stru ctu re of N G AL , a nove l protein associated w ith hu man neu trophil g elatinase. T he Jou rnal of Biological Chemistry. 1993;268(14):10425-32.

17 1. M atthaeu s T , Schu lze - L ohof f E, I chimu ra T , et al. C o-reg u lation of neu trophil g elatinase- associated lipocalin and matrix metalloproteinase- 9 in the postischemic rat kidney. J Am Soc Nephrol. 2001;12:787A.

17 2. M ori K , T homas L ee H , R apoport D , et al. Endocyt ic delive ry of lipocalin- siderophore- iron complex rescu es the ki dney f rom ischemia- reperf u sion inj u ry . T he Jou rnal of Clinical Investigation. 2005;115(3):610.

17 3. T ong Z , W u X , O vch arenko D . N eu trophil g elatinase associated lipocalin as a su rvi va l f actor. B iochem J. 2005;391:441-8.

17 4 . Porta C , Pag lino C , D e Amici M , et al. Predictive va lu e of b aseline seru m va scu lar endothelial g row th f actor and neu trophil g elatinase- associated lipocalin in adva nced ki dney cancer patients receivi ng su nitinib . K idney I nternational. 20 10 F eb 10 .

17 5 . R asmu son T , G rankvi st K , Jacob sen J, O lsson T , L j u ng b erg B . Seru m insu lin- like g row th f actor- 1 is an independent predictor of prog nosis in patients w ith renal cell carcinoma. Acta Oncol. 2004;43(8):744-8.

17 6 . L otan Y , C apitanio U , Shariat SF , H u tterer G C , K araki ew icz PI . I mpact of clinical f actors, inclu ding a point- of - care nu clear matrix protein- 22 assay and cyt olog y , on b ladder cancer detection. BJU Int. 2009 May 1;103(10):1368-74.

17 7 . Shariat S, Z ippe C , L u decke G , et al. N omog rams inclu ding nu clear matrix protein 22 f or prediction of disease

recu rrence and prog ression in patients w ith T a, T 1 or C I S transitional cell carcinoma of the b ladder. T he Jou rnal of Urology. 2005;173(5):1518-25.

17 8 . H u tterer G C , K araki ew icz PI , Z ippe C , et al. U rinary cyt olog y and nu clear matrix protein 22 in the detection of b ladder cancer recu rrence other than transitional cell carcinoma. BJU Int. 2008 Mar 1;101(5):561-5.

17 9 . O ze r G , Altinel M , K ocak B , Y azi ciog lu A, G onenc F . V alu e of u rinary N M P- 22 in patients w ith renal cell carcinoma. Urology. 2002 Oct 1;60(4):593-7.

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18 1. H u ang S, R hee E, Patel H , Park E, K asw ick J. U rinary N M P22 and renal cell carcinoma. U rolog y . 20 0 0 F eb 1;55(2):227-30.

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18 3. C hou eiri T K , G arcia JA, Elson P, et al. C linical f actors associated w ith ou tcome in patients w ith metastatic clear-cell renal cell carcinoma treated w ith va scu lar endothelial g row th f actor- targ eted therapy . C ancer. 20 0 7 Au g 1;110(3):543-50.

18 4 . D onsko v F , vo n der M aase H . I mpact of immu ne parameters on long - term su rvi va l in metastatic renal cell carcinoma. J Clin Oncol. 2006 May 1;24(13):1997-2005.

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18 6 . Patil S, F ig lin R A, H u tson T , et al., editors. Prog nostic factors for overall survival with sunitinib as first-line therapy in patients w ith metastatic renal cell carcinoma (mR C C ). ASCO; 2009: JCO.

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Co m m i t t e e 5

T r e a t m e n t o f lo c a l i ze d Re n a l

Ce l l Ca r c i n o m a

Ch a i r :H. VA N P O P P E L

Co m m i t t e :F . B E C K E R

J. C A D D E D U I . G I LL

G . J A N E T S C HE K M . J E W E T T

P . LA G U N A M . M A R B E R G E R

F . M O N T O R S I

T . P O LA S C I K

O . U K I M U R A G A N G Z HU

Co r r e s p o n d e n c eProf . D r. H endrik V an PoppelU nive rsity H ospital K .U .L eu ve nD epartment of U rolog y , B - 30 0 0 L eu ve nPhone: 32- 16 - 34 6 6 8 7F ax: 32- 16 - 34 6 9 31E- mail: H endrik. V anPoppel@ u z. ku leu ve n.ac.b e

1 00

T A B le of ConT enT s

I. InT RoD uCT Ion

II. M eT H oD s

III. A CT IVe suRVeIllA nCe foR loCA lIZ eD RCC

IV. RA D ICA l neP H ReCT oM Y foR loCA lIZ eD RCC

V. P A RT IA l neP H ReCT oM Y

VI. eneRG Y A B lA T IVe T H eRA P Ies foR loCA lIZ eD RCC

VII. ConClusIons - lIM IT A T Ions of T H e lIT eRA T uRe

VIII. eA u A nD A uA sT A T eM enT s foR T ReA T M enT of loCA lIZ eD

RCC

IX . Consensus ReG A RD InG T ReA T M enT oP T Ions foR

loCA lIZ eD RCC

X . neW ReseA RCH – fuT uRe D IReCT Ions

X I. eVID enCe T A B le

X III. A lG oRIT H M RenA l T 1 T uM ouRs

1 01

T r e a t m e n t o f lo c a l i ze d Re n a lCe l l Ca r c i n o m a

H. VA N P O P P E L

F . B E C K E R , J. C A D D E D U , I . G I LL, G . J A N E T S C HE K , M . J E W E T T

P . LA G U N A , M . M A R B E R G E R , F . M O N T O R S I , T . P O LA S C I K

O . U K I M U R A , G A N G Z HU

I. InT RoD uCT Ion

D u e to the increased u se of diag nostic imag ing more ki dney tu mou rs are b eing detected incidentally , leading to an increased incidence of asym ptomatic organ-confined small renal masses (SRMs) [1]. SRMs account for 48% to 66% of renal cell carcinoma (RCC) diagnoses [2]. This has resulted in an increased incidence of RCC over the last three decades. There is controversy on the mortality rates of RCC. Some authors mention that mortality rates are rising. Cancer statistics are showing the opposite (38% in 1997 vs. 25% in 2007) [3,4]. Current treatment should be reassessed [1]. Today, the standard of care for clinically localized RCC is su rg ery predominantly in the f orm of nephron-sparing surgery (NSS) because of the durable oncolog ic ou tcome and ove rall su rvi va l. Active surveillance (AS) and minimally invasive ablative technolog ies have emerg ed as potential alternative s to surgery in selected patients. In this chapter, we critically review the recent data on the management of localized RCC with the objective of arriving at a g eneral consensu s.

II. M eT H oD sA comprehensive review of the Medline literature f rom Janu ary 1, 20 0 4 to April 11, 20 10 reg arding the treatment of localized RCC was conducted. The combination of the following words was used: renal cell carcinoma, nephrectomy (MeSH major topic), surgical procedures, minimally invasive (MeSH major topic), nephron-sparing surgery, cryoablation, radiofrequency ablation, surveillance and watchful waiting. Search was limited to English papers. Further references were identified from the reference list of retrieved articles. As few randomised stu dies were available the majority of the conclusions

were drawn from case series or comparative cohort stu dies, b oth prospective and retrospective . A preliminary draft was composed by the chairman of the g rou p and circu lated throu g hou t the memb ers for modifications. After considering all modifications a definite draft was composed, reviewed and su pported b y all memb ers of the g rou p. I n case of statement disagreement consensus was reached by majority.

III. A CT IVe suRVeIllA nCe foR

loCA lIZ eD RCC

1 . InT RoD uCT Ion

SRMs are not uncommonly detected in elderly patients or those with significant co-morbidities. These patients have a higher risk of perioperative mortality and morb idity af ter treatment and a limited lif e exp ectance that of ten appears to exce ed the risk of cancer progression. Moreover, a significant proportion (up to 20%) of these SRMs is benign when biopsied or removed [5-9]. Even when those SRMs are confirmed to be RCC, most have slow growth rates and infrequently metastasize during the first few years after diagnosis [10]. These issues are important arg u ments to su pport an initial su rve illance period f or selected patients and reserve treatment for progression. Active surveillance (AS) of SRMs is now increasingly performed in carefully selected patients with an emerging experience to support this treatment option [ 2,7 ,11- 29 ] .

2 . sM A ll RenA l M A sses A nD T H eIR nA T uRA l H IsT oRY

Most AS studies of SRMs have relatively few subjects and are retrospective with limited follow-up and pathological confirmation of malignancy. Therefore Chawla et al performed a meta-analysis of several

1 02

small AS series and their own institutional cohort [2,12-14,16-18,20,21]. A total of 234 untreated SRMs had a mean follow-up of 34 months. The majority of the lesions (mean size of 2.60 cm, range 1.73 to 4.08 cm) demonstrated a slow growth rate (mean rate 0 .28 per ye ar, rang e 0 .0 9 cm to 0 .8 6 cm per year). Metastasis was reported in 1% of the cases during AS. In total, 86% of the lesions were smaller than 4 cm in maxi mal diameter at presentation. Initial tumour size did not predict overall growth rate (P =0.46). An absolute cut-off for selecting patients f or a su rve illance strateg y does not exi st since at present, the metastatic potential of ob serve d tu mou rs cannot b e predicted. ( fi g . 1 ) There are several important considerations in interpreting the resu lts of the Chawla meta-analysis. Many tumours were not biopsied and may have been benign. Only 46% of the patients had patholog ical eva lu ation and the pathological analysis was incomplete in many cases. Tumours with rapid growth often underwent surgery b ecau se of concern f or prog ression to metastasis. A rapid growing mass is arbitrarily defined as one that doubles it volume within 1 year [2]. Some deg ree of selection b ias may have b een present b y inadvertently selecting patients with slower growth rates during an initial period of AS. Finally, the series had short durations of follow-up (mean 30 months) which may not reect the intermediate and long-term growth potential of these tumours. Overall, the f avo u rab le results in patients undergoing AS should b e interpreted as preliminary as these issu es cou ld bias the findings [21].

Similar findings supporting the absence of baseline predictive factors are found in two recent series from Cleveland and New York. There were no reported

dif f erences in patient’ s or tu mou r characteristics between those tumours that locally progress and those that remain stable [28,29]. Crispen et al reported the radiographic growth kinetics of renal tumours during a period of AS. Smaller tumours seemed to exhibit significantly faster volumetric growth than larger tumours. The authors found that 39% (68 of 173) of patients on AS crossed over to treatment within 2 years of follow-up for a variety of reasons inclu ding patient and physi cian pref erence. AS is associated with a low rate of progression to metastatic disease (1.3%) (2 of 154). However, the actu al prog ression rate may b e hig her than reported b ecau se of seve ral f actors inclu ding the relative short duration of follow-up, inclusion of benign disease in some series, selective interve ntion f or tumours demonstrating accelerated growth kinetics, and the selection b ias inherent to retrospective data sets [ 29 ] .

3 . P RoG nosT IC fA CT oRs foR P RoG RessIon

a) T umour size

The favourable results of the Chawla et al analysis are consistent with data about biological aggressiveness of SRMs. Up to 20% of renal masses are actually benign [5-9]. Only about 20 to 25% demonstrate potentially aggressive characteristics [5,7,30].

Smaller renal tumours are more likely to be benign or to be of lower grade than larger tumours [31] with several studies showing increased growth potential of SRMs with a diameter > 3 cm [5,7,32]. Kunkle et al reported that the risk of b iopsy prove n metastasis goes up 22% with each one centimeter increase in tumour size [24]. However, Remzi et al could not find a clear correlation between tumour size and b enig n histolog y in an analysi s of histopatholog ical parameters in 287 tumours ≤ 4 cm in diameter [7]. They found that Fuhrman grades G3 and G4, higher pathological stage (pT3a or greater) and metastatic disease were seen significantly more frequently in tumours > 3 cm in diameter. This difference was however not observed when masses ≤ 2 cm in diameter were compared with those measuring 2.1 – 3.0 cm. Taking into account that measuring tumour diameters is difficult, is subject to ob serve r va riab ility , and is f requ ently b ased on different imaging modalities, some believe that AS strategies should be limited to patients with tumours ≤ 3 cm [7]. In general however, ≤ 4 cm is used to conform to stage T1a for RCC. Not all SRMs can b e deemed harmless and eve n ve ry small tu mou rs may progress to metastatic disease. Three recent larg e sing le- center stu dies indicate that among st renal cancers 3-4 cm in size, 14-26% are high grade (grade 3 or 4) and 12-36% locally invade peri-renal fat (stage pT3a) [7,8,32]. These 3 series report that small 3- 4 cm cancers have a hig her metastatic

Fig. 1: CT show ing atrophic right k idney and l eft sided smal l renal mass of uncertain pathol ogy

1 03

risk approaching 6-8% [7,8,32]. The changes in morpholog ical characteristics of the tu mou r ab ove 3 cm reported by Remzi et al were more extreme than in other series. K latte et al reported their exp erience with 1.208 patients who underwent nephrectomy for small solid renal tumours. They found that the incidence of metastatic disease in tu mou r rang es of 0 .1 to 1.0 , 1.1 to 2.0 , 2.1 to 3.0 and 3.1 to 4 .0 cm was 7%, 6%, 5% and 8%, respectively ( P = 0.322) [8]. Nguyen and Gill analyzed the national 1998-2003 Surveillance, Epidemiology, and End Results (SEER) data-set and documented a 5.2% prevalence of metastasis at presentation in 8.792 patients with a small (< 4 cm) pathologically-confirmed renal cancer [33]. For size sub-categories ≤ 1, 1.1-2, 2.1-3, and 3.1-4 cm, prevalence of metastasis at diagnosis was 1.4%, 2.5%, 4.7% and 7.4%, with 5-year cancer-specific mortality of 4.2%, 4.3%, 5.5% and 7.9%, respectively. For small renal cancers < 4 cm, 5-year cancer-specific mortality for all patients, and those without and with metastases at presentation was 6.2%, 2.9% and 74.3% respectively. For each cm increase in primary cancer size , the calcu lated prevalence of metastases increased by 3.5% [33]. In all these reports, patients presenting with metastases and those with symptomatic primary tumours were u ndou b tedly inclu ded so the conclu sions shou ld b e applied to the u su al asym ptomatic properly stag ed SRM patient on AS with caution as the AS series report metastases in up to 2.3% [34]. However, when considering AS, tumour size alone may not be a reliable indication or trigger for treatment of SRMs [5,7-9].

b) G row th rate

Chawla et al could not identify a significant correlation between initial tumour size and growth rate in their analysis of 157 post incidentally detected tumours from 5 observational series (P = 0.46) [2,12-14,18,21). This has been confirmed by Crispen et al [29]. Therefore, at this time, initial tumour size may not predict subsequent growth rate. Most authors report the mean tumour growth rate to be between 0.06 cm/yr and 0.21 cm/yr for tumours < 4.0 cm in size [2,17,25,26,35]. Growth appeared to be slow even in those patients diagnosed with larger masses [ 19 ] . F or exa mple, the mean lesion size in the series of Lamb et al was 7.2 cm (range 3.5 – 20.0) with a mean growth rate of 0.39 cm per year [19]. A recent study from the Memorial Sloan-Kettering Cancer Centre has shown that small renal tumours (≤ 3.5 cm) were similar to larger tumours in subtype and growth rate. Faster-growing tumours were more likely to be RCCs of higher grade. No significant correlation was found between the reciprocal of doubling time and initial tu mou r vo lu me, histolog ical su b typ e, or F u hrman g rade [ 36 ] . O ne mu st realize that a su b set of patients may have small rapidly growing renal tumours with aggressive behaviour while under AS.

Volpe et al reported that eight renal masses [25%) doubled their volume within 12 months, and one patient prog ressed to metastatic disease [ 2] . I n the study by Siu et al, a 3-cm mass that had not changed in size f or 6 ye ars dou b led in size ove r 6 months, and metastatic disease developed [37]. The value of volume doubling time is still uncertain. Nevertheless, L ee et al su g g ested that more accu rate assessment of tumour growth rate and volume doubling time may b e u sef u l f or u nderstanding the natu ral history of renal tu mou rs [ 38 ] .

c) H istol ogy

A SRM has been reported to be more malignant if growth is observed. However in the Canadian prospective, multicenter study with needle biopsy, there was no difference in growth rate between benign and malignant tumours [39]. However, it remains difficult to predict biological behaviour of SRMs, even if they do not show growth . L ack of growth on serial CT scanning is not a reliable predictor of benign histology as even RCCs with zero growth rates have demonstrated prog ression. K u nkl e et al revealed that 26% to 33% of renal tumours followed by AS do not grow at 29 months median follow-up. Importantly, these tumours with zero growth rates had similar rates of malignancy compared to growing lesions (83% and 89%; respectively; P = 0.56) [22]. The authors concluded that growth rate does not correlate with prognosis [22]. These observations and those of the Canadian study raise questions about the biology of SRMs that need to be better understood to define better prognostic factors.

d) A ge

A meta- analysi s of pu b lished ob serva tional series [ 2,11,16 - 18 ,21] demonstrated an inve rse correlation between increasing age and tumour growth rate. Kouba et al found a more rapid growth in younger patients (≤ 60 years) (0.77 cm versus 0.26 cm per year) [40]. Therefore surveillance is currently not recommended in fit and young patients [10].

e) P rogression to metastatic disease

There is no published report of metastasis occurring in the absence of tumour growth but the Canadian series has reported 2 patients who were found to have metastases at 4 and 12 months af ter enrolment while their SRMs were about 2 cm in diameter and there had been minimal or no growth (average 0.5 mm/yr, P = 0.41) [39]. The low rate of metastatic progression in most AS series may be inuenced by the short follow-up as well as, the b enig n histolog y of a nu mb er of solid renal masses, the small tu mou r size and the retrospective natu re of the studies. Youssif et al reported a surveillance study with a mean of 47.6 months follow up. Two patients developed metastatic disease (5.7%; 2 of 35) after 29 and 40 months, respectively, in a group

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of tumours < 4 cm in diameter. The renal masses in these 2 patients had a growth rate of 0.95 cm/year and 0.9 cm/year, which is a faster growth rate than the mean of 0.15 cm/year observed in the 17 patients who were still being followed actively at the time of last follow-up. Until we have more information on this important prognostic factor, faster growth during the su rve illance period shou ld alert physi cians to the potential risk f or prog ression to metastatic disease and b e considered as a trig g er point f or a treatment recommendation [ 26 ] .

f) I maging

I mag ing characteristics do not provi de a reliab le prog nostic f actor f or prog ression at this time [ 9 ] . No parameter was able to predict progression or overall prognosis [21,30,32,37,41]. No difference was noted in tumour size at presentation or tumour growth rate between oncocytomas and RCCs in the meta-analysis by Chawla et al [21]. When comparing independent compu terize d tomog raphy (CT) measurements of tumour size, differences less than 3.1 mm f or inter- ob serve r and less than 2.3 mm for intra-observer evaluations are situated within the rang e of measu rement va riab ility and shou ld not be attributed to tumour growth. As tumour volume is exp onentially related to tu mou r diameter, the accu racy of measu ring tu mou r vo lu me is associated with a greater error (inter-and intra-observer variability for tumour volume: 2.515 mm3 and 2.075 mm3, respectively) [42]. Ficarra et al recently proposed The Preoperative Aspects and Dimensions Used for an Anatomical (PADUA) classification of renal tumours that takes into consideration five anatomical aspects of the tu mou r plu s its maxi mal diameter. The study demonstrated that the PADUA score is ab le to predict the risk of su rg ical and medical perioperative complications in patients who underwent OPN [43]. This classification differs from the R.E.N.A.L nephrometry scoring system recently proposed b y K u tik ov et al to qu antif y the anatomical characteristics of renal masses (size, location and depth) on computerized tomography (CT)/magnetic resonance imaging (MRI) [44]. The main differences are the definition of the sinus lines and the evaluation of the anatomical relationship between the tu mou r and the u rinary collecting syst em or renal sinus [43]. Furthermore, SRMs are not necessarily spheroidal which increases the error in measuring tumour volume. Therefore, neither tumour size nor tumour volume are reliable parameters for defining management of SRMs [45].

Two papers addressed the histological diagnosis of SRMs on CT. One study showed that the enhancement pattern of double-phase helical CT was different among the subtypes of RCC, but did not differentiate between RCC and other solid tumours. All clear cell RCCs (n=29) showed a peak attenuation in the corticomedullary phase (CMP)

of > 100 HU (type A). All chromophobe cell RCCs (n=2) showed a peak attenuation value in CMP of < 100 HU (type B) and all papillary RCCs (n=5) showed a gradual enhancement with the attenuation value in the CMP of < 100 HU (type C). However oncocytomas (n=2) and metanephric adenomas (n = 2) also showed patterns similar to these subtypes of RCC. Therefore the diagnosis of oncocytoma and metanephric adenoma is u nreliab le on the b asis of enhancement [46]. A more recent study showed that when using a multi-detector CT (MDCT) and thin overlapping reconstructions (3 mm section thickness, 50% overlap), renal cysts as small as 5 mm can be diagnosed with more certainty than is possible with standard reconstructions (5 mm thickness and no overlap). Of 45 masses between 5 and 10 mm, 38 (84%) could be characterized as cysts with the experimental protocol, compared with only 13 (29%) with the standard protocol. The overall number of indeterminate renal masses was reduced using the experimental protocol (86 of 161 lesions; 53%), compared with the standard protocol (101 of 146 lesions; 69%). Despite technical progress in technique, at this time, the majority of detected renal masses are smaller than 5 mm and cannot be characterize d [ 4 7 ] .

4 . RenA l T uM ouR B IoP sY

A retrospective study by Remzi et al reported that 81.9% of all renal masses were RCC and only 17% were correctly defined as benign on preoperative CT. In total 42% of renal masses underwent surgery for benign lesions not correctly identified as benign on preoperative CT. Surgery could potentially have been avoided in these patients [9]. Thus, a more refined preoperative diagnostic evaluation, in particular needle biopsy is needed for defining management of SRMs [9] and can help in selecting patients suitable for AS [45]. Due to advances in b iopsy and imag ing techniqu es the resu lts of needle biopsies have improved significantly [48]. The overall complication rate in these studies was low (<5%) and major complications were rare (< 1%). The most frequent complication was hemorrhage, which is almost always self-limiting. Renal tumour biopsy has theref ore b ecome a saf e and accu rate techniqu e (45,49,50) that provides useful material for diagnosis in > 90% of cases in centres with expertise [49].

Several issues have prevented widespread adoption of pretreatment b iopsy . B iopsy accu racy remains a concern although the first order question of malignant vs. benign is approximately 80% accurate when tissue is obtained. There remains up to 20% of b iopsies that are non- diag nostic du e to tu mou r misses and this rate varies with experience and tumour size [51]. Three prospective studies have evaluated CT-guided SRM biopsy. In these studies, ranges of b iopsy accu racy f or detecting b enig n and malig nant tissue, histologic subtype, and Fuhrman grade were

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89-96%, 70-76%, and 78-92%, respectively [52-54]. In the study of Schmidbauer et al, 42% of the renal masses were larger than 4 cm. While the authors report excellent results of core biopsy, we do not know what is the accuracy of CT guided biopsy in SRMs [54]. In the study of Lechevallier et al, results are not stratified by size; the median size of the masses evaluated is 4 cm, but there are masses of 15 cm in this series [52]. Furthermore, accuracy is based on those biopsies that were diagnostic. In the study of Neuzillet et al 9% of biopsies were non diagnostic. In the studies of Schmidbauer and Lechevallier only 3% and 21% of the biopsies failed, respectively. The corresponding figure was 37% in the 30 SRMs of ≤ 3 cm. In view of those results grade and histological subtype accuracy remains controversial in SRMs [52-54]. As well, pathological confirmation in the study of Neuzillet was obtained only in 70.4% of the cases and in the study of Lechevallier in 50% of those patients with non metastatic lesions (surgery in 27 out of 52 patients) [52,53]. Most of the studies on biopsy exclusively in SRM are retrospective in nature and subject to the same limitations above exposed. The subject is reviewed in a recent paper of Laguna et al [55].

Several other issues include the difficulty with the diag nosis of oncocyt oma ve rsu s hyb rid chromophob e RCC. Waldert et al have recently shown that up to 17% of oncocy toma actu ally harb ou r hyb rid chromophob e RCC [56]. The diagnosis of oncocytoma on biopsy cannot b e relied on f or b eing proof of a b enig n lesion and an u ncritical su rve illance approach. As ab ou t 45% of benign renal tumours are oncocytoma, this is a major problem for the diagnostic accuracy of renal b iopsies [ 9 ] .

The use of preoperative biopsy is likely to reduce u nnecessary treatment if b enig n lesions are initially observed. Multiple tumours probably need to undergo mu ltiple b iopsies b ecau se if one of the tu mou rs is RCC that does not mean that the other is RCC as well. Several new immunohistochemical and molecular f actors are b eing eva lu ated as determinants of the aggressiveness of RCC and molecular profiling of SRMs is now possible [57,58]. Unfortunately, the av ailab le data on molecu lar marke rs are not ye t valid enough for routine, clinical application [58]. Renal mass biopsy enhanced by molecular profiling will further help in decision making about AS. Further research will be required to define the utility and limitations of this approach [ 4 1] .

5 . suRVeIllA nCe sT RA T eG Y

An absolute cut-off for tumour size and growth rate that shou ld prompt interve ntion du ring su rve illance has not been well defined [25]. A working hypothesis has emerg ed that tu mou rs b eyo nd a diameter of 3 or 4 cm or those that dou b le in vo lu me in less than 12 months are at risk of prog ression and shou ld

b e treated [ 2,7 ,8 ,4 8 ] . A larg e mu lticentre series of incidental renal tu mou rs reve aled that a su rve illance strategy should not be advised in patients with a renal tumour >4 cm, if biopsy confirms high Fuhrman grade regardless of the size, or if CT findings suggest advanced T stage [59]. AS with regular radiographic follow-up should be a primary consideration for SRMs in elderly and/or infirm patients with multiple comorbidities that would make them high risk for intervention and in those with limited life expectancy [25,28] [60]. Delayed intervention of more than 1 ye ar af ter diag nosis does not seem to exa cerb ate the prognosis for later metastatic RCC [25,40,61].

Before enrolling a patient in an AS protocol an adequ ate renal tu mou r mass b iopsy shou ld b e considered. In some cases a benign tumour will be shown while mostly the biopsy will confirm malignancy and this will be helpful to further define follow-up [48]. The patient should be cou nselled ab ou t the small b u t non- neg lig ib le risk of tu mou r prog ression du ring the AS period, possible loss of opportunity for NSS, lack of cu rative salva g e therapies if metastatic disease were to develop, limitations of renal mass biopsy, lack of long-term data on surveillance, close follow-u p imag ing and requ ired compliance.

For follow-up during the surveillance period, Rendon et al suggested CT or MRI every 3 months in the first year, every 6 months in the next two years and every year thereafter [23]. This high number of CTs was considered necessary to assu re a saf e su rve illance strategy. However, in this regard, the recognized risk of radiation exposure due to multiple CT scans should be kept in mind. The optimum protocol and imaging modality is unknown at present but ultrasound, with or without contrast, may provide adequate images f or measu rement.

6 . ConClusIons Not all SRMs are RCC. If untreated, the majority grows slowly and have low rate of progression to metastasis, at least in the initial ye ars. A t this time, an initial period of A S w ith regul ar imaging fol l ow - up shoul d onl y be considered for patients with SRMs < 4 cm who are considered unfit for interv ention or hav e l imited l ife ex pectancy or refuse treatment [ 6 2 ] ( G rade C) . D el ayed interv ention shoul d be undertak en in tumours that show fast grow th during A S and therefore may hav e a higher risk of progression to metastatic disease ( G rade C) . At this time, the whole body of literature is insufficient to recommend or disregard biopsy for SRMs. The identification of clinical, imag ing and molecu lar marke rs of disease progression, as well as further research on the role of b iopsy is needed to improve the selection of patients for AS. Until reliable prognostic parameters are formally identified, one must recognize that there is a small b u t non- neg lig ib le risk of deve loping metastatic disease in patients with SRMs followed expectantly.

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Surveillance requires excellent patient compliance and rigorous follow-up with contrast enhanced CT or MRI. Finally, the long-term results of prospective AS studies such as the ongoing multicentre Canadian trial are eagerly awaited to more precisely identify the role of AS in the treatment of localized renal RCC. Molecular studies of prognostic factors for prog ression are in prog ress [ 39 ] .

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59. Bensalah K, Pantuck AJ, Crepel M, Verhoest G, Mejean A, Valeri A, Ficarra V, Pfister C, Ferriere JM, Soulie M, Cindolo L, De La Taille A, Tostain J, Chautard D, Schips L, Zigeuner R, Abbou CC, Lobel B, Salomon L, Lechevallier E, Descotes JL, Guille F, Colombel M, Belldegrun AS, Patard JJ. Prog nostic va riab les to predict cancer- related death in incidental renal tumours. BJU Int 2008;102(10):1376-138 0 .

60. Van Poppel H, Joniau S. Is surveillance an option f or the treatment of small renal masses? Eu r U rol 2007;52(5):1323-1330.

61. Crispen PL, Viterbo R, Fox EB, Greenberg RE, Chen DY, Uzzo RG. Delayed intervention of sporadic renal masses undergoing active surveillance. Cancer 2008;112(5):1051-1057.

62. Heuer R, Gill IS, Guazzoni G, Kirkali Z, Marberger M, Richie JP, de la Rosette JJ. A Critical Analysis of the Actual Role of Minimally Invasive Surgery and Active Surveillance for Kidney Cancer. Eur Urol 2010;57(2):223-232.

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IV. RA D ICA l neP H ReCT oM Y foR loCA lIZ eD RCC

1 . InT RoD uCT Ion

Radical nephrectomy (RN) includes the removal of the tu mou r- b earing ki dney and has b een the traditional approach for treating localized RCC in patients with a normal contralateral kidney [1]. Nowadays it is still the treatment of choice with excellent oncologic efficacy when the tumour is not amenable to NSS. Adrenalectomy and regional lym phadenectomy may b e perf ormed at the time of RN, but their benefit in absence of radiological signs of tumour invasion or in growth has not been prove n in prospective randomised stu dies and consequ ently no hard recommendation can b e made to this respect. According to a recent syst ematic review adrenalectomy should only be considered in select cases in which there are risk factors for adrenal invo lve ment su ch as increased size and T stage, multifocality, upper pole location and ve nou s thromb osis [ 2] . L ym phadenectomy is only desirab le in the presence of enlarg ed lym ph nodes on preoperative imag ing and can increase su rvi va l when combined with adjuvant immunotherapy [3,4]. The randomised EORTC trial 30881 including 732 patients with preoperatively staged N0M0 tumours does show that lymph-node dissection combined with RN does not increase morbidity or mortality, but a su rvi va l adva ntag e cou ld not b e demonstrated. This is mainly due to the low incidence of lymph-node metastases (4%) detected by lymphadenectomy. If RN is truly indicated, for instance for patients with locally adva nced disease, a limited reg ional lym ph node dissection still seems reasonable. There are reports that the remova l of lym ph nodes containing microscopic metastases may be beneficial to some patients [ 3]

2 . fA CT oRs T H A T A ffeCT T H e sT A T us of Rn A s G olD sT A nD A RD foR T ReA T InG RCC

During the last decade, the status of RN has been called into qu estion b ecau se of seve ral f actors including: a) equal oncologic efficacy as partial nephrectomy (PN) for renal tumours < 4 cm [5,6] and tumours between 4 and 7 cm [7,8), b) increased incidental detection of small (< 4 cm) renal masses with a significant proportion of benign tumours (up to 20%) (9-14), c) possibility of late recurrence of RCC in the contralateral kidney, d) a higher risk of chronic kidney disease (CKD) following RN [5,15,16].

Preserva tion of renal f u nction is increasing ly prioritize d in the manag ement of small renal masses and u nderscores the u se of nephron- sparing modalities whenever feasible. Compared to patients

undergoing PN, patients undergoing RN were more likely to have proteinura and CKD (defined by a serum creatinine level > 2.0 mg/dl) during follow-up [5,15]. This finding was later confirmed by the glomerular filtration rate (eGFR) estimated with the abbreviated Modification of Diet in Renal Disease Study equation (16-18). Of the patients with SRMs 26% had pre-existing CKD (GFR < 60 mL/min per 1.7 3 m2) before surgery. After surgery, the 3-year probability of freedom from new-onset CKD (GRF < 60 mL/min per 1.73 m2) was 80% after PN and 35% after RN. Corresponding values for the 3-year probability of freedom of moderate CKD (GFR < 45 mL / min per 1.7 3 m2) were 95% after PN and only 64% after RN. RN remained a significant risk f actor for the development of new-onset CKD even after controlling f or potential conf ou nding f actors su ch as hypertension and diabetes. RN might no longer be reg arded as the g old standard treatment f or small renal tumours and should be reserved for patients with massive renal tumours in whom PN is not an option [ 16 ,17 ,19 ] . I n a recently pu b lished prospective stu dy by Clark et al the postoperative change in creatinine clearance was significantly less (P < 0.0001) in the PN group (-0.09mL/s, -6.1%) compared to the RN group (-0.56mL/s, -31.6%). The authors state that the b est method f or eva lu ating g lob al renal f u nction is the 24 - hou rs creatinine clearance [ 20 ] .

RN is now recognized as a risk factor for the development of CKD, which is known to increase the risk of cardiova scu lar eve nts and all- cau se mortality [21]. This is an important issue as renal tumour patients often are elderly patients with multiple comorb idities su ch as hyp ertension, diab etes, and peripheral va scu lar disease that mig ht lead to deterioration of baseline renal function. Therefore RCC patients undergoing nephrectomy cannot be compared to a healthy ki dney donor popu lation where the occurrence of CKD is exceptional [16,22-24]. Thompson et al compared overall survival (OS) in patients with localized RCC of 4 cm or less and normal contralateral kidney who were treated with RN and PN. Compared with PN, RN was associated with decreased OS in young patients (< 65 years) with SRMs [25].

Relative to PN, RN is associated with an increase in ove rall mortality and non- cancer- related death rate in patients with T1a RCC. Therefore, PN should be performed whenever technically feasible [26].

3 . oP en RA D ICA l neP H ReCT oM Y

Open radical nephrectomy (ORN) can be performed b y a transperitoneal or ext raperitoneal approach. The choice of the surgical access depends on the size and position of the tu mou r, the patient’ s hab itu s and the su rg eon’ s pref erences. ( fi g . 2 , 3 )

Indications for ORN include locally advanced renal tumours with invasion in the perirenal fat and

1 09

adrenal gland (T3a), invasion in the vena renalis or vena cava (T3b and c), tumours that extend in the adjacent organs (T4) and probably also those tumours that will undergo an extensive large lymph node dissection [ 27 ] . ( fi g . 4 )

In a prospective randomised EORTC phase III stu dy , V an Poppel et al f ou nd a perioperative b lood loss < 0.5 l (P < 0.001) and severe hemorrhage (> 1 l) in 96.0% and 1.2% of patients with small renal tumours (≤ 5 cm) treated with ORN. Pleural damage and spleen damage were respectively seen in 9.3% and 0.4% of ORN patients [11]. Blom et al reported that lym ph- node dissection had no impact on the complication rate. The most common adverse events in patients treated with ORN without and with lymph-node dissection, respectively were bleeding (6.5% vs. 9.4%), pleural damage (5.1% vs. 4.4%) and infection (5.7% vs. 5.2%). Less common adverse events were bowel damage, embolism and lymph uid drainage [3].

I n recent long - term retrospective comparisons between ORN, laparoscopic radical nephrectomy (LRN) and hand-assisted LRN (HALRN) for T1 and T2 renal tumours, the 5-year disease-free survival, CSS and OS for ORN were similar at 90%, 93% and 87%, respectively (28-32). Laparoscopic approaches have shown similarly favourable results. The postoperative complication rate for ORN was

Fig. 2 a: L eft hemi- chev ron incision for radical nephrectomy

Fig. 2 b: Chev ron ex posure of the upper abdomen

Fig. 3 : P l anning of a thoraco- phreno- l aparotomy for l arger upper pol e tumors

Fig. 4 a: V iew after l eft radical nephrectomy and ex tended l ymphadenectomy

Fig. 4 b: E x tended l ymphadenectomy for rightsided RCC, comprising the pericav al , inter- aorto- cav al and pre- aortic nodes

1 1 0

acceptably low (9.8%) [28-32]. The most common immediate complication is secondary hemorrhag e [ 33] .

4 . lA P A RosCoP IC RA D ICA l neP H ReCT oM Y

a) I ntroduction

Many still consider LRN the gold standard for the surgical management of T1 and T2 tumours as saf ety , su rvi va l rate and non- recu rrence rate are not significantly different from those associated with ORN. Today, however the majority of T1a and some T1b tumours are more properly treated with nephron-sparing techniqu es [ 32] .

b) I ndications

Currently, LRN is best indicated for the surgical management of T1-2N0M0 tumours that warrant complete removal of the kidney [32]. However, when performed in advanced laparoscopic centres by significantly experienced surgeons, this can b e b roadened to inclu de more ext ensive masses [28,34-36]. Mattar et al summarized the expanding indications for LRN, including very large tumours, locally adva nced disease, renal- ve in thromb i and cy toredu ctive su rg ery [ 37 ] .

c) O ncol ogic outcome

H emal et al eva lu ated the oncolog ic ou tcome of 132 cases of LRN with intact specimen removal for T1-2N0M0 RCC. The 5-year CSS in patients with a pT1a, pT1b and pT2 tumour was 97.2, 86.3 and 82.2%, respectively (significantly lower in pT2 than pT1a, P = 0.008). The 5-year recurrence-free survival in patients with a pT1a, pT1b and pT2 tumour was 97.2, 84.3 and 82.2%, respectively (significantly lower in pT2 than pT1a, P = 0.02) [38]. Another study demonstrated that the efficacy and oncological outcome of LRN in elderly patients (≥ 70 years) was as promising as those in their yo u ng er cou nterparts (< 70 years) [39]. More recently in 2009, Berger et al presented long-term, mean 11.2 years follow-up, in 73 patients undergoing LRN for pathologically-confirmed RCC prior to 1999. All patients had completed a minimum of 10-year follow-up since surgery (range, 10-15 years). Actual 10-year overall, cancer-specific and recurrence-free survival rates were 65%, 92%, 86%, respectively. Twelve-year overall, cancer-specific and recurrence-free survival rates were 35%, 78%, 77%, respectively. At a mean 67 months, 10 patients (14%) developed metastatic disease, of whom 8 (11%) died. The authors conclu ded that long - term oncolog ical ou tcomes af ter LRN for RCC are excellent and appear comparable to open su rg ery [ 4 0 ] .

d) Compl ications

The incidence of complications associated with LRN

ranges from approximately 10 to 20%, and does not significantly differ from that associated with open surgery [36,41]. Compared with the open approach, LRN is associated with significantly less blood loss [41,42], significantly lower dose of analgesic ag ents du ring the postoperative cou rse [ 36 ,4 2] and significantly shorter hospital stay [41,42]. A recent retrospective chart analysi s b y Permpong ko sol including 549 patients reported total and major complication rates after LRN of 20% and 7.3%, respective ly . I ntra- and postoperative complication rates were 6.6% and 13.8%, respectively. The most common complications were related to injury of the adjacent organs (2.37%) or the diaphragm (0.73%). The second most commonly identified complications were vascular complications (2.2%) [43]. One of the most important steps during LRN is the control of the hilum [44]. Open conversions occurred in 2.9% of cases [ 4 3] .

Gong et al compared LRN in patients with T1 (n=98) and T2 renal tumours (n=43). Transfusion rates (8 vs. 23%) and open conversions (1 vs. 12%) were higher for T2 lesions while postoperative complication rates (25 vs. 21%) and hospital stay (2 vs. 2.4 days) were similar between both groups. Complication rates were higher than in other series, which may have b een du e to the patient popu lation and the cau tiou s reporting [45]. The incidence of major complications unique to LRN and number of conversions decreases with surgeon’s experience. Some authors report a minimum experience of 50 procedures is necessary for reducing the risk of major complications [46,47]. Mentoring the surgeon is an effective approach for saf ely introdu cing minimally inva siv e su rg ery su ch as LRN into practice [46,48,49].

e) Comparison of different approaches

Two prospective randomized studies comparing transperitoneal LRN and retroperitoneal LRN found a shorter operative time f or the retroperitoneal method. B oth approaches are similar in terms of other patient outcomes and complications [50,51]. In a retrospective study no significant differences in the two approaches were found [52]. Berglund et al f ou nd a trend f avo u ring the retroperitoneal approach for LRN in the morbidly obese patient [53).

f) L RN v ersus O RN

Portis et al compared LRN and ORN for localized RCC and reported no significant differences in oncologic outcome between the two procedures [54]. Recently, Burgess et al performed the first randomized controlled trial comparing LRN and ORN. Maximum tumour size was 8 cm and groups were well matched between the 45 patients. No significant differences were observed in blood loss, mortality rate, operation-room time and hospital stay. The only significantly differences were less postoperative pain and faster return to normal activities in the LRN

1 1 1

group [55]. A long-term prospective comparison of LRN and ORN for T2 tumours showed that there was no difference in 5-year survival and that patients treated with LRN experienced significantly less b lood loss, had a decreased analg esic requ irement, shorter hospital stay and more rapid conva lescence [28]. A comparison of the 5- and 10-year disease-free survival, CSS and OS of patients with T1 and T2 renal tumours treated with transperitoneal LRN or ORN revealed no significant differences [56].g) P urel y L RN v ersus hand- assisted L RN

( H A L RN ) v ersus O RN Matin et al retrospectively reviewed 271 patients that underwent HALRN or transperitoneal purely LRN. The operative time was shorter for HALRN than for LRN but HALRN was associated with greater use of analgesia and longer hospitalization [57]. Montgomery et al found that wound infections and port-site hernias occurred less frequently with HALRN than with ORN, but more often than with LRN [58]. F ive recent long - term retrospective stu dies inclu ding 647 patients with a mean follow-up of almost 4 years for the laparoscopic cohort compared LRN (pure LRN or HALRN) with ORN for T1-2 lesions. The rate of postoperative complications for LRN and ORN was similar and low. LRN was superior to ORN in terms of hospital stay and convalescence time. The oncologic outcome was similar for both treatment groups [28-32]. Local recurrence rates were low and most stu dies had none, particu larly in patients with less than T3 disease. Furthermore, there were no port-site metastases [32,59] [28-31]. A recent study analyzing 255 LRN showed that approach (standard vs. hand assisted) and specimen handling (morcellation vs. intact extraction) has no discernible impact on oncolog ical perioperative and long - term outcomes after LRN [60]. We can conclude that several comparisons support the superiority of LRN over ORN for the majority of renal tu mou rs. O ncolog ic control is similar, morb idity is low and does not significantly differ from open su rg ery , and conv alescence time is shorter af ter LRN.

5 . RoB oT IC RA D ICA l neP H ReCT oM YH emal et al prospective ly compared the f easib ility and safety of LRN and robotic RN for localized renal tumours (T1-2N0M0). Both groups had comparable oncological and operative outcomes. Robotic RN was associated with longer operative time and increased cost. There were no remarkable advantages of robotic RN observed over LRN [61].

6 . folloW - uP A fT eR RA D ICA l neP H ReCT oM Y

Skolarikos et al published a comprehensive review of the evidence supporting the necessity for follow-up strategies for RCC after nephrectomy [62]. The rationale for postoperative surveillance of

patients with RCC is to monitor for post-operative complications, renal f u nction, local recu rrence, recu rrence in the contralateral ki dney and metastatic disease in order to allow for appropriate treatment. No consensus currently exists on surveillance guidelines after surgical extirpation of RCC. Pu b lications on postoperative su rve illance are based on retrospective studies. The intensity and typ e of su rve illance shou ld b e estab lished according to the risk of recu rrence and metastasis. L eib ovi ch et al deve loped as scoring syst em b ased on tu mou r stag e, reg ional lym ph node statu s, tu mou r size , nu clear g rade, and histolog ic tu mou r necrosis to predict disease progression after RN for patients with clinically localized clear cell RCC [63]. Recently, Kassouf et al published Canadian guidelines for su rve illance af ter nephrectomy f or non metastatic RCC, based on pathological stage [64]. Grades of recommendations are provided using the modified Oxford Centre for Evidence-based Medicine scheme. Recommended surveillance after RN of pT1 tumours inclu des medical history and physi cal exa mination, blood biochemical tests, and chest-X-ray every year. Abdominal CT is recommended at 24 and 60 months (Grade C). Recommended surveillance after RN of pT2 tumours includes medical history and physical examination, blood biochemical tests, and chest-X-ray eve ry 6 months f or 3 ye ars then ye arly . Ab dominal CT is recommended at 12, 36, 60, 84 and 108 months (Grade C) [64]. Most contemporary surveillance protocols have b een b ased on stag e alone [ 6 4 ] . Recently, Siddiqui et al presented a subtype-specific mu ltif actorial su rve illance protocol b ased on va riou s pathological features that have a significant effect on recurrence. This surveillance protocol seems to b e b etter than those b ased on tu mou r stag e alone and can be used to efficiently adapt postoperative imaging to the individual patient [65]. The addition of molecu lar predictors may identif y those patients at high risk of progression in which the follow-up protocol will be more intensive [66].

7 . ConClusIonsRN is no longer the gold standard treatment for small renal tumours. RN as management for clinically localized RCC should be limited to those cases where the tumour is not amenable to nephron-sparing su rg ery . Routine ex tended l ymph node dissection in patients w ith detectabl e l ymph nodes does not improv e surv iv al and can be restricted to staging purposes ( G rade A ) . A drenal ectomy shoul d onl y be considered in sel ected cases in w hich there are risk factors for adrenal inv ol v ement ( G rade B ) . The choice of the transperitoneal or peritoneal approach has no impact on the efficiency and safety of the LRN procedure. LRN is reserved for stage T1 and T2 tumours without strict limitations for tumour size. Complications are mainly vascular of type and are low in the hands of an experienced surgeon. There are no significant differences in oncological

1 1 2

outcome between LRN and ORN. H ow ev er, L RN has benefits over ORN in terms of morbidity. T herefore, L RN shoul d be the standard of care for T 1 and T 2 tumours, prov ided that it is performed in an adv anced l aparoscopic centre by an ex perienced surgeon and N SS is not appl icabl e ( G rade B ) . No consensus currently exists on su rve illance g u idelines af ter su rg ical ext irpation of RCC. The majority of follow-up strategies after RN is cu rrently b ased on tu mou r stag e alone, b u t tends to inclu de more histolog ical prog nostic f actors in the f u tu re to tailor su rve illance to the indivi du al patient.

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46. Simon SD, Castle EP, Ferrigni RG, Lamm DL, Swanson SK, Novicki DE, Andrews PE. Complications of laparoscopic nephrectomy: the Mayo clinic experience. J Urol 2004;171(4):1447-1450.

47. Fahlenkamp D, Rassweiler J, Fornara P, Frede T, Loening SA. Complications of laparoscopic procedures in urology: experience with 2,407 procedures at 4 German centers. J Urol 1999;162(3 Pt 1):765-770; discussion 770-761.

48. Jones A, Eden C, Sullivan ME. Mutual mentoring in laparoscopic u rolog y - a natu ral prog ression from laparoscopic fellowship. Ann R Coll Surg Engl 2007;89(4):422-425.

49. Birch DW, Asiri AH, de Gara CJ. The impact of a formal mentoring prog ram f or minimally inva sive su rg ery on surgeon practice and patient outcomes. Am J Surg 2007;193(5):589-591; discussion 591-582.

50. Nambirajan T, Jeschke S, Al-Zahrani H, Vrabec G, Leeb K, Janetschek G. Prospective, randomized controlled study: transperitoneal laparoscopic ve rsu s retroperitoneoscopic radical nephrectomy. Urology 2004;64(5):919-924.

51. Desai MM, Strzempkowski B, Matin SF, Steinberg AP, Ng C, Meraney AM, Kaouk JH, Gill IS. Prospective randomized comparison of transperitoneal ve rsu s retroperitoneal laparoscopic radical nephrectomy. J Urol 2005;173(1):38-4 1.

52. Okegawa T, Noda H, Horie S, Nutahara K, Higashihara E. Comparison of transperitoneal and retroperitoneal laparoscopic nephrectomy f or renal cell carcinoma: a sing le- center exp erience of 10 0 cases. I nt J U rol 2008;15(11):957-960.

53. Berglund RK, Gill IS, Babineau D, Desai M, Kaouk JH . A prospective comparison of transperitoneal and retroperitoneal laparoscopic nephrectomy in the ext remely obese patient. BJU Int 2007;99(4):871-874.

54. Portis AJ, Yan Y, Landman J, Chen C, Barrett PH, Fentie DD, Ono Y, McDougall EM, Clayman RV. Long-term followup after laparoscopic radical nephrectomy. J Urol 2002;167(3):1257-1262.

55. Burgess NA, Koo BC, Calvert RC, Hindmarsh A, Donaldson PJ, Rhodes M. Randomized trial of laparoscopic v open nephrectomy. J Endourol 2007;21(6):610-613.

56. Permpongkosol S, Chan DY, Link RE, Sroka M, Allaf M, Varkarakis I, Lima G, Jarrett TW, Kavoussi LR. Long-term su rvi va l analysi s af ter laparoscopic radical nephrectomy . J Urol 2005;174(4 Pt 1):1222-1225.

57. Matin SF, Dhanani N, Acosta M, Wood CG. Conventional and hand- assisted laparoscopic radical nephrectomy: Comparative analysis of 271 cases. J Endourol 2006;20(11):891-894.

58. Montgomery JS, Johnston WK, 3rd, Wolf JS, Jr. Wound complications af ter hand assisted laparoscopic su rg ery . J Urol 2005;174(6):2226-2230.

59. Colombo JR, Jr., Haber GP, Aron M, Cocuzza M, Colombo R, Kaouk J, Gill IS. Oncological outcomes of laparoscopic radical nephrectomy for renal cancer. Clinics 2007;62(3):251-256.

60. Gabr AH, Gdor Y, Strope SA, Roberts WW, Wolf JS, Jr. Approach and specimen handling do not inuence oncolog ical perioperative and long - term ou tcomes af ter laparoscopic radical nephrectomy. J Urol 2009;182(3):874-8 8 0 .

6 1. H emal AK , K u mar A. A prospective comparison of laparoscopic and robotic radical nephrectomy for T1-

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2N0M0 renal cell carcinoma. World J Urol 2009;27(1):89-9 4 .

62. Skolarikos A, Alivizatos G, Laguna P, de la Rosette J. A review on follow-up strategies for renal cell carcinoma after nephrectomy. Eur Urol 2007;51(6):1490-1500; discussion 1501.

63. Leibovich BC, Blute ML, Cheville JC, Lohse CM, Frank I, Kwon ED, Weaver AL, Parker AS, Zincke H. Prediction of progression after radical nephrectomy for patients with clear cell renal cell carcinoma: a stratification tool for prospective clinical trials. Cancer 2003;97(7):1663-1671.

64. Kassouf W, Siemens R, Morash C, Lacombe L, Jewett M, Goldenberg L, Chin J, Chetner M, Wood CG, Tanguay S, Aprikian AG. Follow-up guidelines after radical or partial nephrectomy f or localize d and locally adva nced renal cell carcinoma. Can Urol Assoc J 2009;3(1):73-76.

65. Siddiqui SA, Frank I, Cheville JC, Lohse CM, Leibovich BC, Blute ML. Postoperative surveillance for renal cell carcinoma: a multifactorial histological subtype specific protocol. BJU Int 2009;104(6):778-785.

66. Kim HL, Seligson D, Liu X, Janzen N, Bui MH, Yu H, Shi T, Figlin RA, Horvath S, Belldegrun AS. Using protein exp ressions to predict su rvi va l in clear cell renal carcinoma. Clin Cancer Res 2004;10(16):5464-5471.

V. P A RT IA l neP H ReCT oM Y

1 . InT RoD uCT Ion

Partial nephrectomy (PN) includes the complete removal of a localized renal tumour while maintaining as mu ch normal renal parenchy ma as possib le. Advantages of PN are the preservation of renal function, the prevention of Chronic Kidney Disease (CKD) and the avoidance of overtreatment of benign renal masses. PN in solitary kidneys with limited ischemia time resu lts in minimal chang es in long -term renal function [1]. Moreover, some studies show a better quality of life after PN than after RN [2,3].

2 . ConCeRns W IT H T H e use of P A RT IA l neP H ReCT oM Y

a) Risk of recurrence – positiv e surgical margins

Significant concern with the use of PN for treating RCC is the risk of local recurrence in the ipsilateral kidney due to incomplete resection. This concern may be tempered by the low rates of recurrence following PN in the literature (0% to 10%) and even lower recurrence rates (1% to 3%) when performing PN for tumours < 4 cm [4]. Moreover many “local recu rrences” are not du e to incomplete remova l b u t are rather de novo tu mou rs, su ch as mu ltif ocal papillary RCC .

Analysi s of the ava ilab le literatu re reve als that frozen sections or final pathologic examination of the margins have minimal clinical significance and that a normal tissue margin of just 1 mm may be

sufficient to prevent local recurrence and disease progression from RCC. Margin status is more important than marg in size thou g h a positive su rg ical margin does not always result in local recurrence and/or disease progression. Therefore surgeons should be aware that not all patients with positive surgical margins on final pathology need to undergo second surgery immediately. These patients can be judiciously followed with periodic ultrasound and CT scan to monitor their hig her risk of local recu rrence (and disease progression) [5]. There are three recent reports f rom one centre on pu re enu cleation, meaning that the margin size was 0.00 mm. Simple enu cleation of the tu mou r relyi ng on the presence of an intact tumoural pseudocapsule was shown to b e saf e. O nly 2 of the 10 7 patients deve loped a local recurrence (1.9%) after simple enucleation of the tumour, one locally and one associated with distant metastasis [ 6 ] . O ne ye ar later the same g rou p f ou nd no local recu rrence at the leve l of the enu cleation site and three had a k idney recu rrence elsewhere in the kidney after pure enucleation of the tumour in 232 patients. Kidney recurrence was most like ly attrib u tab le to mu ltif ocality [ 7 ] . Another stu dy reported two local recurrences with simultaneous metastatic prog ression and one ki dney recu rrence elsewhere in the kidney after simple enucleation for pT1b tumours [8]. A recent histopathological study showed that if there is pseudocapsula invasion into normal parenchym a, the presence of a thin laye r of tissue can justify the presence of negative surgical marg ins eve n if a simple tu mou r enu cleation is perf ormed [ 9 ] .

A survey on the use of LPN in 17 centres (n= 855 cases) in the United States and Europe revealed that 21 (2.4%) cases had positive surgical margins [10]. Permpongkosol et al identified a positive margin in 9 of the 511 patients (1.8%) undergoing LPN [11]. Frank et al f ou nd a similar su rg ical marg in rate in patients that underwent a LPN for central and peripheral tumours [12]. Positive margin rate was 6.7% in solitary ki dneys [ 13] . L am et al recently reported that the rates of positive margins in PN specimen could be reduced with an optimal visualization of the tumour and the tumour margins. This could be achieved by intraoperative u se of u ltrasou nd f or deeper tu mou rs, cold- scissor parenchym al transection, emb oliza tion, and hilar clamping [14]. Currently, there is controversy on the optimal manag ement of a positive su rg ical margin. For a large (“extensive”) positive margin it seems log ical that additional su rg ery shou ld b e advised, either repeat PN (primary or secondary, open or laparoscopic), or in the appropriate patient, an RN [11,15]. However, recent data indicate that positive su rg ical marg ins af ter a completely deemed resection at the time of PN were not associated with an increased risk of local recu rrence or metastatic disease. Therefore it has been suggested that select patients with microscopic (“focal”) positive margins

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can b e saf ely of f ered close long - term su rve illance without compromising oncologic control [15,16]. While these data demonstrate that patients with a patholog ically positive marg in may b e ob serve d negative surgical margins should always be the goal in any oncologic procedure, including PN. Very recently, Bernhard et al identified three independent predictive factors for ipsilateral recurrence following NSS in RCC: tumour size > 4 cm, tumour bilaterality (synchronous or asynchronous) and positive surgical margins status (hazard ratios were 6.31, 4.57 and 1.15, respectively). Among the 809 NSS procedures with a medium follow-up of 27 months (1-252 months) 25 ipsilateral recurrences (3.2%) occurred at a medium time of 27 (14.5 – 38.2) months. Positive su rg ical marg ins occu rred in only 1.5% of the patients. The authors concluded that a prolonged follow-up should be recommended in patients presenting one or more of the three identified factors. The main limitation of the study was its retrospective nature and a short follow-up (median FU, 27 months) [17]. A previous retrospective study inclu ding data f rom 26 institu tions in Eu rope and the United States analyzed the outcome of 111 patients with positive surgical margins following NSS. Positive su rg ical marg ins statu s occu rred more f requ ently in the imperative group and is associated with an increased risk of recu rrence, b u t marg in statu s was not an independent predictor of both cancer-specific and overall survival [18]. These data taken together suggest that identified predictive factors for local recurrence after NSS do not necessarily affect survival and should not prohibit NSS in that setting. A recent study that reviewed the clinical records of 114 NSS procedures found a positive surgical margin rate of 1.75%. No disease progression or RCC attributable deaths were associated with positive surgical margins. These findings suggest that total nephrectomy shou ld b e avo ided as a response to positive su rg ical marg ins [ 19 ] .

b) H il ar cl amping - w arm and col d ischemia time – renal function – hemostatic agents

D u ring the deve lopment phase there have b een initial concerns with the use of LPN as related to a somewhat longer warm ischemia time and increased risk of major postoperative complications such as urinary leakage and hemorrhage [20]. Therefore the decision to perform an OPN or LPN depends on the ex perience of the indivi du al laparoscopic su rg eon. OPN is most often done through a lumbotomy, after exposure of the kidney and the tumour with its ov erlyi ng f at. ( fi g . 5 , 6 ) With increasing experience, LPN is now being performed at a growing number of tertiary centres worldwide. The technical challenge is to completely resect the tu mou r in a b loodless field followed by hemostatic renorraphy within a limited warm ischemia time. Factors associated with superior outcomes of LPN are routine hilar clamping,

adjunctive use of hemostatic agents and renal parenchym al closu re b y su tu re lig ation [ 21] .

Hilar clamping minimizes blood loss and allows precise tu mou r ex cision and renal reconstru ction in a nearly bloodless field. Today, there is no consensus about the clamping technique to be employed (artery only versus artery & vein) [22].

V ery recently , H u b er et al eva lu ated b leeding complications after open NSS in 196 patients at their institution (from 2005 to 2008). Median tumour diameter was 2.7 cm (range 0.5 – 11.8 cm). Bleeding required conservative (six), interventional (six) or surgical (three) therapy in 15 of the 196 cases (8%). The authors identified multifocality (P =0.039) and imperative indications (P =0.043) as risk factors for hemorrhage after NSS. The management of bleeding was very successful, relying on transarterial embolization (TAE) as an effective and safe treatment. I n rare cases of seve re b leeding su rg ical exploration is unavoidable, with a lower chance of ki dney preserva tion [ 23] .A recent well-designed but small prospective study has investigated separate renal function with effective renal plasma ow and renal parenchymal volume measured from CT scan. The authors could demonstrate that 25 min of warm ischemia time (WIT) is a cut-off for irreversible renal damage [24]. A recent larg e mu lti- institu tional stu dy has eva lu ated

Fig. 5 : I nstal l ation for l umbotomy

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the renal effects of ischemia in patients with solitary kidneys undergoing open NSS. The authors concluded that when vascular clamping during open NSS is necessary efforts should be made to limit WIT to 20 minutes and cold ischemia to 35 minu tes in order to avo id an increased risk of chronic renal insufficiency and acute renal failure [25]. The currently recommended WIT is 20 minutes or less,

reg ardless of su rg ical approach. I f a long er ischemia time is anticipated, cold ischemia shou ld b e institu ted up front at the start of PN. Cold ischemia with ice slu sh [ 26 ] shou ld b e ke pt as short as possib le, ideally within 35 min [27]. After surface cooling of the ki dney b y ice slu sh f or ab ou t 10 minu tes, the ki dney can b e clamped, and a saf e cold ischemia time f or a maximum of 35 min has been described in several studies [13,25,28,29]. Other methods to induce cold ischemia are arterial and u reteral perf u sion [ 30 - 33] . Recently, an early unclamping technique has been suggested by which only the initial parenchymal suturing is performed with the hilum clamped while su tu red renorrhaphy is perf ormed in the u nclamped, revascularized kidney. This resulted in a reduction of WIT by more than 50% (13.9 vs. 31 min, p < 0.0001). Postoperative hemorrhag e and reinterve ntion also tended to be lower but was not statistically significant. The current mean WIT < 14 minutes is lower than or similar to that in contemporary OPN series [34]. Other authors have confirmed these findings [35-37]. Nevertheless, the safe maximum duration of WIT remains in debate. A recent study evaluated the impact of WIT on renal function in 101 LPN patients using the Modification of Diet in Renal Disease (MDRD) equation to determine eGFR. The study results indicated that clinically significant risk for postoperative renal function impairment is evident only at a WIT of > 40 minutes. Incidence of renal function impairment was more than 2-fold higher in patients with WIT > 40 minutes than in the other groups (p =0.077). Larger studies in populations with normal preoperative renal function and with various degrees of CKD are requ ired to clarif y the risk f actors f or postoperative renal function impairment, including WIT. In the meantime eve ry attempt shou ld b e made to redu ce WIT [ 38 ] . Another stu dy reve aled that g reater tu mou r size , central tu mou r location and hig her b ody mass index are associated with longer WIT. By including these 3 factors into a nomogram prolonged WIT (> 30 minutes) may be predicted before surgery [39]. However, the exp erience of the su rg eon may b e the most critical parameter.

Fig. 6 a: E x posure of the k idney in a l umbotomy after compl ete hil ar dissection

Fig. 6 b: Compl ete mobil iza tion of the tumor bearing k idney on its artery, v ein and ureter

Fig. 6 c: Freeing the k idney and the tumor, cov ered by peri- renal fat

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Very recently, Chan et al retrospectively evaluated in 65 patients (35 OPN and 30 LPN) which clinical parameters, alone or jointly, accurately predicted unilateral renal function after OPN and LPN. In the u niva riate reg ression analysi s, intraoperative vi su ally estimated preserved renal parenchyma (P <0.001), tumour size (radiologic, P =0.017; pathologic, P =0.041) and procedure type (laparoscopic vs. open) (P =0.021) were the only factors found to be significantly correlated with postoperative scintigraphic differential renal function. Tumour depth (P=0.050) was borderline significantly correlated with postoperative scintig raphic dif f erential renal f u nction. I ntraoperative vi su al estimation of preserve d renal parenchyma volume was the most accurate predictor of actu al postoperative u nilateral renal f u nction and should be routinely documented during OPN and LPN [40].

The use of hemostatic agents and glues during LPN in 18 centres (n= 1347 cases) in the United States and Europe was shown to be routine in most centres performing LPN (in 77.4%). The rates of postoperative hemorrhag e requ iring transf u sion and urine leakage rates were low in this survey (2.7% and 1.9%, respectively) [41].

c) L ong- term oncol ogic data – risk of compl ications

A randomised prospective phase III trial was conducted (EORTC 30904) comparing OPN and ORN in 541 patients with tumours ≤ 5 cm and a normal contralateral ki dney . V an Poppel et al conclu ded that the complication rate with OPN is slightly higher than with ORN [42]. The long-term oncological results are not ye t ava ilab le.

Porpiglia et al retrospectively analyzed 90 LPN procedures. The only variable that was found to correlate with a significantly higher rate of complications was a corticomedullar tumour growth pattern as opposed to a cortical growth pattern (P = 0.02). It has to be noted that this finding is based on univariate analysis (no multivariate analysis was performed). To reduce the risk of complications associated with LPN the authors recommended selection of patients with cortical renal lesions only [43]. More recently, Turna et al retrospectively analyzed 507 LPN procedures. Presence of a solitary kidney, prolonged WIT and increased intraoperative blood loss were found to be independent risk factors on mu ltiva riate analysi s f or the deve lopment of postoperative complications after LPN [44]. Probably the new categorization as proposed by Ficarra et al and Kutikov et al will be helpful in defining risk factors [45,46].

3 . oP en P A RT IA l neP H ReCT oM Y

a) I ntroduction

Open partial nephrectomy (OPN) is the nephron-

sparing modality with the largest clinical experience and the longest follow-up. OPN continues to be the treatment of choice f or the manag ement of localize d RCC given its wide application over the last two decades and the most su b stantial su pporting b ody of operative and oncolog ic data. I mportantly , u nlike ablative treatment options OPN allows definitive pathological identification (i.e. stage, grade and histology) and proof of complete resection. Essential su rg ical principles inclu de exce llent exp osu re, control of the renal va scu latu re, caref u l exci sion of the tumour with a negative surgical margin and repair of the parenchym al def ect and collecting syst em to minimize the risk of postoperative hemorrhag e or urinary fistula. ( fi g . 7 , 8 )

b) I ndications

The standard indications for NSS according to the EAU guidelines are divided in the following categ ories:

─ absolute (anatomical or functional solitary kidney)

─ relative (functioning opposite kidney that is affected b y a condition that mig ht impair renal f u nction in the future)

─ elective (localized unilateral RCC with a healthy contralateral kidney)

Relative indications also include patients with hereditary forms of RCC, who are at high risk of deve loping a tu mou r in the contralateral ki dney in the future [47]. Since more SRMs are detected now, elective PN has been adopted more frequently f or the treatment of su ch tu mou rs. D u ring the last decade elective PN has become the gold standard for the treatment of T1a tumours (< 4 cm) in patients with a normal contralateral kidney [48,49]. When PN is performed in carefully selected patients in specialize d centres, indications can b e exp anded to include T1b tumours (4-7 cm) [50-61]. ( fi g . 9 , 1 0 ) Also multifocal tumours can be dealt with ( fi g . 1 1 ) as well as centrally located tumours that can need intraoperative u ltrasou nd to localize tu mou rs completely cove red b y healthy parenchym a. ( fi g . 1 2 )

c) O ncol ogical outcome

Lee et al compared RN and OPN for tumours < 4 cm and found equivalent oncological results at 5-years (disease-free survival of 96%) with no local recu rrences [ 4 8 ] . T a b l e 1 presents the oncolog ic ou tcome of larg e series of nephron- sparing su rg ery [48-50,58,62-73]. PN for RCC < 4 cm (T1a) is now established standard. More recently, PN is being proposed for T1b RCC (4-7 cm). Several recent studies indicate that elective PN can achieve similar oncological outcomes as RN for select T1b tumours [50,54,55,57,59,61]. T a b l e 2 presents stu dies assessing the oncologic outcome following NSS in

1 1 8

Fig. 7 c: Cl osure w ith singl e approx imating sutures

Fig. 7 a: W edge resection after bul l dog cl amping of both artery and v ein

Fig. 7 b: O v ersew ing of smal l arteries and v eins

T abl e 1. O ncol ogic outcomes of l arge series of N SS

Au thor No . of patients

Mean tumour size (cm)

5-yr CSS (%)

10 - yr CSS (%)

L ocal recu rrence

(%)

Mean

follow-up (mo)

Steinbach et al (62) 121 5.5 9 0 - 4 .1 4 0Moll et al (63) 14 2 4.5 9 8 - 1.4 35Lerner et al (64) 185 4 .1 8 9 7 7 5.9 4 4Belldegrun et al (65) 14 6 3.6 9 3 - 2.7 7 4Herr et al (66) 7 0 3.0 - 9 7 1.4 120Hafez et al (119) 485 3.4 9 2 - 3.2 4 7Lee et al (48) 7 9 2.5 95 - 0 4 0Lau et al (67) 16 4 3.3 9 8 - 3 4 1Filipas et al (68) 18 0 3.3 9 8 - 1.6 56Delakas et al (69) 118 3.4 9 7 .3 9 6 .4 3.9 10 2Patard et al (50) 314 2.5 9 7 .8 - 0 .8 62.5Fergany et al (70) 4 0 0 ° 4 .2 8 9 8 2 3.5 4 4Becker et al (58) 24 1 3.7 9 7 .8 95.8 1.4 6 6Pahernik et al (71) 715 3.0 98.5 9 6 .7 3.3 8 1Pahernik et al (72) 10 3° 4 .2 8 9 .6 7 6 0 .1 9 6Van Poppel et al (73) 51 3.0 9 8 .0 - 0 .0 7 8

° solitary ki dneys CSS: cancer-specific survivalReprinted from Van Poppel H. Efficacy and safety of nephron-sparing surgery. Int. J Urol, 2010;17(4):314-26.

1 1 9

Fig. 9 a: E x posure of RCC at renal hil us Fig. 9 b: Reconstruction of the k idney after midpol ar tumorectomy

Fig. 9 c: Reconstruction after midpol ar resection

Fig. 10 a: U pperpol e RCC w ith en bl oc adrenal ectomy w ith smal l metastasis

Fig. 10 b: A fter upper pol e amputation and adrenal --ectomy and l ymph node dissection for T 3 a RCC

Fig. 8 a: O pen enucl eoresection of a smal l RCC w ith a rim of heal thy parenchyma

Fig. 8 b: A ppl ication of hemostatic adhesiv e agent ( T achosil )

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Fig. 11a: O ne l arge and mul tipl e smal l papil l ary type I RCC’ s

Fig. 11b: A fter resection of the l arger, and thermo-abl ation of the smal l er l esions

Fig. 12 a: I ntra- operativ e ul trasound for intra- renal RCC

Fig. 12 b: I ntra- operativ e ul trasound to detect an intraparenchymal tumor

Fig. 12 c: U S l ocal iza tion of the intra- renal tumor Fig. 12 d: Resection of ov erl ying renal cortex

Fig. 12 e: E nucl eation of deep intrarenal mass

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relation to tumour size > 4 cm or ≤ 4 cm [8,50,54,55,57,58,60,74). Pahernik et al recently compared PN for pT1a (≤ 4 cm) and pT1b tumours (4-7 cm) in 474 PN procedures; estimated CSS was 97.9% and 95.8% at 5 years, and 94.9% and 95.8% at 10 years. This study failed to demonstrate statistical significant differences in terms of CSS after PN for T1a and T1b tumours [75]. This was also observed in a recent multicentre study of Patard et al [56]. Crispen et al recently reported durable cancer control in 798 patients undergoing PN for T1 renal tumours (≤ 7 cm). They found that overall, CSS, metastasis-free and local recurrence-free survival significantly decreased with each 1 cm increase in size in all tumours treated and in those with pathologically confirmed RCC [76]. A recent multi-institutional study revealed cancer control equivalence between RN and PN in patients with high-grade Fuhrman III- IV or with pT3a histology. Conversely, CSS after PN is statistically less than that after RN in patients with tumours > 7 cm. It has to be noted that only 29 of 925 patients (3.1%) with tumour size > 7 cm were treated with PN at 1 of 13 participating centres. Larger cohorts are required to confirm the results [77].A recent study analysed the data of 1205 T1N0M0 RCC patients treated with NSS. Despite the su g g ested more ag g ressive phenotyp e of the papillary histolog ic su b typ e, the au thors f ou nd no statistically significant differences in cancer-specific mortality among the papillary , chromophob e, and clear cell va riants [ 7 8 ] .

d) Compl icationsWhen performed in appropriate patients and in centres with sufficient expertise, OPN can offer for small renal tumours a perioperative morbidity profile similar to that of ORN. The rate of postoperative complications was 13.7% in a recent multicentre comparative study by Gill et al including 1029 patients with renal tumours (< 7 cm) that underwent OPN. The rate of postoperative hemorrhages and urologic complications was 1.6% and 5.0%, respectively. [28]. The best available evidence on this subject is the prospective randomised EORTC phase III trial which

compared the complications of elective PN and RN in patients with renal tumours ≤ 5 cm. In this study reported by Van Poppel, PN was associated with higher risk of severe perioperative bleeding (3.1% vs. 1.2%), reoperation due to side effects (4.4% vs. 2.4%) and having an abnormal postoperative CT scan (4.4% vs. 2.0%). The rate of urinary fistulas was 4.4% [42]. In a retrospective multicentre study, Patard et al demonstrated in 730 elective OPN procedu res that perioperative morb idity as measu red by blood loss, urinary fistula rate, and need for blood transfusion was significantly increased for tumours > 4 cm in diameter. They concluded that expanding the indications of elective OPN to larger tumours is associated with an increased but acceptable morbidity [56]. In addition, a recent study including 1117 PN revealed that 4.5 % of patients developed postoperative urinary fistula. Patients with tumours > 2.5 cm were 2-fold more likely to develop a urinary fistula compared to patients with tumours < 2.5 cm (P = 0.04) [79].

Renal failure is another complication of PN. A recent study analysed the data of 166 patients with pathological T1-3 N0M0 RCC treated with PN. The investigators identified perioperative blood loss, hilar clamp time and preoperative GFR as independent predictors of renal failure (decrease in GFR of >25%). I t is possib le that su rg ical exp erience cou ld minimize the rate of renal failure especially in patients with pre- exi sting renal f u nction impairment [ 8 0 ] .

The risk of a significant complication may increase with the technical complexity of the case such as larger tumours or centrally located tumours. However, most complications can b e manag ed conserva tive ly and usually resolve without significant morbidity. O ve r the last ye ars, su rg ical techniqu es have b een improvi ng and complication rates f u rther decreasing with increasing surgical experience.

e) Comparison betw een P N and RN McKiernan et al conducted a 10-year prospective study to compare 173 patients who underwent

Table 2. Studies assessing oncologic outcome following NSS in relation to tumour size > 4 or ≤ 4 cmAu thor No . of patients

and pT stage5-yr CSS (%)

10 - yr CSS (%)

L ocal recu rrence

(%)

Metastasis(%)

Mean F U

(mo)Patard et al (50) 314 (pT1a)

65 (pT1b)9 7 .89 3.8

--

0 .83.6

2.47 .1

5162.5

Leibovich et al (55) 91 (30 pT1a, 60 pT1b, 1 pT3a) 9 8 .3 - 5.5 4 .4 10 6 Mitchell et al (74) 33 (21 pT1b, 12 pT3) 9 6 .2 - 2.3 - 34Carini et al (8) 71 (30 pT1a, 31 pT1b, 10 pT3) 85.1 - 4.5 14 .9 7 4Dash et al (57) 45 (41 pT1b and 4 pT3) 8 0 - 2.2 - 14Becker et al (58) 69 (62 pT1b, 4 pT2, 3 pT3a) 10 0 10 0 5.8 5.8 7 4Peycelon et al (60) 61 (42pT1b, 12pT2, 6 pT3a, 1 pT3b) 8 1 7 8 9 .8 19 .7 7 0 .7Joniau et al (54) 67 (13 pT1a, 49 pT1b, 1 pT2, 4 pT3a) 9 9 - 4 .0 6 .0 4 0 .1

Reprinted from Van Poppel H. Efficacy and safety of nephron-sparing surgery. Int. J Urol, 2010;17(4):314-26.

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RN with 117 patients who underwent PN for renal tumours ≤ 4 cm and a normal contralateral kidney. The incidence of risk factors for renal insufficiency did not differ between the two groups. After controlling f or perioperative risk f actors f or renal f ailu re, patients undergoing RN were at a greater risk of chronic renal insufficiency (creatinine ≥ 2.0 mg/dL) than a similar cohort of patients undergoing PN [81]. Moreover, in D ash et al prospective comparison of 19 6 patients undergoing PN and RN for T1b tumours, serum creatinine level at 3 months post-operative was significantly lower in the PN cohort [57].

Patard et al performed a retrospective analysis of 1454 patients undergoing PN or RN for T1N0M0 tumours. In patients treated by PN, the cancer death rate was higher for T1b tumours compared to T1a tumours (6.2% vs. 2.2%, respectively). However, in the group of T1b tumours, there was no significant difference in the rate of cancer specific deaths whether treated with PN or RN (6.2% vs. 9%, respectively). This study su g g ests that it is saf e to exp and the indications of PN to include patients with T1N0M0 tumours up to 7 cm [50]. Likewise, Leibovich et al performed a retrospective analysis of 932 patients undergoing PN or RN for T1b renal tumours. Their study included control groups of T1a tumours for each procedure. There was no statistically significant difference in survival at 5 years between patients treated with PN and RN after adjusting for important pathological features. This study also shows that PN for T1b (4 to 7 cm) RCC can result in excellent outcomes when performed in appropriately selected patients [55]. A recent study confirmed these results and suggested designing a prospective study to compare RN and PN in the management of RCC up to 7 cm [59]. Thompson et al combined data from the Mayo Clinic and Memorial Sloan Kettering Cancer Center of patients with 4 to 7 cm renal masses treated with RN (873) vs. PN (286). They suggest that OS and CSS are not compromised when PN is compared with RN for tumours up to 7 cm. This study adds considerable evidence supporting PN use when technically f easib le [ 6 1] . A recent stu dy represents the larg est and the only popu lation- b ased analyse s of cancer control efficacy of NSS vs. RN in T1bN0M0 RCC. It used Surveillance, Epidemiology, and End Results (SEER) data where 275 NSS were matched with 1100 RN for T1bN0M0 RCC. It indicates that NSS does provide equivalent cancer control relative to RN. NSS should be considered equally effective to RN for T1bN0M0 RCC [82]. None of these studies were randomised like the EORTC 30904 trial comparing PN to RN for patients with RCC up to 5 cm of which the results are pending [42].

A recent analysis of the SEER-9 database revealed that relative to PN, RN predisposes to a rise in overall mortality and non- cancer related mortality rate in patients with T1aN0M0 RCC [83]. Convincing data show equivalence of PN and RN for cancer control and superiority of PN in terms of preserving renal

function, preventing CKD and subsequent long-term cardiac morb idity and mortality and improve d overall survival [53,84]. Therefore, patients with T1 renal tumours should undergo PN whenever technically feasible. The expanding role of PN is the topic of a recent paper of European Urology [85]. A comparative popu lation- b ased stu dy analyze d the rate of PN vs. RN for clinically localized RCC (SEER data 1989-2004). Of 19,733 assessable patients, 2,614 (13.2%) had PN and 17,119 (86.8%) had RN. The use of PN decreased with increasing tumour size and increasing age and increased with more contemporary years of surgery (all P < 0.001). Although the rate of PN use increased over time, unexplained variability remained. Regional and gender differences in PN rates represent findings that need to b e u rg ently addressed and corrected. The PN rate was 16.4% in San Francisco-Oakland, vs. 7.6% in New Mexico (P < 0.001). Women were 10% less likely to have a PN than men. The study has several limitations. There was no information about surgical approach (open vs. laparoscopic vs. robotic) of PN or RN that was performed, tumour location, nu mb er of renal u nits and renal f u nction. I nf ormation on comorbidity status, hospital type (academic vs. community), surgical training and expertise (years in practice) was also unavailable [86].

4 . lA P A RosCoP IC P A RT IA l neP H ReCT oM Ya) I ntroduction

O ve r the last decade, laparoscopic partial nephrectomy (LPN) has gained acceptance as an alternative to the open procedure. Given its more recent development most LPN series understandably have shorter follow-up compared to most OPN series. The preferred choice of access for LPN is the transperitoneal approach. Retroperitoneal access is reserve d f or posterior and particu larly posteromedial tumours [87]. In the largest LPN series to date, Gill et al reported LPN in 1000 patients over a period of 9 years. Of these, 800 LPNs performed by a single surgeon were stratified according to consecutive time periods (era I (1999-2003), era II (2004-2006) and era III (2007-2008).

Tumours in the most recent era were larger, more commonly > 4 cm, central and hilar, and less of ten peripheral < 4 cm. Despite increasing tumour complexity, warm ischemia times were shorter, complication rates (overall, post-operative, urologic) were significantly lower, positive surgical margin rate was only 0.6%, and renal functional outcomes were superior in the most recent era, In patients with pathologically-confirmed cancer, 5-year overall, cancer-specific, and recurrence-free survival was 90%, 99%, and 97%, respectively [88].

If a LPN encounters difficulties, the committee recommends that the optimal surgical plan would be to convert to OPN with LRN being performed in the rare case.

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b) I ndicationsThe initial experience with LPN was limited to small (< 4 cm), low stage, single, peripheral and exophytic lesions. These indications have also been expanded to inclu de more challeng ing masses: central tu mou rs, hilar tu mou rs, cyst ic tu mou rs, mu ltiple ipsilateral tu mou rs, tu mou r in a solitary ki dneys , larg er tu mou rs (T1b and T2 or greater), and intraparenchymal tumours [89]. With regard to the tumour location, during a surgeon’s initial LPN experience, exophytic tu mou rs and non- central tu mou rs not ext ending into the renal sinus may be excised more easily, with a lower incidence of complications [90] ( fi g . 1 3 a – f ) . A new anatomical classification has been recently proposed to categ orize dif f erent locations of renal tumours that could correlate with surgical ease and oncological safety of the PN [45]. A comprehensive standardize d sys tem f or qu antitating renal tu mou r siz e, location and depth is the recently deve loped R.E.N.A.L. nephrometry score [46].

lP n f o r c e n t r a l a n d h i l a r t u m o u r sI n the past, central location of the tu mou r or contact of the tumour with a major renal vessel (hilar tumour) on preoperative cross-sectional imaging was considered to be a contraindication for LPN. The reason was the perceived difficulty in achieving negative surgical margins, while preserving adequate blood supply to the renal remnant. However, a prospective study demonstrated that the thickn ess of the su rg ical marg ins has no ef f ect on the risk of local recu rrence and a g ood prog nosis can b e exp ected as long as the definitive margins are free of cancer [91]. Data on LPN for centrally located and hilar tumours are limited and definitions on central and hilar tumour are not u nif orm maki ng comparison of resu lts among different studies difficult.

Venkatesh and co-workers reported that complications of LPN for 123 renal tumours were associated with location of the tumour in the kidney with lower complication rates for exophytic (10%) than for endophytic (47%) and hilar tumours (50%) [ 9 2] .Two studies performed in centres with adequate laparoscopic expertise reported that LPN in central tumours was associated with comparable outcome as LPN in peripheral tumours. However, long-term follow-up is needed and a longer ischemia time may ensu e f or central/ hilar tu mou rs [ 12,9 3] . F rank et al compared LPN for central (n=154) and peripheral (n=209) tumours. Although the blood loss was similar (median 150 mL) more early postoperative complications occu rred in the central tu mou r g rou p (6% vs. 2%). In addition, central tumours required longer WIT (median 33.5 vs. 30 minutes, p < 0.001) [12]. Nadu et al also compared LPN for central tumours (n=53 including 12 hilar tumours) and peripheral tumours (n=159). Four patients (7.5%) had delayed hemorrhage (arterial pseudoaneurysm)

with late onset hematuria; these 4 patients required ang iog raphic emb oliza tion. O nly one patient had a urine leak (1.9%) after LPN for central tumours. Mean WIT in the central tumour group was longer than in the peripheral tumour group (37 vs. 28 minu tes, P < 0.05) but the median WIT was similar (30 vs. 29 minutes, P > 0.05) [93]. Two recent smaller studies reported that in experienced hands LPN for hilar tumours is feasible and safe while short-term oncologic results are promising [94,95].

lP n f o r t u m o u r i n s o l i t a r y k i d n e y

A recent study from Lane et al compared 169 OPN and 30 LPN for stage T1 tumours in a solitary functioning kidney. By 3 months after OPN or LPN, the ave rag e loss of postoperativ e renal f u nction was similar. LPN compared to OPN was associated with a longer WIT (mean difference of 9 minutes; P < 0.0001), a 2.54-fold higher risk of postoperative complications (P < 0.05) and a higher rate of postoperative dialysis (10 vs. 0.6%, respectively, P = 0.01). Of note, the T1 tumours in this study were not sub-dived into cT1a (< 4 cm) and T1b (4-7 cm) sub-categories. Although LPN is technically feasible for a tumour in a solitary kidney, at this time OPN may b e considered the pref erred treatment approach f or these patients who are at high risk for CKD [96]. This was recently confirmed in a study including 84 patients with solitary kidney [1].

c) O ncol ogical outcome

T a b l e 3 presents oncolog ic ou tcomes of laparoscopic partial nephrectomy [ 13,37 ,9 7 - 9 9 ] . O ncolog ical outcomes are similar when comparing LPN and OPN for localized RCC. A comparison of LPN and OPN performed in 1800 patients with a single renal tumour (< 7 cm) at major centres with greatest expertise showed a similar oncological outcome (3-year CSS: 99.3 vs. 99.2%, respectively) [28]. Lane and Gill reported intermediate-term outcomes of LPN in 56 patients, with an OS and CSS of 86 and 100%, respectively, at 5 years [13]. A retrospective matched-pair comparison of LPN and OPN in 200 pT1 patients showed a 5-year OS of 96% and 85%, respectively. The 5-year local recurrence-free survival was 97% after LPN and 98% after OPN [100]. Most recently, Lane and Gill compared 7-year outcomes of LPN (n=77) with OPN (n=310) for single clinical stage T1 (≤7cm). Cancer recurred inf requ ently , and only rarely cau sed mortality , af ter either LPN or OPN. At 7 years, metastasis-free survival was 97.5% and 97.3% (p=0.47) after LPN and OPN, respectively. On multivariate analysis, predictors of all- cau se mortality inclu ded adva ncing age (p<0.0001), co-morbidity (p<0.0001), pre-operative renal dysfunction (p=0.0001), but not tumour size (p=0.6) or operative approach (LPN vs. OPN, p=0.06). The authors concluded that LPN and OPN provide similarly excellent long-term overall

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and cancer-specific survival, with the vast majority (97%) of patients experiencing metastasis-free su rvi va l [ 10 1] .

d) Compl ications

Porpig lia et al recently reported the incidence of complications in recent LPN series from centres with adequate expertise with a total number of 1062 patients. The overall complication rate was 21.4% (range 9 to 33%). There was a 5.1% rate of hemorrhagic complications (range 1.5 - 10.0%), a 4.2% rate of urine leakage (range 1.4 - 13%) and a 0.7% rate of renal failure (range 0.5 - 2.0) [102].

Turna et al reported a large series focusing on complications after 507 LPNs performed by a single surgeon. Of the 107 complications 49 (46%) were urologic. Of total complications, 22 (20.6%) were grade I, 48 (45%) grade II, 32 (30%) grade III, 5 (4.7%) grade IV and none were grade V. Complications were compared for LPNs performed between 1999 to 2002 and 2003 to 2006. Despite the increase in the nu mb er of total and complex procedures, there was a decrease in the rate of overall complications (29.6% vs. 16.9%, P = 0.001), urological complications (13.6% vs. 7.7%, P = 0.03) and nonurological complications (16% vs. 9.2%, P = 0.02). Urine leakage rate decreased from 4.7% to 1.2% (P = 0.01), while the postoperative hemorrhage rates did not show statistical difference (5.9% vs. 5.6%), likely due to the increased number of complex procedures [44]. Recently, a detailed single-centre review was reported of 144 consecutive LPN (4 surgeons) conducted from November 2002 to January 2008. Standardized grading criteria were used which allows comparison to the series of Turna el al. A total of 39 complications occurred in 29 (20%) patients. Of these, 20 (51%) were urologic. Of total complications 6 (15.4%) were grade I, 19 (48.7%) grade II, 11 (28.2%) grade III and 3 (7.7%) grade IV and none were grade V. Overall results appear consistent with those of other contemporary series of LPN or OPN. Increased American Society of Anesthesiologists (ASA) score and ischemic time are associated with complication risk. Hospital readmission and reintervention was required in 15 (10.4%) and 9 (6.2%) patients, respectively [103].

With the use of more sophisticated laparoscopic techniqu es and the increased exp erience of laparoscopic surgeons the complication rate of LPN has significantly decreased and now appears similar to that of OPN [34,44,104].

e) Comparison betw een L P N and O P N

Gill et al’s recent combined study from 3 major centres with greatest expertise compared 1800 patients with a single tumour (< 7 cm) undergoing either LPN or OPN. Advantages of LPN were less operative time, decreased operative b lood loss and shorter hospital stay. On the other hand, LPN was associated with a 10 minute longer WIT (31 vs. 20 min) and more postoperative complications (18.6 vs. 13.7%) than OPN, particularly postoperative hemorrhage (4.2 vs. 1.6%) and urologic complications (9.2 vs. 5.0%). Importantly, LPN and OPN were similar with regard to intra-operative complications (1.8% vs. 1%). Shorter operative times and less blood loss with LPN than with OPN, but higher rates of urological complications parallel the findings of a recent meta-analysi s of the American U rolog ical Association (AUA) [105]. Oncological outcomes (CSS: 99.3 vs. 99.2% at 3 years), renal function outcomes (97.9 vs. 99.6% at 3 months) and positive surgical margins (1.6 vs. 1%) were similar between LPN and OPN. Local (1.4 vs. 1.5%) and distant (0.9 vs. 2.1%) recurrences were also equivalent. Conversion to open surgery occurred in 2.1% of LPN cases [28].

A retrospective matched-pair comparison of LPN and OPN was recently performed in 200 patients with pT1 RCC. The authors concluded that in experienced hands LPN provides similar oncologic and functional outcomes compared to OPN at a mean follow-up of 3.6 years. Decrease in GFR at last follow-up, positive surgical margin rates, blood loss, and complication rates were comparable for b oth g rou ps. O perative time, ischemia time and hospitalization time were shorter in the LPN group and conversion rate to open surgery was 2% [100]. How often a conversion to LRN was done is not reported. In addition, studies show that LPN has protective ef f ects on the long - term renal f u nction when compared with LRN [106,107].

T abl e 3 . O ncol ogic outcomes of l aparoscopic partial nephrectomyAu thor No. of

patientsMean tu mou r size (cm)

CSS (%) Positive su rg ical margins (%)

L ocal recu rrence (%)

Mean follow-up (mo)

Porpiglia et al (97) 34 3.2 10 0 2.9 0 .0 16Gill et al (98) 4 30 3.6 100 (3-yr) 0 .0 0 .0 30Permpongkosol et al (99) 85 2.4 9 1.4 2.4 2.4 4 0Bollens et al (37) 39 3.2 10 0 2.6 0 .0 15Lane et al (13) 58 2.9 100 (5-yr) 1.7 1.7 6 8

CSS: Cancer-specific survivalReprinted from Van Poppel H. Efficacy and safety of nephron-sparing surgery. Int. J Urol, 2010;17(4):314-26.

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Fig. 13 a: M RI show ing a l arge angiomyol ipoma of the l eft k idney.

Fig. 13 b: T he l eft l ow er pol e is being remov ed in w arm ischemia using col d scissors. T he central part of the angiomyol ipoma can be seen cl earl y

Fig. 13 c: The first running suture incl udes the v essel s of the interstitial tissue as w el l as the col l ecting system. T his suture is secured on both ends w ith a l apra- tyR cl ip.

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Fig. 13 d: A suture through the ful l thick ness of the renal parenchyma hel ps to approx imate the cut edges and prov ides haemostasis.

Fig. 13 e: T he parenchymal suture is secured w ith l arge hem- o- l ok R cl ips w hich al l ow to appl y pressure on the renal parenchyma thereby prov iding optimal haemostasis. A rol l of tabotampR is pl aced underneath this suture to improv e haemostasis.

Fig. 13 f: Final l y, as prev entiv e measure to av oid del ayed hemorrhage, the repair is cov ered w ith fibrin blue and a strip of tabotampR.

Fig. 13 g: T he ex cised l ow er pol e w ith the tumour is pl aced w ith an organ bag for safe remov al .

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f) Contemporary outcomes of L P N : T he State-of - the- A rt

With increasing LPN experience and standardization of ou r early u nclamping techniqu e, contemporary LPN outcomes have improved significantly. Specifically, the two remaining above-mentioned concerns with LPN have now been addressed, leading to decreased ischemia times and redu ced hemorrhag e rates.

Gill et al reported a single-surgeon series of 800 LPN cases encompassing a 9-year period (1999-2008) [88]. The authors divided the entire cohort into 3 chronologic eras: Era I: 1999–2003 (n=276), Era II: 2004–2006 (n=289), and Era III: 2007–2008 (n=235). On comparing eras I, II and III, tumours in the most recent era were larger, more commonly > 4 cm, central and hilar, and less of ten peripheral and < 4 cm (p-value significant for all). Despite such increasing tumour complexity, mean warm ischemia times were shorter in the most recent era: 32 min, 32 min and 14 min (p<0.0001). Overall, post-operative and urologic complications were significantly lower in the most recent era. I n the most recent era, positive su rg ical marg in rate, and incidence of conve rsion to OPN or RN were 0.6%, 0% and 2.1%, respectively. Renal functional outcomes were superior in era III, as reected by lesser percent decrease in estimated GFR (18%, 20% and 11%, respectively). In patients with pathologically-confirmed malignancy (n=744), 5-year overall, cancer-specific, and recurrence-free survival was 90%, 99%, and 97%, respectively. The au thors conclu ded that ove r this 9 - y ear exp erience with 800 consecutive LPNs, tumour characteristics and LPN outcomes had evolved significantly. Despite increasing tu mou r complexi ty in contemporary practice, the 3 key outcomes of LPN (ischemia time, complications, and renal function) have improved significantly. As a result, the authors routinely offer LPN for the majority of tumours hitherto reserved for open NSS [88].

A recent stu dy f rom K avo u ssi’ s g rou p compared ‘off-clamp’ LPN with traditional ‘on-clamp’ LPN. Significant differences (p < 0.05) in the ‘off-clamp’ g rou p relative to the ‘ on- clamp’ g rou p inclu ded shorter operative time (132 vs. 146 min), a higher proportion of exophytic lesions (51% vs. 28%), smaller tumour volume (26 vs. 41cm3) and less hilar tumours (15% vs. 29%). Short term elevation in serum creatinine was significantly less (6% vs. 29%) although long term significance of this finding is unknown. There were no significant differences in b lood loss, transf u sion rate, or complications. As experience improves, an increasing number of LPNs may b e perf ormed ‘ of f - clamp.Finally, Kamoi & Gill compared 150 contemporary patients undergoing OPN (2006–2008) with 150 contemporary patients undergoing LPN (2007–2008). Notably, all OPNs were performed by one

experienced open surgeon (Andrew C. Novick, MD), and all LPNs were performed by one experienced laparoscopic surgeon (Inderbir S. Gill, MD). LPN patients had shorter ischemia time (21 versus 13 minutes, p<0.0001), with more LPN patients having ischemia time < 20 min (52% vs. 97%). Post-operative complications were fewer in the LPN group (19% vs. 8.7%; p=0.01), including hemorrhage (3.3% vs. 2.7%; p=ns) and urine leak (7.3% vs. 1.3%; p=0.02). Patients undergoing elective PN had similar, and those undergoing imperative PN or PN in solitary ki dney had su perior renal f u nctional ou tcomes in the LPN cohort, likely a result of the reduced ischemia time during LPN. Of note, OPN patients had somewhat larger tumours, more solitary kidneys, and a higher incidence of baseline renal dysfunction; however, after adjusting for each of these baseline demographic differences, LPN outcomes were, at a minimum, equivalent to OPN outcomes in each parameter eva lu ated.

These emerging new data indicate that, in experienced hands, LPN is now similar to OPN as reg ards the ke y ou tcomes of ischemia time, u rolog ic complications and renal functional outcomes. This improvement in LPN outcomes has occurred despite increasing tu mou r complexi ty . As a resu lt, seve ral centres now routinely offer LPN for the majority of technically- challeng ing small tu mou rs su ch as hilar, central completely intra-renal, larger (4-7 cm, pT1b) tu mou rs or tu mou rs located in a solitary ki dney [ 8 9 ] .

A recent sing le- centre stu dy b y L if shitz et al compared the technique and outcome between the early (group 1: 50) and recent (group 2: 50) LPN experience between October 2002 and August 2008. Group 2 had larger tumours (3 cm vs. 2.4 cm, P =0.002) and significantly more central tumours (52% vs. 12%, P =0.001). In group 2 the authors stopped the use of u reteral catheters and b olster renorrhaphy , and routinely clamped the renal hilum. The WIT (30 and 27 minu tes, respective ly , P =0.3) and complication rates were similar in group 1 and 2. Overall, patients with tumours sized > 4 cm had more complications (P =0.042). In group 2, the estimated blood loss (243 vs. 14 0 ml, P =0.01) and hospital stay (2.5 vs. 1.4 days, P < 0.001) decreased and the readmission rate was only 5.4%. With growing experience and technical modifications LPN is now performed for patients with larger and more central tumours [108].

5 . RoB oT IC P A RT IA l neP H ReCT oM YShapiro et al reported excellent oncologic outcomes in their recent review of initial experience with robotic PN (n=211). Estimated blood loss, postoperative renal f u nction, su rg ery time and hospital stay seemed to be equivalent to LPN. Mean WIT ranged f rom 21 to 32 minu tes. H ilar clamping continu es to be a difficult aspect of the procedure [109]. Rogers et al reported that robotic PN is safe and feasible in 14 select patients with complex renal tumours including

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hilar, endophytic, and multiple tumours [110]. They also evaluated 11 patients from 2 institutions who underwent robotic PN for renal hilar tumours [111]. A recent sing le- su rg eon analysi s of consecu tive rob otic PN (n=40) and LPN (n=62) procedures revealed that robotic PN can produce results comparable to LPN. In the specific author’s hands mean WIT (19 vs. 25 minu tes, P = 0.03), total operative time (140 vs. 156 minu tes, P = 0.04), and length of hospital stay (2.5 vs . 2.9 days, P = 0.03) were shorter for robotic PN than for LPN [112]. The sliding-clip renorrhaphy, a techniqu e adopted b y most hig her vo lu me su rg eons, and the learning cu rve are b oth responsib le f or a significant reduction in overall operative time and WIT [113]. Recently, Ho et al reported 1 year ou tcomes in 20 patients u nderg oing rob otic- assisted LPN for tumours < 7 cm. There were no late surgical complications, no local recu rrence or impairment of renal function [114]. Benway et al reported the largest comparison of robotic partial nephrectomy (n=129) to LPN (n=118) to date, with oncological outcomes and morbidity equivalent to those of LPN. This study comb ines data f rom seve ral smaller series that have been updated. Robotic PN appears to offer the advantages of a significant reduction in intraoperative blood loss (155 vs. 196 ml, P = 0.03), WIT (19.7 vs. 28 .4 min, P < 0.0001) and hospital stay (2.4 vs. 2.7 days , P < 0.0001) [115]. Very recently, Scoll et al reported the patholog ic, perioperative , and renal functional outcomes from the first 100 robot-assisted partial nephrectomy (RAPN) operations performed at their institution during a 21-month period. They included an objective renal mass scoring system (nephrometry) to grade anatomical complexity of the renal tumours resected. Nephrectomy scores of resected lesions were low in 47.9% of patients, medium in 45.7%, and high in 6.4% of patients. Forty-seven percent of patients had tumours > 50% intraparenchymal, and 61.7% had tumours located less than 7 mm away from the renal sinus or collecting system. In 17% of patients, the tumours were touching a first-order vessel in the renal hilum. Mean WIT was 25.5 minutes. Mean change in postoperative GFR improved 6.32 mL/min/1.73 m2. Histology was RCC in 81% of tumours. Positive margin rate was 5.7%. Major and minor complication rates were 6% and 5%, repectively. There were 2 conversions to open surgery. RAPN seems to be a saf e and technically f easib le minimally inva sive approach to NSS even in more complex cases, with acceptab le patholog ic and renal f u nction ou tcomes comparable to open and laparoscopic PN [116].

Althou g h long - term ou tcome data are cu rrently lacking, early results with robotic PN demonstrate that it is clinically comparable to LPN. Large prospective , randomised stu dies are needed to validate preliminary results of robotic PN and compare with current methods.

6 . folloW - uP A fT eR P A RT IA l neP H ReCT oM Y

There is currently no consensus on follow-up strategies after surgical extirpation for patients with RCC. Recently, Kassouf et al published the Canadian g u idelines f or su rve illance af ter nephrectomy f or nonmetastatic RCC, based on pathological stage [117]. Grades of recommendations were given using the modified Oxford Centre for Evidenced-based Medicine scheme. Patients undergoing PN for pT1 tumours can be followed according to the same surveillance protocol as those undergoing RN since the local recu rrence rates in this popu lation are similar to RN (Grade B). Recommended surveillance will include medical history and physical examination, blood screen, and chest X-ray every year. Abdominal CT will be recommended at 24 and 60 months (Grade C). For patients treated with PN, abdominal CT at 3 months to evaluate the residual renal appearance and annu al ab dominal u ltrasou nd are optional (Grade D) [117].

A recently presented subtype-specific multifactorial protocol can be used to efficiently adapt postoperative imag ing to the indivi du al patient [ 118 ] .

7 . ConClusIonsI n patients w ith a cl inical T 1 renal tumour, P N prov ides eq uiv al ent l ocal tumour control as RN , w hil e minimizi ng dev el opment of new - onset CK D or w orsening of ex isting CK D ( G rade B ) . A s such, P N is the establ ished treatment for T 1a tumours ( < 4 cm) and an emerging standard treatment for T 1b tumours ( 4 to 7 cm) prov ided that the operation is technical l y feasibl e and the tumour can be entirel y and adeq uatel y remov ed ( G rade B ) . A ny tumour- free surgical margin fol l ow ing PN appears sufficient to prevent local recurrence and disease progression from RCC ( G rade B ) . In balancing the therapeutic decision between PN and RN, the individual patient’s performance status, comorb idities and renal f u nction shou ld b e caref u lly weighed.Over the years, OPN has been the reference standard nephron-sparing procedure. Today, at centres lacking advanced laparoscopic expertise, OPN remains the first nephron-sparing treatment option. However, at centres with the requisite minimally invasive expertise, LPN is now a routine procedure, with similar peri-operative and long-term outcomes as OPN, albeit with significantly decreased patient complication profile. As such, current indications for LPN have been expanded to include most renal tu mou rs hitherto reserve d f or open su rg ery . L arg er LPN series with longer follow-up, possibly in a prospective randomised f ashion, are necessary . Robotic techniques may increase penetrance of minimally invasive PN into the community. F u tu re research shou ld f ocu s on decreasing the

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technical complexity of LPN and finding newer techniqu es of eliminating or redu cing ischemia. I n the u ltimate analysi s, savi ng nephrons is the more important goal, which supersedes its technical approach, open or laparoscopic. Non-availability of minimally inva sive exp ertise mu st prompt open partial, not laparoscopic radical nephrectomy .

RefeRenCes

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2. Clark PE, Schover LR, Uzzo RG, Hafez KS, Rybicki LA, Novick AC. Quality of life and psychological adaptation af ter su rg ical treatment f or localize d renal cell carcinoma: impact of the amou nt of remaining renal tissu e. U rolog y 2001;57(2):252-256.

3. Lesage K, Joniau S, Fransis K, Van Poppel H. Comparison between open partial and radical nephrectomy for renal tu mou rs: perioperative ou tcome and health- related qu ality of life. Eur Urol 2007;51(3):614-620.

4. Uzzo RG, Novick AC. Nephron sparing surgery for renal tu mors: indications, techniqu es and ou tcomes. J U rol 2001;166(1):6-18.

5. Van Poppel H, Joniau S. How important are surgical margins in nephron-sparing surgery. Eur Urol Suppl 2007;6:533-539.

6. Lapini A, Serni S, Minervini A, Masieri L, Carini M. Prog ression and long - term su rvi va l af ter simple enu cleation f or the elective treatment of renal cell carcinoma: experience in 107 patients. J Urol 2005;174(1):57-60; discu ssion 6 0 .

7. Carini M, Minervini A, Masieri L, Lapini A, Serni S. Simple enucleation for the treatment of PT1a renal cell carcinoma: our 20-year experience. Eur Urol 2006;50(6):1263-1268; discu ssion 126 9 - 127 1.

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118. Siddiqui SA, Frank I, Cheville JC, Lohse CM, Leibovich BC, Blute ML. Postoperative surveillance for renal cell carcinoma: a multifactorial histological subtype specific protocol. BJU Int 2009;104(6):778-785.

119. Hafez KS, Fergany AF, Novick AC. Nephron sparing su rg ery f or localize d renal cell carcinoma: impact of tumor size on patient survival, tumor recurrence and TNM staging. J Urol 1999;162(6):1930-1933.

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VI. eneRG Y A B lA T IVe T H eRA P Ies foR loCA lIZ eD RCC

1 . T H eRM A l A B lA T IVe T H eRA P Ies

a) I ntroduction

Ab lation of renal tu mou rs is emerg ing as a vi ab le minimally inva sive alternative to resection f or local control of caref u lly selected tu mou rs. Potential adva ntag es of ab lative procedu res are redu ced morb idity , shorter hospitaliza tion, f aster convalescence, preservation of renal function, lower costs and the ability to treat patients who are at hig h- risk f or su rg ery [ 1] . O n the other hand, patients shou ld accept the need f or long - term radiog raphic su rve illance af ter treatment and shou ld b e clearly informed about the non-validated treatment efficacy of ab lative therapies [ 2] . Estab lished ab lative modalities inclu de cryo ab lation and radiof requ ency ablation (RFA), both of which can be performed open, laparoscopically, or percutaneously. The laparoscopic approach is pref erred in anterior tumours and when mobilization away from the adjacent organs is required to avoid damage. The percu taneou s approach is typ ically reserve d f or posterior tu mou rs and f or patients at increased risk f or su rg ery or anesthesia [ 3] . All pu b lished series u sing ab lative techniqu es are retrospective ob serva tional stu dies. D espite seve ral concerns, resu lts of thermal ab lative procedu res in small renal tu mou rs are encou rag ing . F or anatomically u ncomplicated small renal masses conve ntional su rg ery has shif ted to less inva sive ab lative modalities at some institu tions. More complex renal tumours are still treated by PN when technically feasible [4]. Careful patient selection and patient cou nseling are of paramou nt importance in the complex decision- maki ng process f or the manag ement of renal tu mou rs. B iopsies prior to therapy are strongly encouraged [5].

b) I ndications

Ab lative therapy is indicated f or the manag ement of small, incidentally f ou nd renal cortical lesions in elderly patients, patients with genetic predisposition to multiple tumours, patients with a solitary kidney, or bilateral tumours [6]. However, as more experience is gained, it may be extended to the SRM in younger patients and those with a normal contralateral kidney, a similar evolution seen with partial nephrectomy. It has to b e noted that at this time, there is no literatu re to support this. Contraindications include a limited life expectancy of < 1 year or difficulty for successful ou tcome du e to size or location of the tu mou r. I n general, tumours > 4 cm or tumours in the hilum, close to the proxi mal u reter or central collecting syst em are not typ ically recommended f or ab lation. Ab solu te contraindications are irreve rsib le coag u lopathies or seve re medical instab ility , su ch as sepsis [ 6 ] .

Thermal ablation may be best suited for high surgical risk candidates with multiple comorbidities who have small, exophytic renal tumours [7,8]. Nevertheless, it is possible that patients at high risk for surgery who u nderg o thermal ab lation su f f er complications that might necessitate surgery. There is no consensus on the maximum tumour size for ablation. Some authors find 3 cm appropriate as maximum tumour size for cryoablation [9] and RFA [10], others suggest a limitation of 3.5 cm [7] or 4 cm [8] above which su ccess rates su b stantially f all.

c) Concerns w ith the use of thermal abl ativ e therapies

A primary concern in relation to thermal ab lative therapies is the higher local recurrence rate with cryoablation and RFA when compared to surgical excision in recent meta-analyses (4.6%, 7.9%, 2.7 % and relative rates of 7.45, 18.23, and 1.0, respectively) [ 11,12] . A second concern is the controve rsy ove r the validity of the radiographic definition of postablative success. Recent data showed that 46.2% patients (6 of 13 patients) that showed no enhancement on radiographic imaging after RFA demonstrated viable tu mou r cells at a 6 - month post- ab lation b iopsy [ 13] . Another weakness is the absence of histopathologial confirmation of complete tumour destruction and neg ative su rg ical marg ins [ 7 ] . F inally , ab lative procedu res may preclu de or complicate su b sequ ent surgical salvage due to perinephric fibrosis [7]. Long-term oncologic efficacy of ablative procedures remains to be demonstrated. These concerns u nderscore the need f or meticu lou s selection of patients who today may be potential candidates for thermal ab lation.

2 . CRY oA B lA T Ion

a) I ntroduction

Cryoablation causes tumour destruction by rapid freeze and thaw cycles. A recent meta-analysis included 496 localized renal tumours that were treated with cryoablation. Mean weighted follow-up after cryoablation was 18.3 months with the procedu re selective ly perf ormed in older patients with smaller tumours (mean weighted age 65.7 years and mean weighted tumour size 2.56 cm) [12]. One purported advantage of cryoablation over RFA is the ab ility to perf orm continu ou s intraoperative u ltrasou nd monitoring of the ice b all althou g h surgeons experienced with RFA rely on thermal measures at the periphery with similar results. A recent su rve y of B andi et al to determine the cu rrent practice patterns in the u se of ab lative modalities f or the manag ement of small renal masses at 112 academic centres in the United States revealed that cryoablation (79%) was more frequently used than RFA (55%) [14] ( fi g . 1 3 , 1 4 , 1 5 ) .

1 34

b) Choice of surgical access – recent findings

At present, > 75% of the reported renal cryoablation treatments has b een applied throu g h an open or laparoscopic approach. Percu taneou s imag e-g u ided techniqu es have b een u sed mu ch less frequently [15]. Recently, Finley et al retrospectively reviewed 18 patients (19 tumours) who underwent percutaneous cryoablation and 19 patients (24 tumours) who had laparoscopic cryoablation. Percutaneous cryoablation was associated with a statistically significant decrease in operative time, hospital stay and narcotic use and a trend towards fewer complications. The overall complication rate was lower after percutaneous cryoablation (22.2% vs. 40%). The authors considered percutaneous cryo ab lation the treatment of choice f or posterior, lateral and select anterior renal lesions of 3 cm or smaller [ 16 ] . B andi et al condu cted a telephone su rve y to eva lu ate analg esic requ irements, conva lescence and patient satisf action af ter probe ablative procedures. They also found faster conva lescence f or the percu taneou s approach, but did not find a difference in the median opioid analg esic requ irement, and patient satisf action [ 17 ] . I n a recent comparative stu dy , percu taneou s renal cryo ab lation has b een deemed saf e and ef f ective and associated with lower hospital charges than laparoscopic cryoablation [18]. Recently, single-port laparoscopic and natural orifice transluminal endoscopic su rg ery approaches have also b een u sed f or renal cryo ab lation [ 19 ,20 ] . V ery recently , a prospective pilot study showed that stereotactic percu taneou s cry oab lation f or renal tu mou rs of f ers the potential f or saf e, precise cryo prob e placement [ 21] .

c) O ncol ogical outcome

Current 3-year laparoscopic cryoablation data offer

CSS rates of 98% [22,23] and 100% [24] and an OS of 89% [22]. Davol et al reported a 5-year CSS rate of 100%. The cancer-free survival rate after a single cryoablation procedure was 87.5% and improved to 97.5% after a repeat procedure [25]. Mean renal tumour size in these studies was less than 2.7 cm. Three and 5-year survival data are promising and indicate that renal cryo ab lation cou ld b e a g ood alternative in appropriately selected patients who are considered unsuitable for PN or active surveillance. I n a recent sing le- centre stu dy laparoscopic renal cryoablation (n=52) and percutaneous renal cryoablation (n=20) achieved good cancer control with minimal morbidity at a mean follow-up of 30 months in a patient cohort with numerous comorbid conditions. Percu taneou s renal cryo ab lation had a significantly higher primary treatment failure rate [5] than laparoscopic renal cryoablation [2], but re-treatment offered salvage cancer control with no significant complications. Overall CSS and cancer-free survival were 100% and 97%, respectively [26]. T a b l e 4 presents the oncolog ic ou tcome in selected studies of cryoablation [22,23,25,27-30]. Very recently , Aron et al presented long - term oncolog ical outcomes in patients treated with laparoscopic renal cryoablation by a single surgeon. They report on 80 patients with a minimum 5-year follow-up after cryoablation for a small renal mass, including 92% 5-year disease specific survival and 84% overall survival in the 55 patients with biopsy proven RCC. Of these 55 patients 11 (14%) had recurrence, including local recurrence in 5, locoregional recurrence with metastasis in 2 and distant metastasis without locoregional recurrence in 4. Median follow-up was 93 months (range 60 to 132). Mean tumour size was 2.3 cm (range 0.9 to 5.0 cm), median ASA score was 3 and mean BMI was 28 kg/m2. A disease specific survival rate of 83% at 10 years is possible. The authors recommend cryoablation as the initial

Fig. 14 : D raw ing of a cryoneedl e being inserted transcutaneousl y into a right l ow er pol e anterior renal tumor. A templ ate can be pl aced on the sk in to be used as a traj ectory guide.

Fig. 15 : D raw ing of a transabdominal l aparoscopic v iew of a cryoneedl e being percutaneousl y inserted into an ex ophytic, pol ar tumor. O ne or sev eral needles can be placed to provide sufficient ice to achiev e cel l ul ar k il l of the tumor al ong w ith a surrounding margin of parenchyma.

1 35

treatment in patients with a small renal mass who are not suitable candidates for PN [31].

d) I mpact on renal function

I n a recent retrospective analysi s of 123 patients, laparoscopic renal cryo ab lation appears to have minimal impact on renal f u nction, as measu red b y seru m creatinine and creatinine clearance leve ls. I t can b e pref ormed reg ardless of the preoperative renal function [32]. The recent study by Aron et al also shows that cryoablation has minimal impact on renal function. The eGFR before vs. after treatment was 66 vs. 59 ml per minute per 1.73 m2 [ 31] .

e) Compl ications

A multi-institutional review by Johnson et al demonstrated that cryoablation has a low complication profile when used to treat small renal tumours (13.7%; minor 12.2%, major 1.4%) [33]. The most common complication was pain or paraesthesia at the probe insertion site (7.2%).

Recently, it has been shown that laparoscopic cryoablation of larger renal masses (≥ 3 cm) may be associated with increased morbidity and therefore should be reserved for tumours with diameter < 3 cm [ 9 ] . O n the other hand, in another recent stu dy , percu taneou s cryo ab lation of anteriorly located tumours and tumours > 4 cm in diameter was found technically feasible and relatively safe when perf ormed in an exp erienced centre [ 34 ] . L imitations of these studies were the retrospective design and

the short follow-up.

More recently, Laguna et al prospectively collected mu lti- institu tional data on laparoscopic renal cryoablation with ultrathin probes in 144 patients. Perioperative neg ative ou tcomes inclu ding conversion occurred in 17% of cases. Complications according to the Clavien system occurred in 15.5% of the cases; however most of the complications were Clavien grade 1 or 2. Increasing tumour size, the presence of cardiac conditions and f emale g ender were associated with a higher risk of developing a complication. The authors confirmed the tumour size cu t- of f of 3.4 cm as an adequ ate predictor of negative outcomes. This study confirms the relative safety of laparoscopic cryoablation [35].

f) M ul tipl e renal tumours

A recent study shows that synchronous cryoablation is relatively safe and feasible for patients with mu ltiple ipsilateral renal lesions that cou ld b e ve ry challenging to address with an extirpative approach. F ive patients had ab lation of 2 renal lesions, 1 had 3 lesions, and 1 had 4 lesions. The mean greatest diameter of any single tumour was 2.0 cm (range 0.7 – 7.5 cm). Cryoablation of the 17 lesions was associated with few complications and with a median follow-up of 23,3 months (range 7-28 months), serum creatinine in most patients had not significantly changed. No tumour recurrences have b een detected on postoperative imag ing [ 36 ] .

T abl e 4 : Sel ected studies of cryoabl ation

PC: percutaneous; lap: laparoscopic; CSS: cancer-specific survival; RCC: renal cell carcinomaReprinted from Heuer R. et al. A critical analysis of the actual role of minimally invasive surgery and active surveillance for kidney cancer. Eur Urol 2010; 57(2) : 223-32 with permission of Elsevier.

StudyApproach No.

tu mou rsMedian tu mou r

size (cm)

Follow-up (mo)

CSS (%)

Tumour recu rrence af ter one ablation (%)

Gill et al (22) lap 56 (36 proven RCCs) 2.3 36 (mean) 9 8 3.6

Schwartz et al (27) lap/ open 85 (50 proven RCCs) 2.6 10 (mean) _ 2.4

Davol et al (25) lap/ open 48 (38 proven RCCs) 2.6 64 (median) 10 0 12.5, 2.5

Hegarty et al (23) lap 179 (No. of RCC not given)

2.5 36 (median) 9 8 1.7

Cestari et al (28) lap 37 (29 proven RCCs) 2.6 (mean)

20.5 (mean) _ 5.7

Silverman et al (29) PC 26 (24 proven RCCs) 2.6 14 (mean) _ 13

Aron et al (30) lap 88 (No. of RCC not given)

2.3 83 (median)(range: 60-120)

95: at 5-yr 22: at

5 years

1 36

g) I ncreased risk of rel apse after cryoabl ation – w hich l esions fail ?

A recent study analyzed 163 patients who underwent laparoscopic cryoablation (LCA) between 2001 and 2008 with at least 6 months of follow-up. Median tumour size was 2.4 cm (range 0.5-5.0). LCA showed good tumour control over a 5-year follow-up, with an acceptab le recu rrence rate. F or each 1 cm increase in tumour size there was a 4-fold increase in the prob ab ility of local recu rrence. Endophyt ic tu mou rs (in 22.8% patients) were 11 times more likely to recur in this series. Larger tumours and those with endophytic growth pattern may be at increased risk of relapse after LCA [37].

Another recent stu dy analyze d 4 7 renal lesions that underwent LCA. Median tumour size was 2.7 cm (range 1.2-5.4) and median follow-up was 13 months. Treatment failure was noted in 8 of 47 lesions (17%), 7 of which (87.5% of failed lesions) had broad-based contact with the renal sinus. Lesions with broad-based contact with the renal sinus were successfully treated in 53.3% of the time whereas lesions not in contact with the renal sinus were successfully treated in 96.9% ( P <0.01) of the time. The authors suggest that renal lesions which make broad-based contact with the renal sinus are at a significantly higher risk of failure of LCA [38].

3 . RA D IofReQ uenCY A B lA T Ion

a) I ntroduction

RFA causes tumour coagulation by converting the radiofrequency waves to heat, resulting in thermal tissue damage [1]. RFA is one of the most recently developed treatment modalities for localized RCC and a standard techniqu e is still lacki ng in the cu rrent literatu re. A recent meta- analysi s inclu ded 607 localized renal tumours that were treated with RFA. Mean weighted follow-up after RFA was 16.4 months. RFA was selectively performed in older patients with smaller tumours (mean weighted age 67.2 years and mean weighted tumour size 2.69 cm) and is considered a viable treatment option [12]. Patient demographics and selection criteria for RFA are similar as f or cryo ab lation treatment, mainly f or older and high surgical risk patients and tumours with diameter < 3 cm. Gervais et al treated 100 tumours in 85 patients by percutaneous RFA and showed that small-sized tumours (< 3 cm) and exophytic tumours were predictive factors for complete coagulation [10]. A study including 16 patients (20 tumours) with a minimum of 4 years follow-up revealed that RFA treatment of exophytic RCC (< 5 cm) is effective in destroyi ng the tu mou r and comparab le to su rg ical ex cision at 4 ye ars [ 39 ] . A meta- analysi s b y K u nkl e and Uzzo demonstrated that patients treated with RFA may require re-ablation more frequently than those treated with cryoablation (8.5% vs. 1.3%, respectively) [15]. Compared with cryoablation, a

large proportion of tumours managed with RFA had unknown or indeterminate pathology (42.8% vs. 17.7%) [12] which could lead to an overestimation of the actuarial specific CSS rates for RCC. Both phenomena may b e attrib u tab le to the f act that the majority of RFA cases are performed percutaneously. B iopsy is not consistently perf ormed and re- ab lation rates are significantly higher when a percutaneous approach is used. Re-ablation rates seem to correlate with surgeon specialty (interventional radiologist or urologist) [40]. Difficulty of reoperation after ablation also depends on the location of the prior ab lation.

b) Choice of surgical access – nav igational tool s and real - time monitoring systems for RFARFA can be performed percutaneously or laparoscopically under ultrasound, CT- or MRI- guidance. Currently, about 94% of the reported renal RFA treatments have been performed through the percutaneous approach [15], mostly under CT-scan guidance [41]. Only a few centres have used the laparoscopic approach for RFA ablation. To date, no randomised controlled trials have b een condu cted to compare laparoscopic and percutaneous RFA or to compare RFA and cryoablation. Data in the literature reve aled that althou g h the percu taneou s approach is less invasive, RFA and cryoablation re-ablation rates are significantly higher when a percutaneous approach is used and seemed to correlate with su rg eon speciality (interventional radiologist or urologist) [40]. Recently, sophisticated navigational tools and real-time monitoring systems for RFA are being investigated. Carey and Leveillee reported the u se of non- condu cting temperatu re prob es, independent of the RFA electrode, in order to achieve real- time temperatu re monitoring of the ab lation zone. Ablations were continued until the peripheral and deep temperature probes registered 60 °C for at least 15 seconds. All 37 renal tumours between 3 and 5 cm in 36 patients could be successfully ablated in one session. There were two radiographic f ailu res at 9 and 30 months that requ ired second treatment (95% radiographic success rate). This techniqu e redu ces the need f or retreatment sessions, decreases the incidence of ove rtreatment of the normal parenchym a and preve nts collateral damag e of the adjacent organs [42]. Moreover, a recent study has demonstrated that RFA with peripheral fiberoptic real- time temperatu re monitoring is ab le to improve the su ccess rate f or endophyt ic or centrally located renal tumours. In total, 37 of 41 (90.2%) endophytic, hilar, or central tumours were treated successfully in one session [ 4 3] . U ki mu ra et al describ ed the use of real-time virtual ultrasonography (RVS) as a new and promising alternative imaging method for percutaneous RFA of solid RCC. All 10 patients with 13 RCC were treated successfully in one session and none of them had a local tu mou r recu rrence during the follow-up period [44].

1 37

c) O ncol ogical outcome

T a b l e 5 presents the oncolog ic ou tcome in selected studies of RFA [23,39,45,46]. Af ter laparoscopic or percutaneous RFA with a mean follow-up period of 25 months recurrence-free survival, CSS and OS were 96.8%, 98.5%, and 92.3% (68% were RCC). Mean renal tumour size was 2.4 cm [46]. L ong - term data after 34 percutaneous RFA procedures for small renal masses (mean size 2.0 cm) were recently reported. The overall recurrence-free survival was 90.3% at a mean follow-up of 61.6 months and 79.9% for pathologically confirmed RCC at a mean follow-up of 57.4 months [47]. A recent multi-institutional study that u sed g eneral anesthesia- assisted, contrast-enhanced CT-guided percutaneous RFA to treat 163 masses in 151 patients demonstrated excellent intermediate- term ou tcomes and a hig h initial ablation success rate. However, endophytic and interpolar lesions were at higher risk for recurrence. The median follow-up was 18 months (range, 1.5-7 0 ] . O ve rall 1- and 3- ye ar recu rrence- f ree su rvi va l was 97% and 92%, respectively [48]. Further studies of large numbers of patients with long-term follow-up are needed.

d) T umour size and success of RFA treatment

Z ag oria et al demonstrated in a larg e series of percutaneous RFA a significant correlation between the size of the renal mass and success of RFA treatment. They reported that CT-guided percutaneous RFA can accurately destroy RCCs smaller than 3.7 cm. Of the 125 treated and biopsy-proven RCC’s in 104 patients, 116 (93%) were completely ablated (109 after one session, 7 of the 16 failures after a second session). RFA achieved complete ablation after one session in all 95 RCCs smaller than 3.7 cm and in only 14/30 RCCs larger than 3.7 cm [45].

e) I mpact on renal function

Several authors have sought to better define the renal impact of RFA on renal function. Lucas et al concluded that patients with small renal masses < 4 cm undergoing RN or PN were 34.3 and 10.9 times more like ly , respective ly , to deve lop stag e 3 CKD compared with those who were treated with RFA [49]. Two studies focused on RFA for solitary ki dneys. I n the small stu dy b y Jacob sohn et al creatinine clearance declined by 13.3% one week after ablation and by 9.1% at a mean follow-up of 15.3 months [50]. In the study by Raman et al GFR declined by 7.5%, 6 weeks after ablation and remained stable up to 18 months and later [51]. In a more recent study Raman et al analyzed the outcomes from 89 patients with renal masses in a solitary kidney including 47 RFAs and 42 OPNs at a median follow-up of 18.1 and 30.0 months, respectively (P = 0.02). Compared to RFA, patients treated with OPN using cold ischemia had a greater decline in GFR at all times evaluated, including soon after the procedure (15.8% vs. 7.1%), 12 months after surgery (24.5% vs. 10.4%) and at the last follow-up (28.6% vs. 11.4%; all P < 0.001). Median age (65.9 vs. 59.6 years, P = 0.03) and ASA score (3.0 vs. 2.0, P = 0.01) were both higher in patients treated with RFA. The median tumour size (3.9 vs. 2.8 cm, P = 0.001) was greater for tumours treated by OPN while the median preoperative GFR was lower in te RFA group (46.5 vs. 55.9 ml/min/1.73 m2 for OPN, P = 0.04). The authors concluded that RFA might be an attractive option f or manag ing tu mou rs in a solitary kidney at risk of declining function [52]. In a recent retrospective analysis of 63 healthy patients with small renal cortical tumours, RFA appears to have minimal impact on renal f u nction, as measu red b y changes in GFR. The median GFR before and after ablation was 76.3 and 74.3 mL/min/m2 [53].

T abl e 5 : Sel ected studies of RFAApproach No. tumours Median

tu mou r size (cm)

Follow-up (mo)

CSS (%)

Tumour recurrence after one ab lation

(%)

Zagoria et al (45) PC 125 (125 RCCs) 2.7 13.8 (mean)

9 8 13*

McDougal et al (39)

PC 20 (all RCCs) 3.2 55.2 (median)

9 4 5

Hegarty et al (23) PC 82 (No. of RCC not given)

2.5 12 (median) 10 0 11.1

Park et al (46) PC/lap 94 (65 RCCs) 2.4 (mean) 25 (mean)

98.53.2

CSS: cancer-specific survival; RCC: renal cell carcinoma; PC: percutaneous; lap: laparoscopic. * All tumours recurring were > 3.7 cm.Reprinted from Heuer R. et al. A critical analysis of the actual role of minimally invasive surgery and active surveillance for kidney cancer. Eur Urol 2010; 57(2) : 223-32 with permission of Elsevier.

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f) Compl icationsA multi-institutional review of Johnson et al demonstrated that RFA has a low complication profile when used to treat small renal tumours (8.3%; minor 6.0%, major 2.2%) [33]. The most common complication was pain or paraesthesia at the prob e insertion site (3.0%). Two recent RFA studies failed to find a significant association between tumour size and likelihood of complications [45,54]. Veltri et al found that exophytic growth of the tumour is associated with a decreased risk of complications (P < 0.0380) [54]. Weizer et al recommend restricting percutaneous RFA to exophytic, posterior and polar lesions or tumours < 3 cm in diameter. Their experience with percutaneous RFA in 24 patients inclu ding 32 tu mou rs reve aled that thermal complications might be more likely with anteriorly or centrally located tu mou rs, mu ltiple tu mou rs treated in the same setting and in patients with prior PN [55]. In a recent review paper Park et al discuss the most common major and minor complications resulting from image-guided RFA of RCC with an emphasis on cau ses, possib le preve ntion strateg ies and imag ing features. Similar to cryotherapy, major complications include bowel injury, ureteral injury, massive bleeding and residual or recurrent tumour. Minor complications inclu de pain, hematoma, hematu ria, neuromuscular injury, pneumothorax, infarction and inammatory tract mass. The most common cau se of complications is the close proxi mity of the tu mou r to neig hb ou ring organs (bowel, ureter). Non-inva sive methods to preve nt these ab lation- related complications inclu de chang ing the patient’ s position and using the RF electrode as a lever [56]. Invasive methods to avoid bowel injury involve instillation of uid or CO2 between the tumour and the bowel [57-59]. After introduction of a 20- to 22-gauge fine needle under imaging guidance, dextrose in water is instilled into the space between the tumour and the adjacent bowel to increase the distance between the organs and reduce thermal conduction [57]. Dextrose in water is preferred for hydrodisplacement to normal saline b ecau se of its non- ionic and iso- osmolar nature [60]. In addition, collecting system and bowel injuries associated with RFA or cryoablation can be av oided b y b etter patient selection b ased on the patient and tumour characteristics. Care must be take n to avo id damag e to the collecting syst em that may resu lt in loss of the ki dney .

g) Comparison betw een techniq ues

There are currently no prospective studies comparing cryoablation to RFA or to other forms of nephron-sparing su rg ery . L ong - term resu lts comparing conventional OPN to cryoablation are expected.

h) Comparison of l aparoscopic P N w ith l aparoscopic renal cryoabl ation

D esai et al reported that compared to cryo ab lation,

LPN was associated with greater blood loss and significantly higher incidence of delayed complications after hospital discharge. The overall complication rate (intraoperative, postoperative and late complications) was 5-fold higher (32% vs. 6.7%) with LPN compared with cryoablation. Both groups were comparable with regards to operative time, hospital stay , conva lescence and postoperative renal function. Local recurrence was detected over a mean follow-up time of 5.8 months (0.6%) after LPN and 24.6 months (3% ) after cryoablation [ 6 1] . A more recent matched- cohort comparison between LPN and laparoscopic cryoablation in elderly patients showed that LPN had a higher mean estimated b lood loss, a long er operative time and higher relative risk of open conversion. However in this small retrospective eva lu ation of laparoscopic cryoablation and LPN, the overall clinical outcome was similar in terms of morbidity, length of hospital stay and chang es in creatinine and hematocrit after surgery. No recurrences were observed in either group, with a similar follow-up of 9.8 and 11.9 months, respective ly [ 6 2] .

Several groups have shown the ultimate 3-year and 5-year CSS after laparoscopic cryoablation to be 98% to 100% [22,24-26,28,63] which is equivalent to the 5-year CSS (100%) after LPN of small clinically localized renal masses presented by Lane and Gill [ 6 4 ] .

i) Comparison of cryoabl ation and RFA

Currently, CSS rates of cryoablation [22,24,25,28] and RFA [39,45,46] are relatively similar (97 - 98%, respectively) [41]. A recent meta-analysis by Kunkle and U zzo compared the ou tcome of cryo ab lation (n=600; 65% laparoscopically) and RFA (n=775; 94% percutaneously). Cryoablation was associated with a lower re-ablation rate (1.3% vs. 8.5%), lower local tumour progression rate (5.2% vs. 12.9%) and less metastases (1.0% vs. 2.5%, P = 0.06) than RFA. Pretreatment biopsy was performed more frequently in the cryoablation group (82.3% vs. 62.2%) [15]. In another meta- analysi s b y K u nkl e et al cryo ab lation was also associated with lower rates of local recurrence and metastatic progression (4.6% vs. 11.7% and 1.2% vs. 2.3%) compared with RFA [12]. The meta-analyses were awed in that they consisted of retrospective series each with their own selection biases [65,66]. Furthermore, RFA was primarily performed percutaneously (compared to laparoscopic cryoablation) where incomplete treatment and re-ab lation is more commonly acceptab le since re-treatment is easier to perf orm. H eg arty et al f ou nd in their retrospective comparative analysis a CSS of 98% after 3-years of follow-up in the laparoscopic cryoablation group (n=164) and 100% after 1-year follow-up in the percutaneous RFA group (n=82). The rate of radiologic relapse of tumour was 1.8% in the cryoablation group versus 11% in the RFA

1 39

group. Overall complication rates were low for both groups [23]. The problem in comparing the efficacy of ablative techniques is that especially studies with percu taneou s approach tend to g ive ove rall resu lts in terms of CSS without stating the number of repeat procedures needed. Primary efficacy is an important endpoint. I n a recent meta- analysi s b y H u i et al, the primary efficacy rate was 87% after a percutaneous approach and 94% after an open or laparoscopic approach (p < 0.05) with a mean follow-up of only 15 ± 8 months. The secondary efficacy (after repeated treatments) in the percutaneous treatment group (92%) was not significantly different from that in the laparoscopic or open treatment group. The percutaneous approach was safer than the surgical approach (complication rate 3% vs. 7%) and was equally effective but more than one procedure was requ ired to treat the tu mou r completely [ 6 7 ] . I n a multi-institutional review, Johnson et al analyzed complications associated with cryoablation and RFA performed laparoscopically or percutaneously. Complication rates for cryoablation and RFA were 13.7%, (minor 12.2%, and major 1.4%) and 8.3% (minor 6%, major 2.2%) respectively. The most common complication was pain or paresthesia at the probe insertion site. Complications can be attributed to the approach as well as to the ablation alone [33]. Several studies have demonstrated minimal impact on renal function following cryoablation [22,32,68] or RFA [49-51,53]. At this time, there is insufficient long-term data available to show efficacy of ablative therapies to make comparisons between the ablative techniqu es.

j ) Comparison betw een P N and RFA

Stern et al recently reported in a retrospective study that at intermediate follow-up (mean 30 months) RFA (14 laparoscopic/26 percutaneous) for patients with cT1a renal tumours has comparable intermediate oncological outcome to PN (30 open/7 laparoscopic). The 3-year recurrence-free survival rate for all patients was 93.4% and 95.8% for the RFA and PN groups, respectively [69]. However, longer term data are needed.

k ) Fol l ow - up after thermal abl ativ e therapies

Because follow-up after ablative therapy lacks histopathological confirmation of tumour destruction, some centres pref er to add post- ab lation b iopsies to radiographic imaging [22]. Current imaging techniqu es are limited to monitor recu rrences and post-ablation biopsies are encouraged when recu rrence or incomplete ab lation is su spected or as routine in all cases [13]. Existing follow-up criteria are not well-defined and should be more precise and standardize d b ased on radiolog ical and histolog ical f actors. I n radiolog ical terms, a su ccessf u lly ab lated lesion shows absence of enhancement after contrast injection and shrinkage within time. A blanco CT or

MRI have to be systematically performed before contrast injection to rule out calcifications secondary to small hemorrhag es du ring the procedu re. Af ter cryoablation a CT scan tiny enhancement rim may show up in up to 20% of the cryolesions. This rim prog ressive ly disappears du ring the 9 months following cryoablation [70]. Weight et al tried to determine a correlation between imaging findings and histopatholog y af ter prob e ab lative procedu res. They demonstrated a poor correlation between post-RFA radiographic imaging and post-RFA biopsy results and an excellent correlation between the radiographic findings after cryoablation and su b sequ ent percu taneou s b iopsy of the treated lesions. In this study, 6 of 13 patients (46.2%) that showed no enhancement on radiographic imaging after RFA demonstrated viable tumour cells at a 6-month post-RFA biopsy. The 6-month post-ablation biopsy reduced the success rate of RFA from 85% to 64.8% [13]. Raman et al recently su g g ested that presence of tu mou r architectu re on early (< 12 months) biopsy following RFA may be unreliable. They showed that no viable tumour was present in lesions that were biopsied more than 1 year following RFA [71]. A multi-institutional stu dy reve aled that in most cases initial treatment failure following ablation was detected within the first 3 months. Results support a minimum of 3 to 4 abdominal imaging studies in the first year after ablative therapy at months 1, 3, 6 (optional) and 12 [2]. There is no consensus on the optimal follow-up of thermal ablative therapies. Some experts find that this statement does only pertain to RFA because the re- ab lation rate is mu ch hig her and does not pertain to cryo ab lation. A recent laparoscopic cryo ab lation study demonstrated that of the 5 (15.6%) ablation sites that showed enhancement at 3 months three persisted b y 6 months, b u t only one displaye d enhancement by 9 months. This patient with persisted enhancement by 9 months underwent PN that demonstrated no recurrent cancer [72]. Currently, computed tomography (CT) and magnetic resonance imaging (MRI) are usually performed to evaluate residual or recurrent disease after RFA and cryo ab lation of a renal tu mou r [ 7 3] .

4 . noVel T ReA T M enT M oD A lIT Ies of RenA l M A sses

O ther minimally inva sive techniqu es su ch as H ig h Intensity Focused Ultrasound (HIFU), Radiosurgery, Microwave Thermotherapy (MWT), Laser Interstitial Thermal Therapy (LITT), and Pulsed Cavitational Ultrasound (PCU) should at this time be considered experimental. Clinical series are small and no long-term follow-up data have been reported.

a) H igh I ntensity Focused U l trasound

H I F U is attractive as non- inva sive therapy of malig nancies, b ecau se there is no need to pu nctu re

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the tu mou r and theref ore no risk of hemorrhag e or tumour spillage [74]. However, limited clinical data on extracorporeal HIFU of renal tumours show insufficient results [75-78]. The technique is found to be well tolerated with no serious perioperative complications b u t the eradication of the tu mou r is inadequ ate, mainly du e to acou stic complexi ty of interve ning stru ctu res and the respiratory move ments of the ki dney [ 7 9 ] . An additional disadva ntag e is the inab ility to monitor treatment prog ression in real time [ 7 9 ] .

Problems with respiratory movements of the kidney and acou stical interphases of the ab dominal/thoracic wall and tissue inhomogeneities within the kidney are avoided when the transducer is brought directly to the targ et b y laparoscopic H I F U [ 7 4 ,7 9 ] . A phase I stu dy b y K ling ler et al u sing laparoscopic H I F U ab lated 10 renal tu mou rs less than 3 cm in diameter. No HIFU-specific complications were ob serve d in the stu dy . L aparoscopic H I F U is a nove l approach that may achieve a g reater rate of tu mou r destruction but further studies to refine the technique are needed [80]. To date, HIFU has to be considered experimental. Honeck et al, recently showed in an ex vi v o model of the isolated perf u sed porcine ki dney that magnetic resonance imaging (MRI) is potentially a g ood diag nostic tool f or vi su alizi ng and monitoring the ef f ects of H I F U ab lation of renal masses. B ef ore this imag ing modality can b e u sed u nder clinical conditions, f u rther technical deve lopment is essential, especially with regard to reducing the measuring times [81]. A recent 3-year follow-up study evaluated the safety, feasibility and efficacy of HIFU in 17 patients with radiologically suspicious renal tumours (mean tumour size 2.5 cm). Renal HIFU achieved stable lesions in two-thirds of patients, with minimal morbidity, and might be appropriate in selected cases [ 8 2] .

b) Radiosurgery ( Cyberk nife)

The Cyberknife is a frameless image-guided radiosurgery device. The 2 main elements are the radiation produ ced b y a small linear accelerator and a robotic arm that allows the energy to be directed at any part of the body from any direction. The Cyberknife divides the high-dose radiation necessary to ab late the lesion completely into u p to 120 0 separate radiation beams. The individual dose of each radiation b eam indu ces ve ry little ef f ect on the surrounding tissue. However, high radiation doses are delive red to the f ocal point, destroyi ng tu mou r tissu e and minimizi ng collateral damag e [ 8 3] .

Ponsky et al reported a phase I stu dy invo lvi ng 3 patients with a renal tumour of ≤ 4 cm who underwent radiosurgery followed by a PN after 8 weeks. The patients were treated with a radiation dose of 4 Gy per fraction for 4 fractions. No acute toxicities and no changes in renal function were noted, with a mean

follow-up of 12 months. One patient had a necrotic tumour while two others had pathologic evidence of viable RCC [84]. The results were promising considering that in animal models, ablation was not observed until a target of 40 Gy was obtained [83]. Preclinical data showed that radiosurgery (single doses of 24-40 Gy) for predetermined lesions in 16 porcine kidneys with sequential histological evaluations at 4, 6 and 8 weeks achieved complete fibrosis after 8 weeks [83].

I n a prospective stu dy inclu ding 30 patients, the safety and local efficacy of radiosurgery in metastatic or inoperable primary RCC was evaluated. In total, 82 lesions were treated with high-dose fraction stereotactic radiotherapy . D ose/ f ractionation schedu les va ried depending on targ et location and size (8 Gy x 4, 10 Gy x 4, 15 Gy x 2 or 14 Gy x 3) [85]. Radiosurgery is a promising new technology as it resulted in a high local control rate with generally low toxicity. However, radiosurgery is currently an experimental modality and the first human studies in patients with localized RCC are underway. At present, the role of radiosu rg ery f or the manag ement of renal tu mou rs is u nclear and f u rther stu dies are needed to address its oncolog ical and f u nctional resu lts.

c) O ther modal ities

1. M I CRO W A V E T H E RM O T H E RA P Y

In MWT, microwave energy is delivered through an antenna inserted directly into the lesion cau sing an electromagnetic field, which leads to ion oscillation and increase in kinetic energy which is converted to heat, resulting in coagulative necrosis. MWT may generate heat 100 times faster than RFA and may b e less su sceptib le to the heat sink phenomenon. MWT did not appear to be effective for destruction of experimental VX-2 renal tumours in rabbits [8]. MWT followed by nephrectomy has been evaluated in a single phase I study in which it could safely and qu ickl y g enerate larg e ab lation lesions of renal neoplasms. No skip areas were observed within the ab lation zo nes [ 8 6 ] . I n a recent pilot stu dy of 12 patients with pathologically proven RCC (1.3 to 3.8 cm in diameter) ultrasound guided percutaneous microwave ablation appears to be safe and effective. Complete necrosis was induced in a single session in all tumours. No complications were observed, perhaps in part du e to the excl u sion of tu mou rs adjacent to the bowel and ureter. No residual tumour or recurrence was observed at a median follow-up of 11 months (range 4 to 20). The ablation zone was well defined on contrast enhanced CT and contrast enhanced ultrasound, and it gradually shrank with time. Additional experience with this technique should be required before its widespread clinical use [ 8 7 ] .

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2 . L A SE R I N T E RST I T I A L T H E RM A L T H E RA P Y

LITT also known as Laser Thermal Ablation (LTA) delive rs energ y throu g h insertion of laser fibres into the tumour, followed by coagulative necrosis by raising the tissue temperatures to > 55°C (1,88]. I n a pilot stu dy of 9 patients u nsu itab le f or su rg ery , MRI-guided LTA of renal tumours was proven safe, feasible (being well tolerated by the patient) and significantly reduced the mean percentage enhancement (% of approximate tumour volume that is viable) from 73.7% before to 29.5% after ablation. However, the clinical implications of this finding are not clear [ 8 9 ,9 0 ] .

3 . P U L SE D CA V I T A T I O N A L U L T RA SO U N D

A limitation of thermal ab lation is that the thermal zo ne of destru ction cannot b e precisely predicted du e to su b tile dif f erences in tissu e character, tissu e heterog eneity and va riations in b lood perf u sion [91]. The transcutaneous, nonthermal, mechanical effects of US waves (cavitation) were thought to have an adva ntag e ove r temperatu re- b ased ab lation systems. PCU utilizes cavitational effects to destroy the tumour by varying acoustic parameters. The delive ry of transcu taneou s hig h intensity u ltrasou nd to indu ce cavi tational tissu e ab lation is termed histotripsy. Cavitation is a phenomenon by which alternating zo nes of compression and raref action induce microbubble formation, which leads to subcellular tissue fragmentation [91]. With this approach no thermal collateral damag e is cau sed to adjacent tissues, structures or collecting system. Data about PCU are limited to two preclinal studies invo lvi ng an i n vi tr o porcine model [ 9 1] and an i n vi vo stu dy in rab b its [ 9 2] . Additional research is needed to optimize the parameters f or in vi vo cavi tational tissu e ab lation, inclu ding the impact of tissu e perf u sion and to elucidate any relationship between metastasis and histotripsy treatment [ 9 1] .

5 . ConClusIons

Cryosurgery and RFA by open, laparoscopic or percu taneou s approaches are promising minimally inva sive nephron- sparing treatment options f or localized RCC for most small (mainly < 3.0 cm), low grade renal tumours in patients who are at high surgical risk. However, no randomised comparisons have been performed between the outcome of ablative techniques and RN or PN. Cryoablation and RFA are associated with acceptable short and intermediate survival results and low morbidity. However, long-term oncological outcome remains to be established. Retrospective, non-controlled stu dies su g g est that cryo ab lation may b e associated with a lower re-ablation rate and local recurrence rate compared with RFA. However, variables as surgical approach (laparoscopic versus percutaneous), renal parenchyma reserve, anesthesia (general versus sedation) and physician performing the procedure

(surgeon versus radiologist) can strongly inuence these rates. B oth ab lative procedu res appear to have minimal impact on renal f u nction. Perf ect assessment of the ab lated tu mou rs at postprocedu ral imag ing is cru cial f or eva lu ating the adequ acy of treatment and guiding further management. There is an urgent need f or pre- and postoperative alg orithms, strong , u nif orm and exp licit indications and a standard consensu s f or follow-up schedules in the use of ablative therapies, which is nonexistent at this moment.

At this time, there is insufficient long-term data av ail abl e to mak e adeq uate comparisons betw een abl ativ e techniq ues. T herefore abl ativ e therapies shoul d be reserv ed for careful l y sel ected high surgical risk patients w ith SRM s < 4 cm ( G rade C) . The alternative option in many patients is active surveillance, which at the present seems to have a similar outcome (with all limitations of poor data) at clearly lower invasiveness and complications. This is also qu ite apparent in the meta- analysi s u sed f or the 2008 AUA Guidelines on SRMs [93,94].

To date, the use of other minimally invasive techniques, such as HIFU, radiosurgery, microwave thermotherapy , laser interstitial thermal therapy and pu lsed cavi tational u ltrasou nd shou ld b e considered exp erimental. F u rther stu dies are requ ired to determine their oncolog ical and f u nctional role in the management of localized RCC.

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66. Cadeddu JA, Raman JD. Renal tumor ablation is a function of patient selection and techniqu e- - not the ab lation technology. Cancer 2008;113(10):2623-2626.

67. Hui GC, Tuncali K, Tatli S, Morrison PR, Silverman SG. Comparison of percutaneous and surgical approaches to renal tu mor ab lation: metaanalysi s of ef f ective ness and complication rates. J Vasc Interv Radiol 2008;19(9):1311-1320 .

68. Shingleton WB, Sewell PE, Jr. Cryoablation of renal tumours in patients with solitary kidneys. BJU Int 2003;92(3):237-239.

69. Stern JM, Svatek R, Park S, Hermann M, Lotan Y, Sagalowsky AI, Cadeddu JA. Intermediate comparison of partial nephrectomy and radiof requ ency ab lation f or clinical T1a renal tumours. BJU Int 2007;100(2):287-290.

70. Beemster P, Phoa S, Wijkstra H, de la Rosette J, Laguna P. Follow-up of renal masses after cryosurgery using computed tomography; enhancement patterns and cryolesion size. BJU Int 2008;101(10):1237-1242.

71. Raman JD, Stern JM, Zeltser I, Kabbani W, Cadeddu JA. Ab sence of vi ab le renal carcinoma in b iopsies perf ormed more than 1 year following radio frequency ablation confirms reliability of axial imaging. J Urol 2008;179(6):2142-2145.

72. Stein AJ, Mayes JM, Mouraviev V, Chen VH, Nelson RC, Polascik TJ. Persistent contrast enhancement several months af ter laparoscopic cryo ab lation of the small renal mass may not indicate recu rrent tu mor. J Endou rol 2008;22(11):2433-2439.

73. Kawamoto S, Solomon SB, Bluemke DA, Fishman EK. Computed tomography and magnetic resonance imaging appearance of renal neoplasms af ter radiof requ ency ablation and cryoablation. Semin Ultrasound CT MR 2009;30(2):67-77.

74. Marberger M. Ablation of renal tumours with extracorporeal

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high-intensity focused ultrasound. BJU Int 2007;99(5 Pt B):1273-1276.

75. Kohrmann KU, Michel MS, Gaa J, Marlinghaus E, Alken P. H ig h intensity f ocu sed u ltrasou nd as noninva sive therapy for multilocal renal cell carcinoma: case study and review of the literature. J Urol 2002;167(6):2397-2403.

76. Marberger M, Schatzl G, Cranston D, Kennedy JE. Extracorporeal ablation of renal tumours with high-intensity focused ultrasound. BJU Int 2005;95 Suppl 2:52-55.

77. Illing RO, Kennedy JE, Wu F, ter Haar GR, Protheroe AS, Friend PJ, Gleeson FV, Cranston DW, Phillips RR, Middleton MR. The safety and feasibility of extracorporeal high-intensity focused ultrasound (HIFU) for the treatment of liver and kidney tumours in a Western population. Br J Cancer 2005;93(8):890-895.

78. Hacker A, Michel MS, Marlinghaus E, Kohrmann KU, Alken P. Ext racorporeally indu ced ab lation of renal tissu e b y high-intensity focused ultrasound. BJU Int 2006;97(4):779-785.

79. Klatte T, Marberger M. High-intensity focused ultrasound f or the treatment of renal masses: cu rrent statu s and future potential. Curr Opin Urol 2009;19(2):188-191.

80. Klingler HC, Susani M, Seip R, Mauermann J, Sanghvi N, Marberger MJ. A novel approach to energy ablative therapy of small renal tu mou rs: laparoscopic hig h- intensity f ocu sed ultrasound. Eur Urol 2008;53(4):810-816; discussion 817-8 18 .

81. Honeck P, Peters K, Wendt-Nordahl G, Bolenz C, Alken P, Michel MS, Jenne JW, Hacker A. Magnetic resonance imag ing as a techniqu e f or assessing noninva sive tissu e ab lation u sing hig h- intensity u ltrasou nd: an exp erimental study. J Endourol 2009;23(1):161-168.

82. Ritchie RW, Leslie T, Phillips R, Wu F, Illing R, Ter Haar G, Protheroe A, Cranston D. Extracorporeal high intensity focused ultrasound for renal tumours: a 3-year follow-up. B JU I nt 20 10 .

83. Ponsky LE, Crownover RL, Rosen MJ, Rodebaugh RF, Castilla EA, Brainard J, Cherullo EE, Novick AC. Initial evaluation of Cyberknife technology for extracorporeal renal tissue ablation. Urology 2003;61(3):498-501.

84. Ponsky LE, Mahadevan A, Gill IS, Djemil T, Novick AC. Renal radiosurgery: initial clinical experience with histological evaluation. Surg Innov 2007;14(4):265-269.

85. Svedman C, Sandstrom P, Pisa P, Blomgren H, Lax I, Kalkner KM, Nilsson S, Wersall P. A prospective Phase I I trial of u sing ext racranial stereotactic radiotherapy in primary and metastatic renal cell carcinoma. Acta O ncol 2006;45(7):870-875.

86. Clark PE, Woodruff RD, Zagoria RJ, Hall MC. Microwave ab lation of renal parenchym al tu mors b ef ore nephrectomy: phase I study. AJR Am J Roentgenol 2007;188(5):1212-1214 .

87. Liang P, Wang Y, Zhang D, Yu X, Gao Y, Ni X. Ultrasound guided percutaneous microwave ablation for small renal cancer: initial experience. J Urol 2008;180(3):844-848; discu ssion 8 4 8 .

88. Ankem MK, Nakada SY. Needle-ablative nephron-sparing surgery. BJU Int 2005;95 Suppl 2:46-51.

89. Dick EA, Joarder R, De Jode MG, Wragg P, Vale JA, Gedroyc WM. Magnetic resonance imaging-guided laser thermal ablation of renal tumours. BJU Int 2002;90(9):814-8 22.

90. Deane LA, Clayman RV. Review of minimally invasive renal therapies: Needle-based and extracorporeal. Urology 2006;68(1 Suppl):26-37.

91. Kieran K, Hall TL, Parsons JE, Wolf JS, Jr., Fowlkes JB, Cain CA, Roberts WW. Refining histotripsy: defining the

parameter space f or the creation of nonthermal lesions with high intensity, pulsed focused ultrasound of the in vitro kidney. J Urol 2007;178(2):672-676.

92. Roberts WW, Hall TL, Ives K, Wolf JS, Jr., Fowlkes JB, Cain CA. Pulsed cavitational ultrasound: a noninvasive technology for controlled tissue ablation (histotripsy) in the rabbit kidney. J Urol 2006;175(2):734-738.

93. Campbell SC, Novick AC, Belldegrun A, Blute ML, Chow GK, Derweesh IH, Faraday MM, Kaouk JH, Leveillee RJ, Matin SF, Russo P, Uzzo RG. Guideline for management of the clinical T1 renal mass. J Urol 2009;182(4):1271-127 9 .

94. Novick AC, Campbell SC, Belldegrun A, Blute ML, Chow GK, Derweesh IH, Kaouk J, Leveillee RJ, Matin SF, Russo P, Uzzo RG. Guideline for management of the clinical stag e 1 renal mass. American U rolog ical Association 2008;http://www.auanet.org/content/guidelines-and-qu ality - care/ clinical- g u idelines/ main- reports/ renalmass0 9 .pdf .

VII. ConClusIons - lIM IT A T Ions of T H e lIT eRA T uRe

The recent meta-analysis of Kunkle et al including 9 9 stu dies representing 6 4 7 1 tu mou rs illu strates that PN, cryoablation, RFA and active surveillance are vi ab le approaches to the manag ement of SRMs. Although long-term data have demonstrated excellent outcomes for PN, extended oncological efficacy remains to be established for thermal ablation and active surveillance. Compared with PN, current data demonstrate a significantly hig her incidence of local tu mou r recu rrence following cryoablation and RFA with cryoablation predominantly perf ormed laparoscopically resu lting in less local tumour progression than RFA generally performed percutaneously (RR 1.00, 7.45, 18.23, respectively). However, no statistical differences were detected in progression to metastatic RCC regardless of treatment option (PN, cryoablation or RFA) or absence of treatment (active surveillance) (RR 1.00, 1.24, 3.21, 0.11, respectively). These data raises concern ove r a possib le ove rtreatment bias for SRMs [1]. Delayed intervention for SRMs appears to b e a saf e treatment strateg y in selected patients [2]. Currently, no hard recommendations can b e made ag ainst a g ive n treatment modality f or localized, SRMs because of the limitations of the cu rrent stu dies.

We identified the most important limitations of the exi sting literatu re on manag ement of localize d renal cell carcinoma. The main limitation seen across all treatment options was the lack of well-designed prospective or randomised studies. Selection bias (i.e. differences in patient age, tumour size and follow-up durations) is clear across interventions. For example active su rve illance and ab lative therapies g enerally have b een perf ormed selective ly in older patients with smaller tumours and favourable radiographic findings. Other weaknesses include the absence of

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transparent selection criteria, standardize d technical application of the interventions, clear definitions of su ccess and standardize d methodical reporting of complications and other outcomes. Renal function was usually reported as pre- and posttreatment creatinine levels or as estimated glomerular filtration rate (eGFR) or creatinine clearance measurements f rom 24 - hou r u rine collection. F u rthermore, the lack of pathologic data in ablative and expectantly followed series remains a confounding factor when attempting to compare outcomes for renal lesions treated with other interventions. The category of tumours with unknown pathology certainly includes a number of b enig n tu mou rs and thu s, measu res of treatment efficacy may be overestimated. Limited clinical follow-up of some studies may make their oncologic outcomes subject to follow-up bias. For example, some series of ab lated lesions tend to inclu de shorter post-treatment follow-up compared with published series of surgically managed or expectantly followed tumours. Reporting and publication biases probably also exist; studies with higher complication or recu rrence rates or other poor ou tcomes tend not to be published. For example, few data regarding the morbidity of RN were published until the introduction of LRN. In addition, there is the problem of technique b ias in the interpretation of the resu lts. F or exa mple, percutaneous therapy is repeated without difficulty whereas laparoscopic therapy is not. This certainly inuences the behaviour of the treating physician at the time of therapy .

In conclusion, the findings reported here must be interpreted within the context of the limitations outlined above. In order to allow better comparisons between treatment options for localized renal cell carcinoma, f u tu re research attempts shou ld minimize these limitations b y promoting prospective randomize d eva lu ations.

VIII. eA u A nD A uA sT A T eM enT s foR T ReA T M enT of loCA lIZ eD

RCC

1 . eA u sT A T eM enT s ( uP D A T e 2 0 0 9 ) [ 3 ]

Surgical therapy is the only curative approach for the treatment of RCC. Routine extended lymph node dissection in patients without detectable lymph nodes does not improve su rvi va l and can b e restricted to staging purposes (Grade A). Adrenalectomy, together with nephrectomy, except in the case of large upper pole tumours where direct invasion of the adrenal gland is likely, can be spared in most patients (Grade B). Embolisation as a palliative approach can be beneficial in patients unfit for surgery with massive hematuria or profound local pain (Grade C).

NSS is an established curative approach for the treatment of RCC (Grade B). NSS for tumours ≥

4 - 7 cm maxi mu m diameter can b e perf ormed in centres with expertise in selected patients (Grade B). A minimal tumour-free surgical margin following partial resection of RCC appears appropriate to avoid the increased risk of local recurrence (Grade B). If tumours of larger size are treated with NSS, follow-up should be intensified due to increased risk of intrarenal recurrence (Grade B).

L aparoscopic tu mou r nephrectomy shou ld b e performed in centres with laparoscopic expertise (Grade B). Laparoscopic tumour nephrectomy is likely to become a widely distributed treatment option. I t can b e promoted in specialised centres treating kidney tumours (Grade B).

OPN currently remains the standard of care (Grade C). LPN should be limited to experienced centres (Grade C).

Currently, patients not suitable for OPN due to poor performance status with smaller peripheral tumours shou ld b e considered f or non- su rg ical alternative techniques (Grade B).

These techniques include image-guided percu taneou s and minimally inva sive techniqu es, e.g. percutaneous RFA, cryoablation, microwave ab lation, laser ab lation and hig h- intensity f ocu sed ultrasound ablation (grade B).

2 . A uA sT A T eM enT s 2 0 0 8 [ 4 ]The statements are graded with respect to the degree of exibility in application. A “standard” is the most rigid treatment policy. A “recommendation” has significantly less rigidity, and an “option” has the largest amount of exibility.

F o r a l l p a ti en ts

Standard: high quality cross-sectional imaging (CT or MRI) with and without contrast.

Standard: discuss the current understanding of the natu ral history of clinical stag e 1 renal masses, the relative risks of b enig n vs. malig nant patholog y and the potential role of active su rve illance.

Standard: percutaneous renal mass core biopsy with or without fine needle aspiration in all patients u nderg oing thermal ab lation and in patients f or whom, it might impact management, particularly patients with radiographic findings suggestive of lym phoma, ab scess or metastasis.Standard: review the available treatment options and the attendant benefits and risks, including oncologic considerations, renal f u nctional considerations and potential morb idities.Standard: counsel patients about potential advantages of NSS in imperative and elective settings (avoidance of the need for dialysis, reduced risk of developing CKD with attendant morbidity and mortality .

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A healthy patient with a clinical T1a (≤ 4 cm) enhancing renal mass

Standard: PN

Alternate standard: RN when PN is not technically f easib le

O ption: thermal ab lation b u t hig her risk f or recu rrence

O ption: active su rve illance b u t small non- neg lig ib le risk f or tu mou r prog ression

An elderly patient with major comorbidities and a clinical T1a (≤ 4 cm) enhancing renal mass

Standard: PN with increased surgical risk

Standard: RN with increased surgical risk

Recommendation: thermal ablation because less inva sive in this hig h- risk patient

Recommendation: active surveillance with delayed interve ntion in this hig h- risk patient

A healthy patient with a clinical T1b (4.0 to 7.0 cm) enhancing renal mass

Standard: RN for patients with normal contralateral ki dney

Standard: PN, particularly when there is need to preserve renal f u nction

O ption: thermal ab lation b u t hig her risk f or recu rrence

Option: active surveillance with delayed intervention b u t small non- neg lig ib le risk f or tu mou r prog ression

An elderly patient with major comorbidities and a T1b (4.0 to 7.0 cm) enhancing renal mass

Standard: RN for patients with a normal contralateral ki dney , b u t increased su rg ical risk and increased risk of CKD

Recommendation: PN when there is need to preserve renal f u nction althou g h increased u rolog ic morb idity

O ption: thermal ab lation b ecau se less inva sive in this hig h- risk patient b u t clearly hig her risk f or recu rrence

Recommendation: active surveillance in this high-risk patient

IX . Consensus ReG A RD InG T ReA T M enT oP T Ions foR

loCA lIZ eD RCC

1 . A CT IVe suRVeIllA nCe

Active su rve illance is an acceptab le option f or the treatment of SRMs that should be discussed with

all patients. Active surveillance should be a first treatment option for SRMs < 4 cm in unfit patients or those w ith l imited l ife ex pectancy ( G rade C) . D el ayed interv ention shoul d be undertak en in tumours that show fast grow th during activ e surv eil l ance ( G rade C) . Patients shou ld b e cou nselled ab ou t the small b u t non- neg lig ib le risk of tu mou r prog ression du ring the ob serva tion period, possib le loss of the opportu nity f or nephron-sparing su rg ery , lack of cu rative salva g e therapies if metastatic disease deve lops, limitations of renal mass b iopsy , lack of long - term data on su rve illance, close follow-up imaging and required compliance. A significant number of SRMs (< 4 cm) are actually benign tumours (20%). No more than about 20 to 25% of SRMs have potentially aggressive characteristics. Several studies have shown increased aggressive potential of renal masses with a diameter > 3 cm. Data of surveillance series reveal that the majority of untreated localized renal tumours grow slowly and have little tendency to metastasize, at least in the first few years. Delayed intervention should be restricted to tumours that show fast growth during observation and have a hig her risk of prog ression to metastatic disease. Renal mass biopsy enhanced by molecular profiling holds promise for assessing aggressive potential. Further research will be required to define the u tility and limitations of this approach to improve the selection of patients f or active su rve illance. Larger tumours beyond a diameter of 3 or 4 cm, with aggressive behaviour and rapid growth are at risk of prog ression to metastatic disease and shou ld b e treated proactive ly .

2 . P A RT IA l A nD RA D ICA l neP H ReCT oM YNephron-sparing surgery should be a primary consideration in all patients with localized SRMs. This is based on the information that PN of small renal tu mou rs preserve s as mu ch normal renal parenchym a as possib le, provi des equ iva lent adequate oncologic outcomes as RN and is associated with a reduced risk of developing CKD compared with RN. Data have demonstrated that RN can result in a higher risk of CKD which is associated with increased risk of cardiovascular events and mortality . Partial nephrectomy is the ref erence standard for the treatment of SRMs, whether for imperative or elective indications. At present, PN is seriously underutilized while it is often feasible even f or a centrally located tu mou r or a tu mou r in the renal hilum when performed by an experienced surgeon. Laparoscopic PN can provide faster convalescence, but initial LPN reports were associated with somewhat longer ischemia times and increased risk of postoperative hemorrhage compared to OPN. However the more recent data presented in this chapter demonstrates that these concerns are no longer valid, and that contemporary LPN outcomes are similar to contemporary OPN outcomes, given adequ ate minimally inva sive exp ertise.

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I n patients w ith a cl inical T 1 renal tumour, P N prov ides eq uiv al ent l ocal tumour control as RN , w hil e minimizi ng dev el opment of new - onset CK D or w orsening of ex isting CK D ( G rade B ) . A s such, P N is the establ ished treatment for T 1a tumours ( < 4 cm) and an emerging standard treatment for T 1b tumours ( 4 to 7 cm) prov ided that the operation is technical l y feasibl e and the tumour can be entirel y and adeq uatel y remov ed ( G rade B ) . A ny tumour- free surgical margin following PN appears sufficient to prevent local recurrence and disease progression from RCC ( G rade B ) .RN remains a viable option in cases when PN is not technically f easib le b ased on tu mou r size , location or radiog raphic appearance as determined b y the urologic surgeon. When RN is required, laparoscopic RN should be considered as it is a recognized standard now. It is associated with low morbidity and f aster retu rn to normal activi ties, g ive n adequ ate su rg eon exp ertise. T herefore, L RN shoul d be the standard of care for T 1 and T 2 tumours, prov ided that it is performed in an adv anced l aparoscopic centre by an ex perienced surgeon and N SS is not appl icabl e ( G rade B ) . Robotic-assisted partial nephrectomy is rapidly emerg ing as an alternative to LPN for the treatment of renal malignancy.

3 . T H eRM A l A B lA T Ion

Cryoablation and RFA are reasonab le minimally invasive treatment options for most small (mainly < 3 cm) low grade renal tumours in patients who are at high surgical risk, who are not candidates for active surveillance and who accept the need for long - term radiog raphic su rve illance af ter ab lation. Percutaneous tumour core biopsy with or without fine needle aspiration should always be performed prior to ablation to define histology. Posttreatment biopsies may be necessary when recurrence or incomplete ablation is suspected. When deciding on thermal ab lation, it is important to cou nsel patients reg arding the slig htly increased risk of local recu rrence and the potential need f or retreatment when compared to surgical excision. Counselling ab ou t thermal ab lation shou ld f u rther inclu de the ab sence of estab lished radiog raphic measu res of post-ablative success, the potential for difficult surgical salvage therapy due to perinephric fibrosis if tu mou r prog ression deve loped, and the su b stantial limitations of the exi sting literatu re on thermal ab lation. L arg er tu mou rs b eyo nd a diameter of 3 or 4 cm and those with irregular form or infiltrative growth pattern may be associated with increased risk of recurrence when treated with thermal ablative therapies.

At this time there is insufficient long-term data av ail abl e to mak e adeq uate comparisons betw een abl ativ e techniq ues. T herefore abl ativ e therapies

shoul d be reserv ed for careful l y sel ected high surgical risk patients w ith SRM s < 4 cm ( G rade C) .

X . neW ReseA RCH – fuT uRe D IReCT Ions

To allow comparison of the different treatment options for localized RCC, future studies should b e prospective ly desig ned, have identical selection criteria, standardize d treatment protocols and consistent follow-up strategies using markers of clinical su ccess and ideally b e condu cted in a randomised way [5]. In addition, as newer treatment options b ecome ava ilab le, f u tu re stu dies shou ld include quality of life (QOL) and cost-efficacy ou tcomes [ 6 ] .

The most widely used system to provide prognostic information for RCC is currently the tumour, nodes, metastasis (TNM) staging system. The recent detection of molecu lar tu mou r b iomarke rs is expected to refine the staging and prognostication of RCC. There is already evidence that gene expression profiles obtained with high throughput microarray technolog y can identif y histolog ical subtypes of RCC and predict clinical outcomes of the disease. Biomarkers will eventually improve our ab ility to predict the malig nant potential of a tu mou r and to stratif y patients into more sophisticated risk categories [7]. Further active surveillance series with long-term follow-up are required to determine the real risks associated with this approach. Molecular profiling of SRMs is now possible but the available data on molecu lar marke rs are not ye t va lid enou g h for general use in clinical practice. Research will be required to define the utility and limitations of renal mass biopsy enhanced by molecular profiling [8,9].

F u rther endeavo u rs are requ ired to clarif y the long - term metab olic consequ ences of a decreased number of functioning nephrons following RN for RCC. This may result in a better understanding of the pleiotropic effects of CKD in patients treated with RN, and may offer a further rationale for the implementation of nephron- sparing strateg ies f or the treatment of localized RCC. Moreover, novel protective measu res to minimize ischemic renal damage (pharmacologic, immunologic) should be f u rther exa mined in order to improve the f easib ility and saf ety of nephron- sparing su rg ery [ 10 ] .

The use of the DaVinci Robot for robotic-assisted LPN is currently being evaluated at specialized laparoscopic centres [11,12]. Since 2004, four centres have reported their experience with robotic-assisted LPN. Robotic-assisted LPN may potentially enable more urologists to perform LPN, thereby allowing wider dissemination of minimally invasive nephron-sparing surgery [12). In addition, new developments su ch as sing le- port access laparoscopic su rg ery

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and natural-orifice translumenal endoscopic surgery (NOTES) have received increased attention from the urological community. These techniques will continu e to evo lve and mig ht lead to more adva nced therapeu tic options f or minimally- inva sive renal surgery [13,14]. Novel surgical image-navigation sy stem has also b een emerg ed recently . I mag e-guided surgery is a new field in which visualization of the surgical anatomy beyond the surgical view helps the su rg eon to enab le percu taneou s, laparoscopic, or robotic surgery more precisely and safely. Recent reports describ ed the nove l clinical capab ility of image-fusion system of ultrasonography (US) with computed tomography (CT) or Magnetic Resonance Imaging (MRI), real-time 3-dimensional US (3D US) navigation system, MRI-compatible navigation system, and augmented reality technology [15-18]. D ig ital- imag e- b ased compu terize d control of the su rg ical procedu res has g reat potential to improve precision of tumour ablation/removal with maximizing of preserva tion of the renal f u nction and su rrou nding healthy anatomy .

Major advances in the understanding of the molecular biology of RCC have led to the development of several new therapies that target ligands at the molecular level, so-called “targeted therapies”. The molecular targets important in clear cell RCC include vascular endothelial growth factor (VEGF) receptors, the mammalian target of rapamycin, and the VEGF molecule itself. The small molecule tyrosine kinase inhib itors su nitinib and soraf enib , the mammalian targ et of rapamyci n inhib itor temsirolimu s and the comb ination of the monoclonal antib ody bevacizumab with interferon-alpha are currently approved for treatment of metastatic RCC [19]. These new agents improve quality of life and seem ab le to stab ilise metastatic RCC for a prolonged period of time [20]. Recently-reported and ongoing studies compare combination therapies with single agents and determine the efficacy of single agents as adjuvant therapy for higher-risk localized and locally-advanced disease. However, there is currently no role f or targ eted molecu lar therapy in the treatment of localized RCC outside of a clinical trial.

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ated

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Co m m i t t e e 6

lo c a l l y A d v a n c e d D i s e a s e

Ch a i r :

C . G . W O O D

M e m b e r s :

T . W . C HO N G , Y . HI R A O ,S . J O N I A U ,M . K U C Z Y K ,

B . LE I B O VI C H,V. M A R G U LI S ,V. M A S T E R ,S . R A W A L,M . W I R T H,

Co r r e s p o n d e n c e :C hristopher G . W ood, D epartment of U rolog y- U nit 137 3T he U nive rsity of T exa s M . D . Anderson C ancer C enter15 15 H olcomb e B ou leva rdH ou ston, T exa s 7 7 0 30Phone: 7 13- 5 6 3- 7 4 6 3F ax: 7 13- 7 9 2- 34 7 4cg w ood@ mdanderson.org

1 54

T A B le of ConT enT s

I. InT RoD uCT Ion

II. Venous InVA sIon

1 . eVA luA T Ion2 . M A nA G eM enT3 . onColoG IC ouT CoM es

III. T H e Role of lY M P H noD e D IsseCT Ion A nD M A nA G eM enT

of noD A l M eT A sT A ses

1 . loCA llY A D VA nCeD RCC2 . M eT A sT A T IC RCC3 . P A T IenT seleCT Ion foR

lY M P H A D eneCT oM Y

IV. A D J A CenT oRG A n InVA sIon

V. A D J uVA nT / neoA D J uVA nT( P Re- suRG ICA l) T H eRA P Y foR

RenA l Cell CA RCInoM A

1 . A D J uVA nT T H eRA P Y

2 . neoA D J uVA nT T H eRA P Y

VI. M A nA G eM enT of loCA l ReCuRRenCe

VII. suM M A RY

1 55

lo c a l l y A d v a n c e d D i s e a s e

C . G . W O O D

T . W . C HO N G , Y . HI R A O , S . J O N I A U ,M . K U C Z Y K , B . LE I B O VI C H, V. M A R G U LI S ,

V. M A S T E R , S . R A W A L, M . W I R T H,

D espite the increased detection of small, asym ptomatic renal masses throu g h the increased use of abdominal imaging for non-specific complaints or f or non- renal malig nancy stag ing eva lu ation, there remains a significant subset of patients that present w ith locally adva nced and/ or metastatic renal cell carcinoma (R C C ). R eg arding locally adva nced R C C , these inclu de patients w ith ve nou s thromb i, ex tra- capsu lar and adj acent org an invo lve ment, as w ell as nodal disease. L ocally recu rrent R C C after definitive surgical therapy should also be inclu ded in this g rou p of patients. T he su rg ical manag ement of these patients can b e ext remely dau nting and complex, and despite exp ert su rg ical manag ement, many are destined to su f f er relapse, either locally , distantly , or b oth[ 1] . I n concert w ith su rg ical manag ement of these locally adva nced tu mors, clinical research ef f orts have f ocu sed on the deve lopment of ef f ective adj u va nt and/ or neoadj u va nt therapy that can ef f ective ly redu ce the risk of disease recu rrence f ollow ing su rg ical ex tirpation. Sadly , ef f ective adj u va nt/ neoadj u va nt therapy does not exi st f or renal cell carcinoma in the ye ar 20 10 , despite the condu ct of many phase I I I clinical trials testing ag ents that have show n promise in the setting of metastatic disease[ 2, 3] . C u rrently , the new targ eted therapies are b eing tested in b oth the adj u va nt and neoadj u va nt setting f or locally adva nced renal cell carcinoma, and w e anxi ou sly aw ait the resu lts of these important ong oing clinical trials.

I n this article, w e w ill discu ss the manag ement and ou tcomes f or patients w ho present w ith locally advanced RCC, focusing specifically on the manag ement of renal ve in and inf erior ve na cava

thromb i, the role of lym ph node dissection and the manag ement of nodal metastases, the manag ement of adj acent org an inva sion, the manag ement of local recu rrences in the ab sence of metastatic disease, and the role of adj u va nt and neoadj u va nt therapy . W e w ill present leve ls of evi dence f or each of ou r findings, and a consensus statement derived from f u rther delib eration b y committee memb ers.

II. Venous InVA sIon

Approxi mately 10 % of patients w ith R C C have ve nou s tu mor thromb u s in the renal ve in (R V ) or inf erior ve na cav a (I V C ) w ith approxi mately 1% havi ng tu mor thromb u s ext ending u p to the rig ht atriu m.[ 4 ] ( fi g .1 ) V enou s tu mor thromb u s patients requ ire more exp editiou s care than many other R C C patients secondary to the associated risks and complications inclu ding ve nou s cong estion, emb olic eve nts, and the possib ility of thromb osis w ith b land b lood clot. F u rthermore, proxi mal prog ression of tu mor thromb u s secondary to delay in manag ement increases complexi ty and potential morb idity of su rg ical resection.[ 5 , 6 ]

1 . eVA luA T Ion

Appropriate manag ement of R C C w ith tu mor thromb u s requ ires accu rate stag ing . Enhanced mag netic resonance imag ing (M R I ) has b een determined to b e the most reliab le method of imag ing tu mor thromb u s ext ent, invo lve ment of ve in trib u taries, detection and dif f erentiation of tu mor thromb u s ve rsu s b lood clot, and assessing f or ve ssel occlu sion.[ 7 ] R ecently , mu ltidetector compu terize d tomog raphy (C T ) has b een show n to correlate well with intraoperative findings including extent of thrombus as well as pathological findings at the time

I. InT RoD uCT Ion

1 56

of resection of R C C w ith tu mor thromb ectomy . [ 8 ] D u e to possib le rapid prog ression of tu mor thromb u s, operative manag ement shou ld b e preceeded b y ve ry recent imag ing . Stag ing f or b ony , ab dominal, thoracic, and intracranial metastatic invo lve ment shou ld f ollow standard protocols.

2 . M A nA G eM enT

C ase reports of tu mor thromb u s dow nstag ing w ith targ eted ag ents indicate that neoadj u va nt therapy may b ecome a vi ab le approach,[ 9 - 11] how eve r, u ntil f u rther data is ava ilab le this practice shou ld b e limited to clinical trials. (l e v e l o f e v i d e n c e : 4 ) U ntil su ch data are ava ilab le, therapy f or the patient w ith tu mor thromb u s is b ased u pon su rg ical resection of the primary tu mor along w ith the entire b u rden of intrava scu lar tu mor thromb u s. Some data f rom case cohort series indicate that su rg ical manag ement of R C C w ith tu mor thromb u s may provi de su perior su rvi va l to non- su rg ical manag ement (median of 19 .8 ve rsu s 6 .9 months, respective ly) .[ 12] H ow eve r, the cohorts were significantly different with higher tu mor b u rden in the non- su rg ical g rou p.

A recent retrospective revi ew of a larg e case series provi des an exce llent g u ide to manag ement b ased on tu mor thromb u s leve l.[ 5 ] ( l e v e l o f e v i d e n c e : 3 b ) O perative manag ement is dictated primarily b y the ext ent of the tu mor thromb u s. I solation of the va scu lar stru ctu res is the initial step in dissection. Ligation of the ipsilateral renal artery is the first step and is b est accomplished b y approaching the aorta directly f or b oth lef t and rig ht tu mors. Preoperative ang ioemb oliza iton is not recommended and w as show n to of f er no adva ntag e in a larg e case control series and w as associated w ith increased

complications.[ 13] Af ter arterial lig ation the next step is ve nou s control and ext raction of thromb u s. L ig ation of minor trib u taries to the I V C inclu ding some lu mb ar and minor hepatic b ranches may b e necessary to provi de adequ ate hemostasis and tu mor vi su aliza tion du ring tu mor ext raction.[ 5 ] H ow eve r, in cases of complete or near complete occlu sion, meticu lou s dissection of all collateral ve ins is to b e avo ided as these represent the maj ority of ve nou s retu rn and are needed to maintain preload u ntil the I V C can b e cleared. M inimal manipu lation of the ki dney and tu mor redu ce the risk of emb oliza tion and theref ore the nephrectomy is completed af ter ext raction of the thromb u s.

For thrombus that is confined to the renal vein or j u st entering the I V C (w hich can b e retracted b ack into the renal vein) minimal modification to standard approaches to open radical nephrectomy are requ ired to assu re complete remova l of thromb u s w ith neg ative marg ins.[ 5 ] Sev eral reports of su ccessf u l minimally inva sive approaches to su ch low leve l thomb u s have b een pu b lished.[ 14 - 16 ]

T hromb u s that is ab ove the renal ve in ostiu m and b elow the hepatic ve ins can b e manag ed w ith occlu sion of the ve na cava ab ove and b elow the thromb u s as w ell as occlu sion of the contralateral renal ve in. Su ch cases rarely requ ire b yp ass. Ext raction of the thromb u s en b loc w ith the ipsilateral renal ve in and tu mor is accomplished vi a a ve na cavo tomy on the anterior I V C and inclu ding the ostiu m of the ipsilateral renal ve in. T he interior of the IVC should be ushed and inspected to assure complete clearance of tu mor.[ 5 ]

T hromb u s at the leve l of the hepatic ve ins and

Level ILevel I 39 (41%)39 (41%)Level IILevel II 28 (29%)28 (29%)Level IIILevel III 7 (7%)7 (7%)Level IVLevel IV 14 (16%)14 (16%)

Fig. 1: Level of Tumor Thrombus

1 57

b elow the diaphrag m may requ ired b yp ass b u t can b e perf ormed w ith simple occlu sive measu res in many cases.[ 5 ] T he u se of intraoperative transesophag eal sonog raphy can b e ve ry helpf u l f or monitoring hemodyn amics and assessing the thromb u s. Ext raction of thromb u s is accomplished with occlusion of the inow to the liver (Pringle manu ve r) along w ith control of the I V C b elow the thromb u s as w ell as ab ove the liv er and control of the contralateral renal ve in w ith a ve na cavo tomy w hich ends inf rahepatically . Af ter ext raction of the thromb u s, the I V C can b e clamped inf rahepatic and the su prahepatic clamp can b e released to allow restoration of ow to the liver.

T hromb u s ab ove the diaphrag m necessitates opening the rig ht atriu m w ith silmu taneou s manipu lation of thromb u s f rom ab ove and vi a an inf rahepatic ve na cavo tomy b elow to assu re complete clearance. Seve ral case series su pport the u se of b yp ass techniqu es inclu ding ve no- ve no b y pass and cardiopu lmonary b yp ass w ith or w ithou t circu latory arrest.[ 17 - 20 ] T he decision to u se b yp ass is dependent u pon the ext ent of occlu sion of the I V C preoperative ly as w ell as hemodyn amics u pon clamping the va scu lar stru ctu res intraoperative ly . A recent larg e case series reported the u se of some b y pass techniqu e in 10 0 % of cases of thromb u s ab ove the diaphrag m, 29 % of cases b elow the diaphrag m and w ithin the intrahepatic I V C , and in only 2% of I V C thromb u s cases that w ere b elow the live r.[ 5 ] I n all cases invo lvi ng the I V C complete clearance of adherent or inva sive tu mor thromb u s may requ ire complete or partial resection of the ve na cav a and reconstru ction w ith a patch or g raf t. Preve ntion of emb oliza tion of distal b lood clot may requ ire interru ption of the ve na cava , or placement of an IVC filter.[21]

3 . onColoG IC ouT CoM es

The prognostic significance of the level of tumor thromb u s has b een eva lu ated ext ensive ly .[ 5 , 22-31] (l e v e l o f e v i d e n c e : 3 b ) M ost of these case series do not find a difference in survival based on leve l of tu mor thromb u s w ithin the I V C . A recent retrospective revi ew of 4 22 patients w ith pT 3b R C C evaluated the cancer specific survival based on leve l of tu mor thromb u s.[ 24 ] Patients w ith I V C tu mor thrombus were significantly more likely to die from R C C compared w ith patients w ith tu mor thromb u s confined to the renal vein even after adjusting f or reg ional lym ph node invo lve ment and distant metastases.[ 24 ] T he presence of renal ve in ostial w all inva sion b y tu mor thromb u s has b een reported to b e associated w ith poor prog nosis relative to patients w ithou t w all inva sion.[ 30 ]

Tumor specific features that are associated with diminished su rvi va l are similar to R C C w ithou t ve nou s invo lve ment and inclu de presence of f at

inva sion, lym ph node invo lve ment, metastases, histolog ic tu mor necrosis, sarcomatoid f eatu res, and hig h tu mor g rade.[ 5 ] M edian su rvi va l among 5 0 3 patients w ith clear cell renal cell carcinoma treated w ith su rg ery and no adj u va nt therapy in a larg e retrospective revi ew w as 3.1 ye ars w ith 5 ye ar su rvi va l of 5 9 % f or patients w ithou t metastases and neg ative lym ph nodes.[ 5 ]

Re c o m m e n d a t i o n s G r a d e

•en h a n c e d M RI o r m u l t i d e t e c t o r CT Ap r o v i d e i m p o r t a n t a n a t o m i c i n f o r m a t i o n r e g a r d i n g t h e m a g n i t u d e o f t h e t u m o r t h r o m b u s e x t e n s i o n , n e c e s s a r y f o r s t a g i n g , p r o g n o s i s a n d s u r g i c a l p l a n n i n g

•up - f r o n t s u r g i c a l t h e r a p y w i t h r a d i c a l An e p h r e c t o m y a n d c o m p l e t e t u m o r t h r o m b e c t o m y s h o u l d b e p e r f o r m e d i n a p p r o p r i a t e s u r g i c a l c a n d i d a t e s

•Ro u t i n e r e n a l a r t e r i a l Bt h r o m b o e m b o l i za t i o n p r i o r t o r a d i c a l n e p h r e c t o m y i s n o t a d v o c a t e d

•on c o l o g i c o u t c o m e s a f t e r r a d i c a l Bn e p h r e c t o m y a r e d r i v e n b y e s t a b l i s h e d p r o g n o s t i c f e a t u r e s o f t h e p r i m a r y t u m o r r a t h e r t h a n t h e e x t e n t o f t h e v e n o u s t h r o m b u s

III. T H e Role of lY M P H noD e D IsseCT Ion A nD M A nA G eM enT

of noD A l M eT A sT A ses

The potential therapeutic benefits of lymph node dissecton (L N D ) at the time of radical nephrectomy (R N ) are tw o- f old. F irst, the remova l of reg ional nodal metastases can provi de cu re in patients whose disease is confined to the retroperitoneum, concu rrently allow ing appropriate selection of these hig h- risk patients to receive adj u va nt syst emic targ eted therapy in the context of a clinical trial. Alternative ly , reg ional L N D in patients w ith syst emic micro- and macro- metastatic disease may provi de sufficient cytoreduction to improve therapeutic efficacy and tolerability of post-surgical systemic treatments.

1 . loCA llY A D VA nCeD RCC

Seve ral contemporary series, demonstrate that ag g ressive remova l of reg ional nodal metastases translates into improved cancer specific survival and provides long term cures in a significant number of patients.[ 32- 34 ] (l e v e l o f e v i d e n c e : 3 a ). Pantu ck et al, f ou nd that 4 3 R C C patients w ith clinically

1 58

su spected nodal invo lve ment, w ithou t distant metastases, w ho u nderw ent some f orm of L N D , demonstrated a 5 month improve ment in median su rvi va l, compared to patients in w hom clinically positive L N s w ere lef t in situ at the time of R N .[ 32] M oreove r, L N D dissection w as an independent predictor of su rvi va l in their mu ltiva riab le analysi s. I nve stig ators f rom M . D . Anderson C ancer C enter reported ou tcomes of 4 0 patients w ith reg ional nodal invo lve ment w ithou t evi dence of syst emic metastatic disease, all of w hom u nderw ent complete ext ended L N D .[ 33] O nly cases in w hich all g ross disease w as completely remove d w ere considered su ccessf u l resections and included in the final analysis. Median cancer specific survival was 20.3 months and 30% of patients had no evi dence of disease at a median f ollow - u p of 18 months.[ 33]

I n contrast to the data presented ab ove in the setting of clinically positive L N ’ s, nu merou s retrospective studies have found no therapeutic benefit of rou tine L N D in the setting of the lack of clinically su spiciou s lym phadenopathy . T he only randomize d prospective clinical stu dy to eva lu ate the role of rou tine lym phadenectomy at the time of R N f or R C C w as condu cted b y Eu ropean O rg aniza tion f or R esearch and T reatment of C ancer (EO R T C 30 8 8 1).[ 35 ] I n this trial, 7 7 2 patients w ith clinical T 1- 3N 0 M 0 R C C w ere randomize d to R N only or R N and lym ph node dissection. R N w as perf ormed w ith or w ithou t remova l of retroperitoneal tissu e f rom the cru s of the diaphrag m to the b if u rcation of the aorta. Althou g h proponents of L N D arg u e that the stu dy has not reached matu rity , preliminary resu lts f rom the randomize d trial f ailed to demonstrate any significant differences in cancer-specific survival b etw een the stu dy g rou ps (l e v e l o f e v i d e n c e : 1 b ). D u e to hig h preva lence of low risk R C C , this stu dy was significantly underpowered to detect a survival adva ntag e af f orded b y L N D . N ot su rprising ly , only 3% of patients w ho u nderw ent lym ph node dissection at the time of R N had lym ph node metastases, and ve ry f ew patients (17 % ) prog ressed or died f rom RCC, thus making it extremely difficult to draw conclusions about the therapeutic efficacy of lymph node dissection in R C C .[ 35 ] ( fi g . 2 , 3 )

2 . M eT A sT A T IC RCC

Stu dies that have eva lu ated the role of L N D at the time of cyt oredu ctive R N f or metastatic R C C also su pport ag g ressive deb u lki ng of reg ional nodal disesase in addition to cyt oredu ctive R N ( l e v e l o f e v i d e n c e : 3 a ). V asselli and colleag u es, at the N ational C ancer I nstitu te. eva lu ated a cohort of patients treated w ith cyt oredu ctive R N and I L - 2 immu notherapy and compared 8 2 patholog ically node neg ative patients w ith 7 2 similar patients w ho had pathologically confirmed involvement of regional L N s.[ 36 ] N ot su rprising ly , these au thors f ou nd a

median su rvi va l of 14 .7 months and 8 .5 months, in node neg ative and positive g rou ps, respective ly (P = .0 0 0 4 ). T here w as no statistical dif f erence in su rvi va l b etw een patients w ith node positive disease w ho u nderw ent complete nodal dissection and patients w ith pN 0 disease. Similarly , in a report describ ing the U C L A exp erience w ith 129 patients w ith g rossly positive lym ph nodes and syst emic metastases, the median su rvi va l af ter I L - 2 immu notherapy w as approxi mately 5 months long er f or patients w ho u nderw ent L N D compared to those w ho did not.[ 32]

3 . P A T IenT seleCT Ion foR lY M P H A D eneCT oM Y

R ealizi ng the limitations of cu rrent radiolog ic imag ing techniques, a rational approach for identification of patients at hig h risk of harb oring su b - clinical L N metastases w as reported b y the M ayo C linic g rou p.[ 37 ] T heir analysi s of more than 1,6 0 0 patients with clear cell renal cell carcinoma identified five histolog ical f eatu res that placed patients at increased risk f or reg ional lym ph nodes metastases: hig h stag e, hig h nu clear g rade, larg e size , a sarcomatoid component, and presence of histolog ical tu mor necrosis. I n their protocol, the au thors estab lished a ” risk cu t point” of tw o f eatu res as a threshold f or placing a patient at significant risk of regional lymph node invo lve ment, if present ( T a b l e 1 ) . Similarly , a pre- su rg ical prog nostic nomog ram f or prediction of reg ional nodal metastases w as deve loped b ased on 139 (2.9 % ) node positive patients ou t of the 4 ,8 4 4 patients w ho u nderw ent R N at the M ayo C linic and M emorial Sloan K ettering C ancer C enter.[ 38 ] T he nomog ram u tilize d ag e, g ender, perf ormance statu s, co- morb idity index, sym ptoms at presentation, radiolog ic lym phadenopathy , tu mor size and location, presence of necrosis, pre- operative hemog lob in, and history of hematu ria to predict the prob ab ility of patholog ically positive L N w ith an accu racy of 7 6 .1% .[ 38 ] I f va lidated in ext ernal patient cohorts, these predictive tools cou ld serve as a va lu ab le g u ide to selective ly targ et patients f or ext ended L N D at the time of R N .

T o date, there are no u nif ormly accepted g u idelines on the ext ent or anatomic b ou ndaries of L N D w hen perf ormed as an adj u nct to R N f or R C C . Ava ilab le data, how eve r, su g g ests that a more thorou g h LND provides a significant improvement in staging accuracy.[39, 40] Based on these findings and the kn ow ledg e g ained f rom the classic renal lym ph node mapping stu dies, para- aortic dissection f rom the cru s of the diaphrag m to the b if u rcation of the aorta is perf ormed f or the lef t sided tu mors; how eve r, f or the rig ht sided tu mors b oth para- cava l and inter- aortocava l dissection f rom the diaphrag matic cru s to the b if u rcation of the g reat ve ssels is recommended.[ 4 1] ( l e v e l o f e v i d e n c e : 4 )

1 59

T A B L E 1. T he M ayo Cl inic risk factors for prediction of regional nodal metastases in RCC. [ 3 7 ]

fe a t u r e oR ( 9 5 % CI) pG r a d e 3 + 4 5 .2 5 ( 1 .9 9 - 1 3 .8 2 ) < 0 .0 0 1sa r c o m a t o i d c o m p o n e n t 4 .1 1 ( 2 .0 8 - 8 .1 2 ) < 0 .0 0 1T u m o r 1 0 c m o r g r e a t e r 2 .1 7 ( 1 .2 7 - 3 .7 0 ) 0 .0 0 5 P r i m a r y s t a g e p T 3 + p T 4 2 .0 0 ( 1 .1 3 - 3 .5 5 ) 0 .0 1 7 H i s t o l o g i c a l t u m o r n e c r o s i s 1 .8 6 ( 1 .0 0 - 3 .4 8 ) 0 .0 5 1

no . fe a t u r e s no . p n0 / p nx ( % ) no . p n1 / p n2 ( % ) 0 7 2 6 ( 9 9 .6 ) 3 ( 0 .4 ) 1 2 9 9 ( 9 9 .0 ) 3 ( 1 .0 ) 2 2 6 4 ( 9 5 .7 ) 1 2 ( 4 .4 ) 3 1 8 3 ( 8 7 .6 ) 2 6 ( 1 2 .4 ) 4 1 0 5 ( 8 6 .8 ) 1 6 ( 1 3 .2 ) 5 7 ( 4 6 .7 ) 8 ( 5 3 .3 )

Randomized phase III trial of RN alone or with complete Randomized phase III trial of RN alone or with complete lymph node (LN) dissection showed no benefit of lymph node (LN) dissection showed no benefit of dissectiondissection

BlomBlom JH et al. JH et al. EurEur UrolUrol.. 1999;36:570.1999;36:570.

GroupGroup NN Metastasis Rate Metastasis Rate Within GroupWithin Group

All patientsAll patients 772772 3.3%3.3%Patients in LN dissection Patients in LN dissection arm without palpable LNarm without palpable LN

299299 1%1%

Patients in LN dissection Patients in LN dissection arm with palpable LNarm with palpable LN

4343 16%16%

Patients in RNPatients in RN--only arm only arm with palpable LN at surgerywith palpable LN at surgery

2929 21%21%

Fig. 2: Result of the EORTC 30881: Lymph Node Dissection in Localized RCCWithoutlymph-node

dissection(n=389)

Withcomplete

lymph-nodedissection

(n=383)

Hazardratio

95%confidence

intervalp

value

Death 135 (35%) 137 (36%) 1.02 0.80-1.29 0.87Local regional progression 34 (9%) 26 (7%) 0.77 0.46-1.28 0.31

Distantprogression 58 (15%) 60 (16%) 1.05 0.73-1.50 0.81

Local or distant progression 93 (24%) 87 (23%) 0.95 0.71-1.27 0.70

Progression or death 156 (40%) 159 (42%) 1.02 0.82-1.28 0.84

Second primary 45 (12%) 36 (9%) 0.79 0.51-1.22 0.28

Fig. 3: Result EORTC 30881: Lymph Node Dissection in Localized RCC

BlomBlom et al., et al., EurEur UrolUrol, 2008, 2008

Without lymph-node

dissection

With complete lymph-nodedissection

% n %

1 4 1

5 21 6

T2 230 pTcategory n 63

T3 96 T0 5 29

T4 2 T1 19 1

TX 2 1 3 1

Fig. 2: Result of the EORTC 30881: Lymph Node Dissection in Localized RCC

Fig. 3: Result EORTC 30881: Lymph Node Dissection in Localized RCC

1 60

Re c o m m e n d a t i o n s G r a d e

•No therapeutic benefit of retroperi- At o n e a l l y m p h a d e n e c t o m y h a s b e e n d e m o n s t r a t e d In p a t i e n t s w i t h o u t c l i n i c a l e v i d e n c e o f l y m p h a d e n o p a t h y

•Re m o v a l o f g r o s s r e g i o n a l n o d a l Bm e t a s t a s e s c a n r e s u l t i n i m p r o v e d cancer specific survival in and can p r o v i d e l o n g t e r m c u r e

•W h e n i n d i c a t e d , p a r a - a o r t i c d i s s e c t i o n Cf r o m t h e c r u s o f t h e d i a p h r a g m t o t h e b i f u r c a t i o n o f t h e a o r t a i s p e r f o r m e d f o r t h e l e f t s i d e d t u m o r s ; f o r t h e r i g h t s i d e d t u m o r s b o t h p a r a - c a v a l a n d i n t e r -a o r t o c a v a l d i s s e c t i o n i s n e c e s s a r y

IV. A D J A CenT oRG A n InVA sIon

R C C may rarely present w ith locally adva nced disease, in the ab sence of distant metastatic disease, w ith reported preva lence of approxi mately 1- 1.5 % at centers su ch as M SK C C and M D AC C , as w ell as the SEER reg istry .[ 4 2- 4 4 ] T he incidence of adva nced tu mors has increased ove r time.[ 4 5 ] AJC C stag ing of k idney cancer describ es T 4 R C C as that w hich has penetrated b eyo nd G erota’ s f ascia to ascending colon or du odenu m f rom the rig ht ki dney , descending colon f rom the lef t ki dney , diaphrag m, peritoneu m, tail of pancreas, psoas mu scle, rib s, liv er, spleen, stomach, aorta, or contralateral ki dney , adrenal g land, or u reter, and is Stag e I V disease. Earlier reports in the literatu re w ere rou tinely pessimistic ab ou t the va lu e of su rg ical resection f or su ch adva nced disease, b u t this important issu e has b een recently revi sited in seve ral pu b lications. I t is important to note that all su ch stu dies are case series or retrospective cohort stu dies (l e v e l o f e v i d e n c e 4 a n d 2 b , r e s p e c t i v e l y ).

The first modern data on this patient population is f rom M D AC C .[ 4 2] 30 patients ou t of an institu tional datab ase of ove r 30 0 0 patients ove r a 15 ye ar accrual period, were identified as having T4NxM0 R C C and u nderw ent complete resection of the primary tu mor, w ith adj acent org an resection, all w ith neg ative su rg ical marg ins. T he most common sites of resection w ere colon, pancreas and diaphrag m, althou g h live r, spleen and b ow el mesentery inva sion w ere also seen. N o reliab le preoperative predictors of invasion were identified. Of the important messag es in this report, perhaps the most important, w as that 6 0 % of patients thou g ht to have T 4 disease w ere dow nstag ed to < pT 4 disease, inclu ding 2 patients w ho w ere f ou nd to only have pT 2 disease. O n mu ltiva riate C ox reg ression analysi s the only predictors of su rvi va l w as the presence

of pT 4 disease and most importantly , lym ph node metastases (R R 17 , p= .0 0 2) w ith 3 ye ar ove rall su rvi va l of 6 6 % in L N neg ative patients ve rsu s 12% in lym ph node positive patients, w hich comprised a third of patients. T his report conclu ded that actu al patholog ical invo lve ment f rom R C C is rare, and not reliab ly predicted f rom preoperative or intraoperative findings. Most patients are clinically overstaged. T hese su rg eries are possib le to perf orm w ith acceptab le patient morb idity (mean leng th of stay 9 days, rang e 4 - 22) and no perioperative deaths.

Another va lu ab le stu dy on this rare patient su b set w as f rom M SK C C . I nstead of looki ng at patients w ith clinically su spected locally adva nced renal cancer inva ding other org ans, this g rou p looke d at 38 patients ou t of a total of approxi mately 25 0 0 patients w ho had patholog ical T 3 or T 4 disease w ith resection of adj acent org ans or stru ctu res. Approxi mately one qu arter had positiv e lym ph nodes. M ost patients had neg ative patholog ic marg ins, b u t 36 % had a positiv e marg in. Presence of a positive margin was significantly associated with decreased su rvi va l (p = .0 0 6 ). 8 9 % of patients died w ith a median survival of 11.7 months (range 5-29). A final stu dy f rom Sou th Asia stu died 18 patients w ith R C C su spiciou s f or adj acent org an invo lve ment. Similar to the report f rom M D AC C , althou g h less f requ ent, 3/ 18 patients did not have tru e org an inva sion on the final resection specimen. Interestingly, while 15 patients died at a median du ration of 7 .5 months, 3 patients w ere still alive at a median of 13,16 and 25 months. There were no differences identified in terms of patient, tu mor and lab oratory va riab les b etw een those patients w ho live d and those w ho died. L acki ng f rom this particu lar series w as any description of nodal patholog y .

I n an ef f ort to u nderstand the important issu e is w hether the resu lts of radical nephrectomy f or T 4 renal cancer comb ined w ith adj acent org an or structure extirpation is confined only to true centers of exp ertise, and the important qu estion of w hat happens to patients if su rg ery is not perf ormed. C apitanio exa mined 310 patients w ith clinical T 4 N 0 -2 R C C in the SEER reg istry , w hich is thou g ht to b e representative of the U S popu lation, w ho u nderw ent resection (24 6 ) or no su rg ery (6 4 ). T hose w ho u nderw ent su rg ery had a median su rvi va l of 4 8 months compared to only 6 months f or those w ho u nderw ent no su rg ery (H aza rd ratio of 2.2). T he ef f ect of su rg ery f or those patients (125 ) w ho had T 4 N 0 disease w as eve n strong er, w ith a haza rd ratio of 3.7, with a cancer specific mortality of approximately 4 0 % at 10 ye ars, eve n af ter controlling f or other cau se mortality , w hich mig ht b e exp ected (M I , stroke ) after this kind of extensive surgery. No benefit was seen in those patients w ith node- positive disease. As an important cave at f or the commu nity u rolog ic su rg eon, the stu dy w as conf ou nded b y only stu dyi ng

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9 SEER reg ions (ou t of 17 ), and f ou r of these reg ions contained academic medical centers with significant u rolog ic oncolog y exp ertise.

T hu s, it may b e pru dent f or patients w ith this ki nd of disease to b e cared f or in centers w here a tru e mu ltidisciplinary team of su rg eons f amiliar w ith this ki nd of resection, and of su b sequ ent reconstru ction (hepatob iliary , pancreatic, colorectal, va scu lar, b ody w all) may b e present. I n su mmary , in patients fit to undergo surgery with no clinical evidence of metastatic disease, and no evi dence of patholog ical retroperitoneal adenopathy , rather than deeming patients w ith clinical T 4 not cu rab le or u nresectab le, and of f ering palliative treatment only , su rg ery is like ly to be of benefit.

U nansw ered qu estions remain w hich concern patient selection b ef ore committing a patient to ext ensive su rg ery , particu larly the role of preoperative /postoperative prog nostic f actors, inclu ding seru m b iomarke rs, and of the role of neoadj u va nt targ eted ag ent chemotherapy .[ 4 6 ] I t is possib le that the u se of these new er chemotherapeu tic ag ents b e u sed in conj u nction w ith su rg ical ext irpation of localize d disease. M u lti- institu tional reg istries may b e of va lu e in tryi ng to eva lu ate su ch ou tcomes.

Re c o m m e n d a t i o n s G r a d e

•A d j a c e n t o r g a n i n v a s i o n b y RCC i s Cn o t r e l i a b l y p r e d i c t e d b y p r e o p e r a t i v e r a d i o l o g i c i m a g i n g o r i n t r a o p e r a t i v e findings

•A p p r o p r i a t e s u r g i c a l c a n d i d a t e s Cs h o u l d b e m a n a g e d w i t h r a d i c a l n e p h r e c t o m y a n d e n - b l o c r e m o v a l o f a d j a c e n t t i s s u e o r o r g a n s i f d i r e c t i n v a s i o n i s s u s p e c t e d

V. A D J uVA nT / neoA D J uVA nT( P Re- suRG ICA l) T H eRA P Y foR

RenA l Cell CA RCInoM A

1 . A D J uVA nT T H eRA P Y

W hile su rg ery remains the cu rative f or the va st maj ority of patients w ith locally adva nced renal cell carcinoma, there remains a significant population of patients that remain at hig h risk f or disease relapse, both locally and distantly, after definitive surgical therapy . A larg e f ocu s of clinical research in renal cell carcinoma has b een the deve lopment of an ef f ective adj u va nt therapy to decrease risk of recu rrence and improve su rvi va l in patients at hig h risk f or relapse af ter su rg ery . L og ically , therapeu tic deve lopment in the adj u va nt setting has f ocu sed on therapy w ith

some evi dence of activi ty in the setting of metastatic disease. T o date, in the ye ar 20 10 , ef f ective adj u va nt therapy does not exi st f or renal cell carcinoma.

I nitial phase I I I randomize d clinical trials f ocu sed on hormonal therapy su ch as medroxyp rog esterone acetate in the adj u va nt setting . T hese stu dies demonstrated significant toxicity associated with adj u va nt therapy and no recu rrence f ree or ove rall survival benefit for the treatment arm[47, 48]. ( l e v e l o f e v i d e n c e : 1 b ) I n addition, adj u va nt radiation therapy has b een stu died and may decrease the risk of local recu rrence b u t had no impact on the occu rrence of distant metastases or su rvi va l[ 4 9 ] . (l e v e l o f e v i d e n c e : 3 a ) W ith the deve lopment and implementation of immu notherapy f or the treatment of metastatic renal cell carcinoma, clinical research f ocu sed on the u tility of this treatment modality in the adj u va nt setting . N u merou s phase I I I clinical trials have stu died interf eron and interleu ki n 2, either alone or in comb ination w ith va riou s chemotherapeu tics, in the adj u va nt setting . T o date, none have demonstrated a benefit regarding recurrence free or ove rall su rvi va l f or patients[ 2, 3, 5 0 - 5 5 ] . (l e v e l o f e v i d e n c e : 1 a ) I mmu notherapeu tic strateg ies in the adj u va nt setting have also f ocu sed on va riou s va ccine f ormu lations. T he attraction of va ccines in this setting is that they are relative ly non- toxi c and rely on a competent host immu ne syst em f or their anti- tu moral activi ty . W hile some, su ch as vi tespen, have show n evi dence of activi ty in su b set analyse s focused on specific patient populations, none of the clinical research perf ormed w ith a w ide va riety of va ccine f ormu lations in the adj u va nt setting can su pport their implementation into clinical practice at the cu rrent time[ 5 6 - 6 1] . (l e v e l o f e v i d e n c e : 1 a ) T he antiang iog enic ag ent thalidomide has also b een eva lu ated in the adj u va nt setting f or renal cell carcinoma, b u t like all other ag ents that demonstrated some modicu m of activi ty in the metastatic setting , no benefit was seen in the adjuvant setting[62]. ( l e v e l o f e v i d e n c e : 1 b ) A phase I I I clinical trial exa mining the role of the antib ody G 25 0 (AR I SER ), w hich targ ets the carb onic anhyd rase I X protein and indu ces antib ody dependent cellu lar cyt otoxi city , has recently completed accru al b u t the resu lts of this stu dy have not b een reported in the literatu re to date[ 2] .

W ith the introdu ction of small molecu le targ eted therapy , su ch as the tyr osine ki nase inhib itors su nitinib and soraf enib , in the treatment of metastatic renal cell carcinoma, there has b een g reat exci tement ab ou t the potential activi ty of these ag ents in the adj u va nt setting . C u rrently , there are three larg e phase I I I randomize d placeb o controlled trials exa mining the activi ty of these ag ents in the adj u va nt setting ( T a b l e 2 ) . T hese inclu de the ASSU R E trial (EC O G 28 0 5 ), w here patients are randomize d to 1 ye ar of soraf enib or su nitinib ve rsu s placeb o, the S- T R AC trial, w here patients are randomize d to 1 ye ar of su nitinib ve rsu s

1 62

placeb o, and the SO R C E trial, w here patients are randomize d to 3 ye ars of soraf enib or 1 ye ar of soraf enib ve rsu s placeb o[ 3, 6 3, 6 4 ] . W hile these trials remain ong oing at present, there have b een significant concerns raised regarding the toxicity of these ag ents in the adj u va nt setting . I n f act, several modifications and amendments have been made to these trials, inclu ding dose redu ctions and increases in accru al g oals, to help accou nt f or the not insignificant patient dropout rates related to drug intolerab ility[ 2, 6 5 ] .

2 . neoA D J uVA nT T H eRA P Y

T here have b een no randomiz ed clinical trials ex amining the role of neoadj u va nt therapy in the treatment of renal cell carcinoma. I n f act, u ntil ve ry recently , the only modality stu died in the neoadj u va nt setting has b een the issu e of preoperative emb oliza tion prior to nephrectomy[ 6 6 , 6 7 ] . ( l e v e l o f e v i d e n c e : 3 a ) I n these retrospective non- randomize d stu dies, there is a su g g estion that patients w ho had renal artery emb oliza tion prior to nephrectomy had a b etter ove rall su rvi va l relative to those that u nderw ent nephrectomy alone. T hese findings have not been confirmed prospectively.

Prior to the dev elopment of targ eted therapy , an ax iom in the manag ement of patients w ith renal cell carcinoma w as the f act that the primary tu mor rarely , if eve r, demonstrates a reliab le response to syst emic therapy[ 6 8 , 6 9 ] . (l e v e l o f e v i d e n c e : 4 ) T his, in part, serve d as the impetu s to perf orm cy toredu ctive nephrectomy in the manag ement of metastatic disease. W ith the increased u tiliza tion of targ eted therapy in the setting of metastatic renal cell carcinoma, anecdotal case reports and small sing le institu tional series of patients treated w ith their primary tu mor in place, demonstrating impressive responses in the primary tu mor, b eg an to appear in the literatu re[ 11, 4 6 , 7 0 ] . (l e v e l o f e v i d e n c e : 4 ) T hese impressive responses have prompted a revi siting of the concept of neoadj u va nt or presu rg ical therapy in b oth locally adva nced and metastatic renal cell carcinoma. I n an initial report of 17 patients treated w ith su nitinib w ith their primary tu mor in place, V an der V eldt and colleag u es reported that 23% of patients had a response as defined by RECIST criteria, and the mean vo lu me of tu mor redu ction in the primary tu mor w as 31% . Su b sequ ently , how eve r, initial phase I I stu dies su g g est that pre- su rg ical targ eted therapy is safe, but reliable and significant primary tu mor dow nstag ing or dow nsizi ng is u ncommon w ith the cu rrent g eneration of targ eted ag ents[ 4 6 , 7 1- 7 5 ] . (l e v e l o f e v i d e n c e : 2 b ) I n the maj ority of these stu dies, the primary tu mor demonstrated little if any response to syst emic therapy prior to su rg ery . D ramatic redu ctions in tu mor siz e, and thankf u lly , dramatic prog ressions in disease, w ere rare eve nts. C u rrently , phase I I and I I I stu dies are planned to f u rther eva lu ate the role of targ eted ag ents in the

neoadj u va nt setting f or b oth locally adva nced and metastatic renal cell carcinoma ( T a b l e 2 ) . ( fi g . 4 , 5 )

Re c o m m e n d a t i o n s G r a d e

•ne o a d j u v a n t o r a d j u v a n t t h e r a p y Af o r RCC r e m a i n s e x p e r i m e n t a l

•ne o a d j u v a n t t a r g e t e d t h e r a p y p r i o r Bt o s u r g e r y i s s a f e , h o w e v e r d e g r e e o f c y t o r e d u c t i o n i s u n p r e d i c t a b l e and oncologic efficacy is not e s t a b l i s h e d

VI. M A nA G eM enT of loCA l ReCuRRenCe

L ocal recu rrences w ithin the renal f ossa can represent recu rrent disease w ithin the adrenal g land, the retroperitoneal lym ph nodes, or the sof t tissu e tissu es in the area of the prior renal tu mor. W hile recu rrence w ithin the adrenal or retroperitoneal lym ph nodes represent metastatic prog ression, recu rrence in the sof t tissu es may represent a locally aggressive tumor but may also reect the results of a su rg ical mishap w ith tu mor vi olation at the orig inal nephrectomy . I solated local recu rrence w ithou t evi dence of distant metastases is a rare eve nt, w ith a reported incidence of 1- 2% f ollow ing radical nephrectomy w ith cu rative intent[ 7 6 - 7 9 ] . As su ch, the leve ls of evi dence reg arding natu ral history and methods of manag ement are L eve l 4 at b est.

O ve rall, the manag ement of renal f ossa recu rrence is predominately su rg ical. All of the case series reported in the literatu re advo cate ag g ressive su rg ical resection f or a local recu rrence in the ab sence of metastatic disease[ 7 6 - 7 9 ] . (l e v e l o f e v i d e n c e : 4 ) Esrig et al. reported on 10 patients w ho u nderw ent su rg ical resection of locally recu rrent renal cell carcinoma in the ab sence of metastatic disease[ 7 7 ] . I n this series, 4 of 10 patients achieve d du rab le disease f ree su rvi va l f ollow ing su rg ical resection, w ith one patient w ithou t evi dence of disease 18 ye ars af ter su rg ery . I n the series b y T ang u ay et al., 15 of 16 patients u nderw ent complete su rg ical resection of locally recu rrent disease, w ith 3 patients havi ng positive su rg ical marg ins[ 7 8 ] . T he au thors f ou nd that those patients treated w ith neoadj u va nt and/ or adj u va nt interf eron therapy w ere tw ice as like ly to remain w ithou t evi dence of disease f ollow ing su rg ery . I tano et al. reported on 30 patients in the M ayo C linic exp erience w ith local recu rrence[ 7 9 ] . O f these 9 w ere treated w ith ob serva tion, 11 w ere treated w ith therapy other than su rg ery , and 10 w ere treated w ith su rg ery alone or in comb ination w ith other therapies. W ith a median f ollow u p of 3.3 ye ars, the au thors f ou nd that patients w ho u nderw ent ag g ressive surgical resection had a 5-year cause specific

1 63

T A B L E 2 . O ngoing cl inical trial s of neoadj uv ant and adj uv ant systemic therapy in patients w ith l ocal l yadv anced RCC.

T r i a l / In s t i t u t i o n D e s i g n T h e r a p yN eoadj uv antU T M D Anderson Phase I I Axi tinib

U T Sou thw estern Phase I I Eve rolimu s

A dj uv antAR I SER Phase I I I mAb G 25 0 vs. Placeb o

ASSU R E Phase I I I Su nitinib vs. Soraf enib vs. Placeb o

S- T R AC Phase I I I Su nitinib vs. Placeb o

SO R C E Phase I I I Soraf enib vs. Placeb o

T A B L E 3 . Features predictiv e of systemic disease rel apse after surgical resection of l ocal RCC recurrence. [ 7 6 ]

fe a t u r e oR 9 5 % CI pP o s i t i v e s u r g i c a l m a r g i n a f t e r r e s e c t i o n o f l o c a l r e c u r r e n c e 3.20 7 1.0 6 5 - 9 .6 5 4 0 .0 38si ze o f r e c u r r e n t t u m o r 1.34 0 1.17 5 - 1.5 29 0 .0 0 1P r e s e n c e o f s a r c o m a t o i d f e a t u r e s i n r e c u r r e n c e s p e c i m e n 11.6 4 8 4 .0 0 0 - 33.9 21 0 .0 0 1A b n o r m a l s e r u m a l k a l i n e p h o s p h a t a s e a t t h e t i m e o f r e c u r r e n c e

13.7 5 4 3.0 6 6 - 6 1.6 9 4 0 .0 0 1

A b n o r m a l s e r u m l a c t a t e d e h y d r o g e n a s e a t t h e t i m e o f r e c u r r e n c e

17 .0 8 9 4 .14 4 - 7 0 .4 7 9 0 .0 0 1

Fig. 4: Possible complication in wound healing by pre-surgical targeted therapy

Fig 5. : Impact of Targeted Therapy On The Primary Tumor

N %

sunitinib 57 39.9

bevicizumab 26 18.2bevicizumab/

erlotinib 26 18.2

sorafenib 17 11.9

temsirolimus 10 7bevicizumab/

chemo 5 3.5

erlotinib 2 1.4

Total 143 100

SunitinibBevacizumabBevacizumab + Erlotinib

Sorafenib

TemsirolimusBevacizumab + Chemotherapy

Erlotinib

Abel et al. ASCO GU 2010Abel et al. ASCO GU 2010

Fig 5. : Impact of Targeted Therapy On The PrimaryTumor

Fig. 4: Possible complicatt tion in wound healing by pretsurgical targetedtherapy

1 64

su rvi va l of 5 1% , as compared to 18 % w ith therapy other than su rg ery , and 13% w ith ob serva tion alone. F inally , M arg u lis et al reported on 5 4 patients w ith renal f ossa recu rrence treated w ith su rg ery , w hich represents the larg est sing le institu tional series in the literatu re[ 7 6 ] . O f these, 6 9 % u nderw ent perioperative adjunctive systemic therapy. The authors identified 5 f actors associated w ith a w orse prog nosis af ter su rg ical resection, inclu ding size g reater than 5 cm, the presence of sarcomatoid dedif f erentiation, a positive su rg ical resection marg in, eleva ted alka line phosphatase, and eleva ted lactate dehyd rog enase ( T a b l e 3 ) . Patients w ith none of these risk f actors demonstrated a cancer specific survival of 111 months, w hereas patients w ith more than one of these risk factors had a cancer specific survival of only 8 months.

I n the ab sence of metastatic disease, ag g ressive su rg ical resection, either alone or in comb ination w ith perioperative (neoadj u va nt + / - adj u va nt) sy stemic therapy appears to provi de the b est ou tcomes f or locally recu rrent renal cell carcinoma. Limited data are available on the efficacy of the new targ eted ag ents in this setting , shou ld b e considered preoperatively if any of the adverse features identified b y M arg u lis et al. exi st.

Re c o m m e n d a t i o n s G r a d e

•su r g i c a l e x t i r p a t i o n r e m a i n s t h e Cs t a n d a r d o f c a r e f o r p a t i e n t s w i t h i s o l a t e d l o c a l r e c u r r e n c e o f RCC

•Cl i n i c a l p r o g n o s t i c f a c t o r s c a n b e Cu t i l i ze d f o r e x p e r i m e n t a l i n t e g r a t i o n o f p e r i o p e r a t i v e s y s t e m i c t h e r a p i e s i n p a t i e n t s a t h i g h r i s k o f d i s e a s e r e l a p s e a f t e r s u r g e r y

VII. suM M A RY

T he manag ement of locally adva nced R C C remains a dau nting , su rg ically demanding endeavo r b u t can b e associated w ith exce llent ou tcomes. W ith the exce ption of the role of lym ph node dissection and adj u va nt therapy in patient manag ement, the va st maj ority of treatment recommendations are made b ased on leve l 3 and leve l 4 evi dence. I n f act, despite leve l 1 evi dence to the contrary , the au thors w ou ld still advo cate lym ph node dissection, eve n in the presence of clinically neg ative ly mph nodes, to provi de more accu rate stag ing inf ormation and the potiential to eliminate micro- metastatic disease. T he deve lopment of ef f ective adj u va nt and neoadj u va nt therapy remains the sing le g reatest challeng e in improvi ng the ou tcome of patients w ith locally adva nced disease.

RefeRenCes

1. L eib ovi ch B C , B lu te M L . Su rg ical manag ement of renal cell carcinoma. Seminars in oncolog y . 20 0 6 O ct: 33: 5 5 2-6 2

2. Jacob sohn K M , W ood C G . Adj u va nt therapy f or renal cell carcinoma. Seminars in oncolog y . 20 0 6 O ct: 3 3 : 5 7 6 - 8 2

3. H aas N B , U zzo R . Adj u va nt therapy f or renal cell carcinoma. C u rrent oncolog y reports. 20 0 8 M ay: 1 0 : 24 5 -5 2

4 . M arshall V F , M iddleton R G , H olsw ade G R , G oldsmith EI . Su rg ery f or renal cell carcinoma in the ve na cava . T he Jou rnal of u rolog y . 19 7 0 Apr: 1 0 3 : 4 14 - 20

5 . B lu te M L , L eib ovi ch B C , L ohse C M , C hevi lle JC , Z incke H . T he M ayo C linic exp erience w ith su rg ical manag ement, complications and ou tcome f or patients w ith renal cell carcinoma and ve nou s tu mou r thromb u s. B JU I nt. 20 0 4 Ju l: 9 4 : 33- 4 1

6 . B oorj ian SA, Seng u pta S, B lu te M L . R enal cell carcinoma: ve na cava l invo lve ment. B JU I nt. 20 0 7 M ay: 9 9 : 1239 - 4 4

7 . O to A, H erts B R , R emer EM , N ovi ck AC . I nf erior ve na cava tu mor thromb u s in renal cell carcinoma: stag ing b y M R imag ing and impact on su rg ical treatment. AJR Am J R oentg enol. 19 9 8 D ec: 1 7 1 : 16 19 - 24

8 . G u zzo T J, Pierorazi o PM , Schaef f er EM , F ishman EK , Allaf M E. T he accu racy of mu ltidetector compu terize d tomog raphy f or eva lu ating tu mor thromb u s in patients w ith renal cell carcinoma. T he Jou rnal of u rolog y . 20 0 9 F eb : 1 8 1 : 4 8 6 - 9 0 ; discu ssion 9 1

9 . K araki ew icz PI , Su ardi N , Jeldres C , et al. N eoadj u va nt su tent indu ction therapy may ef f ective ly dow n- stag e renal cell carcinoma atrial thromb i. Eu r U rol. 20 0 8 Apr: 5 3 : 8 4 5 -8

10 . D i Silve rio F , Sciarra A, Parente U , et al. N eoadj u va nt therapy w ith soraf enib in adva nced renal cell carcinoma w ith ve na cava ext ension su b mitted to radical nephrectomy . U rol I nt. 20 0 8 : 8 0 : 4 5 1- 3

11. Shu ch B , R ig g s SB , L aR ochelle JC , et al. N eoadj u va nt targ eted therapy and adva nced ki dney cancer: ob serva tions and implications f or a new treatment paradig m. B JU I nt. 20 0 8 Sep: 1 0 2 : 6 9 2- 6

12. H af erka mp A, B astian PJ, Jako b i H , et al. R enal cell carcinoma w ith tu mor thromb u s ext ension into the ve na cava : prospective long - term f ollow u p. T he Jou rnal of u rolog y . 20 0 7 M ay: 1 7 7 : 17 0 3- 8

13. Su b ramanian V S, Stephenson AJ, G oldf arb D A, F erg any AF , N ovi ck AC , K rishnamu rthi V . U tility of preoperative renal artery emb oliza tion f or manag ement of renal tu mors w ith inf erior ve na cava l thromb i. U rolog y . 20 0 9 Ju l: 7 4 : 15 4 -9

14 . H enderson A, M u rphy D , Jag anathan K , R ob erts W W , W olf JS, Jr., R ane A. H and- assisted laparoscopic nephrectomy f or renal cell cancer w ith renal ve in tu mor thromb u s. U rolog y . 20 0 8 Au g : 7 2 : 26 8 - 7 2

15 . M artin G L , C astle EP, M artin AD , et al. O u tcomes of laparoscopic radical nephrectomy in the setting of ve na cava l and renal ve in thromb u s: seve n- ye ar exp erience. J Endou rol. 20 0 8 Au g : 2 2 : 16 8 1- 5

16 . R og ers C G , L inehan W M , Pinto PA. R ob otic nephrectomy f or ki dney cancer in a horseshoe ki dney w ith renal ve in tu mor thromb u s: nove l techniqu e f or thromb ectomy . J Endou rol. 20 0 8 Au g : 2 2 : 15 6 1- 3; discu ssion 3

17 . B ertini R , R oscig no M , L apenna E, et al. R adical nephrocapsu lectomy and cava l thromb ectomy w ith

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ext racorporeal circu lation and deep hy pothermic circu latory arrest in rig ht anterior minithoracotomy: a minimally inva sive approach. U rolog y . 20 0 8 M ay: 7 1 : 9 5 7 - 6 1

18 . M azzo la A, G reg orini R , V illani C , et al. C avo atrial tu mor thromb ectomy w ith syst emic circu latory arrest and anteg rade cereb ral perf u sion. Ann T horac Su rg . 20 0 7 Apr: 8 3 : 15 6 4 - 5

19 . C how dhu ry U K , M ishra AK , Seth A, et al. N ove l techniqu es f or tu mor thromb ectomy f or renal cell carcinoma w ith intraatrial tu mor thromb u s. Ann T horac Su rg . 20 0 7 M ay: 8 3 : 17 31- 6

20 . G ranb erg C F , B oorj ian SA, Schaf f H V , et al. Su rg ical manag ement, complications, and ou tcome of radical nephrectomy w ith inf erior ve na cava tu mor thromb ectomy f acilitated b y va scu lar b yp ass. U rolog y . 20 0 8 Ju l: 7 2 : 14 8 -5 2

21. B lu te M L , B oorj ian SA, L eib ovi ch B C , L ohse C M , F rank I , K arnes R J. R esu lts of inf erior ve na cava l interru ption by greenfield filter, ligation or resection during radical nephrectomy and tu mor thromb ectomy . T he Jou rnal of u rolog y . 20 0 7 Au g : 1 7 8 : 4 4 0 - 5 ; discu ssion 4

22. H atcher PA, Anderson EE, Pau lson D F , C arson C C , R ob ertson JE. Su rg ical manag ement and prog nosis of renal cell carcinoma inva ding the ve na cava . T he Jou rnal of u rolog y . 19 9 1 Jan: 1 4 5 : 20 - 3; discu ssion 3- 4

23. K im H L , Z isman A, H an K R , F ig lin R A, B elldeg ru n AS. Prognostic significance of venous thrombus in renal cell carcinoma. Are renal ve in and inf erior ve na cava invo lve ment dif f erent? T he Jou rnal of u rolog y . 20 0 4 F eb : 1 7 1 : 5 8 8 - 9 1

24 . L eib ovi ch B C , C hevi lle JC , L ohse C M , et al. C ancer specific survival for patients with pT3 renal cell carcinoma-can the 2002 primary tumor classification be improved? T he Jou rnal of u rolog y . 20 0 5 M ar: 1 7 3 : 7 16 - 9

25 . M arshall F F , D ietrick D D , B au mg artner W A, R eitz B A. Su rg ical manag ement of renal cell carcinoma w ith intracava l neoplastic ext ension ab ove the hepatic ve ins. T he Jou rnal of u rolog y . 19 8 8 Ju n: 1 3 9 : 116 6 - 7 2

26 . M ontie JE, Pontes JE, N ovi ck AC , et al. R esection of inf erior ve na cava tu mor thromb i f rom renal cell carcinoma. Am Su rg . 19 9 1 Jan: 5 7 : 5 6 - 6 1

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28 . N ovi ck AC , K aye M C , C osg rove D M , et al. Exp erience w ith cardiopu lmonary b yp ass and deep hyp othermic circu latory arrest in the manag ement of retroperitoneal tu mors w ith larg e ve na cava l thromb i. Ann Su rg . 19 9 0 O ct: 2 1 2 : 4 7 2- 6 ; discu ssion 6 - 7

29 . R eissig l A, Janetschek G , Eb erle J, et al. R enal cell carcinoma ext ending into the ve na cava : su rg ical approach, techniqu e and resu lts. B r J U rol. 19 9 5 F eb : 7 5 : 138 - 4 2

30 . Sw ierze w ski D J, Sw ierze w ski M J, L ib ertino JA. R adical nephrectomy in patients w ith renal cell carcinoma w ith ve nou s, v ena cava l, and atrial ext ension. Am J Su rg . 19 9 4 Au g : 1 6 8 : 20 5 - 9

31. Moinzadeh A, Libertino JA. Prognostic significance of tu mor thromb u s leve l in patients w ith renal cell carcinoma and ve nou s tu mor thromb u s ext ension. I s all T 3b the same? T he Jou rnal of u rolog y . 20 0 4 F eb : 1 7 1 : 5 9 8 - 6 0 1

32. Pantu ck AJ, Z isman A, D orey F , et al. R enal cell carcinoma w ith retroperitoneal lym ph nodes: role of lym ph node dissection. T he Jou rnal of u rolog y . 20 0 3 Ju n: 1 6 9 : 20 7 6 -8 3

33. Canfield SE, Kamat AM, Sanchez-Ortiz RF, Detry M, Sw anson D A, W ood C G . R enal cell carcinoma w ith nodal metastases in the ab sence of distant metastatic disease (clinical stag e T xN 1- 2M 0 ): the impact of ag g ressive

su rg ical resection on patient ou tcome. T he Jou rnal of u rolog y . 20 0 6 M ar: 1 7 5 : 8 6 4 - 9

34 . K araki ew icz PI , T rinh Q D , B hoj ani N , et al. R enal C ell C arcinoma w ith N odal M etastases in the Ab sence of D istant M etastatic D isease: Prog nostic I ndicators of Disease-Specific Survival. Eur Urol. 2006 Dec 14:

35 . B lom JH , Schroder F H , H ammond B , Syl ve ster R . R adical nephrectomy w ith and w ithou t lym ph node dissection: preliminary resu lts of EO R T C Protocol 30 8 8 1. T he EO R T C G enitou rinary G rou p. Prog C lin B iol R es. 19 9 2: 3 7 8 : 16 1- 7

36 . V asselli JR , Y ang JC , L inehan W M , W hite D E, R osenb erg SA, W alther M M . L ack of retroperitoneal lym phadenopathy predicts su rvi va l of patients w ith metastatic renal cell carcinoma. T he Jou rnal of u rolog y . 20 0 1 Ju l: 1 6 6 : 6 8 - 7 2

37 . B lu te M L , L eib ovi ch B C , C hevi lle JC , L ohse C M , Z incke H . A protocol f or perf orming ext ended lym ph node dissection u sing primary tu mor patholog ical f eatu res f or patients treated w ith radical nephrectomy f or clear cell renal cell carcinoma. T he Jou rnal of u rolog y . 20 0 4 Au g : 1 7 2 : 4 6 5 - 9

38 . T hompson R H , R aj G V , L eib ovi ch B C , R u sso P, B lu te M L , K attan M W . Preoperative nomog ram to predict positive lym ph nodes du ring nephrectomy f or renal cell carcinoma. Proceeding s f rom American U rolog ic Association. 20 0 8 :

39 . T errone C , G u ercio S, D e L u ca S, et al. T he nu mb er of lym ph nodes exa mined and stag ing accu racy in renal cell carcinoma. B JU I nt. 20 0 3 Jan: 9 1 : 37 - 4 0

4 0 . Joslyn SA, Sirintrapu n SJ, K onety B R . I mpact of lym phadenectomy and nodal b u rden in renal cell carcinoma: retrospective analysi s of the N ational Su rve illance, Epidemiolog y , and End R esu lts datab ase. U rolog y . 20 0 5 Apr: 6 5 : 6 7 5 - 8 0

4 1. Parke r AE. Stu dies on the main posterior lym ph channels of the ab domen and their connections w ith the lym phatics of the g enito- u rinary syst em. Am J Anat. 19 35 : 4 0 9

4 2. M arg u lis V , Sanchez- O rtiz R F , T amb oli P, C ohen D D , Sw anson D A, W ood C G . R enal cell carcinoma clinically invo lvi ng adj acent org ans: exp erience w ith ag g ressive su rg ical manag ement. C ancer. 20 0 7 M ay 15 : 1 0 9 : 20 25 -30

4 3. K arellas M E, Jang T L , K ag iw ada M A, K innaman M D , Jarnag in W R , R u sso P. Adva nced- stag e renal cell carcinoma treated b y radical nephrectomy and adj acent org an or stru ctu re resection. B JU I nt. 20 0 9 Jan: 1 0 3 : 16 0 -4

4 4 . C apitanio U , Perrotte P, Z ini L , et al. N ephrectomy improve s su rvi va l in patients w ith inva sion of adj acent vi scera and ab sence of nodal metastases (stag e T 4 N 0 renal cell carcinoma). B JU I nt. 20 0 9 Sep: 1 0 4 : 7 9 5 - 9

4 5 . H ock L M , L yn ch J, B alaj i K C . I ncreasing incidence of all stag es of ki dney cancer in the last 2 decades in the U nited States: an analysi s of su rve illance, epidemiolog y and end resu lts prog ram data. J U rol. 20 0 2 Jan: 1 6 7 : 5 7 - 6 0

4 6 . B ex A, va n der V eldt AA, B lank C , et al. N eoadj u va nt su nitinib f or su rg ically complex adva nced renal cell cancer of dou b tf u l resectab ility: initial exp erience w ith dow nsizi ng to reconsider cyt oredu ctive su rg ery . W orld J U rol. 20 0 9 Au g : 2 7 : 5 33- 9

4 7 . Pizzo caro G , Piva L , Salvi oni R , D i F ronzo G , R onchi E, M iodini P. Adj u va nt medroxyp rog esterone acetate and steroid hormone receptors in categ ory M 0 renal cell carcinoma. An interim report of a prospective randomize d stu dy . T he Jou rnal of u rolog y . 19 8 6 Jan: 1 3 5 : 18 - 21

4 8 . Pizzo caro G , Piva L , D i F ronzo G , et al. Adj u va nt medroxyp rog esterone acetate to radical nephrectomy in renal cancer: 5 - ye ar resu lts of a prospective randomize d stu dy . T he Jou rnal of u rolog y . 19 8 7 D ec: 1 3 8 : 137 9 - 8 1

4 9 . M aka rew icz R , Z arzycka M , K u linska G , W indorb ska W .

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T he va lu e of postoperative radiotherapy in adva nced renal cell cancer. N eoplasma. 19 9 8 : 4 5 : 38 0 - 3

5 0 . R odrig u ez A, Sext on W J. M anag ement of locally adva nced renal cell carcinoma. C ancer C ontrol. 20 0 6 Ju l: 1 3 : 19 9 -210

5 1. Atzp odien J, Schmitt E, G ertenb ach U , et al. Adj u va nt treatment w ith interleu ki n- 2- and interf eron- alpha2a- b ased chemoimmu notherapy in renal cell carcinoma post tu mou r nephrectomy: resu lts of a prospective ly randomised trial of the G erman C ooperative R enal C arcinoma C hemoimmu notherapy G rou p (D G C I N ). B ritish j ou rnal of cancer. 20 0 5 M ar 14 : 9 2 : 8 4 3- 6

5 2. M u lders PF , D e M u lder PH . T he role of adj u va nt immu notherapy in renal cell carcinoma. C u rrent u rolog y reports. 20 0 2 F eb : 3 : 4 4 - 9

5 3. Jeon SH , C hang SG , K im JI . T he role of adj u va nt immu notherapy af ter radical nephrectomy and prog nostic f actors in pT 3N 0 M 0 renal cell carcinoma. Anticancer research. 19 9 9 N ov- D ec: 1 9 : 5 5 9 3- 7

5 4 . B asting R , C orvi n S, H andel D , H inke A, Schmidt D . Adj u va nt immu notherapy in renal cell carcinoma- -comparison of interf eron alpha treatment w ith an u ntreated control. Anticancer research. 19 9 9 M ar- Apr: 1 9 : 15 4 5 - 8

5 5 . M ig liari R , M u scas G , Solinas A, et al. I s there a role f or adj u va nt immu nochemotherapy af ter radical nephrectomy in pT 2- 3N 0 M 0 renal cell carcinoma? Jou rnal of chemotherapy (F lorence, I taly) . 19 9 5 Ju n: 7 : 24 0 - 5

5 6 . R epmann R , G oldschmidt AJ, R ichter A. Adj u va nt therapy of renal cell carcinoma patients w ith an au tolog ou s tu mor cell lysa te va ccine: a 5 - ye ar f ollow - u p analysi s. Anticancer research. 20 0 3 M ar- Apr: 2 3 : 9 6 9 - 7 4

5 7 . W ood C , Sriva stava P, B u ko w ski R , et al. An adj u va nt au tolog ou s therapeu tic va ccine (H SPPC - 9 6 ; vi tespen) ve rsu s ob serva tion alone f or patients at hig h risk of recu rrence af ter nephrectomy f or renal cell carcinoma: a mu lticentre, open- lab el, randomised phase I I I trial. L ancet. 20 0 8 Ju l 12: 3 7 2 : 14 5 - 5 4

5 8 . U emu ra H , D e V elasco M A. T u mor va ccines in renal cell carcinoma. W orld j ou rnal of u rolog y . 20 0 8 Apr: 2 6 : 14 7 - 5 4

5 9 . K u b ler H , V iew eg J. V accines in renal cell carcinoma. Seminars in oncolog y . 20 0 6 O ct: 3 3 : 6 14 - 24

6 0 . Jocham D , R ichter A, H of f mann L , et al. Adj u va nt au tolog ou s renal tu mou r cell va ccine and risk of tu mou r prog ression in patients w ith renal- cell carcinoma af ter radical nephrectomy: phase I I I , randomised controlled trial. L ancet. 20 0 4 F eb 21: 3 6 3 : 5 9 4 - 9

6 1. G allig ioni E, Q u aia M , M erlo A, et al. Adj u va nt immu notherapy treatment of renal carcinoma patients w ith autologous tumor cells and bacillus Calmette-Guerin: five-ye ar resu lts of a prospective randomize d stu dy . C ancer. 19 9 6 Ju n 15 : 7 7 : 25 6 0 - 6

6 2. M arg u lis V , M atin SF , T annir N , et al. R andomize d trial of adj u va nt thalidomide ve rsu s ob serva tion in patients w ith completely resected hig h- risk renal cell carcinoma. U rolog y . 20 0 9 F eb : 7 3 : 337 - 4 1

6 3. K apoor A, G haraj eh A, Sheikh A, Pinthu s J. Adj u va nt and neoadj u va nt small- molecu le targ eted therapy in hig h- risk renal cell carcinoma. C u rrent oncolog y (T oronto, O nt. 20 0 9 M ay: 1 6 su p p l 1 : S6 0 - 6

6 4 . K u nkl e D A, H aas N B , U zzo R G . Adj u va nt therapy f or hig h-risk renal cell carcinoma patients. C u rrent u rolog y reports. 20 0 7 Jan: 8 : 19 - 30

6 5 . W ood C G . Adj u va nt approaches to renal cell carcinoma. C lin Adv H ematol O ncol. 20 0 8 Jan: 6 : 19 - 21

6 6 . K alman D , V arenhorst E. T he role of arterial emb oliza tion in renal cell carcinoma. Scandinavi an j ou rnal of u rolog y and nephrolog y . 19 9 9 Ju n: 3 3 : 16 2- 7 0

6 7 . Z ielinski H , Szm ig ielski S, Petrovi ch Z . C omparison of preoperative emb oliza tion f ollow ed b y radical nephrectomy w ith radical nephrectomy alone f or renal cell carcinoma. American j ou rnal of clinical oncolog y . 20 0 0 F eb : 2 3 : 6 - 12

6 8 . Spencer W F , L inehan W M , W alther M M , et al. I mmu notherapy w ith interleu ki n- 2 and alpha- interf eron in patients w ith metastatic renal cell cancer w ith in situ primary cancers: a pilot stu dy . T he Jou rnal of u rolog y . 19 9 2 Jan: 1 4 7 : 24 - 30

6 9 . W ag ner JR , W alther M M , L inehan W M , W hite D E, R osenb erg SA, Y ang JC . I nterleu ki n- 2 b ased immu notherapy f or metastatic renal cell carcinoma w ith the ki dney in place. T he Jou rnal of u rolog y . 19 9 9 Ju l: 1 6 2 : 4 3- 5

7 0 . va n der V eldt AA, M eij erink M R , va n den Eertw eg h AJ, et al. Su nitinib f or treatment of adva nced renal cell cancer: primary tu mor response. C lin C ancer R es. 20 0 8 Apr 15 : 1 4 : 24 31- 6

7 1. Silb erstein JL , M illard F , M ehrazi n R , et al. F easib ility and efficacy of neoadjuvant sunitinib before nephron-sparing su rg ery . B JU international. Apr 15 :

7 2. C ow ey C L , Amin C , Pru thi R S, et al. N eoadj u va nt clinical trial w ith soraf enib f or patients w ith stag e I I or hig her renal cell carcinoma. J C lin O ncol. M ar 20 : 2 8 : 15 0 2- 7

7 3. Jonasch E, W ood C G , M atin SF , et al. Phase I I presu rg ical f easib ility stu dy of b eva cizu mab in u ntreated patients w ith metastatic renal cell carcinoma. J C lin O ncol. 20 0 9 Sep 1: 2 7 : 4 0 7 6 - 8 1

7 4 . W ood C G , M arg u lis V . N eoadj u va nt (presu rg ical) therapy f or renal cell carcinoma: a new treatment paradig m f or locally adv anced and metastatic disease. C ancer. 20 0 9 M ay 15 : 1 1 5 : 235 5 - 6 0

7 5 . M arg u lis V , W ood C G . C yt oredu ctive nephrectomy in the era of targ eted molecu lar ag ents: is it time to consider presu rg ical syst emic therapy? Eu ropean u rolog y . 20 0 8 Sep: 5 4 : 4 8 9 - 9 2

7 6 . M arg u lis V , M cD onald M , T amb oli P, Sw anson D A, W ood C G . Predictors of oncolog ical ou tcome af ter resection of locally recu rrent renal cell carcinoma. T he Jou rnal of u rolog y . 20 0 9 M ay: 1 8 1 : 20 4 4 - 5 1

7 7 . Esrig D , Ahlering T E, L iesko vsky G , Ski nner D G . Exp erience w ith f ossa recu rrence of renal cell carcinoma. T he Jou rnal of u rolog y . 19 9 2 Ju n: 1 4 7 : 14 9 1- 4

7 8 . T ang u ay S, Pisters L L , L aw rence D D , D inney C P. T herapy of locally recu rrent renal cell carcinoma af ter nephrectomy . T he Jou rnal of u rolog y . 19 9 6 Jan: 1 5 5 : 26 - 9

7 9 . I tano N B , B lu te M L , Spotts B , Z incke H . O u tcome of isolated renal cell carcinoma f ossa recu rrence af ter nephrectomy . T he Jou rnal of u rolog y . 20 0 0 Au g : 1 6 4 : 322-5

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Co m m i t t e e 7

T r e a t m e n t o f M e t a s t a t i c D i s e a s e

Ch a i r s :

J. - J. P A T A R D ,

J. B E LLM U N T

M e m b e r s :

A . B E X ,R . B U K O W S K I ,T . C HO U E I R I ,

T . E I S E N ,B . E S C U D I E R ,R . M O T Z E R ,

B . R I N I ,J. R O I G A S ,

C . S T E R N B E R G ,

Co r r e s p o n d e n c eJ.J. PatardC entre H ospitalier B icê treD epartment of U rolog yL e K remlin B icê treF rance

J. B ellmu ntH ospital D el M arM edical O ncolog y Servi ceB arcelonaSpain

1 68

T A B le of ConT enT s

I. InT RoD uCT Ion

II. eVID enCe A CQ uIsIT Ion

III. eVID enCe sY nT H esIs

1 . CuRRenT T ReA T M enT A P P RoA CH es uT IlIZ InG noVel T A RG eT eD A G enT s

2 . T ReA T M enT - nA Ï Ve P A T IenT s

3 . CY T oK Ine- RefRA CT oRY P A T IenT s

4 . VeG f- T A RG eT eD T H eRA P Y - RefRA CT oRY P A T IenT s A nD seQ uenT IA l T H eRA P Y ConCeP T .

5 . D RuG CoM B InA T Ion

6 . T H e Role foR neP H ReCT oM Y In T H e eRA of T A RG eT eD T H eRA P Ies

7 . T H e Role of M eT A sT A seCT oM Y .

IV. P A nel Consensus ReCoM M enD A T Ions.

1 69

T r e a t m e n t o f M e t a s t a t i c D i s e a s e

J. - J. P A T A R D , A . B E X , R . B U K O W S K I , T . C HO U E I R I ,

T . E I S E N , B . E S C U D I E R , R . M O T Z E R , B . R I N I , J. R O I G A S ,C . S T E R N B E R G , J. B E LLM U N T ,

R enal cell carcinoma (R C C ) accou nts f or 2% of all cancers. I n Eu rope, 4 0 ,0 0 0 patients are diag nosed w ith R C C each ye ar, leading to 20 ,0 0 0 deaths [ 1] .

O ne- third of patients are initially diag nosed w ith locally inva sive or stag e I V disease. R ecu rrence occu rs in ab ou t 25 % of patients havi ng su rg ical resection f or localize d disease eve n thou g h it w as considered as cu rative . T he prog nosis f or patients w ith distant disease w as g enerally poor, w ith a 5 - ye ar su rvi va l rate not exce eding 10 % [ 2] . U ntil the past 4 ye ars, sy stemic treatments in patients w ith metastatic R C C (mR C C ) have prove n larg ely inef f ective . R eg arding chemotherapy or hormonal therapy , no sing le ag ent has b een reported to achieve a consistent response rate in more than 10 % of patients [ 3] .

O nly a ve ry small percentag e of patients are like ly to deve lop long - term disease- f ree su rvi va l f ollow ing interf eron- α (I F N ) and/ or interleu ki ne- 2 (I L - 2) b ased therapy [ 4 - 5 ] . At M emorial Sloan K ettering C ancer C enter (M SK C C ), the ove rall median su rvi va l in 6 7 0 patients w ho w ere treated w ith chemotherapy or immu notherapy in 24 consecu tive clinical trials f rom 19 7 5 to 19 9 6 w as 10 months [ 6 ] .

T w o ke y pathw ays are essential to the pathophysi olog y of the clear cell R C C su b typ e: the hyp oxi a response pathw ay associated w ith inactiva tion of the vo n H ippel- L indau (V H L ) tu mou r su ppressor g ene and the mT O R (mammalian targ et of rapamyci n) sig naling pathw ay [ 7 ] . Seve ral therapies, targ eting these tw o pathw ays inclu ding su nitinib , soraf enib , temsirolimu s, b eva cizu mab and eve rolimu s are av ailab le f or clinical u se and have revo lu tionize d the treatment of mR C C [ 8 ] . T his article revi ew s cu rrent targeted treatment approaches in the first- and second-line mRCC settings, as well as modifications

to exi sting treatment alg orithms, b ased on recently ava ilab le data.

II. eVID enCe A CQ uIsIT Ion

M edical literatu re w as retrieve d f rom Pu b M ed u p u ntil D ecemb er 20 0 9 . Additional releva nt articles and ab stract revi ew s w ere inclu ded f rom the b ib liog raphies of the retrieve d literatu re. All data w as reviewed and final statements were approved by experts in the field.

III. eVID enCe sY nT H esIs

1 . CuRRenT T ReA T M enT A P P RoA CH es uT IlIZ InG noVel T A RG eT eD A G enT s

At present, treatment f or m clear cell R C C w ith molecu larly targ eted ag ents can b e b roadly divi ded into the f ollow ing categ ories: previ ou sly u ntreated patients, those ref ractory or intolerant to immu notherapy , and those w ho have f ailed treatment w ith V EG F - targ eted therapy [ 2] . An important consideration that inuences treatment decisions is the M emorial Sloan- K ettering C ancer C enter (MSKCC) prognostic risk stratification system, which is widely used to define patient profiles and provi des an indication of ove rall su rvi va l (O S) [ 6 ] . I n this syst em, derive d f rom patients treated w ith interf eron- b ased therapy on six prospective clinical trials at a single center in the US, five prognostic f actors are u sed to categ orize patients w ith mR C C into three risk g rou ps: f avo u rab le (ze ro risk f actors), intermediate (1– 2 risk f actors) and poor (3 risk f actors). M edian O S times f or patients w ith g ood risk is 30 months, intermediate risk is 14 months and poor risk is 5 months [ 8 ] .

I. InT RoD uCT Ion

1 70

2 . T ReA T M enT - nA Ï Ve P A T IenT s

a) T reatment- naï v e patients w ith fav ourabl e or intermediate prognosis

Su nitinib is a mu lti- ki nase inhib itor (T K I ) that acts mainly on the V EG F receptor (V EG F R ) and platelet-derive d g row th f actor receptor (PD G F R ). I n a Phase I I I trial of su nitinib ve rsu s interf eron alpha (IFN-α) in untreated patients with mRCC, sunitinib demonstrated significant improvements in objective response rate (O R R ; independent revi ew , 31% vs 6 % ; p < 0 .0 0 0 0 0 1), median prog ression- f ree su rvi va l (PF S; 11 mo vs 5 mo; p < 0 .0 0 1) and ove rall su rvi va l (O S; 26 .4 mo vs 21.8 mo; haza rd ratio [ H R ] , 0 .8 21; p = 0 .0 5 1 ) [ 9 - 10 ] . T hese data have led to sunitinib being recommended as a first-line therapy f or patients w ith mR C C [ 11] (figure 1).

B eva cizu mab , a monoclonal antib ody targ eting the VEGF ligand directly, in combination with IFN-α, has shown efficacy in two Phase III trials in patients w ith previ ou sly u ntreated mR C C [ 12- 15 ] . I n the first of these studies, median PFS was 10.4 mo for bevacizumab plus IFN-α compared with 5.5 mo for IFN-α alone (p < 0.0001) [12]. No significant dif f erence in ove rall su rvi va l w as ob serve d (23.3 mo vs 21.3 mo; p = 0 .129 1) [ 16 ] . C onsistent resu lts w ere seen in the second stu dy , perf ormed b y the C ancer and L eu k emia G rou p B , w ith median PF S of 8 .4 mo and 4 .9 mo, respective ly (p < 0 .0 0 0 1) [ 13] . Ag ain, no significant difference in OS was observed (18.3 mo vs 17 .4 mo; p = 0.069) [17]. The PFS benefits seen in these trials are similar to those ob tained w ith su nitinib in therapy- naï ve patients w ith adva nced

RCC [9], and supports bevacizumab plus IFN-α as another acceptable and effective therapy in the first-line setting [ 11] (figure 1).

Pazo panib has a similar b road spectru m of ki nase inhib ition, inclu ding V EG F R 1– 3, PD G F R - A and - B , and c- K it [ 18 ] . T he resu lts of a phase 3 trial ve rsu s placeb o in patients w ho either receive d no prior therapy or w ho f ailed on prior therapy w ith cyt oki nes or b eva cizu mab has recently b een reported [ 19 ] . Four hundred thirty-five therapy naive and cytokine-pretreated mR C C patients w ere randomize d to oral pazo panib or placeb o (randomisation 2: 1 f or pazo panib ), w ith PF S as the primary endpoint. I n b oth treatment naï ve and pretreated patients there was a significant benefit in PFS. The median PFS f or pazo panib as compared to placeb o w as 9 .2 vs 4 .2 months and in treatment naï ve patients, 11.1 vs 2.8 months, respective ly (p < 0 .0 0 0 0 0 0 1). D ata are immatu re w ith reg ards to O S. T his data have led to pazo panib receivi ng F D A approva l in the U S (figure 1 ).

b) T reatment- naï v e patients w ith poor prognosis

T emsirolimu s is an intrave nou sly administered inhib itor of mT O R . A randomize d, Phase I I I trial compared monotherapy w ith temsirolimu s ve rsu s I F N - α ve rsu s temsirolimu s plu s I F N - α as first-line treatment in patients w ith mR C C and poor prog nosis [ 20 ] . Patients w ere requ ired to have at least three of six predictors of a poor prog nosis and su rvi va l according to a prognostic factor scheme modified f rom the M SK C C model. Patients w ho receive d temsirolimu s alone, compared w ith those w ho

Figure 1. Treatment schematic for patients with metastatic clear-cell renal cell carcinoma in the first-l ine setting

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receive d I F N - α alone or the comb ination had g reater PF S (5 .5 vs 3.1 vs 4 .7 mo, respective ly) , O S (10 .9 vs 7 .3 vs 8 .4 mo) and O R R (8 .6 % vs 4 .8 % vs 8 .1% ). T he results of this trial justify mTOR as a target for renal cancer treatment and recent Eu ropean g u idelines recommend that temsirolimus be considered as first-line treatment in poor- risk patients [ 11] (figure 1).

3 . CY T oK Ine- RefRA CT oRY P A T IenT s

Soraf enib is a small- molecu le mu ltiki nase inhib itor of V EG F R and related receptors, and also inhib its the intracellu lar sig nalling of R af ki nase. I n a placeb o-controlled, Phase I I I trial invo lvi ng patients w ith mR C C w ho had f ailed previ ou s cyt oki ne therapy , a PF S adva ntag e f or soraf enib of 5 .5 mo ve rsu s 2.8 mo (p < 0 .0 0 1) w as ob serve d [ 21- 22] . Partial responses w ere reported as the b est response in 10 % of patients receivi ng soraf enib and in 2% of placeb o recipients (p < 0 .0 0 1). D isease control rate w as hig her f or soraf enib than placeb o (6 2% vs 37 % ; p < 0 .0 0 1) [ 21] . An improve d O S w ith soraf enib w as ob serve d af ter censoring placeb o patients w ho had crossed ove r to soraf enib (17 .8 mo vs 14 .3 mo; p = 0 .0 28 7 ) [ 22] . B ased on the resu lts of this trial, soraf enib is recommended as a second- line ag ent in cy toki ne- ref ractory patients [ 11] (figure 2).

The efficacy of sunitinib in a total of 169 patients with mR C C w ho prog ressed on prior cyt oki ne therapy w as demonstrated in tw o Phase I I trials [ 23- 24 ] . Across the tw o trials, partial responses w ere reported in 34 –4 0 % of patients and a median PF S of 8 .3– 8 .7 mo w as ob serve d.

T ake n tog ether, these data indicate that either soraf enib or su nitinib may b e va lid second- line

treatment options f or patients w ho have f ailed prior cyt oki ne- b ased therapies.

Pazo panib , in the recently reported phase I I I trial comparing its efficacy over placebo in naïve and cyt oki ne ref ractory patients also demonstrated a PF S adva ntag e in the latest g rou p (median PF S 7 .4 vs 4 .2 months, p va lu e < 0 .0 0 1) [ 19 ] . T his has lead to pazo panib ’ s approva l b y the F D A in the second line setting af ter cyt oki ne f ailu re (figure 2) and is u nder eva lu ation b y the EM EA.

4 . VeG f- T A RG eT eD T H eRA P Y - RefRA CT oRY P A T IenT s A nD seQ uenT IA l T H eRA P Y ConCeP T .

Substantial clinical benefit has been obtained f rom retrospective or phase I I trials b y nove l T K I s, inclu ding su nitinib , soraf enib and axi tinib , in patients w ith mR C C f ailing a V EG F - targ eted therapy [ 25 - 29 ] . T he R EC O R D - 1 trial has exp lored the possib ility to sw itch to an ag ent w ith a dif f erent mechanism of action and molecu lar targ et, i.e. an mT O R inhib itor su ch as eve rolimu s [ 30 ] . I n this Phase I I I trial, patients receivi ng eve rolimu s (10 mg once daily; n = 27 2) had significantly prolonged PFS versus those on placeb o (n = 138 ; 4 .0 mo vs 1.9 mo; H R , 0 .30 ; p < 0 .0 0 0 1). T he end of the dou b le- b lind analysi s f rom this trial indicated a f u rther improve ment in PF S w ith eve rolimu s treatment (4 .9 0 mo [ n = 27 7 ] ve rsu s 1.8 7 mo [ n = 139 ] ; H R , 0 .33; p < 0 .0 0 1). T he PFS benefit following treatment with everolimus was maintained across patients w ith f avo u rab le ( n = 120 ), intermediate (n = 235 ) or poor ( n = 6 1) M SK C C prog nosis. At the end of the dou b le- b lind analysi s, median O S w as 14 .7 8 mo in the eve rolimu s g rou p

Figure 2 . T reatment schematic for patients w ith metastatic cl ear- cel l renal cel l carcinoma in the second- l ine setting

Second-line systemic therapy

sorafenib*sunitinib†

pazopanib*

Prior cytokines Prior VEGF-targeted therapies

everolimus*sequential TKI treatment†

Prior mTOR therapies

clinical trial‡

Second-line systemic therapy

sorafenib*sunitinib†

pazopanib*

Prior cytokines Prior VEGF-targeted therapies

everolimus*sequential TKI treatment†

grade B recommendation; ‡grade C recommendation

Prior mTOR therapies

clinical trial‡

* g rade A recommandation; + g rade B recommendation; + + g rade C recommendation

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and 14 .39 mo in the placeb o g rou p. C rossove r f rom placeb o to the active treatment arm w as allow ed af ter disease prog ression, potentially conf ou nding O S; 8 1% of placeb o recipients w ho prog ressed crossed ove r to eve rolimu s treatment.

T w o other randomize d phase I I I trials are cu rrently recru iting to look f or the position of temsirolimu s and axi tinib as second line options. T he AX I S trial is testing axi tinib ve rsu s soraf enib in patients f ailing any of the first line regimens such as sunitinib, b eva cizu mab + interf eron, temsirolimu s or cyt oki nes. T he second trial is a prospective randomize d phase I I I trial of temsirolimu s ve rsu s soraf enib as second line therapy in patients who have failed first line su nitinib option. I n b oth trials, PF S is the primary endpoint.

O ther trials are ong oing to determine the optimal T K I s/ T K I s or T K I ss/ mT O R inhib itors dru g sequ ence. B ased on seve ral retrospective reports show ing that the sequ ence of soraf enib g ive n prior to su nitinib may b e su perior w hen compared to the reve rse sequ ence, an ong oing phase 3 trial (SW I T C H trial) has been designed to define the best sequence of T K I s. Another trial is the R EC O R D - 3 stu dy . T his is an open- lab el, mu lticenter phase I I stu dy to compare first-line everolimus followed by second-line sunitinib versus the opposite sequence (first-line sunitinib f ollow ed b y second- line eve rolimu s) in the treatment of patients w ith mR C C (N C T 0 0 9 0 317 5 ).

5 . D RuG CoM B InA T Ion

T he concept of anti- ang iog enic dru g comb ination is to enhance drug monotherapy efficacy by vertical or horizo ntal b locka de. T he inhib ition of seve ral steps of the same pathw ay (H I F - V EG F R - V EG F R ) is a “ ve rtical” b locka de w hile targ eting in parallel 2 separate pathw ay s w ith dif f erent f u nctions (PD G F R , V EG F R , EG F R ) is considered as an horizo ntal “ b locka de” [ 31] .

T he comb ination of b eva cizu mab and su nitinib has b een ex plored in a phase I stu dy [ 32] . N ineteen patients w ith mR C C receive d escalating doses of sunitinib from 25 to 50 mg daily with fixed- dose b eva cizu mab (10 mg / kg I V ). D ose- limiting toxi city (D L T ) w as g rade 4 haemorrhag e in one patient in each of the hig her doses and one f atal myo cardial inf arction at the hig hest dose. All leve ls of treatment indu ced a 37 % PR . T he toxi city seen w ith these tw o ag ents preclu ded f u rther deve lopment of the comb ination.

T he comb ination of b eva cizu mab and soraf enib has b een exp lored in a phase I trial [ 33] . Sixt een patients w ere inclu ded f or a dose- escalation. G rade 3 proteinu ria and u ncontrolled g rade 3 hyp ertension w ere the D L T s at the hig hest lev el, corresponding to the maxi mu m tolerated dose (M T D ). T he recommended dose w as soraf enib at 20 0 mg tw ice

daily (B I D ) and b eva cizu mab at 5 mg / kg . I nteresting syn erg istic antitu mor activi ty w as ob serve d w ith this comb ination.

O ther phase I trials have exp lored the comb ination of T K I s inhib itors w ith I F N . I n these trials, patients receive d su nitinib or soraf enib and I F N - α w ith D L T s that inclu ded f atig u e and mye losu ppression. O nly inf erior dosag es of b oth su nitinib or soraf enib and I F N - α, compared to optimal dosag es in monotherapy , w ere manag eab le. Phase I I stu dies have eva lu ated the comb ination of soraf enib and I F N - α at standard or low dose without clear superior benefit for the comb ination [ 34 - 37 ] .

T emsirolimu s and b eva cizu mab w ere comb ined in a phase I stu dy du ring w hich the recommended w eekl y dose of temsirolimu s 25 mg / kg I V and b eva cizu mab at a dose of 10 mg / kg / 2 w eeks w ere u tilize d. D L T s encou ntered w ere g rade 3 stomatitis and hyp ertryg lyce ridemia. Among 12 eva lu ab le patients, 8 PR w ere reported. B ased on the preliminary resu lts reported, a randomize d phase I I I trial (I N T O R AC T ) is ong oing comparing temsirolimu s/ b eva cizu mab w ith b eva cizu mab / I F N .

T he temsirolimu s and soraf enib comb ination has also b een eva lu ated [ 38 ] . Patients w ere treated w ith escalating continu ou s oral doses of soraf enib (20 0 and 4 0 0 mg B I D ) and w eekl y I V temsirolimu s (15 mg , 25 mg ). T hirty- three eva lu ab le patients show ed D L T s inclu ding g rade 3 hand- f oot syn drome, mu cositis, rash, thromb ocyt openia, neu tropenia and creatinine eleva tion. T he f u ll recommended dose of b oth dru g s appeared u nachieva b le mainly du e to mu cositis.

B eva cizu mab in comb ination w ith the oral mT or inhib itor eve rolimu s is a promising comb ination in first and second line settings [39]. Presently, a randomize d phase I I trial is ong oing comparing b eva cizu mab / eve rolimu s w ith b eva cizu mab / I F N (R EC O R D - 2).

O ther randomize d phase I I or I I I trials are b eing condu cted. T he B eST trial is a 4 arms randomize d EC O G phase 2 trial (E28 0 4 ) exa mining f ront line therapy w ith b eva cizu mab vs. temsirolimu s and b eva cizu mab vs soraf enib and b eva cizu mab vs. temsirolimu s and soraf enib . T he T O R AV A trial is a phase I I trial comparing b eva cizu mab plu s interf eron vs b eva cizu mab plu s temsirolimu s vs su nitinib . Enrolment is closed and resu lts shou ld b e ava ilab le shortly [ 31] . T he cu rrent opinion of most inve stig ators reg arding comb ination therapy is that u ntil it has clearly show n to b e su perior to monotherapy , it shou ld not b e u sed ou tside the context of clinical trials. R esu lts of ong oing trials are eag erly aw aited.

6 . T H e Role foR neP H ReCT oM Y In T H e eRA of T A RG eT eD T H eRA P Ies

T w o randomize d stu dies have demonstrated that

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nephrectomy is associated w ith a su rvi va l adva ntag e in selected I F N treated mR C C patients [ 4 0 - 4 1] . B ased on these resu lts, primary tu mou r remova l is cu rrently part of the standard of care in mR C C . H ow eve r, no equ iva lent evi dence has b een ob tained w ith anti- ang iog enic dru g s so f ar eve n thou g h it remains reasonab le to remove larg e tu mou rs that are like ly to cau se local complications u nder treatment. B y contrast to cyt oki ne b ased therapy , TKIs are indeed able to cause significant responses w ithin the primary ki dney tu mou r [ 4 2] . T heref ore, TKIs could be used in the neo-adjuvant setting for selecting those g ood and intermediate risk patients who may benefit from nephrectomy [43]. In several phase I I trials presu rg ical su nitinib or b eva cizu mab has demonstrated sufficient safety and efficacy [44-4 6 ] . A su b g rou p analysi s f rom the phase I I I trial comparing temsirolimu s w ith I F N in poor risk patients demonstrated similar survival benefit for temsirolimu s reg ardless of patient nephrectomy statu s, thu s su g g esting that nephrectomy may have a limited role in poor risk patients [ 4 7 ] . T w o phase I I I randomize d stu dies, addressing respective ly the qu estions of the role of u pf ront therapy and of the timing of nephrectomy , are cu rrently ong oing in Eu rope [ 4 8 ] . T he C AR M EN A trial is a phase I I I randomize d stu dy comparing nephrectomy plu s su nitinib vs su nitinib w ithou t nephrectomy in first-line metastatic RCC. Primary end point is ove rall su rvi va l. T he EO R T C trial (SU R T I M E trial) is a randomize d phase I I I trial comparing su nitinib f ollow ed b y nephrectomy in case of non- prog ressive metastases f ollow ed b y su nitinib vs nephrectomy f ollow ed b y su nitinib in patients w ith sy nchronou s metastatic renal cell carcinoma. T he primary endpoint is prog ression f ree su rvi va l.7 . T H e Role of M eT A sT A seCT oM Y .F ive ye ars su rvi va l rate f or patients u nderg oing R C C metastases resection rang es f rom 35 to 6 0 % [ 4 9 ] . I nterva l f rom R C C diag nosis to occu rrence of metastases su perior to 1 ye ar, a u niqu e metastatic site and age inferior to 60 years have been identified as f avo rab le su rvi va l predictive f actors f ollow ing R C C metastases resection [ 5 0 ] . I n case of pu lmonary resection, delay f rom R C C diag nosis to metastases occu rrence, complete resection, nu mb er of nodu les to remove, metastatic nodule size appear as major prog nostic f actors [ 5 1- 5 4 ] . F ive ye ars su rvi va l rate seems to b e su perior in case of pu lmonary resection (5 4 % ) than in case of b rain resection (18 % ) [ 5 0 ] . Pancreatic metastases are like ly to occu r late in the natu ral history of the metastatic disease and seem to have a g ood prog nosis w hen a su rg ical resection is f easib le [ 5 5 ] . D u e to the emerg ence of ef f ective targ eted therapies, the concept of tu mou r metastasectomy needs to b e revi sited f or potentially rendering patients f ree of disease f ollow ing comb ined su rg ical and medical treatments [ 4 9 - 5 6 ] .

IV. P A nel Consensus ReCoM M enD A T Ions.

1. Su nitinib monotherapy and b eva cizu mab in comb ination w ith I F N - α may be considered first-line treatment options in patients w ith metastatic or u nresectab le clear- cell R C C and f avo u rab le or intermediate prog nosis according to M SK C C criteria (G rade A).

2. In the first line setting, temsirolimus is recommended in patients w ith poor prog nostic features according to modified MSKCC criteria (G rade A).

3. I n the second- line setting , soraf enib treatment is recommended f or patients w ith mR C C ref ractory to cyt oki nes (G rade A).

4 . I n the second- line setting , eve rolimu s treatment is recommended f or patients ref ractory to V EG F -targ eted therapy (G rade A).

5. Pazopanib is a new therapeutic option in first line setting or in cyt oki ne ref ractory patients (G rade A).

6 . C yt oki nes, inclu ding hig h- dose interleu ki n- 2 remain an option for first-line treatment of highly-selected patients w ith m clear cell R C C and g ood prog nosis (G rade B ).

7 . Su nitinib is a possib le alternative to temsirolimu s as first-line treatment in patients with poor prognosis and also as an alternative to soraf enib as a second-line treatment af ter cyt oki nes (G rade B ).

8 . F or patients ref ractory to mT O R inhib itors, enrolment in clinical trials is advi sed (G rade C ).

9 . Anti- ang iog enic dru g comb inations are still inve stig ational (G rade B ).

10 . T he sequ ential therapy concept is va lidated b y phase I I and I I I trials. F u rther trials are needed to determine the optimal intra or inter dru g class sequ encing (G rade B ).

11. B ased on previ ou s randomize d stu dies w ith I F N , u pf ront nephrectomy is advi sed in appropriately selected patients. H ow eve r, f u rther phase I I I clinical trials shou ld clarif y its exa ct role in the cu rrent therapeu tic era. N ephrectomy is not like ly to b e u sef u l in poor risk patients according to M SK C C criteria (G rade B ).

12. Su rg ical R esection of a u niqu e metastasis shou ld b e considered as a va lu ab le therapeu tic option, particu larly in cases of delay b etw een R C C diag nosis and occu rrence of metastasis exce eding 1 ye ar, yo u ng ag e or f avo u rab le prog nostic f eatu res and w hen a complete resection is exp ected. T he concept of tu mou r metastases resection shou ld b e revi sited in the era of targ eted therapy (G rade C ).

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