Invest in Health- Build a Safe Future Editorial Vol.II, No.2, March... · influenza virus at the...

1Journal of Postgraduate Medical Education, Training & ResearchVol. II, No. 2, March-April 2007

1Invest in Health- Build a Safe Future

P.S. ShankarGoverning Body Member, National Board of Examinations

Editorial

Health is a precious and mostvaluable possession that hasbeen considered as the second

blessing, and vital principles of bliss.Without health life is considered no life,and all our happiness lies in health.People all over the world have realizedthe importance of health and thefollowing proverbs of different languageshighlight the importance given to health:Health is wealth (Kannada); Health isbetter than wealth (English); Frombitterness of disease man learns thesweetness of health (Spanish); Goodhealth or bad makes our philosophy(French); Every healthy man is king(Gaelic); Wealth without health is halfsickness (Italian); One can always behealthy as long as one is not ill (Russian).

Benjamin Disraeli had said ‘the health ofpeople is really the foundation uponwhich all their power as a State depend’.World Health Organization (WHO) hasgiven the slogan ‘Invest in health, build asafe future’ for WHO Day on 7th April2007. The slogan addresses to one of themost vital concerns of the current times.Globalization and rapid travelsurpassing the international time-zoneshave enabled the easy spread of the newand existing diseases beyond the nationalborders and have affected the collectivesecurity.

Avian influenza and severe acuterespiratory syndrome (SARS) havespread from one country and region tothe next. Avian influenza (flu) epidemicswept across South Korea, Japan, Taiwan,Vietnam, Thailand, Cambodia, Laos,

Indonesia, China and Pakistan during2006. This is an infectious disease causedby a highly contagious virus. The diseaseappears to have jumped the speciesbarrier, infecting human and causingdeath. It necessitated culling of millionsof chicken, ducks, geese and other birdsto prevent the spread of the disease. Thepublic health authorities were put onhigh alert to prevent the occurrence of apandemic in human beings. The speed atwhich this virus spread wasunprecedented.

There is a risk that humans could becomeinfected with both the avian and humaninfluenza virus at the same time. Avianflu virus could swap genetic material withhuman flu to produce a highly contagiousmutant. The parts of Asia affected by theoutbreak of avian flu were put on strictmeasures of isolation and culling ofmillions of chicken infected with a strainof bird flu and isolation of personsthought to be infected. The 2006outbreak affected every countrycontiguous either by land or sea. Theentry of any poultry products were notallowed from those regions. The presenceof antibodies against H5N1 virus wastested. The country should be vigilantabout persons entering the country whoappear to be presenting features of flu-likeillness.

A mysterious form of highly contagiouspneumonia was reported in GuangdonProvince of People’s Republic of Chinain later part of 2002 and subsequentlyspread to parts of South-east Asia duringthe early months of 2003. The illness has

been referred to as SARS. The diseasecauses flu-like symptoms initially,rapidly to be followed by respiratoryproblems, often serious leading to highermortality.

SARS is a highly infectious disease causedby a corona virus. It is transmitted byclose contact with aerosolized dropletsand bodily secretions from an infectedperson. It causes diffuse alveolar damage.The person exhibits fever, cough,shortness of breath and difficultbreathing. There should be history of aclose contact with a person who wasknown to have suffered from SARSwithin the past 10 days or travel withinpast 10 days of onset of symptoms toplaces which have reported cases of thedisease. Prevention of SARS involvesavoidance of close contact with SARSpatients. Persons suspected of havingSARS must be isolated and should limittheir interactions outside hospitalsettings. Quarantine of patients beforethey spread disease, quarantine or closemonitoring of all the people they havecome into contact with and a clampdownof social gatherings and travel areimportant.

HIV/AIDS since 25 years has been racingacross nations, adversely impacting theireconomics and threatening their stability.New diseases have appeared and old oneshave re-emerged as epidemic/pandemicprone diseases to present an acute threatto life. Climate change, natural disasters,chemical and nuclear accidents andbioterrorism also hold the potential tothreaten international public health

Journal of Postgraduate Medical Education, Training & ResearchVol. II, No. 2, March-April 2007

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security.

Global warming is occurring at analarming speed due to combustion offossil fuels. It is associated withanthropogenic emission of greenhousegases, air-borne particulates, nitrogen andsulphur dioxide. Global warming havinghealth impact has emerged as a publichealth challenge. Global warmingassociated with rainfall, humidity, water-logging, active photosynthesis ofvegetation, is changing the ecology ofmany arthropod vectors transmittingdiseases to human beings. Warmertemperatures increase mosquito and tickvector overproduction, biting andtransmission of disease such as malaria,Rift Valley fever, and Lyme disease.Dengue fever and Chickungunya feverspread by the mosquito, Aedes aegypti,have widened their geographicalboundaries in tropical regions. Thespread and activities of the sandflies,vectors of Leishmaniasis, is stronglyinfluenced by ambient temperature.There is an explosion of the mousepopulation following heavy rainfall andthey may increase the chances ofoutbreak of Hantavirus pulmonarysyndrome.

The climate change in the coming yearsthreatens human population with healthhazards by disrupting water and foodsupplies, and increased spread of vector-borne diseases. It has called for reductionof green house gas emissions by reducingcombustion of fossil fuels, developmentof renewable energy technology,establishment of stations equipped withremote sensing and geographicinformation system to monitor sea-levelrise and extreme weather conditions.

The dissemination of anthrax sporesthrough US mails and the resultantcutaneous and inhalation anthrax led to

a campaign for preparedness againstbioterrorism. Bioterrorism refers to theuse of chemical or biological weapons forterrorism. Though the morbidity andmortality caused by bioterrorism havebeen very small compared to thatproduced by the use of other weapons,there is need for preparedness against anypossible bioterrorism.

Natural disasters such as earthquake,floods, cyclone, tsunami, and faminestrike the globe frequently. WHO hasdefined disaster as ‘any occurrence thatcauses damage, economic disruption, lossof human life and deterioration in healthservices on a scale sufficient to warrantan extraordinary response from outsidethe affected community or area’. Thereis ecologic disruption which exceeds thecapability of the affected community tomake adjustments. The rescue and relieffaces many difficulties. In addition tomedical relief, quick removal anddisposal of corpses, restoration of watersupply, food and maintenance ofsanitation are important to preventwidespread epidemics. The casualties areto be evacuated from the site as fast aspossible to a place where propertreatment can be given on priority basis.

William Mayo once said, ‘of allcooperative enterprises public health isthe most important and gives the greatestreturns’. Hence there is need forinvestment in health. Health emergenciescause global concerns and an effectiveresponse requires internationalcooperation. This has been amplyexhibited by different nations followingtsunami disaster and outbreak of SARS.The WHO slogan highlights the vital needto invest in human resources andstrengthen the health systems to enablethe international community toeffectively meet the public health risks

and challenges. WHO is assisting thecountries to strengthen their publichealth risks and challenges.

The revised and broadened internationalhealth regulations 2005 are coming intoeffect in June 2007 to provide support tothe countries to stabilize global health.Under this international agreement themember states of WHO are obliged toprevent and control the spread of diseaseinside and outside their borders. Theyhave to maintain core surveillance andexhibit their capabilities to detect, assess,notify and report public health events toWHO and to respond to public healthrisks and public health emergencies. Allmust keep in their mind about the closingphrase found in many Latin letters: ‘ curaut valeas’ (Guard your health).

Ancient Greece

While surgeons are nowconsidered to bespecialised physicians,

the profession of surgeon and thatof physician had differenthistorical roots. For example,Greek tradition was against openingthe body, and the Hippocratic Oathwarns physicians against thepractice of surgery. Specifically,cutting persons laboring under thestone (i.e. lithotomy, an operationto relieve kidney stones) was to beleft to such persons as practice [it].Of course, most knowledge ofsurgery comes from dissectingbodies, a science which wasrepulsive to many healers.


2Drug-Resistant Tuberculosis

P.S. ShankarGoverning Body Member, National Board of Examinations Commentary

Multi-drug resistant (MDR)tuberculosis (TB) is beingincreasingly recognized in the

recent years all over the world. The termrefers to the disease due to M. tuberculosisthat is resistant to the two most effectivecurrent anti-tuberculosis drugs, isoniazidand rifampicin with or withoutresistance to other drugs (poly-resistance)1. It is an iatrogenic problem. Extensively(Extremely) drug-resistant (XDR)tuberculosis is caused by a strain ofMycobacterium tuberculosis resistant toisoniazid and rifampicin (as in MDR-TB) in addition to any fluoroquinolonesand at least one of the three injectabledrugs such as capreomycin, kanamycinand amikacin 2.

Multi-drug resistant tuberculosis

After dramatic outbreaks of multi-drug-resistant tuberculosis in the early 1990s,resistance became recognized as a globalproblem. MDR-tuberculosis (TB) nowthreatens the inhabitants of the countriesin Asia, Africa, Europe and the Americas.A new research finding from SouthAfrica on an extensively drug-resistantstrain of M tuberculosis that causestuberculosis is alarming the experts 3. Thenew strains of multi-drug resistant-, andextremely drug-resistant strains oftubercle bacilli have emerged despiteavailability of effective anti-tuberculosis,and it is due to their ineffectiveadministration. They have greatsignificance for the public health field.The causes of drug resistance are many(Table- 1) 4.

Table -1, Causes of resistancePoor adherence to treatmentPrescription of inappropriatecombinations of drugsPrescription of inadequate dosage ofdrugsInappropriate rhythm ofadministrationUse of unreliable combinationsAddition of another drug to a failingregimenErratic drug supplyMalabsorption of properly prescribeddrugs

Drug resistance has to be suspected in apatient who continues to remain sputum-positive after four months of regulartreatment with an established short-course chemotherapy regimen. A historyof anti-tuberculosis treatment predictsthe occurrence of MDR-TB. Non-compliance with the anti-tuberculosisdrugs therapy, and HIV-infectionaggravate the situation.

Extensively drug resistanttuberculosis

Looking at the emergence of extremelydrug resistant strains of tuberculosisbacilli, the World Health Organization(WHO) has expressed concern and hascalled for urgent measures to strengthenand to implement effectively theprevention of the global spread of thedeadly strains of tuberculosis. The newlyidentified strains of XDR strains oftubercle bacilli leaves the patients,

including those living with human-immunodeficiency virus (HIV),virtually untreatable with the currentlyavailable anti-tuberculosis drugs, anddeath becomes imminent.

The description of XDR-TB was firstgiven in early 2006 following a jointsurvey by World Health Organization(WHO) and the US Centres for DiseaseControl and Prevention (CDC).Resistance to anti-tuberculosis drugs is areflection of poorly managedtuberculosis. The care-giver, patient anddrugs play a part in the emergence ofdrug-resistant strains. The reasonsinclude incorrect drug prescribingpractices by the care-giver, poor qualityof drugs or erratic supply of drugs, andpatient non-adherence.

Epidemiology of XDR-TB

The findings from a survey carried outby WHO and CDC on data from 2000 to2004 has shown that XDR-TB isencountered in at least 17 countries of theWorld. However its occurrence wasmore frequent in the countries of formerSoviet Union and Asia 5.

The survey has shown that in UnitedStates, 4% of isolates of MDR-TB met thecriteria for XDR-TB. 15% of isolates ofMDR tuberculosis in the Republic ofKorea were XDR strains. In Latvia, acountry with one of the highest rates ofMDR-TB, 19% of MDR-TB cases met thecriteria for XDR-TB (5). The data on therecent outbreak of XDR-TB in an HIV-positive population in KwaZulu-Natal,a province of South Africa has shown


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alarmingly high rates of rapid death. Ofthe 544 patients studied at a ruralhospital, 221 had MDR-TB. Of them 53were defined as XDR-TB. Among them44 had been tested for HIV and all ofthem were HIV-positive. 52 of 53patients died of tuberculosis on anaverage, within 25 days including thosegetting benefit from anti-retroviraltherapy 6.

Scarce drug-resistance data is availablefrom Africa. While populationprevalence of drug-resistant TB appearsto be low compared to Eastern Europeand Asia, drug-resistance in the region ison the rise. Given the underlying HIVepidemic, drug-resistant tuberculosiscould have a severe impact on mortalityin Africa and other countries and itrequires an urgent preventive action.

Immune defense mechanism

There is an increased resistance to re-infection in persons infected withtubercle bacilli either naturally fromvirulent strains of M tuberculosis orartificially following vaccination withattenuated, live tubercle bacilli. Inaddition, those infected develop adelayed hypersensitivity to tuberculo-protein. These two changes-acquiredresistance (tuberculo-immunity) andtuberculin hypersensitivity- are specificimmunological reactions and are cell-mediated. These responses are acquiredand develop only after the specificantigenic stimulus. They play a key rolein the pathogenesis of tuberculosis 7.

Lenzini and co-workers have establisheda spectrum of progressive humantuberculosis on a cl inical andimmunologic basis. 8 The patients arecategorized into four groups: one polargroup exhibits fully active cell-mediatedreactivity and the other un-reactive

polar group that does not demonstrate anycell-mediated immunity. Between themare two intermediate groups, leaningtowards the reactive group and anotherone leaning towards the un-reactivegroup. There is predominance oflymphocytes and epitheloid cells to thereactive group. The number of tuberclebacilli in the tissues and the level ofantibodies increase towards the un-reactive group and there is rapid spreadof bacilli and lesions in the lungs and otherorgans 8.

The studies on the immune defenses ofpeople with tuberculosis have shown thatthe problem is not so much of an inabilityof the body’s defenses to deal with theorganism but abnormally-regulateddefense mechanisms. Thus, in activetuberculosis, the immune responsesrather than attacking the tubercle bacilli,cause gross tissue destruction with theformation of huge cavities in the lung aswell as causing systemic manifestationssuch as fever and wasting.

Masjedi and co-workers from Iranobtained sputum specimens from a totalof 2030 patients with tuberculosis anddigested, examined microscopically forpresence of acid-fast bacilli and theninoculated into Lowenstein-Jensen slantsby standard procedure 9. Testing ofsusceptibil ity to first- l ine anti-tuberculosis drugs was performed for1284 isolates of M. tuberculosis .Subsequently, the strains that wereidentified as multi-drug resistant Mtuberculosis (113 isolates) were subjectedto susceptibility testing for second-linedrugs. Spot-ligotyping and restrictionfragment-length polymorphism wereperformed for strains that wereidentified as XDR-M tuberculosis.

A total of 12 (10.9%) of 113 multi-drugresistant M tuberculosis strains were

resistant to all 8 second-line drugs testedand therefore, were denoted as XDR Mtuberculosis. Retrospective analysis ofthe cases of XDR-TB showed that all ofthem belonged to 1 of 2 epidemiologicalclusters, either a single-family cluster (4cases) or a cluster of close contacts (8cases). The strains were identified asbelonging to the M tuberculosis super-families Haarlem I and East AfricanIndian.

Management

Early, accurate diagnosis and institutionof effective treatment properly undersupervision for a proper duration areessential in the control of tuberculosis.The treatment of patients whoseorganisms are resistant to the standardanti-mycobacterial agents poses manydifficulties. The tubercle bacilli andtheir progeny remain viable and multiplyin the presence of anti-mycobacterialagents in a concentration that wouldnormally destroy or inhibit theirgrowth. Inadequate treatment select outdrug-resistant strains which thenproliferate. Further inadequate andimproper treatment maintains thevicious cycle leading to emergence ofstrains that are resistant to other drugsuntil creation of MDR and later XDRtuberculosis. Drug resistance poses aserious limitation to the successfultreatment and control of tuberculosis.

There is decreased clinical response,persistence of acid-fast bacilli in thesputum, and radiological deteriorationeven after continuous therapy for sixmonths. These are indications that theinfecting organisms are resistant to thedrugs used in the treatment.Inappropriate use of second-line anti-tuberculosis drugs in a patient for whomfirst-line drugs are failing ends in XDR-TB. The patient then spreads the infection


to individuals in close contact whoacquires primary XDR-TB.

XDR-TB poses a grave public healththreat, especially in populations withhigh rates of HIV infection and wherethere are few health care resources.Treatment regimens for drug-resistanttuberculosis are less effective, moreexpensive and prolonged. Further thepatient having drug resistant tuberculosisposes public health danger of spread ofresistant organisms.

The efficacy of treatment of resistantcases-both of MDR and XDR-TB- isworse than that of the original treatment.Hence, the initial intensive treatmentwith proper chemotherapy has vitalimportance. Initial intensive treatmentreduces the total bacterial population tosuch a low number that the risk of theemergence of resistant strains becomesinsignificant. The loss of sensitivity oftubercle bacilli to standard drugs is anundesirable and harmful phenomenon.

Drug resistance has to be suspected in apatient who continues to remain sputumpositive after four months of regulartreatment with an established short-course chemotherapy regimen. A historyof improper and inadequate anti-tuberculosis treatment predicts theoccurrence of MDR-TB and of XDR-TB.Non-compliance with the therapy, andHIV-infection aggravate the situation.

The treatment of MDR-TB and of XDR-TB poses many challenges to the treatingphysician. The treatment is less effective,more toxic and expensive. A detailedhistory of previous treatment fortuberculosis has to be obtained. It shouldinclude the names of drugs-both first-lineand second-line-the dosage, duration andregularity of intake. Drug susceptibilitytesting is necessary to ensure that patients

receive a quick diagnosis and properlyselected drugs for adequate duration. Itwill facilitate to interruption oftransmission of drug-resistant organisms.

WHO guidelines

WHO Guidelines for the Programmaticmanagement of drug resistanttuberculosis include the following:

• strengthen basic TB care to preventthe emergence of drug-resistance

• ensure prompt diagnosis andtreatment of drug resistant cases tocure existing cases and preventfurther transmission

• increase collaboration between HIVand TB control programs to providenecessary prevention and care to co-infected patients, and

• increase investment in laboratoryinfrastructure to enable betterdetection and management ofresistant cases.

The patient with MDR-TB should begiven at least four drugs which he/she hasnot received in the past or to which thebacilli have demonstrated susceptibilityby laboratory testing 11. The chance ofreceiving at least two drugs having invitro activity against tubercle bacilli aregreater if greater number of drugs, usuallysix or seven are used in the treatment.However use of more number of drugs isassociated with greater toxicity, drug-drug interactions and expense. Thetreatment of XDR-TB poses furtherproblems as the organisms are resistantto most of second-line of anti-tuberculosisdrugs. The patients have to receiveindividually tai lored regimenscontaining at least four drugs which theyhad not received previously or to whichthey were known to be susceptible.Second-line anti-tuberculosis drugs must

be administered for at least 18 monthsunder strict monitoring supervision.

Increasing threat

XDR-TB presents an increasing threat toglobal tuberculosis control. XDR-TB hasmain implications for the managementof patients with HIV and for HIVcontrol. High prevalence of HIV predictsextreme vulnerability to tuberculosis.Most crucial management issues in XDR-TB treatment remain unanswered.Emergence of drug resistance isprevented by identifying cases of drug-susceptible disease and treating them withwell tested regimens in a proper dosagefor a proper duration. It has to be ensuredthat the patient completes full course oftreatment till cured. There is need totreat patients with established MDR-TBwith a complicated regimen includingsecond-line drugs, and followed for alonger duration to prevent relapses andemergence of XDR-TB. Antiretroviraldrugs protect against tuberculosis byrestoring patients’ immuno-competence.

Conclusion

Retrospective cohort studies have shownthe emerging threat of extremely drugresistant tuberculosis. Such a conditionrequires an aggressive treatment regimenand high-end dosing of drugs. The second-line drugs have low potency andincreased toxicity. The treatment has tobe carried out under direct observationto achieve compliance. High cost oftreatment puts great hurdle in resource-poor settings. Emergence of CDR-TBreflects a failure to implement themeasures recommended in the WHO’sStop TB Strategy 11. The strategyemphasizes the extensive use of DOTSprogram, addressing HIV-associatedtuberculosis and drug resistancestrengthening health care system andprimary core services. Opportunities to


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treat XDR-TB in developing countrieshas been made possible through Globalfund to fight AIDS, TB and malaria, andthe Green Light committee for access tosecond-line anti-tuberculosis drugs. Morestudies are needed to guide clinicians inthe management of this emergingproblem.

References1. Veen J. Drug resistant tuberculosis:

back to sanatoria, surgery and codliver oil? (Editorial) Eur Respir J1995; 8: 1073

2. Roviglione MC, Smith IM. XDRtuberculosis-implications for globalpublic health. N Engl J Med. 2007;356: 656-9

3. Emergence of XDR-TB. Geneva,World Health OrganizationSeptember 5, 2006

4. Shankar PS. Multi-drug resistanttuberculosis in Principles andManagement of Tuberculosis, 3rd

edn, New Delhi, Churchil lLivingstone, 2002; 205-207

5. Emergence of Mycobacteriumtuberculosis with extensiveresistance to second-line drugs-worldwide, 2000-2004. Centres forDisease Control and Prevention(CDC) MMWE Morb Mortal WklyRep 2006; 55: 301-305

6. Gandhi NR, Moll A, Sturm AW, etal. Extremely drug-resistanttuberculosis as a cause of death inpatients co-infected withtuberculosis and HIV in a rural areaof South Africa. Lancet. 2006; 368:1575-80

7. Dannenberg AM Jr. Delayed-typehypersensitivity and cell mediatedimmunity in the pathogenesis oftuberculosis. Immunol Today.1991; 1: 228-33

8. Lenzini L, Rottoli P, Rottoli L. Thespectrum of human tuberculosis.Clin Exp Immunol 1977; 27: 230

9. Masjedi MR, Farnia P, Sorooch S, etal. Extensively drug resistancetuberculosis : A 2-years ofsurveillance in Iran. Clin Infect Dis.2006; 43: 841-47

10. Iseman MD. Treatment of multi-drug resistant tuberculosis N Engl JMed. 1993; 329: 784-91

11. Roviglione MC, Uplekar MW.WHOs’ new Stop TB Strategy.Lancet 2006; 267: 952-5

History of Surgery atMayo Clinic

Surgery at Mayo Clinic beganwith the frontier practice ofDr. William Worrall Mayo.

Dr. Mayo’s two sons, William J. andCharles H., assisted him in hispractice at very early ages. SaintMarys Hospital opened in Rochesteron Sept. 30, 1889 & Dr. Charlieremoved a cancerous tumor of theeye, his first surgery, assisted by hisbrother and father. Between 1889 and1905, the Mayos did all operationsat Saint Marys Hospital, themselves.To handle the growth of theirpractice, the Mayos opened a thirdoperating room at Saint Marys in1905.

The Mayos maintained an “open-door” policy to other members of themedical profession. Duringoperations, the brothers alwaysdiscussed their procedures for thebenefit of visitors. Over the operatingtables, large adjustable mirrorsprovided a complete view of theoperating field. This demand foradvanced medical training led the

Mayos to establish the country’s firstgraduate program in clinicalmedicine in 1915.

Each physician devoted attention toa particular area of medicine, and allphysicians combined skills toprovide superior patient care. Thisspecialization led to the developmentof new surgical disciplines, including:orthopedics, neurosurgery,ophthalmology, thoracic surgery,dental surgery and more.The Mayobrothers routinely visited othermedical centers around the world tolearn more about new procedures andideas. They brought their findingsback to Rochester to implement.This practice sparked a habit ofinnovation at Mayo. For example,early Mayo surgical contributionsinclude the development of the lowanterior resection for colon andrectal cancer, endoscopic injection ofesphageal varices, and advances inresection of the stomach for cancer.In addition, many operatingtechniques and instruments still inuse today were developed by MayoClinic surgeons, including theBalfour retractor, the Mayo stand,the Mayo scissors, the Adson pickups,the Harrington Behrens, and theAdson-Beckman retractors.MayoClinic history includes more than acentury of innovations in the surgicaltreatment of patients, from the firstopen-heart surgery in 1955 to the firsttotal hip replacement in 1969 to theearly use of robotic laparoscopicsurgery in 2002. Today, 255 MayoClinic surgeons treat more than76,000 surgical patients each year,proving that the Mayo legacy ofsurgical teamwork and innovation isstill alive.


About 70% of newly detectedcases are exophytic papillarytumors confined largely to the

mucosa (Ta) (70%) or less often to thesubmucosa (T1) (30%). These tumorstend to be friable and have a highpropensity for bleeding. Their naturalhistory is characterized by a tendency torecur in the same portion or another partof the bladder over t ime(a phenomenon termed“polychronotropism”) and theserecurrences can be either at the same stageas the initial tumor or at a more advancedstage. Papillary tumors confined to themucosa or submucosa are generallymanaged endoscopically by completeresection. Progression to a moreadvanced stage may result in localsymptoms or, less commonly, symptomsrelated to metastatic disease. It isestimated that 10% to 70% of patientswith a tumor confined to the mucosa willhave a recurrence or a new occurrence ofurothelial (transitional cell) carcinomawithin 5 years. These probabilities ofprogression vary as a function of theinitial stage and grade. Refining theseestimates for the individual patient is anarea of active research.

Staging and grading

The most commonly utilized stagingsystem is the tumor, node, metastasis(TNM) system, as shown in. Bladdercarcinomas are graded as welldifferentiated (G1), moderatelydifferentiated (G2), poorlydifferentiated or undifferentiated (G3-4). However, the determination of grade

3Cancer Bladder Pathology & Natural History

Lt. Gen. S. MukherjeeArmed Forces Medical College, Pune

Commentray

has a greater impact on the managementof noninvasive tumors because mostmuscleinvasive tumors (ie, greater thanT1) are G3. An alternative gradingsystem of low or high grade has beenproposed, and it is our intent to transitionto this classification system over the nextthree years. We will retain the presentclassification system for now since it iscommonly used by practicing urologists.A comparison of the differentclassification systems is presented in thePrinciples of Pathology Management.

Papillomas are considered to be benigntumors that closely resemble the normalurothelium. Grade 1 papil larycarcinoma in contrast can be recognizedhistologically because they have morethan the normal seven epithelial layers,normal polarity of the nuclei, andminimal pleomorphism. Papillomas andG1, Ta carcinomas are managed almostexclusively by endoscopic means becausethey generally do not progress to a higher,more lethal stage. In contrast,Ta, G3tumors have a much higher chance ofprogression to a more advanced stage.

Once stage and grade have beendetermined, treatment decisions arebased on the depth of invasion and extentof disease. The treatment of bladdercancer entails the disciplines of urologicsurgical oncology, radiation oncology,and medical oncology. For many of thecomplex strategies the involvement ofmultidisciplinary teams will optimizeresults. The general principles forsurgery, chemotherapy and radiationtherapy are explained on respectively.

Non muscle-invasive tumors are dividedinto noninvasive papillomas orcarcinomas (Ta), those invading thelamina propria (T1), and CIS. Thesetumors have previously been referred toas “superficial” tumors, an impreciseterm which should be avoided. In somecases, a papillary or T1 lesion will bedocumented as having an associated insitu component (Tis). The standardtreatment in such cases is the repeat ofTUR. However, depending on the depthof invasion and grade, intravesicaltherapy may be recommended. Thissuggestion is based on the estimatedprobability of recurrence (ie, a newtumor formation within the bladder) andprogression to a more advanced, usuallyinvasive stage - events that should beconsidered independently.

Cystectomy is rarely considered for a Ta,G1 or G2 lesion. Intravesical therapy isused in two general settings: asprophylactic or adjuvant therapyfollowing a complete endoscopicresection or, rarely, as therapy aimed ateradicating residual disease that could notbe completely resected. This distinctionis important, as most published datareflect prophylactic or adjuvant use withthe aim of preventing recurrence and/ordelaying progression to a higher grade orstage. In many cases, intravesical therapyis given to patients who do not require itbecause the probability of recurrence orprogression is low. Management of thedifferent histologic subtypes of differentgrades is outlined below.

Papilloma/Ta, G1 or G2


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TUR without intravesical therapy is thestandard treatment for Ta, G1 and Ta,G2 tumors. Since patients diagnosed withthese tumors have a relatively high riskof recurrence, in addition to observation,the panel also offers consideration of asingle dose of intravesicularchemotherapy (not immunotherapy)within 24 hours of resection.Closefollow-up is needed, even though the riskof progression to a more advanced stageis low. As a result, these patients areadvised to undergo a cystoscopy at 3months initially, and then at increasingintervals. If no recurrences developduring the first year, the interval betweenevaluations can be increased. Patients inwhom a recurrence is documented aretreated with TURBT and adjuvanttherapy based on the stage and grade ofthe recurrent lesion, and they are thenfollowed at 3-month intervals .Intravesical therapy is recommended forpatients who have a history ofrecurrences.

Ta, G3 disease

Tumors staged as Ta, G3 lesions areconsidered to be high-grade papillarytumors with a relatively high risk ofrecurrence and progression towardsmore invasiveness. For this reason, inaddition to observation, they are treatedwith intravesical Bacillus Calmette-Guérin (BCG) or mitomycin (MMC), inthe same manner as T1, G1-2 tumors withBCG being the preferred option for post-operative treatment.

Tis

Primary Tis is a high-grade lesion that isbelieved to be a precursor of invasivebladder cancer. Standard therapy for thislesion is a complete endoscopic resectionfollowed by intravesical therapy withBCG. This is generally given once a weekfor 6 weeks, followed by a 4-6 week rest

period, with a full reevaluation at week12 (ie, 3 months) after the start of therapy.Patients with Tis who have recurrent/persistent disease at the 12-week (3-month) evaluation can be given a secondcourse of BCG or MMC inductiontherapy (no more than 2 consecutivecourses). If a second course of BCG isgiven and there is residual disease at thesecond 12-week (3-month) follow-up, acystectomy should be stronglyconsidered. Depending upon priortreatment, the extent of the disease, andthe frequency of recurrences, intravesicaltherapy with the different intravesicalagent (mitomycin, or less commonlyvalrubicin, alpha-interferon, or BCGplus alpha-interferon) is an alternative tocystectomy. In some centers, however,these patients might still be candidates forinvestigational therapies. For patientswith complete response at the follow-upcystoscopy, whether one or two coursesof induction therapy were administered,maintenance therapy with BCG isadvised, although this recommendationis not universal. Regardless of whetheror not maintenance therapy isadministered, patients with Tis should befollowed at 3-month intervals with aurinary cytology and cystoscopy for thefirst 2 years, and if no recurrences aredocumented, every 6 months in the thirdand fourth years and then annually.Imaging of upper tract collecting systemevery 1 to 2 years is also recommendedwith or without urinary tumor markers(category 2B) in selected cases. Ifprogression to an invasive lesion isdocumented at any point during follow-up, a radical cystectomy is recommended.Although controversial, patients whopresent with recurrent superficialtumors prior to the documentation of amuscle-invading lesion are generally notconsidered to be candidates for bladder-

sparing approaches.

T1 disease

T1 lesions, those invading laminapropria, are considered to be potentiallydangerous (usually T1G2 or G3) andhave a high risk of both recurrence andprogression. These tumors may occur assolitary lesions or as multifocal tumors,with or without an associated in situcomponent. They, too, are treated with acomplete endoscopic resection followedby intravesical therapy (this is optionalfor G1 or G2 lesions). Within thecategory of T1 disease, two risk strata canbe identified: low-risk (G1, G2, orsolitary) and high-risk (G3 or multifocallesions, tumors associated with vascularinvasion, or lesions that recur after BCGtreatment).

Low-risk disease

After the initial TUR, patients with low-risk disease are observed or undergointravesical treatment with BCG ormitomycin. Follow-up is similar to thatpreviously outlined above for Ta, G1-2disease, with a urinary cytology andcystoscopy recommended at 3-monthintervals for the first 2 years, repeated atincreasing intervals over the next 2 years,and annually thereafter. If cytology studyis found positive despite the negativeimaging and cytoscopy results, randombiopsies including TUR and prostatebiopsy in male patients arerecommended. Recurrent disease istreated as appropriate for the stagedocumented at the time of relapse.

High-risk disease

Patients with high-risk disease (T1, G3)can be treated with a course of BCG(preferred, category 1), mitomycin, orradical cystectomy after a certain andsatisfied resection. If the completeresection is uncertain based on the tumor


size and location, no muscle is shown inthe specimen, lymphovascular invasion,or inadequate staging is speculated, repeatresection of tumor or cystectomyfollowed by intravesical therapy withBCG (category 1) or mitomycin isrecommended ( ). Evolving data suggestthat the preferred approach may be earlycystectomy if residual disease is found dueto the high risk of progression to a moreadvanced stage. If highrisk disease ismanaged conservatively and does notrespond to BCG, a cystectomy should beperformed.

Before any treatment is advised, thefollowing workup procedures arerecommended to determine the clinicalstaging. Laboratory studies such ascomplete blood cell count (CBC) andchemistry profile including alkalinephosphate need to be done, and the patientshould be assessed for the presence ofregional and/or distant metastases. Thisevaluation should include a cystoscopy,EUA/TURBT, chest x-ray, bone scan inpatients with symptoms or elevatedalkaline phosphate, and evaluation of theupper tracts with a CT or MRI scan of theabdomen and pelvis. Some physiciansadvocate performing magnetic resonanceimaging (MRI) to determine the depth ofinvasion within the bladder and, inparticular, to ascertain whether a tumorhas reached the perivesical fat (T3b).Unfortunately, CT scans, ultrasound, orMRI cannot accurately predict the truedepth of invasion.

Organ-confined disease (T2a,T2b)

Surgical treatment with radicalcystectomy is still the most effective localtherapy in muscle invasive bladdercancer. Two critical issues exist in themanagement and prognosis of thesepatients: (1) whether or not a palpable

mass is appreciated at the time of theEUA, and (2) whether or not the tumorhas extended through the bladder wall.Tumors that are organ-confined (T2)have a better prognosis than those thathave extended through the bladder wallto the perivesical fat (T3) and beyond.Primary surgical treatment for T2lesions include radical cystectomy withthe consideration of neoadjuvantchemotherapy in selected patients, andsegmental cystectomy only in patientswith a single tumor (solitary lesion in asuitable location), and no any presenceof CIS, nor previous multifocal bladdercancers. If no neoadjuvant chemotherapywas given, post-operative adjuvantchemotherapy is considered in thosepatients based on the pathologic risk suchas positive nodes and pathologic T3lesions. If segmental cystectomy had beenperformed, adjuvant RT orchemotherapy based on pathologic risk(positive nodes, positive margin, high-grade, and pathologic T3 lesions) shouldbe considered. For patients withsuperficial muscle invasive T2 diseaseand without hydronephrosis, bladder-sparing treatment (category 2B) withchemotherapy and radiation therapymay be possible following completeTURBT. In highly selected patients withextensive comorbid disease or poorperformance status, chemotherapy aswell as radiation therapy or TURBT isrecommended. For those patients notundergoing cystectomy, evaluation withcystoscopy and tumor site re-biopsy isnecessary after the primary treatment.Radical cystectomy is the standardtreatment if tumor is found. Otherwise,observation, further consolidationchemotherapy with radiation, and/oradjuvant chemotherapy alone isrecommended.

Relapses in the bladder after

bladder-sparing approaches

Treatment of relapses is based on theextent of disease at the time of relapse,with consideration given to the priortreatment that a patient has received. Tis,Ta, or T1 tumors are generally managedwith intravesical BCG therapy. If thereis no response, a cystectomy is advised. Apositive cytology with no evidence ofdisease in the bladder should promptselective washings of the upper tracts andan evaluation of the prostatic urethra. Ifthe selective cytologies are positive,patients are managed as described belowunder treatment of upper tract tumors.Invasive disease is generally managed byradical cystectomy and a second attemptat bladder preservation is not advisable.All patients who relapse after bladder-sparing therapy and are being consideredfor radical cystectomy should beevaluated for medical comorbidities andundergo a full restaging evaluation toensure that there is no metastatic disease.As is the case with primary cystectomy,an exploratory laparotomy is performedfirst to ensure that there is noinvolvement of the lymph nodes,omentum, or other organ sites. Even inpatients who have no extravesical spread,the morbidity of radical cystectomy canbe significant although the operativemortality is low (1% to 3%). Althoughsalvage cystectomy is the preferredapproach, it may not be possible for apatient who has received a full course(greater than 65 Gy) of external-beam RTand has bulky residual disease. For thesepatients, salvage chemotherapy isadvised, generally with a regimen that isnon-cross-resistant to the one that thepatient has previously received. Thosetreated with single-agent cisplatin can beconsideredor a standard three- or four-drug regimen, whereas those who havealready received a three-drug (eg, MCV)


10

or four-drug (eg, M-VAC) regimen maybe considered for therapy with paclitaxel,gemcitabine, or ifosfamide, as outlinedbelow under salvage chemotherapy. If thepatient has not received RT, a course ofRT should be considered. Metastaticdisease is managed with salvagechemotherapy using a regimen to whichthe patient has not been previouslyexposed.

Non-organ-confined disease(T3a, T3b/T4a, T4b)

The primary surgical treatment for atumor that has extended beyond theconfines of the bladder wall and that isstill considered resectable, based on themobility of the bladder, is radicalcystectomy with consideration ofneoadjuvant chemotherapy, as outlinedpreviously. Except in highly selectedcases (see below), bladder preservation isnot an option in such patients since theproportion rendered tumor-free usingchemotherapy alone is generally less than10%. Tumors that are pathologic stageT3 or T4 with nodal involvement orvascular invasion have a high risk(greater than 50%) of systemic relapseand, therefore, may be considered fortreatment with adjuvant chemotherapyor radiotherapy. The followup schemais the same as that previously outlined forhigh-risk patients in the section onadjuvant chemotherapy. Owing to thehigh risk of systemic relapse in thisgroup, based on historical series usingsurgery alone, a number of groups arealso investigating combined-modalityapproaches using neoadjuvantchemotherapy followed by surgery orneoadjuvant chemotherapy and radiationfollowed by surgery. If possible, thesepatients should be placed on clinical trials.Bladder preservation can be consideredin selected cases in which there is no

palpable mass on EUA and nohydronephrosis. This approach shouldalso be used in the context of aninvestigational protocol, or be consideredfor patients who are deemed unsuitablefor surgery based on medicalcomorbidities. Evaluation withcystoscopy, biopsy, or cytology study isnecessary following the bladderpreservation treatment. If resectabletumor is found, surgical approach withcystectomy is considered. Patients withunresectable tumors undergo salvagetherapy. If no tumor is detected,observation, consolidation withchemotherapy and concurrent RT, oradjuvant chemotherapy is recommended.The general approach to this bladder-sparing strategy for these patients issimilar to that outlined previously underbladder-sparing strategies in patients withorgan-confined disease. Patients aretreated with a course of inductiontherapy (eg, RT with concurrentchemotherapy, neoadjuvantchemotherapy alone or neoadjuvantchemotherapy plus RT with or withoutconcurrent chemotherapy) with adeferred decision on management of theprimary lesion.

T4a, T4b disease

Patients with unresectable disease,defined as a fixed bladder mass, or thosewith positive nodes prior to laparotomyare considered for chemotherapy aloneor chemotherapy with RT. An initialstratification is based on the results oftransaxial imaging. For patients whoshow no nodal disease on CT scans, thetreatment recommendation includes twoto three courses of chemotherapy with orwithout RT followed by cystoscopy andCT scan. If the tumor has responded,options include surgery or consolidationchemotherapy with or without RT. If no

response is noted, chemotherapy with RTor a new chemotherapy regimen can beused. In highly selected T4a node-negativepatients, surgery with or withoutchemotherapy could be anothertreatment option. If pelvic lymph nodesgreater than 2 cm on imaging aredocumented, a biopsy is advised toexclude nodal spread. Baseline renalfunction, the presence or absence ofcardiac disease, and overall performancestatus must also be considered whenmaking a treatment recommendation.Patients with a good performance statusand no significant comorbid disease maybe considered for chemotherapy with orwithout RT if their nodes are positive. Ifcomplete response is obtained, patientsmay be managed with observation, boostwith RT, or surgery may becontemplated. Chemotherapy optionsare discussed below under metastaticdisease, whereas combined-modalityapproaches using chemotherapy and RTare discussed above. For patients whocannot tolerate multidrug combinationswith radiotherapy, an alternative is to useRT with a radiation sensitizer, such ascisplatin, administered starting on day 1and day 21, or 5-FU with a variety ofschedules. Patients are initially treatedwith 45 Gy of radiation to the pelvis andbladder, with a boost of approximately20 Gy to sites of disease within thebladder. In highly selected patients withmetastatic disease who have a completesystemic response to chemotherapy,salvage surgery may be performed torender the patient disease-free. Data fromseveral groups show that this aggressiveapproach can result in long-termsurvival. Prior to exploratory surgery,metastatic disease must be excluded withappropriate imaging studies. If theexploration is negative for metastaseswithin the abdomen, salvage surgery can


be performed. Patients who have residualinvasive disease in the bladder or nodalspread after combined-modality therapyhave a high risk of local and systemicrelapse and should be followed asoutlined previously. If there is noresponse, a change in chemotherapy isrecommended or, depending on thepatient’s symptoms from the primarylesion, palliative radiotherapy may beconsidered.

Metastatic disease

Patients who present with unresectableor metastatic disease or whosubsequently develop metastatic diseaseare generally treated with systemicchemotherapy or radiotherapy. Thesepatients should undergo a stagingevaluation that includes a chest x-ray,transaxial imaging of the abdomen andpelvis, and determination of creatinineclearance. The specific chemotherapyregimen recommended depends, in part,on the presence or absence of medicalcomorbidities, such as cardiac disease andrenal dysfunction, along with the riskclassification of the patient based ondisease extent. In general, long-termsurvival with combinationchemotherapy alone has been reportedonly in good-risk patients, defined asthose with good performance status, novisceral (liver, lung) or bone disease, andnormal alkaline phosphatase or lacticdehydrogenase (LDH) levels. Poor-riskpatients, defined as those with a poorperformance status or visceral disease,have consistently demonstrated verypoor tolerance to multiagentcombination programs and few completeremissions-a prerequisite for cure.Currently there are three active drugtypes that are active in the managementof advanced bladder cancer: cisplatin, thetaxanes, and gemcitabine. Varieties of two

or three drug combinations of these agentshave demonstrated clinical benefit. Acommonly used combination in good-riskpatients is a multidrug cisplatin-basedregimen, such as M-VAC or MCV. Analternative is cisplatin and gemcitabine,based on a direct comparison to M-VAC.More recently, the taxanes have beenshown to be active as both front-line andsalvage therapies, and both gemcitabineand ifosfamide have shown utility assalvage therapy. Based on these results, anumber of groups are exploring two- andthree-drug combinations using theseagents, with and without cisplatin, asinitial therapy. A major determinant ofthe regimen to be used is the performancestatus of the patient, and the use ofregimens with lower toxicity profiles isrecommended in patients withcompromised liver or renal status orserious co-morbid conditions. Theregimens effective for urothelialcarcinoma (transitional cell) histologieshave limited efficacy for patients withnon-urothelial (non-transitional cell)carcinomas. These individuals are oftentreated on the basis of the identifiedhistology (eg, adenocarcinomas withregimens typically used for coloncancers, and squamous tumors withregimens typically used for tumorsoriginating in the head and neck).However, overall experience withchemotherapy in non-urothelialcarcinomas (non-transitional celltumors) is limited. Independent of thespecific regimen used, patients withmetastatic disease are reevaluated aftertwo to three cycles of chemotherapy, andtreatment is continued for two morecycles in patients whose disease respondsor remains stable. Surgery orradiotherapy may be considered inpatients who show a major partialresponse in an unresectable primary

tumor or who have a solitary site ofresidual disease that is resectable afterchemotherapy. In selected series, thisapproach has been shown to afford asurvival benefit. If disease is completelyresected, consideration can be given totwo additional cycles of chemotherapydepending on patient tolerance. Those inwhom surgery or radiotherapy are notconsidered options are generally treatedwith chemotherapy for a maximum ofsix cycles depending on their response.

If there is no response after two cycles orif s ignificant morbidities areencountered, a change in therapy isadvised. The change should take intoaccount the patient’s currentperformance status, extent of disease, andthe specific prior therapy that has beenadministered. The same would apply forpatients who have relapsed systemicallyafter adjuvant chemotherapy. Patientswho cannot tolerate cisplatin-basedtherapy because of medical comorbiditiesmay be considered for a carboplatin-based regimen or, alternatively,paclitaxel or gemcitabine as a single agent.For salvage therapy, paclitaxel (if it hasnot been used earlier), gemcitabine, orifosfamide is advised depending upon thepatient’s current status


12

Prostate Specific Antigen (PSA)Satish Jain, Shubh Mahindru, S JainDepartment of Surgery & Surgical Oncology

Mohan Dai Oswal Cancer Institute & Research Foundation, Ludhiana.

4Commentary

With the advent of PSAscreening, a greater numberof men require education

about prostate cancer and how it isdiagnosed, staged, and treated in order toselect the most appropriate treatment.However, one should keep in mind thatit is a prostrate specific and not a prostratecancer specific antigen. So prostatespecific antigen (PSA) and digital rectalexamination (DRE) should be offeredtogether. Information should beprovided to patients regarding potentialrisks and benefits of intervention. Mostprostate cancer is slow growing - only 30percent of men diagnosed with prostatecancer will die from the disease.

Historical background

It was first identified in seminal plasmain 1971 by Hara and associates. Wang andassociates1 isolated it from prostratetissue. Since the test wasintroduced into clinical practicein 1986, the early diagnosis andmanagement of prostate cancerhas been revolutionized andmuch has been learned about thestrengths and weaknesses of thisassay.

Structure

PSA is a 33-kd proteinconsisting of a single-chainglycoprotein of 237 amino acidresidues, 4 carbohydrate sidechains, and multiple disulfidebonds. PSA is homologous withthe proteases of the kallikreinfamily and is a androgen-

regulated serine protease. PSA issynthesized in the ductal and acinarepithelium as an inactive 244 amino acidproenzyme (pro-PSA) that is activated bycleavage of seven n-terminal amino acids.PSA that enters the circulation intact israpidly bound by protease inhibitors,primarily alpha1-antichymotrypsin andá2 macroglobulin, although a fraction isinactivated in the lumen by proteolysisand circulates as free PSA. Thisproteolytic inactivation, as well as thecleavage of pro-PSA to PSA, is lessefficient in prostate cancer.

The upper limit of normal PSA is 0-4 ng/ml. PSA is abundant in seminal fluid, atconcentrations up to 3.0 mg/ml, amillion times more abundant than inserum. Thus, there is considerableoverlap in values between patients withprostate cancer and those with benign

conditions, such as benign prostatichyperplasia and prostatitis. Half-life ofPSA is 2.2 -3.2 days.

Function

The enzymatic activity of PSA inducesliquefaction of seminal clot. Seminalclotting is because of seminogelin 1 and 2and fibronectin. PSA targets seminogelincomponent and liquefy seminal clot andthe release of spermatozoa, hence helpsin sperm motility.

Clinical application

The sensitivity for detecting cancer witha PSA greater than 4ng/ml isapproximately 80%. For men with a PSAlevel of 4 to 10 ng/ml, ultrasound-guidedbiopsies detect cancer in 25%, of which75% are pathologically confined. If thePSA is greater than 10 ng/ml, 60% havecancer, but only 40% to 50% are

confined. The specificity is 15% to20% that is, one of five or six menwithout cancer will have anelevated PSA. Poorlydifferentiated adenocarcinomaproduces less PSA for samevolume as compared to well-differentiated cancer. AlthoughPSA levels cannot be used todiagnose prostate cancer and is nota specific prostate cancer marker,the benefits of PSA testingoutweigh its drawbacks. Serumtotal PSA level are increased inprostate cancer, and PSAscreening has dramatically alteredprostate cancer presentation andmanagement. Under pathologic


conditions, PSA reaches serum throughthe disrupted epithelial basementmembrane, passing into capillaries andlymphatics. Unfortunately, althoughhigh PSA levels are predictive ofadvanced prostate cancer, a large fractionof organ-confined cancers present withmuch lower total PSA values thatoverlap those levels found in menwithout prostate cancer. Measurement offree versus total PSA can increasespecificity for prostate cancer, and testsunder development to measure forms ofpro-PSA may further enhance the abilityto detect early-stage cancer.

Problems in PSA testing

• The lack of standardization betweenassays and laboratories is a majorproblem. Efforts are underway tocorrect this s ituation, butinconsistency between assays maymake comparisons difficult.

• Another problem involves thehandling and processing of the bloodsamples in physicians’ offices or inthe laboratories. The blood sampleshould be centrifuged and the serumshould be separated within 2-3 hours.If the assay is not performed withinthe next 2-3 hours, the serum shouldbe frozen. Once frozen at -20°c or -70°c, the enzyme remains stable forat least a month.

• The next problem involves thedecision to perform a biopsy inpatients with PSA levels in the rangeof 4-10 ng/ml. In clinical practice,the test often is repeated after a 2- to4-week course of antibiotics such asdoxycycline or a fluoroquinolone,and, if confirmed, a biopsy isperformed. The intention is to usethe antibiotics to treat any prostatitispresent. Prostate cancer would, of

course, not be affected by standardantibiotics. The fPSA, PSAd, andother manipulations do not replaceclinical judgment.

Change in PSA levels

• PSA value change occurs afterbiopsy, TURP and prostatitis, so oneshould wait for 3 to 6 weeks beforeperforming PSA again2.

• The serum PSA level can be alteredby various medications likeFinasteride and dutasteride, 5-alphareductase inhibitors that arecommonly prescribed for thetreatment of BPH, can produce adecrease in total prostate levels by50% within 6 months of therapy.This alteration fluctuates widely,ranging from -81% to +20%. After3-4 months of therapy, another PSAmeasurement can be obtained toestablish a new baseline. Alpha1-aDREnergic antagonists, which arefrequently used to treat thesymptoms of BPH, do not alter PSAlevels.

• Herbal products such as sawpalmetto do not affect PSA levels.

• Any medications that altertestosterone levels can affect theserum PSA. The use of luteinizinghormone-releasing hormone (lhrh)agonists and antagonists to stopproduction of testosterone by thetesticles is a cornerstone in thetreatment of prostate cancer. Thismanipulation produces a profoundreduction in PSA levels, usuallymaking them undetectable. Raisingtestosterone levels may increase PSAlevels, but not to the same degree asreducing testosterone production.

Some helpful hints for obtaining a

maximally accurate PSA testinclude:

• Abstain from ejaculation for 2 daysprior to having a PSA test

• Take history of any drugs used totreat BPH and baldness, will likelylower PSA levels.

• Be sure that the biopsy is performedafter drawing blood for the PSA test,as the it can artificially raise PSAlevels.

• Herbal supplements can also affectPSA levels. Be sure to ask about anysupplements that patient is takingbefore the PSA test.

To increase the sensitivity and specificityvarious other forms of PSA can becalculated e.g. age specific PSA, PSAvelocity, PSA density, free and total PSA,PSA transition zone and PSA doublingtime.

Age-specific reference ranges

The standard PSA reference range of 0.0-4.0 ng/ml does not account for age-related volume changes in the prostatethat are related to the development ofBPH. Oesterling et al (1993) presentedthe concept that age-related referenceranges would improve cancer detectionrates in younger men and would increasethe specificity of PSA testing in oldermen. Using reference ranges of 0-2.5 formen aged 40-49 years, 0-3.5 for men aged50-59 years, 0-4.5 for men aged 60-69years, and 0-6.5 for men aged 70-79 years,they reported an overall specificity of95%. A different reference range wasused for black men3. With a PSA range of0-2 for men aged 40-49 years, specificitywas 93%. A PSA range of 0-4 produced aspecificity of 88% for men aged 50-59years, a PSA range of 0-4.5 produced aspecificity of 81% for men aged 60-69


14

years, and a PSA range of 0-5.5 produceda specificity of 78% for men aged 70-79years.

The use of age-specific reference rangesin clinical practice results in the diagnosisof more cancers in men younger than 60years at the expense of more negativefindings on biopsy. However, earlypotentially curable cancers should bediagnosed in this age group. An increasingnumber of men in the fifth and sixthdecades of life are being diagnosed withsignificant cancers as a result of using age-specific reference ranges in addition toPSA density and PSA velocity. No easyanswer is available to decide whenbiopsies may be avoidable and when theyare necessary. Clinical judgment andexperience dictate the answer to thisdilemma until a perfect test is developed,and that is unlikely. The influence of raceon age-specific referenceranges has been studied.Reports indicate that PSAlevels are higher in black mencompared to white men, evenwhen controlled for age,clinical stage, and Gleasongrade.

Percent free PSA

This test measures how muchPSA circulates freely in theblood and how much is bound with otherproteins. Free PSA is reported as apercent. The more free PSA that ispresent the better it is (or the more likelya man is to be “free” of cancer). So, if aman has an elevated total PSA, but mostof it is “free PSA,” then it is most likelycoming from BPH rather than cancer4. Conversely if most of the total PSA iscoming from PSA that is bound toproteins, it is more likely that the patientwill have cancer. In one study,researchers used a free-PSA cutoff range

of 19% in men with total PSA levelsbetween 3 and 4 and detected 90% of allcancers. In another study of men withtotal PSA levels between 4 and 10,biopsies were performed only in menwith free PSA of less than 25% of the totalPSA. They detected 95% of the cancersand reduced unnecessary biopsies by 20%.The lower the ratio of free-to-total PSA,the higher the likelihood of cancer. Using25% as the cutoff, 95% of cancers can bedetected in both African Americans andwhites. A cutoff of 22% maximizes cancerdetection and minimizes unnecessarybiopsies. Generally, these percents areuseful in patients who have a PSA levelin the range of 4-10 ng/ml.

PSA density

In 1992, Benson et al5 introduced theconcept of PSAd to correlate PSA andprostate volume. PSA density is the value

of the PSA divided by the size of theprostate, which can be determined by atransrectal ultrasound (TRUS). Thelikelihood of prostate cancer is increasedwhen the PSAd value is high. In otherwords, if you have a relatively smallprostate that is producing large amountsof PSA, there is a greater likelihood thatcancer is present. If the prostate is largerelative to the PSA score, there is a greaterchance that BPH to blame. Theoretically,PSAd could help distinguish between

prostate cancer and BPH in men whosePSA levels are 4-10 ng/ml6. The value ofPSAd is l imited because of itsdependency on the individualperforming the prostate volumemeasurement. In addition, the BPHvolume does not always correlate withserum PSA values because of thevariation that exists between individualsin their epithelial-to-stromal ratios. PSAis made only by the epithelial cells, whichproduces a lower PSA level even thoughthe total volume of the prostate is high.The value of PSAd could improve thedetection rate of cancer at a cutoff of 0.15.

PSA velocity

In 1992, Carter7 et alintroduced the concept of PSA-v in aneffort to improve the ability of PSA todetect prostate cancer. Calculating thePSA velocity tracks changes in the PSA

blood level over time - forexample, how quickly thePSA level rises over thecourse of several months. PSA velocity may aid theinterpretation of borderlinePSA results by measuringwhether the PSA levels areincreasing over a short periodof time. The test is used as atool to keep track of how PSAlevels change, but it is not

used to diagnose prostate cancer. If PSAincreases dramatically in a short period,it may be one indicator that prostatecancer has progressed. PSA-v is used tomonitor the change in PSA over timeusing longitudinal measurements.Greater changes in PSA-v were detectedin men with cancer compared to thosewithout cancer 5 years before thediagnosis was made. Additional studieshave shown that this difference can bedetected up to 9 years before prostate

Probability of Prostate Cancer

Standard PSA Probability Percent free Probabilityof cancer PSA of cancer

0-2 ng/mL 1% 0-10% 56%

2-4 ng/mL 15% 10-15% 28%

4-10 ng/mL 25% 15-20% 20%

>10 ng/mL >50% 20-25% 16%


cancer diagnosis.

PSA-v is calculated using the followingequation:

I/2 ([PSA2 - PSA1 / time 1 in years] +[PSA3 - PSA2 / time 2 in years])

PSA1=first PSA measurementPSA2 = second PSA measurementPSA3 = third PSA measurement

At least 3 PSA measurements are neededduring a 2-year period or at least 12-18months apart to obtain maximal benefitfrom the results.

A PSA-v of 0.75 ng/ml or greater peryear was suggestive of cancer (72%sensitivity, 95% specificity). A PSA-v of0.75 ng/ml or greater correlated with thediagnosis of cancer in 72% of the patients,and only 5% had no cancer. Thelimitations of PSA-v testing include thatit is difficult to calculate, that PSA is notcancer specific, and that PSA variessignificantly with time and with differentassays. Nevertheless, a PSA-v greater than0.75 ng/ml per year is useful in somesituations in helping to decide the needfor initial or repeat biopsy.

PSA transition zone density

Kalish introduced prostate-specificantigen density of the transition zone(PSA-tz) as a refinement of the originalPSAd. This refinement is predicated on2 assumptions, f irst measuringtransitional Zone volume by transrectalultrasonography is more accurate thanmeasuring the entire prostate volumebecause of the difficulty in measuring thetrue border of the apex in thelongitudinal view, and secondly most ofthe PSA entering the circulation arisesfrom the tz.

Peripheral zone fraction

Zisman et al (2000) have offered a new

index using the peripheral Zone fractionof PSA to predict the presence of prostatecancer in men with PSA levels of 4-10ng/ml. They point out that the pzcontributes little to the amount of tPSA.The peripheral Zone fraction can becalculated using the following formula:

TPSA x (total prostate volume - tzvolume) / total prostate volume

Pz volume is measured by subtracting thetz volume from the entire prostatevolume while neglecting the central zone.They compared the positive and negativepredictive values using tPSA, PSAd, PSA-tz, and prostate-specific antigenperipheral zone density (PSA-pz). Theefficacy of PSA and PSA-tz was similar,at 60%. PSA-pz was 70% and PSAd was80%. The negative predictive values weresuperior to the positive predictive values.The negative predictive value for PSAand PSAd ranged from 78-83% and 78-88%, respectively. The negativepredictive value of PSA-tz and PSA-pzranged from 87-92% and 81-100%,respectively. Using roc curves, both PSA-tz and PSA-pz were significantly largerthan PSA and PSAd. When patients withnegative DRE findings were studiedusing the roc curve, the area under thePSA-pz curve was larger than that of thePSA-tz curve.

PSA doubling time

Patel8 et al in 1997 reported that PSAdoubling time was a better predictor oftime to clinical recurrence thanpreoperative PSA, stage, andpathological gleason score. A PSAdoubling time of 6 months or less aftersurgery indicated metastatic disease.They reported that 80% of 77 patientswith detectable PSA postoperatively anda doubling time longer than 6 monthsremained clinically disease-free,

compared to 64% with a PSA doublingtime shorter than 6 months. Pound andassociates (1999) used a doubling time of10 months to derive similar conclusions.They cautioned against treating patientswith long PSA doubling times too earlybecause most of these men lived for manyyears before evidence of clinical diseasewas detected.

PSA after treatment

PSA-v and pathology stage have beenstudied to determine treatment failureand the need for additional intervention.A detectable PSA level in a patient withmicrometastatic lymph node disease, agleason score greater than 7, and/orseminal vesicle invasion indicates distantmetastatic disease. Partin et al9 in 1994used multivariate analysis to study PSA-v, gleason score, and pathologic stage topredict local recurrence and distantmetastases. In patients whose PSA becamedetectable a year or more followingsurgery, a PSA-v less than 0.75 correlatedwith local recurrence in 94% of patients,while a velocity greater than 0.75predicted distant disease in more than50% of patients. A detectable PSA withinthe first 2 postoperative years isindicative of distant metastases andcorrelates with other risk factors such asstage and grade. This is important indetermining which patients might benefitfrom local radiation therapy followingprostatectomy. A pattern of PSA riseafter local therapy distinguishes betweenlocal and distant recurrence. Distantdisease can be predicted if the PSA doesnot become undetectable followingradical prostatectomy, begins to risewithin 12 months, or has a doubling timeof 6 months. The same characteristicsapply to radiation therapy andcryotherapy, although the time to nadiris prolonged. Patients whose PSA level


16

becomes detectable 24 months or moreafter radical prostatectomy likely havelocal recurrence. Patients with PSAdoubling times of 12 months or morefollowing surgery, radiation therapy, orcryotherapy are likely to have localrecurrence.

Significance of PSA testing

• DRE and TRUS are examinerdependant but PSA is an objectivetest with highest positive perdictivevalue for cancer prostrate.

• It increases the lead time for cancerprostrate thus result in detection ofcap that are more often confined toprostrate as compared to cancerdiscovered by DRE alone.

• It can be used to diagonosis as well asto monitor the response of treatmentin cancer prostrate.

Recommendation for PSAscreening

Cost-effective guidelines for PSA testingthat define age to start, age to stop, testinginterval, and PSA threshold for screeninghave not been clearly defined. AlthoughPSA testing detects more cancers thanDRE, a combination of the 2 methods isbetter. Screening should be done

• Asymptomatic men should begin atage 50 years after a discussion of thepotential risks and benefits ofscreening and should be targeted atthose men with more than a 10-yearlife expectancy.

• Annual PSA screening in men athigher risk, such as AfricanAmericans or Scandinavian race andthose with an affected first-degreerelative, should be tested earlier, atage 40 or 45 years.

Prostate specif ic antigen and

breast cancer

PSA in breast cancer is associated withthe expression of estrogen receptor andprogesterone receptor. A number ofstudies have indicated that elevated PSAlevels are a favourable prognostic factorin breast cancer. In particular, a largecohort study of 953 women with breastcancer (Yu, 1998)10 found that survivaland relapse free survival weresignificantly better in patients with levelshigher than the 30th percentile of PSAcompared to PSA-negative patients. PSAexpression was significantly associatedwith smaller tumours, smallerproportion of S-phase cells, diploidtumors and younger age. PSA remained asignificant independent prognosticfactor after taking into account otherclinical and pathological features.

References

1. Wang MC, Valenzuela LA, MurphyGP: Purification of a humanprostate specific antigen. Invest urol1979 Sep; 17(2): 159-63

2. Oesterling JE, Rice DC, GlenskiWJ: Effect of cystoscopy, prostatebiopsy, and transurethral resectionof prostate on serum prostate-specific antigen concentration.Urology 1993 Sep; 42(3): 276-82

3. Morgan TO, Jacobsen SJ, McCarthyWF: Age-specific reference rangesfor prostate-specific antigen in blackmen. N Engl J Med 1996 Aug 1;335(5): 304-10

4. Catalona WJ, Partin AW, Slawinkm, et al: Use of the percentage offree prostate-specific antigen toenhance differentiation of prostatecancer from benign prostatic disease:a prospective multicenter clinicaltrial. JAMA 1998 May 20; 279(19):

1542-7

5. Benson MC, Whang IS, Olsson CA,et al: The use of prostate specificantigen density to enhance thepredictive value of intermediatelevels of serum prostate specificantigen. J Urol 1992 Mar; 147(3 pt2): 817-21

6. Benson MC, Whang IS, Pantuck a, etal: Prostate specific antigen density:a means of distinguishing benignprostatic hypertrophy and prostatecancer. J Urol 1992 Mar; 147(3 pt2): 815-6

7. Carter HB, Pearson JD, Metter EJ:Longitudinal evaluation of prostate-specific antigen levels in men withand without prostate disease. JAMA1992 Apr 22-29; 267(16): 2215-20

8. Patel A, Dorey F, Franklin J:Recurrence patterns after radicalretropubic prostatectomy: clinicalusefulness of prostate specificantigen doubling times and log slopeprostate specific antigen. J Urol1997 Oct; 158(4): 1441-5

9. Partin AW, Pearson JD, Landis PK,et al: Evaluation of serum prostate-specific antigen velocity after radicalprostatectomy to distinguish localrecurrence from distant metastases.Urology 1994 May; 43(5): 649-59

10. Yu H, et al. Prognostic value ofprostate-specific antigen for womenwith breast cancer: a large UnitedStates cohort study. Clin Cancer Res1998; 4(6):1489


Abstract

The objective of the study was toanalyze study the operativemorbidity and mortality and

disease recurrence afterabdominoperneal resection (APR) forcarcinoma anorectum in 100 patientsoperated at our institution. 100 patientsoperated for APR at our institutionbetween September 1992 and July 2004were included in our study. Thesepatients were followed upto November2004. Patients not surgically treated atour center but outside were excludedfrom the present study. 54 males and 46females, who underwent APR at ourcenter were studied. The mean age was53.07 years. The most commonpresenting complaint was bleeding perrectum. Three patients developed intra-operative complication and there were,two immediate post operativemortalities in our 100 patients. Theimmediate post operative complicationsobserved were abdominal and perinealwound infection and dehiscence. Thedelayed post operative complicationswere genito-urinary complications seenin 32 patients, adhesive small bowelobstruction in 23 patients, colostomyrelated complications in 4 patients andincisional hernia in 6 patients. In termsof disease recurrence, after APR in thefollow up period, 11 patients developeddistant metastasis, most common beingLiver metastasis followed by inguinalLymph Node metastasis in 6 patients.Local disease recurrence in pelvis wasseen in 23 patients. Abdominoperineal

5Original

Article

Complications following Abdomino perineal Resection forCarcinoma Anorectum

Satish Jain, Puneet Jain, Amreek Singh, T. Singh, S. Jhanjee, Shubh Mahindru, Sumeet JainDepartment of Surgery & Surgical Oncology, Mohan Dai Oswal Cancer Treatment &

Research Foundation, Ludhiana

resectin (APR) remains the “goldstandard” for low lying advancedcarcinoma anorectum. APR carries lowmortality but high morbidity rate withrespect to both immediate and delayedpost operative complications.

Key words- AbdominoperinealResection, Carcinoma Anorectum,Complications, Distant metastasis, localrecurrence.

Introduction

Colorectal cancer is the most commoncancer of gastro intestinal tract. Inwomen, Gastro intestinal cancer is 2nd

only to cancer breast as a cause of cancerrelated death. In men it is the third mostlethal cancer preceded by lung andprostate. Approximately one half of thesetumors are located in the rectosigmoidregion.It was estimated thatapproximately 13000 new cases ofcolorectal cancer occurred in the USAin 2000 and approximately 500 patientswould die because of this disease. Recentdata indicate that in the USA, the averageage related incidence of colorectalcancers for males is 46.5 and for femalesis 37.2 per lac per year.Rectal cancer issimilar to colon cancer in that themajority of malignant neoplasms ofrectum are Adenocarcinoma. Themanagement of Squamous CellCarcinoma differs significantly fromAdenocarcinoma. Adjuvant treatmentthat is radiotherapy and chemotherapyhave a definite role in both locallyadvanced carcinoma anorectum and forDuke’s C Stage.Nigro’s Chemoradiation

regimen has become the first choice forthe carcinoma anal canal ahead ofAbdomino-perineal resection. Withimprovement in diagnostictechniquesand with advances in adjuvanttherapy, there is a definite trend towardsphincter preserving techniques insteadof APR, whenever possible.Complications resulting from surgicalmanagement of rectal cancers besidesthose associated with any majorabdominal surgeries like Sepsis,Myocardial infarction, Pulmonaryembolism, and wound infection, include– Injury to sexual function – A 50%incidence of significant impotence inmen following resection of rectum forcancer has been reported. Malfunctioningof urinary system – since perinealdissection of rectum comes very close tomembranous urethera. Patients can haveurinary incontinencedue to loss ofneurological control of urethera Stomarelated complication – Ischemia,Retraction, hernia, Stenosis, Prolapseand Fistula.

Perhaps the most important prognosticconsideration lies in the status of cancerwith respect to distant metastasis andlocal recurrence. Cancer rectum spreadslocally via the lymphatics and directinvasion, which is mainly in the upwarddirection along the superiorhemorrhoidal vessels.

Hematogenous spread to the liverthrough the portal system occurs in 30%to 50% of patients dying of rectal cancer.Other sites of distant hematologicalmetastasis include lung, bone, brain,


18

spleen and ovaries. Local recurrence inthe pelvis after surgical resection iscommon and can occur with and withoutmetastatic disease. Death in patients withpelvic resection is characterised byextreme discomfort and poor quality oflife. This situation has stimulated effortsto eliminate pelvic recurrence and haslead to use of adjuvant Pre opradiotherapy. This study has been donewith the objective to highlight thatoperative mortality and morbidity anddisease recurrence after APR in 100Patients operated at our institutionbetween September 1992 and July 2004.

Abdomino perineal resection (APR) hasremained the standard treatment formalignancies of distal one thirds rectumsince it was first described in 1908 byErnest Miles. APR shares withmastectomy the honour of dominatingsurgical thoughts about a majormalignancy for the last about hundredyears of surgical practice2. APR isindicated in -poorly differentiated (G-3) or T3 lesions, lower thirds of rectum;cancers located less than 3 cm proximalto dentate line or 5 cm from anal vergeare generally not amenable to restorativeresection; advanced rectal cancer (T4) aspalliative resection, especially inelderly/poor risk patients; as salvageprocedure for local recurrence or ifthere is biopsy proven tumor after initialchemo radiation, as suggested by NormanNigro, for anal canal cancers3.

Material and Methods

A combined retrospective as well asprospective analysis of the clinical andpathological data along with results aftersurgery in terms of complications &disease recurrence was done in our study.Analysis of 75 patients of carcinomaanorectum undergoing abdominoperineal resection (APR) at our center

between September 1992 to December2001 was done retrospectively and 25patients operated between January 2002to July 2004 and followed up toNovember 2004 were analyzedprospectively. The case records of thepatients were obtained from the medicalrecords department and scrutinized. Theinclusion criteria for patients in ourstudy were-Histo-pathologically provencases of carcinoma anorectum; Patientsoperated at our center only. Thosepatients who were operated outside ourcenter were not included in the presentstudy.

Results

In our study group of 100 patients (75studied retrospectively and 25 studiedprospectively) operated forabdominoperineal resection, there were54 males and 46 females. Male to femaleratio was 1.17:1. Mean age was 53.07 yearsand median age was 53 years. Theyoungest patient in our study was 28 yearsold and the oldest patient was 89 yearsold. The most common presentingcomplaint of the patients studied wasbleeding per rectum seen in 80 patients(80%) followed by altered bowel habitsi.e. constipation or diarrhea in 51patients (51%). Bowel obstruction wasseen in 1 (1%) patients.

Table – 1, Clinical profile ofretrospective & prospectivegroup of patients

Retrospective(N=75)

Sex (Male/Female) (38/37)Mean Age (year) 52.45+11.99

Chief Complaints

Bleeding per rectum 60Altered Bowel Habits 38

Distance of Growth fromanal verge

0-2 cm 202-4 cm 37>4 cm 18Histopathology

Adenocarcinoma Anorectum 62Squamous cell carcinoma 8Malignant Melanoma 3Staging (Post Operative)

Dukes’ B 43Dukes’ C 24

Table -2, Showing incidence ofvarious post-operative complicationsafter APR

Retrospective(N=75)

Intra operative complications 3Operative mortality 2

Abdominal wound complications

Wound infection 9Would Dehiscence 11Perineal Wound complication

Wound infection 9Wound Dehiscence 2Genito urinary Complications 24

Adhesive bowel obstruction 20Colostomy related complications 2

Incisional Hernia 4


Prospective(N=25)(16/9)

54.92+14.16

2013

1465

193-

148

Prospective(N=25)

--

11

418

32

2

Table – 3, Showing Disease recurrence after APR

Distant Metastasis Retrospective Prospective(N=75) (N=25)

Total 7 4Liver 6 3Lung 3 -Brin 2 -Dukes’B 4 1Dukes’ C 1-Malignant Melanoma 2 -

Inguinal Lymph Node Metastasis 4 2

Dukes’B 3 1Dukes’ C -1Malignant Melanoma 1 -Local Recurrence

Total 17 6Prostate 2 -Posterior Vaginal wall/ Vault recurrence5-Dukes’B 14 1Dukes’C 3 3Ana plastic Malignancy - 2

The distance of the growth from the anal verge was (0-2) cm in 34 patients(34%), (2-4) cm in 43 patients (43%) and (>4)cm in 23 patients (23%)operated for APR. The distance of growth from anal verge remains thecritical criterion for deciding about sphincter preservation or not insurgery for carcinoma anorectum.

Post operatively, adenocarcinoma anorectrum was the most commonhistopathology, seen in 81 patients (81%) followed by squamous cellcarcinoma in 11 patients (11%). Malignant melanoma was seen in 3patients (3%). Dukes’ B (T3/ T4 N0 M0) was the most common histo-pathological stage seen in 57 (57%) patients followed by Dukes’ C (AnyT N1 M0) in 32 patients (32%). In our study group, three patients haditraoperative complications: two patients had ureteric injuries duringdissection. For which primary repair was intestinal obstruction withsuccessful in one but the other patient required boari flap constructionand psoas hitch operation. One patient developed anterior sacral venousplexus ooze, which was managed successfully with packing. There weretwo immediate post operative mortalities (2%) in our 100 patients, seenwith in 30 days of surgery. The cause of death in one patient was intestinalobstruction with septicemia and acute renal failure. The second mortalitywas in a known case of bronchial asthma, who died because of respiratoryfailure and septicemia. The other post operative complications observedin our study were abdominal wound infection in 10 patients (10%),

abdominal wound dehiscence in 12patients (12%), out of these 11 patientsrequired mass closure. Perineal woundinfection was seen in 13 patients (13%)and perineal wound dehiscence was seenin 3 patients (3%).

The delayed complications after APRobserved in our study were:Genitourinary complications seen in 32patients (32%) with incontinence ofurine being the most common, seen in 12patients followed by symptomaticurinary tract infection, retention ofurine and radiation cystitis, all seen infour patients each. Difficulty in passingurine, post operatively was seen in threepatients. These patients with retention ofurine and difficulty in passing urinerequired either urethral dilatation (inthree patients) or cystoscopy andchannel’s operation (in two patients).The rest were managed by urethralcauterization. Adhesive small bowelobstruction was seen in 23 patients (23%).Among these 23 patients, 16 had receivedlocal radiotherapy prior to episodes ofobstruction. Four patients had episodesof repeated small bowel obstruction.Exploratory laparotomy withadhesiolysis was done in 8 of these 23patients. Resection – anastomosis of thesmall bowel was done in 3 patients. Righthemi-colectomy and ileotransverseanastomosis was required in 5 patients.Conservative management was successfulin 6 patients and one patient died becauseof septicemia and acute renal failure.Colostomy-related complications wereseen in 4 patients (4%). There were twocases each of colostomy stenosis and ofparacolostomy hernia, all four of whichrequired surgical repair.

Incisional hernia as a delayed postoperative complication was seen in 6 ofour 100 patients (6%).


20

Only one of these patients underwenthernioplasty with polypropylene mesh.In terms of disease recurrence after APRin the follow up period, 11 of ourpatients (11%) developed distantmetastasis. Among these liver metastasiswere the most common, seen in 9 patients(9%) followed by Lung metastasis in 3patients (3%) and Brain metastasis in 2patients (2%). In these 23 patients,Dukes’B stage was seen in 15 patients,Dukes’C in 6 patients and two patientshad anaplastic (Undifferentiated) type ofmalignancy. Five of our female patients(5%) developed posterior vaginal wallor vault recurrence whereas two of ourmale patients (2%) developed localrecurrence involving the prostate. Themean period of detection of localrecurrence after APR was 11.1 monthsand two deaths were reported in these 23patients where as the rest wee lost offollow up.

Discussion

Abdominoperineal resection (APR) hasbeen regarded as the “gold standard” forthe treatment of rectal cancers for manyyears3. Several authors have described thecomplications & disease recurrence afterAPR over the years. In our study of 100patients operated for APR, there were 54males (54%) and 46 females (46%) withmean age of 53.07 years and age range of28-89 years. Petrelli, Negel et al4 found38 males (68%) and 18 females (32%)among their 56 patients operated forAPR. They found the mean age of theirpatients to be 59 years with age range of37-80 years. Zaheer, Pemberton et al 1observed bleeding per rectum as the mostcommon presenting complaint: in 61%of their 514 patients operated for APRfollowed by change in bowel habits seenin 33% patients. Intestinal obstructionwas seen in 1% patients. Almost the same

pattern was seen in our study with 80%patients presenting with bleeding perrectum, 51% with altered bowel habitsand 1% with bowel obstruction.Fleshman, Wexner et al5 quoted anincidence of adenocarcinoma anorectumof 92% (140 patients) and of squamouscell carcinoma of 6.6.% (10 patients) intheir study group of 152 patients. In ourstudy the incidence was 81% (81 patients)and 11% (11 patients) respectively.Petrelli, Nagel et al. found an incidenceof Dukes’ B of 48.2% and of Dukes’ C of34% in their 56 patients. In our study,the incidence was 57% and 32%respectively. With regards to intra-operative complications, Petrelli, Nagelet al have quoted haemorrhage fromsacral venous plexus in 2 patients (3%)and transected left ureter in one patient(2%) amongst their 56 patients. The sameauthors have described 2 deaths in their56 patients (3%) within 30 days ofsurgery. The cause of death in one wasexsanguinating haemorrhage from sacralvenous plexus and due to pulmonaryembolism in the other. Zaheer,Pemberton et al observed an overallmortality of 1.8% after APR. Rosen,Veidenheiner, Coller9 have reported anoverall mortality of 1.7% in 230 patientswho underwent APR. In our study theincidence of interaoperativecomplications was 3% and the postoperative mortality was 2%.

Amongst the wound complications afterAPR, Luna Perez et al6 found an incidenceof 14.6% (20/137) of perineal woundcomplications. On the other hand,Slanetz, Herter et al7 found abdominalwound complications in 5.8% (11/190)patients. In our study, the incidence ofperineal wound complications was 16%and of abdominal wound complicationswas 22%. The greater incidence ofabdominal wound complications in our

study was likely due to poor generalcondition, debility and associated co-morbid illnesses in our patients. Withregards to genitourinary complications,Slanetz, Herter et al. quoted an incidenceof 35% (66/190) patients, while Petrelli,Nagel have stated an incidence of 34%(19/56) with urinary retention being themost common urinary complaintfollowed by incontinence of urine. Inour study, 32% of our 100 patientsdeveloped genitor-urinary complicationswith space bar incontinence of urinebeing the most common complaintfollowed by retention of urine.

Nissan, Guillem et al8 reported 9.9% (29/292) incidence of adhesive small bowelobstruction amongst their patients 20%of these patients (6/29) had receivedlocal radiotherapy. Our incidence ofadhesive bowel obstruction was greater:23% but 69.5% of these patients (16/23)had received local radiotherapy. Hencelocal radiotherapy, especially postoperative radiotherapy can contribute toincreased incidence of adhesive bowelobstruction. With regards to colostomyrelated complications, Petrelli, Negal etal found that only one of their 56 patientsrequired revision of colostomy for thesecomplications. Our incidence ofcolostomy –related complications was4%. Hence contrary to general belief,APR is associated with low incidence ofcolostomy-related complications.

With regards to incidence of distantmetastasis, Zaheer, Pemberton et al foundLiver as the most commonly involvedorgan & 11.2% (19/169 patients)incidence of distant metastasis. WhereasLuna, Perz et al quoted an incidence ofdistant metastasis of 25.7% (35/137) intheir patients. In our study, the incidenceof distant metastasis after APR was 11%and liver was the most commonly


involved organ (Table – 3) . The localdisease recurrence rates reported byMcFarlane 10 et al after APR was 22%and that by Braun et al 21%. Ourincidence of local disease recurrence was23%. Hence, APR was found to beassociated with significant localrecurrence rates, which contributed toboth morbidity and mortality.

In conclusion, Abdominoperinealresection (APR) carries low postoperative mortality rate but a significantmorbidity rate with respect to bothimmediate and delayed complications.The incidence of disease recurrence afterAPR is comparable with sphincter savingprocedures. During the last two decades,low anterior resection with colo-anal orcolo-rectal anastomosis has replaced APRas the primary surgical therapy for rectalcancer and the concept of TotalMesorectal Excision (TME) has becomethe standard of care for this malignancy.But despite these recent trends, to quoteMurray and Veidenheimer, “APRremains the gold standard to which allother operations must be compared forall cancers of the lower thirds and forbulky tumors of the middle third ofrectum”.

References

1. Zaheer S; Pamberton J.H, Farouk R,et al. Surgical Treatment ofAdenocarcinoma of the rectum”,Ann Surg 1998; 227 (6): 800-811.

2. Heald RJ, Smedh RK, Kold A,Sexton R et al. “Abdominoperinealexcision of the rectum- anendangered operation. Dis ColonRecum 1997; 40 (7): 47-57.

3. Glattli A, Barras JP, Metazger U. “Is there st i l l a place for

abdominoperineal resection of therectum?, European Journal of Surg.Oncology 1995; 21 (1): 11-15.

4. Petrelli N.J., Negel S, Piedmonte etal: Morbidity and mortalityfollowing abdominoperinalresection for rectal adenocarcinoma.American Surgeon 1993; 59(7): 400-403.

5. Fleshman J.W., Wexner SD, AnariM et al, Laparoscopic v/s openabdomino perineal resection forcancer, Dis. Colon Rectum 1999;42(7): 930-939.

6. Luna-Perez, Rodrigurez- Ramirez etal, Morbidity and Mortalityfollowing abdominoperinealresection for low rectaladenocarcinoma.

7. Slanetz C, Herter F, Grinnell R.Anterior Resection V/Sabdominoperinal resection forcancer of the rectum andrectosigmoid. Am. J. surg 1972;123:110-115.

8. Nissan A, Guillen J, Patty P et al.Abdominoperineal resection forrectal cancer at specialty center. Dis.Colon rectum 2001; 44:27-36.

9. Rossen L, Veidenheimer MC, CollarJA et al. Mortality and Morbiditypatients of recurrence afterabdominoperineal resection forcancer of rectum. Dis. ColonRectum 1982;25:203.

10. Isenberg J, Keller HW et al. Middleand lower third rectum carcinoma:Sphincter Saving orAbdominoperinal Resection?.Eurpoean J. Of Surg. Onco. 1995; 21(3): 265-268.

Ancient India

Indian physician Sushruta (c. 600BC) taught and practiced surgeryon the banks of the Ganges, now

Benares in Northern India. Sushrutais a series of volumes he authored,known as the Susrutha Samhita. It isthe oldest known surgical text and itdescribes in exquisite detail theexamination, diagnosis, treatment,and prognosis of numerous ailments,as well as procedures on performingplastic surgery, i.e. cosmetic surgeryand rhinoplasty. In the Sushrutaschool, the first person to expoundÂyurvedic knowledge wasDhanvantari who then taught it toDivodasa who, in turn, taught it toSushruta, Aupadhenava, Aurabhra,Paushakalâvata, Gopurarakshita, andBhoja. He is also known by the title“Father of Surgery.” The Samhita hassome writings that date as late as the1st century, and some scholars believethat there were contributions andadditions to his teachings fromgenerations of his students anddisciples. Susrutha is also the fatherof Plastic Surgery and CosmeticSurgery since his technique offorehead flap rhinoplasty, that heused to reconstruct noses that wereamputated as a punishment forcrimes, is practiced almost unchangedin technique to this day. Thisknowledge of plastic surgery existedin India up to the late 18th century ascan be seen from the reportspublished in Gentleman’s Magazine(October 1794).The SusruthaSamhita contains the first knowndescription of several operations,including the uniting of bowel, theremoval of the prostate gland, theremoval of cataract lenses and thedraining of abscesses. Susrutha wasalso the first surgeon to advocate thepractice of operations on inanimateobjects such as watermelons, clayplots and reeds; thus predating themodern practice of the surgicalworkshop by half a millennium.


22

It is a nonspecific inflammatorydisease of unknown aetiology,affecting the bowel. A number of

other conditions which are associatedwith inflammation of the bowel are –Bacterial Colitis; Parasitic Colitis;Radiation Colitis; Ischemic Colitis.Unless the cause of Ulcerative Colitis andCrohn’s disease are not known the terminflammatory bowel disease serves auseful purpose to distinguish theseconditions from other bowel disorders.It is most commonly seen in the age groupof 15 to 25 years, however a second peakin the incidence of IBD is seen at 60 to 70years age. About 15 % of patientssuffering from IBD have a close relativewho also have IBD.

Ulcerative colitis- It is a nonspecificinflammatory disease of unknownaetiology affecting the large bowel. It isseen in both sexes and at any age butmostly affecting the second to fourthdecades of life. Auto immunity, allergyto milk protein and genetic factors mostlypredisposes to aetiological factors.

Clinical features- The severity variesfrom mild inflammation of mucosa tofulminating ulceration of colonicmucosa. The disease shows exacerbationand remission of varing intervals. Itaffect the variable part of large bowel, asproctitis, proctosigmoiditis, left sidedcolitis and pancolitis. The disease doesnot involve the small intestine but attimes reactionary inflammatory changesare seen in terminal ileum which is calledas back-wash ilitis. In mild case it maypresent with increased frequency of

6Reviewarticle

Inflammatory Bowel DiseaseBarin Bose

Jabalpur Hospital and Research Centre, Jabalpur

stools. In severe cases massive diarrhoea,bleeding PR, tenesmus, abdominalcramps and and fever are present. Thepredominant symptoms are bloodystools and diarrhoea. The severity ofbleeding is in proportion to the stage ofthe disease, and nocturnal diarrhoea isfrequent. Signs are minimal andnonspecific in mild cases. In severe casesabdominal tenderness, abdominaldistension, fever, tachycardia, raisedTLC are present. Bad prognosis isindicated by -a sudden and severe initialattack; disease involving the whole ofcolon ; increasing age especially after 60years. Prognosis is good if disease involvethe left half of colon.

Pathology- Microscopically acute andchronic inflammatory response is seen inthe mucosa and submucosa withulceration and regeneration. Multiplecrypt abscesses are seen.During remissionphase acute response is absent. The mucosais atrophic,reduced goblet cells, cryptsare distorted, submucosa thickened.Other coats are not involved and theinflammatory lesions are limited tomucosa and sub-mucosa. The mucosabecome swollen, friable, which leads toulceration, which involves the fullthickness of mucosa. In early stage smallulcers are present on mucosa,which latercoalesces to give extensive denudation.Secondary infection occurs on thesedenuded areas. In chronic stage the diseasestarts in rectum leading to proctitis, laterit extends proximally to involve thesigmoid colon, descending colon -proctosigmoiditis – left half colitis. Insevere cases pancolitis results. The

episode of ulceration leaves behind islandof mucosa which regenerates in chroniccase to form polyp like structures whichare called pseudopolyps.In severefulminating cases the wall of colonbecomes thinned out, specially seen intransverse colon, which become dilatedleading to toxic megacolon, at this stagethe colon may perforates, resulting inperforation peritonitis.

Malignant changes- Frequency ofmalignant change in ulcerative colitis ishigh. The high risk factors includes -childhood onset; pancolitis; duration ofdisease is more than 10 years.

Investigations –Proctoscopy –Loss of normal vascular pattern ofmucosa due to mucosal edema. Mucosashows edematous, inflamed, granularityand friability. Ulceration and bleedingpoints.Fine granularity is seen in acutecases and coarse granularity is seen inchronic disease. Biopsy in acute stageshows nonspecific inflammatory changesand is not diagnostic.

Colonoscopy and biopsy-This isdone to -establish the extent of disease;distinguish between Ulcerative Colitisand Crohn’s Disease; monitor theresponse of treatment; multiple biopsiesare taken to know the dysplastic changesin diseases which are more than 10 yearsduration.

Barium enema- This shows loss ofhaustrations specially in distal colon;mucosal changes due to granularity;pseudopolyps; in chronic cases a narrowand contracted colon; in Chronic cases


colonic stricture may be seen. ( Colonicstricture in Ulcerative colitis should betaken as malignancy unless provedotherwise.) If the disease is more than 10years old annual colonoscopy is to bedone even if the disease is quiescent torule out malignant changes.

Extraintestinal manifestation-These could be as arthritis; skin lesions(Pyoderma gangrenosa); clubbing offingers; Iritis; Liver disease ( SclerosingCholangitis); Bile duct malignancy.

Medical treatment

Diet and nutrition - Patients withmild attack of IBD are able to take foodorally. Fibres are restricted during activesymptoms. Patient with Crohn’s Diseasehave terminal ileal involvement andsteatorrhoea. These patient with Crohn’sdisease require fat soluble vitaminsupplementation. Parenteral B12supplimentation. Iron replacement. Insevere IBD patient are nil by mouth andrequire TPN.

Drugs- Sulphasalazine &aminosalicylates are the most commonlyused drugs in IBD It has been shown to beeffective in the treatment of active as wellas remitted case of ulcerative colitis andCrohn’s disease, when colon isinvolved.The drug sulfasalazine consistsof two drugs, a Supfapyridine and a 5Aminosalicylic acid (5 ASA) which arelinked by azobond. Intestinal bacteriabreaks the azobond and release the 2components. The sulfapyridine issystemically absorbed and is excreated inthe urine. The active component 5 ASAis not absorbed and remains in the gutlumen in contact with the mucosa and isexcreated with the stools.. Side effect –Abdominal discomfort, it is due to theeffect of salicylates on the upper GItract.This problem can be minimised bygiving Supfasalazine with

meals.Sulfasalazine competes withfolates for absorption so patients becomefolate deficient.Other side effect are skineruption, bone marrow depression is dueto sulfapyridine part. Dosage : The initialdaily dose is low (1 Gm) to minimize GIside effects . A therapeutic dose of 3 to 4Gms per is appropriate. CBC and liverchemistry is done every 3 monthsinitially then every 6 months in the longterm treatment. Maintenance treatmentof 2 to 3 Gms per day in divided dose hasbeen shown to reduce the frequency ofexacerbations of ulcerative colitis.

Other 5 ASA Preparations- The sideeffect of sulfasalazine is due to theSulfapyridine part of the durg. So theinterest is to develop a drug which hasthe sal icylate part but not thesulfapyridine part.Several oral 5ASApreparations are available, Olsalazinewhich consists of two 5ASA moleculesjoined by an azobond and which requirebacterial degradation in the colon torelease the 2 molicules of 5ASA. Asacoland Pentasa are controlled release tabletsof 5ASA . Balsalazine is a newer 5ASApreparation which is effective in thetreatmrnt of IBD involving left sidedcolon. Topical 5ASA preparations areMesacol enema and Mesacolsuppositories. 5ASA preparations arealso recommended in patients withCrohn’s disease to prevent post operativerecurrence.

Corticosteroids- Corticosteroids hasbeen used in the treatment of severeulcerative colitis and Crohn’s disease toreduce remission. IV Hydrocortisone100 to 200 Mgs 6 hourly is used. OrMethylprednisolone in the dose of 10 to20 Mgs IV 6 hourly are usually used insuch patients. When patients can take oralmedicines, prednisolone tablets in a doseof 40 to 60 Mgs per day usually given for3 to 4 weeks.When symptoms improves

the durg is tapered off in several months.Steroids are not recommended formaintenance therapy of Ulcerativecolitis and Crohn’s disease becausesteroids do not prevent relapse of UC andCrohn’s disease and they have major sideeffects. Many patient become Steroiddependent when recurrence of symptomsoccure when dose of steroids are reduced.In such cases one strategy is to useimmunomodulators such asAzathioprim, 6 Mercaptopurine,Methotrixate, Cyclosporin, in steroiddependent patients to help tapper the doseof steroids, second option is Surgery.Corticosteroid enemas are also availablefor the treatment of proctitis and distalcolitis.

Antibiotics- Most patients with mildto moderare IBD are successfully treatedby Sulfasalazine or 5ASA andoccasionally may require systemic ortopical steroids therapy to treat diseaserelapse. However 20 to 30 % of patientswith Ulcerative colitis and 30% ofpatients with Crohn’s disease requireadditional therapy for refractory disease.Bacteria is known to play an importantrole in the pathogenesis of Crohn’sdisease and Ulcerative colitis. In Crohn’sdisease antibiotics are used to treatperianal abscesses and fistula,microperforation,localized peritonitis,bacterial overgrowth in chronicstricture. Antibiotics should beconsidered in patients not responding to5ASA preparations prior to initiatingsteroid therapy.

Metronidazole- Has been shown to beeffective in patients with Crohn’s diseaseof the colon of combined small bowel andlarge bowel disease, and in perirectal andfistulizing Crohn’s, some patient withUlcerative colitis also responds toMetronidazole.


24

Ciprofloxacine- Useful in patientswith colonic Crohn’s and in perirectaland fistilising Crohn.

Combination of Metronidazoleand Ciprofloxacine.

Bile acid binding resins – Becauseof patients with Crohn’s disease haveinvolvement of terminal ileum whichresults in bile acid malabsorption,diarrhoea, steatorrhoea. Treatment withbile acid binding resins are indicatedsuch as Cholestyramine.

Surgical management

Indication for Surgery – Risk ofcolectomy is 20% in overall ranging from5% in those patients with only proctitisto 50 % in those patients with severeattack of pancolitis.

• Severe fulminating disease failing torespond to medical therapy for 7days.

• Chronic disease with anemia.

• Steroid dependent disease – Here thedisease is not severe but remissioncannot be maintained withoutsubstantial dose of steroids.

• Severe haemorrhage, stenosis,obstruction, perforation.

• Extraintestinal manifestations.

Operations –Total abdominalcolectomy with end ileostomy, is donein emergency situation as a firstaidprocedure.The restorative surgery isdone at a later date ;when the patient isno longer on steroid and in optimalnutritional condition –Ileorectal orileoanal anastomosis.

(2) Proctocolectomy with ileostomy.Restorative protocolectomy with anileoanal pouch anastomosis. J Pouch, SPouch, W Pouch. Colectomy withileorectal anastomosis when the rectumis minimally involved.

Toxic megacolon and severe IBD– Toxic megacolon ia a condition inwhich the colon becomes atonic anddilated because of transmural

inflammation. It is mostly associatedwith severe ulcerative colitis, but it maybe associated with any severeinflammatory condition of the bowel-Crohn’s disease, Bacterialcolit is ,Parasit ic colit is ,Pseudomembranous colitis, Ischemiccolitis, Radiation colitis. Some patientwith severe ulcerative colitis do not havetoxic megacolon but they requireintensive treatment, because at any timetoxic megacolon can be precipitated.Patient with toxic megacolon areseriously i l l . They have fever,tachycardia, raised TLC, bloodydiarrhoea and sepsis.

Pathogenesis – In most instances ofcolitis inflammatory process is confinedto the mucosa and submucosa. Toxicmegacolon developes as a result of theextension of the inflammatory processto the muscularis mucosa and serosa,leading to peritonitis and some timesperforation. Several factors predisposesto the development of toxic megacolon

• Reduction in the medication of IBD.

• Hypokalemia causing paralyticileus.

• Narcotics.

• Anticholenergic drugs.

• Drugs which dimnish bowelmovements.

• Cessation of smoaking in patientwith Ulcerative Colitis.

Bowel stasis facilitates extension ofinflammatory process. The sign andsymptoms are – At initial stages there isworsening of diarrhoea (more than 6stools per day), fever, techycardia,abdominal tenderness, abdominaldestension. As the disease progress thestool frequency diminish and the colonbecome atonic and dilated. Physical

Indications of Immunomodulator Drugs

Crohn’s disease Ulcerative ColitisRefractory Crohn’s Refractory Ulcerative

colitisSteroid Dependent Steroid DependentRemission & maintenance Remission & maintenanceCrohn’s of UCFistulizing Crohn’sPrevention of Post operativerecurrence

Immunomodulator Drugs are-Azathioprim, 6 Merkaptopurine,Cyclosporin, Methotrixate, Infliximab.Infliximab is an antibody against HumanTumour Necrosis Factor -2. which playan important role in pathogenesis ofCrohn’s disease. Infliximab is effectivein the treatment of moderate to severeactive Crohn’s disease and fistulisingCrohn’s. It may also be beneficial insevere active UC. Further studies areunderway to see the long term use ofInfliximab in IBD. It is advisable tocontinue the use of 5ASA, antibiotics,steroids and immunomodulator drugs,during and after the infusion ofInfliximab.

Nicotine –In enema form has beenshown beneficial in Ulcerative colitis.

Anti-diarrhoeal drugs – I fdiarrhoea does not improve with theabove mentioned medical therapy theantidiarrhoeal drugs can be used. Codineis most effective. Imodium and Lomotilis used in mild to moderate IBD. In severeIBD they should not be used as they tendto precipitate toxic megacolon.


examination shows :

• Patient appear severely ill.

• Sign of systemic toxicity. Fever,techycardia, change in mental status.

• Abdomen is diffusely tender.

• Abdomen is distended.

• Bowel sounds are abscent.

• Sign of peritonitis.

• P/R shows bloody stools.

Severe case of ulcerative colitis areregarded as medical emergency andshould be treated in hospital. Patientshould be examined twice a day for signsof peritonitis. Abdominal girth ismeasured . Scout film abdomen is donedaily to (a) see the diameter of transversecolon, a diameter more than 6 Cms areregarded as abnormal. (b) Perforation iscommon in toxic megacolon thus uprightor lateral decubitus films should be takento rule out free gas.Barium enema andColonoscopy is contraindicated.Limited sigmoidoscopy by anexperienced endoscopist is safe andindicated.The examination should belimited to rectum and distal sigmoid. Theseverity of mucosal injury is asscessed. Toknow the other causes of severe colitis -Crohn’s disease, Ischaemic colitis,pseudomembranous colitis, parasiticcolitis.

Management of toxic megacolon

General management –Nil bymouth; IV Fluids; RT aspiration; Opiatesand anticholenergics should be stoped;Correct electrolyte imbalance; Correctanemia by blood transfusion.

Antibiotics – Should be treated withbroad spectrum antibiotics, giving a goodanarobic coverage.

Corticosteroids – Hydrocortisone

given IV in the dose of 100 to 200 Mgs 6hourly.

Cyclosporin and Azathioprim or 6Merkeptopurine are started.

Surgery – Patients with severeUlcerative Colitis or toxic megacolonshould be treated by a surgeon early inthe course of the disease. The indicationsof surgery are – perforation; unremittedcolonic haemorrhage; failure of theclinical status to improve even afterintensive treatment with IV Steroid incombination with Cyclosporin. If thepatient does not improve within 7 daysof this regimen should be subjected tosurgery. Surgery is subtotal colectomywith ileostomy,is considered theconservative procedure of choice inpatients with systemic toxicity. But inpatients without systemic toxicity –Total proctocolectomy with ileoanalpouch anastomosis is possible.

Crohn’s disease - It was first reportedby Crohns in 1932. It can affect any partof gastrointestinal tract, from mouth toanal margin.but ileocoecal involvementis the most common presentation. It isslightly more common in females thanin males. It is seen in young patients ofthe age group of 25 to 40 years. Butanother peak of incidence is seen aroundthe age group of 17 years. Although theCrohn’s disease has some featuressuggestive of chronic infection but nodefinite causative organisms has beenfound till now. It differs from theUlcerative colitis by its segmentalinvolvement and it can affect any part ofthe gut.

Aetiology –Similarities betweenCrohn’s disease and tuberculosis hasfocused attention on mycobacterium.Penetration of bowel mucosa by E.Coliwas thought to set the inflammatory

process. Hereditary seems to play a strongrole. Ulcerative colitis can affect therelatives of patients with Crohn’s diseasebut not vise versa. About 10% of thepatient with Crohn’s disease have a firstdegree relative suffering with the disease.Focal ischaemia has been postulated as thecausative factor, possibly originatingfrom vasculit is aris ing fromimmunological process. Smoakingincrease the risk by 3 folds. Cell mediatedimmune function is defective in patientswith Crohn’s disease, but it is not knownthat it is due to the consequence of thedisease or it is the effect of malnutritionand medical treatment. Crohn’s diseasecan predispose to cancer although theincidence of malignant change is not sohigh as in ulcerative colitis.

Pathology – Ileal disease is mostcommon, accounting for 60% of the cases,30% of the cases are limited to largebowel.. Anal lesions are common,butCrohn’s disease of the mouth, oesophagus,stomach and duodenum are uncommon.Resected specimen shows fibroticthickening of small bowel wall withnarrowed lumen. The bowel proximal tothe stricture is dilated. The mucosa showslinear or snake like deep musosal ulcers.Oedema of the mucosa between the ulcersgive a cobble stone appearance. There istransmural extension of theinflammation giving rise to adhesion,mesenteric abscesses, fistula, into theadjacent organs. Serosa is opaque andmesentry is thickened with enlargedmesenteric lymph nodes. Similar lesionsmay be present proximally but thecondition is discontinuous with the otherinflamed area being separated withnormal intestine. These are called as skiplesion. Microscopically – there are focalareas of chronic inflammation involvingall the layers of the intestinal wall.Thereare noncaseating giant cell granulomas


26

most commonly seen in the lesions ofanorectal disease. The earliest mucosallesions are the aphthous ulcers. Recentstudies have shown multifocal arterialocclusion in muscularis propia.

Clinical features – Presentationdepend on the area of involvement. Thedisease has an insidious onset of pain inabdomen, anemia, hypoprotenemia.Acute Crohn’s disease occure in 5% ofcases. Sign and symptoms resembles thatof Acute Appendicitis. But there isdiarrhoea preceding the attack. Rarelythere is perforation of small intestineresulting in local or deffused peritonitis.Acute colitis with or without toxicmegacolon can occur in Crohn’s diseasebut it is less common than in ulcerativecolitis. In chronic Crohn’s disease thereis often history of mild diarrhoea whichis accompanied by intestinal colic sincemany months. Patient complains of painin right iliac fossa,there may be tendermass palpable.Intermittent fever,anemia, hypoproteinemia, weight lossare common. Perianal abscess and fissuremay be the first presentating feature inCrohn’s disease. The cause is infected analcrypts due to diarrhoea. As the diseasebecome chronic fistulae develops due toCrohn’s disease itself.(1) Entero-entericFistula.(2) Entero-colic Fistula (3)Entero-vesical Fistula which may causerecurrent urinary tract infection andpneumaturia.(4) Entero-cutaneousFistula is rare but may develop followingsurgery.

Investigations

Sigmoidoscopic examination – Itis normal but ulceration in anal canalmay be seen.

Colonoscopy – Rectal mucosa isnormal in patients who have Crohn’sdisease without rectal involvement.Rectal Crohns shows patchy

involvement. The mucosal edema,deepleniar ulcers and fibrosis are the featuresof chronic disease. A rare variety withinvolvement of colon and rectum incontinuity with granular and friablemucosa is extremely difficult todifferentiate from Ulcerative colitis,unless Histopathological examination isdone which shows giant cells in Crohn’sdisease.

Radiology – Barium meal &follow through, the charactersticfeatures are – (a) Skip lesion. (b) Ironedout Valvulae Conniventis. (c)Absence ofperistalsis and lead pipe like segments.(d)Longitudinal and transverse fissuresprojecting outside in the bowel wallgiving cobble stone mucosal pattern. (e)Constriction of terminal ileum,narrowstricture.When longer length of ileum isinvolved then string sign of Kantoris seen. (f) Dilatation of proximal ileum.Sinogram- In enterocutaneous fistula.CT Scan for intraabdominal abscesses.

Differentiation from ulcerativecolitis. - The following featuresdifferentiate Crohn’s disease from UC –severity of pain, intestinal colicy pain ofCrohn’s disease; absence of blood instools; palpable mass; IntestinalObstruction; small bowel involvement;Fistulae and perianal abscess in rectal andanal involvement; segmental pattern ofinvolvement; aphthous leniar ulcers; fullthickness involvement of bowel wall;Sarcoid type of giant cells in H P R.Preoperative differentiation isimportant as Total Proctocolectomy, .asdone in ulcerative colitis will noteradicate the disease.

Management

Medical therapy

Mild to moderate type of cases aretreated on outpatient basis. But severe

symptomatic cases requirehospitalisation. The drug of choice isSulfasalazine. Starting with 1Gm dailyand increasing to 4 Gms daily until totalremission is achieved then the drug istapered off. Low dose Metronidazole isalso effective. Prednisolone at a dose of60 Mgs per day in 3 to 4 divided dose for10 to 14 days then tapered off.Immunosuppressive agents –Azathioprim, 6 Merkaptopurine.

Surgical therapy

It is indicated in (a) RecurrentObstruction. (b) Perforation. (c)Adhesion and obstruction. (d) Intestinalfistula. (e) Perianal disease. (f) Failure ofmedical treatment. (g) Malignentchanges. Surgical resection will not curethe Crohn’s Disease. So surgery shouldbe limited to treatment of complicationof the disease. Because by removing asegment of diseased bowel does not curethe patient of Crohn’s disease asproctocolectomy cures a patient ofUlcerative Colitis.The aim of thesurgical treatment is to remove as littlebowel as it is necessary to correct theproblem. Patients with single, shortsegment of Crohn’s disease responds bestto surgery. Ileocoecal anastomosis of apatient having had previous ileocaecalresection for Crohn’s disease, recurrentdisease is seen on the ileal side of theanastomosis. Stricturoplasty is thesurgical option in stricturing Crohndisease. Recurrence rate after surgery ishigh- 30% after 5 Years, 50% after 10Years and 70% after 15 Years. The aimof surgery is to remove grossly diseasedbowel and to preserve as much normalappearing bowel as possible. If terminalileun is removed patient should beinvestigated for B 12 deficiency every 6months. Most patient will require B 12injection every month.


Differentiation of Ulcerative Colitis From Crohn’s Disease

Ulcerative Colitis Crohn’s Disease

Site of disease Colon only Any part of GI Tract

Distribution Diffused Focal (Segmental) skip areas

Anatomical plane Mucosa & Submucosa Transmural

Colonic appearance Diffused friability Focal/Apthous ulcers Cobble stone appearance. Linearulcers with normal surrounding mucosa

Histopathology

Crypt architecture Distorted (crypt abscess) Normal or focally distorted

Inflammation Acute & Chronic Normal or acute/chronic

Epithelioid granulomas Never Present

Complications Internal fistulae/abscess never or Fistulae & abscess can occurrarely occurs

Strictures Uncommon Common

Cancer risk after longstanding disease + + + + + +

Development of Surgery indifferent regions

Ancient China

Hua Tuo was a famous Chinesephysician during theEastern Han and Three

Kingdoms era. He was the firstperson to perform surgery with theaid of anesthesia, some 1600 yearsbefore the practice was adopted byEuropeans.

Medieval Europe

Abulcasis (Abu al-Qasim Khalaf ibnal -Abbas Al-Zahrawi) was anAndalusian-Arab physician andscientist who praticised in the Zahrasuburb of Cordova. He is considereda great medieval surgeon, whosecomprehensive medical texts ,combining Middle Eastern andGreco-Roman classical teachings,shaped European surgical procedures

up until the Renaissance. He is oftenregarded as the Father of Surgery.Patients and students from all partsof Europe came to him for treatmentand advice. According to WillDurant, Cordova was in this periodthe favourite resort of Europeans forsurgical operations.

Surgery in Holland (ca. 1690)

By the 13th century, many Europeantowns were demanding thatphysicians have several years of studyor training before they couldpractice. Montpellier, Padua andBologna Universit ies wereparticularly interested in theacademic side to Surgery, and by the15th century at the latest, Surgery wasa separate university subject toPhysics. Surgery had a lower statusthan pure medicine, beginning as acraft tradition until RogeriusSalernitanus composed his

Chirurgia, which laid the foundationfor the species of the occidentalsurgical manuals, influencing themup to modern times.

Europe

Ambroise Paré pioneered thetreatment of wounds by gunshots.Among the first modern surgeonswere battlefield doctors in theNapoleonic Wars who wereprimarily concerned withamputation. Naval surgeons wereoften barber surgeons, who combinedsurgery with their main jobs asbarbers.

In London, an operating theatre oroperating room from the day beforemodern anaesthesia or antisepticsurgery still exists, and is open to thepublic. It is found in the roof space ofSt Thomas Church, Southwark,London and is called the OldOperating Theatre.


28

Renal cell carcinoma accounts forapproximately 3% of adultmalignancies and 85-90% of

neoplasms arising from the kidney. It ischaracterized by a lack of early warningsigns, diverse clinical manifestations,resistance to radiation andchemotherapy, and infrequent butreproducible responses toimmunotherapy agents such as interferonalpha & interleukin (IL)-2.

Pathophysiology- The tissue oforigin for renal cell carcinoma is theproximal renal tubular epithelium.Renal cancer occurs in both a sporadic(nonhereditary) and a hereditary form,and both forms are associated withstructural alterations of the short arm ofchromosome 3 (3p). Genetic studies ofthe families at high risk for developingrenal cancer led to the cloning of geneswhose alteration results in tumorformation. These genes are either tumorsuppressors (VHL, TSC) or oncogenes(MET). Smoking predisposes to renalcancer and smokers develop this cancertwice as often as non smokers.

Mortality/Morbidity- Renal cellcarcinoma is the sixth leading cause ofcancer death. The 5-year survival ratesinitially reported by Robson in 1969were 66% for stage I renal carcinoma,64% for stage II, 42% for stage III, andonly 11% for stage IV. Except for stage I,these survival statistics have remainedessentially unchanged for several decades.

Race- Renal cell carcinoma is morecommon in people of NorthernEuropean ancestry (Scandinavians) and

7Reviewarticle

Renal CancerLt. Gen. S. Mukherjee

Armed Forces Medical College, Pune

North Americans than in those of Asianor African descent. In India the incidenceis 1.4% of all cancers.

Sex- Renal cell carcinoma is twice ascommon in men as in women. The male-to-female ratio is 2:1.

Age- This condition occurs mostcommonly in the fourth to sixth decadesof life, but the disease has been reportedin younger people who belong to familyclusters.

Aetiology- A number of cellular,environmental, genetic, and hormonalfactors have been studied as possiblecausal factors for renal cell carcinoma.Eg smoking, obesity, occupationalexposure to petroleum products, heavymetals, asbestos and solvents, renaltransplantation with its associatedimmunosuppression and VHL disease.

Imaging studies- A large proportionof patients diagnosed with renal cancerhave small tumors discoveredincidentally on imaging studies. Anumber of diagnostic modalities are usedto evaluate and stage renal masses.

Contrast-enhanced CT scanning hasbecome the imaging procedure of choicefor diagnosis and staging of renal cellcancer and has virtually replacedexcretory urography and renalultrasound. In most cases, CT imagingcan differentiate cystic masses from solidmasses and supplies information aboutlymph node, renal vein, and inferior venacava involvement.

Histology- Renal cell carcinoma has5 histologic subtypes, as follows: clear cell

(75%), chromophilic (15%),chromophobic (5%), oncocytoma (3%),and collecting duct (2%).

Staging- The tumor, nodes, andmetastases (TNM) classification isendorsed by the American JointCommittee on Cancer (AJCC). Themajor advantage of the TNM system isthat it clearly differentiates individualswith tumor thrombi from those withlocal nodal disease. The TNMclassification system is as follows:

• Primary tumor (T)

• TX - Primary tumor cannot beassessed

• T0 - No evidence of primary tumor

• T1 - Tumor 7 cm or smaller ingreatest dimension, limited to thekidney

• T2 - Tumor larger than 7 cm ingreatest dimension, limited to thekidney

• T3a - Tumor invades adrenal glandor perinephric tissues but notbeyond the Gerota fascia

• T3b - Tumor grossly extends into therenal vein(s) or vena cava below thediaphragm

• T3c - Tumor grossly extends into therenal vein(s) or vena cava above thediaphragm

• T4 - Tumor invading beyond theGerota fascia

• Regional lymph nodes (N) -Laterality does not affect the Nclassification

• NX - Regional lymph nodes cannot


be assessed

• N0 - No regional lymph nodemetastasis

• N1 - Metastasis in a single regionallymph node

• N2 - Metastasis in more than 1regional lymph node

• Distant metastasis (M)

• MX - Distant metastasis cannot beassessed

• M0 - No distant metastasis, M1 -Distant metastasis

• AJCC Stages

• stage I - T1, N0, M0

• stage II - T2, N0, M0

• stage III - T1-2, N1, M0 or T3a-c, N0-1, M0

• stage IV - T4; or any T, N2, M0; orany T, any N, M1

Treatment

More than 50% of patients with renal cellcarcinoma are cured in early stages, butoutcome for stage IV disease is poor. Theprobability of cure is related directly tothe stage or degree of tumordissemination, so the approach iscurative for early stage disease. Selectedpatients with metastatic disease respondto immunotherapy, but many patients canbe offered only palliative therapy foradvanced disease. The treatment optionsfor renal cell cancer are surgery,radiation therapy, chemotherapy,hormonal therapy, immunotherapy, orcombinations of these.

Surgery- Surgical resection remainsthe only known effective treatment forlocalized renal cell carcinoma, and it alsois used for palliation in metastatic disease.

• Radical nephrectomy, whichremains the most commonlyperformed standard surgical

procedure today for treatment oflocalized renal carcinoma, involvescomplete removal of the Gerotafascia and its contents, including aresection of kidney, perirenal fat,and ipsilateral adrenal gland, with orwithout ipsilateral lymph nodedissection. Radical nephrectomyprovides a better surgical marginthan simple removal of the kidney,since perinephric fat may beinvolved in some patients. Lymphnodes may be involved in 10-25% ofpatients Regionallymphadenectomy adds little interms of operative time or risk andshould be included in conjunctionwith radical nephrectomy.

• Palliative nephrectomy should beconsidered in patients withmetastatic disease for alleviation ofsymptoms such as pain, hemorrhage,malaise, hypercalcemia,erythrocytosis, or hypertension.

Chemotherapy and endocrine-basedapproaches are l imited, and nochemotherapeutic regimen is accepted asa standard of care. Objective responserates, either for single or combinationchemotherapy, usually are lower than15%. Therefore, various biologictherapies have been evaluated.

Renal cell carcinoma is an immunogenictumor, and spontaneous regressions havebeen documented. Many immunemodulators, such as interferon, IL-2(aldesleukin [Proleukin]), bacillusCalmette-Guérin (BCG) vaccination,lymphokine-activated killer (LAK) cellsplus IL-2, tumor-infi ltratinglymphocytes, and nonmyeloablativeallogeneic peripheral blood stem-celltransplantation, have been tried.

Multi-kinase inhibitors- Futuretreatment strategies for advanced renal

cell carcinoma will likely incorporate acombination of molecular approaches,using multidrug regimens consisting ofsmall molecule kinase inhibitors withbiologic therapies and/orimmunomodulatory therapies .Sorafenib (Nexavar) — First oralmultikinase inhibitor that targets serine/threonine and tyrosine receptor kinasesinvolved in tumor cell proliferation andangiogenesis, thereby decreasing tumorcell proliferation. These kinases includedRAF kinase, VEGFR-2, VEGFR-3,PDGFR-beta, KIT, and FLT-3. Indicatedfor advanced renal cell carcinoma. Dosein adults is 400 mg PO bid 1 h ac or 2 h pc.Common adverse reactions include handor foot skin reaction and rash (modifydose); may increase risk of hemorrhage,cardiac ischemia and/or infarction,alopecia, pruritus, or diarrhea. Anotherdrug used is Sunitinib (Sutent) —Mulitkinase inhibitor that targets severaltyrosine kinase inhibitors implicated intumor growth, pathologic angiogenesis,and metastatic progression. Inhibitsplatelet-derived growth factor receptors(ie, PDGFR-alpha, PDGFR-beta),vascular endothelial growth factorreceptors (ie, VEGFR1, VEGFR2,VEGFR3), stem cell factor receptor(KIT), Fms-like tyrosine kinase-3(FLT3), colony-stimulating factorreceptor type 1 (CSF-1R), and the glialcell-line–derived neurotrophillic factorreceptor (RET).Indicated for advancedrenal cell carcinoma. Reduces tumor sizein patients with metastatic kidney cancerwhose tumors have progressed followingcytokine-based therapy. Standard dose:50 mg PO qid on a schedule of 4 week ontreatment followed by 2 week offtreatment.

Chemotherapy- Renal cell carcinomais refractory to most chemotherapeuticagents because of multidrug resistancemediated by p-glycoprotein. Normal


30

renal proximal tubules and renal cellcarcinoma both express high levels of p-glycoprotein. Calcium channel blockersor other drugs that interfere with thefunction of p-glycoprotein can diminishresistance to vinblastine andanthracycline in human renal cellcarcinoma cell lines.

Biologic therapies- The interferonsare natural glycoproteins with antiviral,antiproliferative, andimmunomodulatory properties. Theinterferons have a directantiproliferative effect on renal tumorcells in vitro, stimulate host mononuclearcells, and enhance expression of majorhistocompatibility complex molecules.Interferon-alpha, which is derived fromleukocytes, has an objective response rateof approximately 15% (range 0-29%).

Preclinical studies have shown synergybetween interferons and cytotoxic drugs.In several prospective randomized trials,combinations do not appear to providemajor advantages over single-agenttherapy. Many different types andpreparations of interferons have beenused without any difference in efficacy.

IL-2 is a T-cell growth factor andactivator of T cells and natural killercells. IL-2 affects tumor growth byactivating lymphoid cells in vivo withoutaffecting tumor proliferation directly.

In the initial study by the NationalCancer Institute, bolus intravenousinfusions of high-dose IL-2 combinedwith LAK cells produced objectiveresponse rates of 33%. In subsequentmulticenter trials, the response rate was16%. Subsequent studies also showed thatLAK cells add no definite therapeuticbenefit and can be eliminated from thetreatment. A high-dose regimen (600,000-720,000 IU/kg q8h for a maximum of14 doses) resulted in a 19% response rate

with 5% complete responses. Themajority of responses to IL-2 weredurable, with median response durationof 20 months. Eighty percent of patientswho responded completely to therapywith IL-2 were alive at 10 years. Mostpatients responded after the first cycle,and those who did not respond after thesecond cycle did not respond to anyfurther treatment. Therefore, the currentrecommendation is to continuetreatment with high-dose IL-2 to bestresponse (up to 6 cycles) or until toxiceffects become intolerable. Treatmentshould be discontinued after 2 cycles ifthe patient has had no regression.Combinations of IL-2 and interferon orother chemotherapeutic agents such as 5-FU have not been shown to be moreeffective than high-dose IL-2 alone.

Toxic effects associated with high-doseIL-2 are related to increased vascularpermeability and secondary cytokinesecretion (eg, IL-1, interferon gamma,tumor necrosis factor, nitric oxide). Themanagement of high-dose IL-2 toxicitiesrequires inpatient monitoring, often inan intensive care unit. The major toxiceffect of high-dose IL-2 is a sepsis-likesyndrome, which includes a progressivedecrease in systemic vascular resistanceand an associated decrease inintravascular volume due to capillaryleak. Other toxic effects are fever, chills,fatigue, infection, and hypotension. High-dose IL-2 has been associated with a 1-4%incidence of treatment-related death andshould be offered only to patients withno cardiac ischemia or significantimpairment of renal or pulmonaryfunctions. Management includesjudicious use of fluids and vasopressorsupport to maintain blood pressure andintravascular volume and at the sametime to avoid pulmonary toxicity due tononcardiogenic pulmonary edema from

thecapillary leak. This syndrome isnormally reversible.

Radiation therapy may beconsidered for palliation in patientswhose clinical condition precludessurgery, either because of extensivedisease or poor overall condition. A doseof 4500 centigray (cGy) is delivered,with consideration of a boost up to 5500cGy. Preoperative radiation therapyyields no survival advantage.

Controversies exist concerningpostoperative radiation therapy, but itmay be considered in patients withperinephric fat extension, adrenalinvasion, or involved margins. Howeverthere is no improvement in overallsurvival with adjuvant treatment in formof radiation or systemic therapy in nonmetastatic disease.

Palliative radiation therapy often is usedfor local or symptomatic metastaticdisease, such as painful osseous lesions orbrain metastasis, to halt potentialneurological progression. Surgery alsoshould be considered for solitary brainor spine lesions, followed bypostoperative radiotherapy to themetastatic site.

About 11% of patients develop brainmetastasis during the course of illness.Renal cell carcinoma is a radioresistanttumor, but radiation treatment of brainmetastasis improves quality of life, localcontrol, and overall survival duration.Patients with untreated brain metastasishave a median survival time of 1 month,which can be improved withglucocorticoid therapy and brainirradiation. Stereotactic radiosurgery ismore effective than surgical extirpationfor local control and can be performedon multiple lesions.


Follow up after treatment

For stage I,II and II disease, completehistory, physical examination, chestradiographs, liver function tests, BUNand creatinine, and calcium arerecommended every 6 months for 2years, then annually for 5 years.Abdominal CT scan is recommendedonce at 4-6 months and then as indicated.

Careful surveillance of patients with end-stage renal disease, VHL disease or renaltransplant patients by ultrasonographyand CT scan is recommended. Avoidanceof causative factors such as smoking,obesity, and environmental carcinogensis recommended.

Prognosis

Metastatic disease has increased survivalwith (1) a long disease-free intervalbetween initial nephrectomy and theappearance of metastases, (2) the presenceof only pulmonary metastases, (3) goodperformance status, and (4) removal ofthe primary tumor. Five-year survivalrates are as follows:

The 5-year disease-specific survival rateassociated with T1 renal carcinoma is95% and with stage T2 disease, 88%.Patients with T3 renal carcinoma had a5-year survival rate of 59%, and thosewith T4 disease had a 5-year disease-specific survival rate of 20%.

Patients with regional lymph nodeinvolvement or extracapsular extensionhave a survival rate of 12-25%. Althoughrenal vein involvement does not have amarkedly negative effect on prognosis,the 5-year survival rate for patients withstage IIIB renal cell carcinoma is 18%. Inpatients with effective surgical removalof the renal vein or inferior vena cavalthrombus, the 5-year survival rate is 25-50%.Five-year survival rates for patientswith stage IV disease are low (0-20%).

Patient education

Patients in the high-risk group should bemade aware of the early signs andsymptoms, and the need for earlyintervention for possible cure should bestressed. Patients in early stages who haveundergone treatment should be educatedabout possible relapse.

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22. Yang JC, Sherry RM, Steinberg SM,et al: Randomized study of high-doseand low-dose interleukin-2 inpatients with metastaticrenal cancer.J Clin Oncol 2003 Aug 15; 21(16):3127-32

introduced compulsary handwashingfor everyone entering the maternalwards and was rewarded with a plungein maternal and fetal deaths. Lister wasable to quickly improve infection ratesno end, a process that was further helpedby his subsequent introduction oftechniques to sterilise equipment, haverigorous hand washing and a laterimplementation of rubber gloves.Lister published his work as a series ofarticles in The Lancet (March 1867)under the title “Antiseptic Principle ofthe Practice of Surgery”. The gradualdevelopment of germ theory hasallowed the final step to be taken tocreate the highest quality of asepticconditions in modern hospitals and thishas allowed us to (theoretically)perform infection free surgery.

PainBefore the advent of anesthesia(discovered by 2 American dentists,Horace Wells (1815-1848) & WilliamMorton), surgery was a traumaticallypainful procedure and surgeons wereencouraged to be as swift as possible tominimize patient suffering. This alsomeant that operations were largelyrestricted to amputations and externalgrowth removals. Beginning in the1840s, surgery began to changedramatically in character with thediscovery of effective and practicalanaesthetic chemicals such as ether andchloroform

Doctor or Mister?In the UK, Australia, South Africa andNew Zealand surgeons aredistinguished from physicians by beingreferred to as “Mister.” This traditionhas its origins in the 18th century, whensurgeons were barber-surgeons and didnot have a degree, unlikephysicianshaving medical degree. Bythe beginning of the 19th century,surgeons had obtained high status, andin 1800, the Royal College of Surgeons(RCS) in London began to offersurgeons a formal status via RCSmembership. The title Mister became abadge of honour.

Development of modernsurgery

To make its transition to themodern era the art of surgeryhad to overcome three major

problems that were effectively

preventing surgery from progressing tobecome the widely respected disciplinewe see today. These three great barrierswere, bleeding, infection & painBleedingThere was a very real threat that apatient would bleed out on the tableduring an operation or bleed to deathwhile being attended after an accidentor wound. The first real progress incombating bleeding had come whenearly cultures realized they could closewounds using extremes of heat, aprocedure called cauterizing. The earlycauterization was successful, but onlyuseable in a limited fashion, highlydestructive, and painful, with terriblelong term outcomes. The next realbreakthrough to come was theinvention of ligatures, somethingwidely believed to have originated withAmbrose Pare during the 16th century.A ligature is a piece of material used totie closed the end of a cut blood vesselpreventing any further bleeding byserving to occlude it. Ligatures form thebasis of modern control bleeding, butat the time, they were more of a hazardthan a help because the surgeons usingthem had no concept of infectioncontrol. A final barrier to be overcomewas the problem of replacing blood lost.Limiting bleeding is important, butultimately, a surgeon is fighting a losingbattle if blood cannot be replaced, andthis final barrier was only conqueredwhen early 20th century research intoblood groups allowed the first effectiveblood transfusions.

InfectionBig holes into sealed internalenvironments lead to infections,especially if the surgeon is usingunsterilised tools, covered in blood andwearing his normal clothes. The firstprogress in combating infection wasmade by the Hungarian doctorSemmelweiss who noticed that medicalstudents fresh from the dissecting roomwere causing excess maternal deathcompared to midwives. Semmelweiss,despite ridicule and opposition,


Despite major advances intechniques for the managementof ventilator-dependent

patients and the routine use of effectiveprocedures to disinfect respiratoryequipment, ventilator-associatedpneumonia (VAP) continues tocomplicate the course of 8 to 28% of thepatients receiving mechanicalventilation (MV)1. Prolonged (more than48 hours) MV is the most importantfactor associated with nosocomialpneumonia. However, VAP may occurwithin the first 48 hours after intubation.Rates of pneumonia are considerablyhigher among patients hospitalized inintensive care units (ICUs) comparedwith those in hospital wards, and the riskof pneumonia is increased 3- to 10-foldfor the intubated patient receiving MV2.Because several studies have shown thatappropriate antimicrobial treatment ofpatients with VAP significantlyimproves outcome, more rapididentification of infected patients andaccurate selection of antimicrobial agentsrepresent important clinical goals3.However, consensus on appropriatediagnostic, therapeutic, and preventivestrategies for VAP has yet to be reached.

Definition

VAP is defined as an inflammation of thelung parenchyma caused by infectiousagents not present or incubating at thetime MV was started. VAP refers to aninfection of the lung parenchymafollowing intubations and MV for at least48 hours.

8Ventilator Associated Pneumonia (VAP) - an Update

Sunil Kumar, A.K.Pandit , A.P. JainDepartment of Medicine, Mahatama Gandhi institute of Medical Sciences, Sewagram

Reveiwarticle

Classification and pathogenesis

VAP is typically categorized as either a)early-onset VAP (occurring in the first3-4 days of mechanical ventilation) or b)late-onset VAP. This distinction isimportant microbiologically. Early-onset VAP is commonly caused byantibiotic-sensitive community-acquiredorganisms (e.g. , Streptococcuspneumoniae, Haemophilus influenzae,and Staphylococcus aureus). Late-onsetVAP is commonly caused by antibiotic-resistant nosocomial organisms (e.g.,Pseudomonas aeruginosa, methicillin-resistant Staphylococcus aureus ,Acinetobacter species, and Enterobacterspecies). Pneumonia results frommicrobial invasion of the normallysterile lower respiratory tract and lungparenchyma caused by either a defect inhost defenses, challenge by a particularlyvirulent microorganism, or anoverwhelming inoculum. The normalhuman respiratory tract possesses a varietyof defense mechanisms that protect thelung from infection, for example:anatomic barriers, such as the glottis andlarynx; cough reflexes; tracheobronchialsecretions; mucociliary lining; cell-mediated and humoral immunity; and adual phagocytic system that involvesboth alveolar macrophages andneutrophils4. When these coordinatedcomponents function properly, invadingmicrobes are eliminated and clinicaldisease is avoided, but when these defensesare impaired or if they are overcome byvirtue of a high inoculum of organismsor organisms of unusual virulence,pneumonitis results. As suggested by the

infrequent association of VAP withbacteremia, the majority of theseinfections appear to result fromaspiration of potential pathogens thathave colonized the mucosal surfaces ofthe oropharyngeal airways. Intubation ofthe patient not only compromises thenatural barrier between the oropharynxand trachea, but may also facilitate theentry of bacteria into the lung by poolingand leakage of contaminated secretionsaround the endotracheal tube cuff5. Thisphenomenon occurs in most intubatedpatients, whose supine position mayfacilitate its occurrence. In previouslyhealthy, newly hospitalized patients,normal mouth flora or pathogensassociated with community-acquiredpneumonia may predominate. In sickerpatients who have been hospitalized morethan 5 days, GNB and S. aureusfrequently colonize the upper airway6.

Other sources of pathogens causing VAPinclude the paranasal sinuses, dentalplaque, and the subglottic area betweenthe true vocal cords and the endotrachealtube cuff. The role of the gastrointestinaltract as a source of oropharyngeal andtracheal colonization by GNB is morecontroversial7. A sequence of eventsleading to colonization from the stomachto the trachea, with increasing frequencyin direct correlation to the gastric pH,was reported by several investigators,with 27 to 45% of patients havingprimary colonization of the gastric juiceand subsequent colonization of thetracheobronchial tree 2 days later8.Other studies have clearly proven, bymeans of radio-labeled gastric juice or


34

other techniques, that the gastric juice ofintubated patients is aspirated into thetracheobronchial tract within a fewhours9.

In fact, there is more than one potentialpathway for colonization of theoropharynx and trachea in such a setting,including fecal-oral cross-infection on thehands of health care personnel, andcontaminated respiratory therapyequipment. Patient care activities, suchas bathing, oral care, tracheal suctioning,enteral feeding, and tube manipulations,provide ample opportunities fortransmission of pathogens when infectioncontrol practices are substandard10.

In summary, the relationship betweenVAP and tracheal, pharyngeal, and/orgastric colonizations remains to beelucidated for patients with anendotracheal tube. To date, these findingslead to the following conclusions: (1)tracheal colonization precedes VAP inmost, but not all, patients; (2) only aminority of patients with trachealcolonization develop VAP; (3) thestomach can be a reservoir for pneumoniapathogens, although this is not the case inmany ICU patients requiring MV.

Diagnosis

VAP can be accurately diagnosed by anyone of several standard criteria:histopathologic examination of lungtissue obtained by open lung biopsy, rapidcavitation of a pulmonary infiltrate inthe absence of cancer or tuberculosis,positive pleural fluid culture, samespecies with same antibiogram isolatedfrom blood and respiratory secretionswithout another identifiable source ofbacteremia, and histopathologicexamination of lung tissue at autopsy11.However, these criteria are based oninvasive procedures for obtaining lungtissue or on uncommon manifestations or

complications of VAP. Given theinvasive nature of lung biopsy and theinfrequent occurrence of othermanifestations used as standard criteria,another approach is needed for thedefinitive diagnosis of VAP. In 1979, afiberoptic bronchoscopic technique wasintroduced for obtaininguncontaminated lower respiratory tractsecretions, which were culturedquantitatively12. Two bronchoscopictechniques have been introduced for theaccurate diagnosis of VAP. The protectedspecimen brush (PSB) collects 0.001 mLof lower respiratory tract secretions andhas a diagnostic threshold of >103 CFU/mL13. BAL, an unprotected technique,samples approximately one millionalveoli and has a diagnostic threshold of>104 CFU/mL13. A protected BALtechnique with a balloon-tipped catheterhas also been described. Detection of>5% of neutrophils or macrophages withintracellular organisms on a Wright-Giemsa stain of a smear ofcytocentrifuged BAL fluid is alsodiagnostic of VAP14 (table)

Diagnostic techniques Sensitivity Specificity Negative Positivepredictive predictive

value value

PSBb cultures 82% 89% 90% 89%(>103 CFU/mL)

BAL cultures 91% 78% 83% 87%(>104 CFU/mL)

Microscopic examination 91% 89% 91% 89%of BAL fluid (>5%intracellular organisms)aFrom ref 10.bPSB = protected specimen brush; BAL = bronchoalveolar lavage.

Because of the invasive nature and cost ofbronchoscopy, investigators haveevaluated other techniques for collectinglower respiratory tract secretions. Thesenon bronchoscopic techniques involvepassage of a catheter or telescopingcatheters through the endotracheal tubewith advancement to a wedged positionin the lung. Samples may be taken bytelescoping catheters containing a brush(blind PSB)15, aspiration of secretions intoa distally wedged catheter, or BALthrough a distally wedged catheter. BALmay be performed by using a balloon-tipped catheter with the balloon inflatedafter the catheter has been advanced tothe wedged position (protected BAL), byusing telescoping catheters, or by placinga catheter into the wedged position witha guide wire. Despite broad clinicalexperience with the PSB and BALtechniques, it remains, nonetheless,unclear which one should be used inclinical practice. Their operatingcharacteristics for diagnosing VAP areprobably similar, with only smalldifferences in their sensitivities and

specificities. Most investigators prefer to use BAL rather than PSB to diagnose bacterialpneumonia, because BAL (1) has a slightly higher sensitivity to identify VAP-causativemicroorganisms, (2) enables better selection of an empiric antimicrobial treatment


before culture results are available, (3) isless dangerous for many critically illpatients, (4) is less costly, and (5) mayprovide useful clues for the diagnosis ofother types of infections. However, itmust be acknowledged that a small returnon BAL may contain only dilutedmaterial from the bronchial rather thanthe alveolar level and thus give rise tofalse-negative results, particularly forpatients with severe COPD. In thesepatients, the diagnostic value of BALtechniques is greatly diminished and thePSB technique should be preferred.Therefore, the choice of procedure(s)may eventually depend on thepreferences and experiences of individualphysicians and the patient’s underlyingdisease(s).

VAP is more common in patients withARDS than in those with other causes ofrespiratory failure16; it occurs later and iscaused by more resistantmicroorganisms. The diagnosis of VAPis more difficult in such patients becauseARDS and VAP have very similarclinical manifestations. Given theseverity of illness of patients with ARDS,particularly when complicated by VAP,and the great difficulty in differentiatingVAP from ARDS on clinical andradiographic grounds, the most effectiveapproach to diagnosis of VAP in patientswith ARDS is quantitative culture andmicroscopic examination of lowerrespiratory tract secretions.

Treatment

Successful treatment of patients withVAP remains a difficult and complexundertaking for several reasons. First, thecriteria for a definitive diagnosis of VAPin critically ill patients remain to beestablished. Although it is difficult toclinically distinguish between bacterialcolonization of the tracheobronchial tree

and true nosocomial pneumonia, nearlyall previous therapeutic investigationshave relied solely on clinical diagnosticcriteria and, therefore, have probablyincluded patients who did not havepneumonia. Second, most of those studiesused tracheal secretions as the majorsource of specimens for microbiologiccultures, despite the fact that the upperrespiratory tract of most ventilatedpatients is usually colonized withmultiple potential pathogens. Finally,the lack of an adequate technique todirectly sample the infection site in thelung has hampered the study of theability or inability of antibiotics toeradicate the causative pathogens fromthe lower respiratory tract and,therefore, to predict their bacteriologicefficacy.

Antibiotics

Two factors appear to render the choiceof antibiotics particularly difficult incritically ill patients. First, VAPs arelikely to result from highly resistantorganisms, especially in patients whowere previously treated with antibiotics.Second, multiple organisms arefrequently cultured from the pulmonarysecretions of patients considered to havepneumonia. Because of the emergence ofmultiresistant, extended spectrumlactamase-producing GNB in manyinstitutions and the increasing roleplayed by gram-positive bacteria, such asMRSA, even a protocol combiningceftazidime or imipenem and amikacinwould not ensure adequate coverage ofall cases of VAP in these ICUs. Therefore,no “magic bullet” exists to cover all themicroorganisms potentially responsiblefor VAP.

Core organisms responsible for ventilator-associated pneumonia and

recommended antimicrobial therapy17

Core Organisms CoreAntibiotics

Early- onset VAP,no specific risk factor

Enteric gram negative Cephalosporin(nonpseudomonal)

Enterobacter spp. Second generation

Escherichia coli Nonpseudomonal3rd generation

Klebsiella spp. Or

Proteus spp. Lactam-lactamase inhibitorcombination

Serratia marcescens

Haemophilus influenzae If allergic topenicillin:

MSSA Fluoroquinolone

Or

Streptococcus pneumoniaeClindamycin + aztreonam

Late-onset VAP

Core organisms plus Aminoglycoside orciprofloxacin plus one of thefollowing:

Pseudomonas aeruginosa Antipseudomonalpenicillin

Acinetobacter baumannii Lactam Lactamaseinhibitor combination

Ceftazidime orcefoperazoneImipenemAztreonam

Consider MRSA ±Vancomycin

Definition of abbreviations: MRSA= methicillin-resistant S. aureus; MSSA= methicillin-sensitive S. aureus; VAP= ventilator-associated pneumonia.Adapted from the American ThoracicSociety (33).

Because the guidelines have not beenupdated since their publication in


36

1996, they do not include newer therapies(e.g., cefepime, meropenem, and newerfluoroquinolones) that may be effectiveand/or associated with less resistance.

Duration of antimicrobialtherapy

A “long” treatment, that is, a minimumof 14 to 21 days, is prescribed for thefollowing situations: multilobarinvolvement, malnutrition, cavitation,gram-negative necrotizing pneumonia,and/or isolation of P. aeruginosa orAcinetobacter spp. This duration isessentially justified by the hightheoretical risk of relapse. A “short”treatment, lasting 7 to 10 days, isrecommended for S. aureus orH. influenzae pneumonia.

However, a regimen of insufficientduration can be the source of therapeuticfailure or relapse, defined as thereappearance of signs of pneumonia andisolation of the same pathogen(s), whichmay or may not have acquired resistance.The risk is probably small for bacteriaconsidered susceptible but might be highfor certain strains, especial lyP. aeruginosa and MRSA, which areparticularly difficult to eradicate fromthe respiratory tract 18. This situation iseven further aggravated in certainimmunocompromised patients. Thus, atpresent, a short-term regimen is rarelyprescribed, despite the potential majoradvantages it could have in terms ofbacterial ecology, the prevention of theemergence of multiresistant bacteria, and,obviously, lower costs. Lowering theamount of antibiotics administered topatients in the ICU is indeed a primaryobjective of every strategy aimed atpreventing the emergence anddissemination of such bacteria .

Prevention of Ventilator-

Associated Pneumonia

Four practices that carry the potentialto reduce the incidence of VAP inpatients receiving mechanicalventilation are:

Patient positioning- Semi-recumbent Positioning and ContinuousOscillation. Aspiration of gastricsecretions likely contributes to thedevelopment of VAP. Semi-recumbentpositioning of mechanically ventilatedpatients may help reduce the incidenceof gastroesophogeal reflux and lead to adecreased incidence of VAP. Semi-recumbent positioning is generallydefined as elevation of the head of the bedto 45 degrees. This position should beavoided in the following conditions:recent abdominal or neurologic surgery(<7 days), shock refractory tovasoactive therapy, and previous recentendotracheal intubation (<30days).Oscil lation - Continuousoscillation utilizes mechanical beds thatemploy either rotating platforms oralternating inflation/deflation ofmattress compartments to turn patientsfrom side to side. These beds achieve 40to 60 degrees of tilt and can cycle every5-30 minutes as programmed.

Continuous aspiration ofsubglottic secretions -Trachealintubation interrupts the body’sanatomic and physiologic defensesagainst aspiration, making mechanicalventilation a major risk factor for VAP.The accumulation of contaminatedoropharyngeal secretions above theendotracheal tube cuff may contribute tothe risk of aspiration. Removal of thesepooled secretions through suctioning ofthe subglottic region, termed continuousaspiration of subglottic secretions(CASS), may reduce the risk ofdeveloping VAP.

Selective digestive tractdecontamination- Selective digestivetract decontamination (SDD) involvesthe use of non-absorbable antibioticstopically applied to the gastrointestinaltract in an effort to sterilize theoropharynx and stomach. Most studieshave used a combination of topicalpolymixin, tobramycin or gentamicin,and amphotericin applied to theoropharynx (by hand) and the stomach(by nasogastric tube). About half of thestudies also included a short (3-4 day)course of systemic intravenousantimicrobial therapy, most commonlyceftriaxone. In general, topicalantibiotics were applied several timesdaily from the time of intubation untilextubation (or shortly thereafter).

Sucralfate and prevention ofVAP-It has been observed that gastriccolonization by potentially pathogenicorganisms increases with decreasinggastric acidity, leading to the hypothesisthat pH-altering drugs may causeincreased rates of VAP. H2-antagonisttherapy, widely used in mechanically-ventilated patients for stress ulcerprophylaxis significantly elevates gastricpH. Sucralfate, an alternativeprophylactic agent that does not affectgastric pH, may allow less gastriccolonization with potentially pathogenicorganisms than H2-antagonists andtherefore prevent some cases of VAP. Ingeneral, 1 g of sucralfate suspension isgiven through a nasogastric tube everyfour to six hours.

References

1. Chastre J, Fagon JY. Pneumonia inthe ventilator-dependent patient. In:Tobin MJ, editor. Principles andpractice of mechanical ventilation.New York: McGraw-Hill; 1994. p.857-890.


2. Chevret S, Hemmer M, Carlet J,Langer M. Incidence and risk factorsof pneumonia acquired in intensivecare units . Results from amulticenter prospective study on996 patients. European CooperativeGroup on Nosocomial Pneumonia.Intensive Care Med 1993; 19: 256-264 [Medline].

3. Kollef MH, Sherman G, Ward S,Fraser VJ. Inadequate antimicrobialtreatment of infections: a risk factorfor hospital mortality amongcritically ill patients. Chest 1999;115: 462-474.

4. Strausbaugh L. Nosocomialrespiratory infections. In: MandellGL, Bennett JE, Dolin R, editors.Principles and practice of infectiousdiseases. Philadelphia, PA:Churchill Livingstone; 2000. p.3020-3027.

5. Craven DE, Steger KA. Nosocomialpneumonia in mechanicallyventilated adult patients:epidemiology and prevention in1996. Semin Respir Infect 1996; 11:32-53 [Medline].

6. American Thoracic Society.Hospital-acquired pneumonia inadults: diagnosis, assessment ofseverity, initial antimicrobialtherapy, and preventive strategies. Aconsensus statement, AmericanThoracic Society, November1995. Am J Respir Crit Care Med1996;153:1711-1725

7. Bonten MJ, Gaillard CA, de LeeuwPW, Stobberingh EE. Role ofcolonization of the upper intestinaltract in the pathogenesis ofventilator-associated pneumonia.Clin Infect Dis 1997; 24: 309-319

8. Atherton ST, White DJ. Stomach assource of bacteria colonisingrespiratory tract during artificialventilation. Lancet 1978; 2: 968-969.

9. Torres A, Serra-Batlles J, Ros E,Piera C, Puig de la Bellacasa J, CobosA, Lomena F, Rodriguez-Roisin R.Pulmonary aspiration of gastriccontents in patients receivingmechanical ventilation: the effect ofbody position. Ann Intern Med1992; 116: 540-543.

10. Bonten MJ. Controversies ondiagnosis and prevention ofventilator-associated pneumonia.Diagn Microbiol Infect Dis 1999;34: 199-204

11. Fagon J-Y, Chastre J, Hance AJ,Domart Y, Trouillet J-L, Gibert C.Evaluation of clinical judgment inthe identification and treatment ofnosocomial pneumonia inventilated patients. Chest1993;103:547-53.

12. Wimberley N, Faling LJ, BartlettJG. A fiberoptic bronchoscopytechnique to obtain uncontaminatedlower airway secretions for bacterialculture. Am Rev Respir Dis 1979;119:337-43.

13. Meduri GU, Chastre J. Thestandardization of bronchoscopictechniques for ventilator-associatedpneumonia. Infect Control HospEpidemiol 1992;13:640-9.

14. Chastre J, Fagon J-Y, Bornet-LecsoM, Calvat S, Dombret M-C, KhaniRA, et al . Evaluation ofbronchoscopic techniques for thediagnosis of nosocomial pneumonia.Am J Respir Crit Care Med1995;152:231-40.

15. Marik PE, Brown WJ. A comparisonof bronchoscopic vs blind protectedspecimen brush sampling in patientswith suspected ventilator-associatedpneumonia. Chest 1995;108:203-7.

16. Meduri GN, Reddy RC, Stanley T,El-Zeky F. Pneumonia in acuterespiratory distress syndrome. Aprospective evaluation of bilateralbronchoscopic sampling. Am JRespir Crit Care Med 1998;158:870-5.

17. Jean Chastre and Jean-Yves Fagon.Ventilator - associated pneumonia.Am. J. Respir. Crit. Care Med.,Volume 165, Number 7, April 2002,867-903.

18. Rello J, Mariscal D, March F, JubertP, Sanchez F, Valles J, Coll P.Recurrent Pseudomonas aeruginosapneumonia in ventilated patients:relapse or reinfection? Am J RespirCrit Care Med 1998; 157: 912-916


38

Current Concepts in Management of Cancer EsophagusR.P. Gupta

Shanti Mukand Hospital, Delhi

Esophageal cancer is a challengingdisease with a poor outlook andhence there is justification for a

wide spread pessimism, that affectsclinicians who manage these patients. Incancer of Esophagus not every patient hasa bad prognosis and there are many, whosedisease can be cured, and for those whoare incurable, methods of palliationcontinue to improve. In U.K. Incidenceis 7.2 cases / lac and in Japan incidence is5.7 cases / lac. It accounts for over 2.5%cases of cancer in males and 2% of allcancers in females. In 11% cases morethan one lesion of cancer is found inoesophagus.

Predisposing factors- These are-Achalasia, Collumnar lined loweroesophagus (Barrett’s Oesophagus),Corrosive Lye Structure, Peterson KellySyndrome, Patient with tylosis,Smoking, Alcohol, Intake ofnitrosamines as seen in bantu people. It isalso important to be aware of thepotential for further improvement thatis offered by developments in oncology,laser and by evolving surgical techniques

Epidemiology-Mostly are squamouscell carcinoma. Adeno carcinoma is adifferent disease with a differentetiology. It is due to malignant change inbarretts oesophagus and is more commonin western countries.

Clinical history - Any one above 40years of age and complaints of painfulswallowing or Dysphagia first to solidsand then to semisolids and to liquids;should undergo appropriate diagnosticstudies; Anemia; Respiratory infection

due to regurgitation overflow orfistualisation; Chest pain

Clinical examination-withexamination of the neck to see for anylymphadenopathy

Chest X-ray-To see for nodes inmediastinum and any sign of aspirationor fistula formation; secondaries in lungand ribs etc.

Barium swallow- To see extent andsite of obstruction; to see for change inthe axis of oesophagus; any evidence offistulisation

Endoscopy -To see the level of thedisease; type of lesion, obstructive orulcerative; to plan surgical resectionaccurately; synchronuos lesions; regularannual endoscopy and biopsy in case ofbarretts oesophagus; minimum of fourquadrantric biopsies at 2cm intervals.

Video endoscopy-Modern endoscopygives excellent views of the wholeoesophagus and even small lesions can beclearly seen. Lesions with a modular orirregular surface tend to invade deeperthan those with a granular or fine surface.

Thus lesions which are easily detectableby conventional endoscopic observation,have already been invaded into thesubmucosal layer or deeper. It is for thisreason that oesophageal irrigation andiodine staining is widely used in Japan.All cancerous lesions at any depth ofinvasion remain stained with iodine. Notall unstained lesions are carcinoma.

Ultra sound- To see for lymphnodesmetastasis in neck, chest, mediastinum,

celiac axis and secondaries in the liver.

Endoscopic ultrasonography-This is used for staging for primarylesion and evaluating lymphnode spread.This is the best method.With highfrequency probes normal oesophagealwall is seen as a five layer structure andsometimes seven layers of alternatinghyperechoic and hypoechoicbands.E.U.S. (Endoscopic Ultrasound)Seems particularly useful for assessingvery early cancer that may be amenableto mucosal resection or ablation.It couldalso have a place for the selection of thegroup of patients who might be enteredinto prospective randomized studies ofpreoperative treatment with drugs orradiation.The depth of tumor invasioncan be assessed with 85% accuracy byE.U.S. Lymph node invasion can bedetected with 87% accuracy, becausesmaller nodes can be seen and the internalarchitecture can be assessed

Limitation of E.U.S-Main limitationat present is that the instrument has a 4cm Rigid Tip & is 13mm in diameter andit may not be possible to pass it throughthe tumor. Newer probes that can bepassed down the biopsy channel of astandard endoscope have. However, beendeveloped and are better for assessingsurgical lesion than the deeply invadinglesion that is likely to produce markedstenosis

CT Scan & MRI- CT Scan of chest,liver, lung and bone. Before embarkingon a resection, CT of thorax is done tosee for lymph node invasion. In a studyfrom Osaka City University Hospital

9Reviewarticle


3661 nodes were analysed which wereremoved in 72 patients who had extendedlymphnadenectomy. It showed that 8 mmdiameter gave the best discriminationbetween invaded and noninvaded nodeswith a sensitivity of 65% and specificityof 76%. CT & MRI can detect nodes of 1cm diameter. Nodes detected on CT have86% chance of being invaded. However,nodes below the tracheal bifurcation maybe larger yet still not invaded.

MRI- It may be better than CT fordetecting tracheo bronchial invasion ifthe criterion for a positive examinationincludes disappearance of a high intensitysignal between the oesophageal wall, thetrachea or bronchus. This strong signal isthought to be generated by the normaltracheo bronchial membrance.

Patient assessment- Once thediagnosis is made all patients ofoesophageal cancer should be assessed ascandidates for curative treatment. Theaim of this assessment is-to offerpotentially curative treatment to thosein whom there is a reasonable expectationof cure;to avoid inappropriatelyaggressive treatment in those who are notlikely to be cured. Presence of metastaticdisease detected by any method ofimaging should be confirmed by biopsyif at all possible. None of the imagingmethod is 100% reliable and it is atragedy to refuse potentially curativetreatment to a patient, because of overinterpretation of CT scan or ultrasound.Lymphnodes are detected as ovalhypoechoic areas. Nodes as small as 3 mmcan be detected; the diagnosis ofmetastasis is based on diameter of thenode and the ratio of the smaller : largerdiameter >0.5 indicates invasion;Characteristics of the border and theinternal echo of the node are also helpful.Nodes with a clear border and unevencoarse, scattered, internal echo can be

diagnosed as metastatic with an accuracyof 87%.

Surgical treatment-Surgical excisionof oesophagus for the treatment of cancerhas improved considerably in recentyears because of developments inAnesthetic management; SurgicalTechnique; Preoperative care; Painrelief. It is accepted that reasonableresults can be achieved with surgicalexcision provided that careful attentionis paid to case selection and to the detailsof operative techniques. Goodnutritional advice and the sensible use ofdietary supplements and substitutes,particularly liquid diet is an importantaspect of the treatment.

Surgery radical excision- I tinvolves removal of primary tumor andother tissues that might be invaded.Tumors in oesophagus have a propernsityfor extensive proximal spread in thesubmucosal lymphatics and hencesurgical clearance should take account ofthis and generous proximal clearance iscommonly recommended.

General support-Oesophagealcancer, and the process of assessment andtreatment are extremely stressful to thepatient and their relatives even when cureis achieved hence considerable effortneeds to be directed to general care, tocounselling and to psychological support.

Surgery

Iver Lewis Or Lewis Tannerprocedure-Most widely practicedprocedure. This is the most straightforward and versatile method of access.Anastomosis may be done at thoracic inletor in neck.

Transhiatal oesophagectomy-Without thoracotomy has enjoyedconsiderable popularity. It is moredifficult to perform truly radical

resection. Complete lymphadenectomyis impossible by transhiatal surgery. Itshould be reserved for those who are unfitfor radical surgery or for when palliationis all that can be achieved. Salama andleong (Nottingham) reported overall 5years survival of 36% for squamous cellcarcinoma but only 3% for adeno CA.This shows that cancer oesophagus is a baddisease but it is not untreatable. Survivalas with all caners is stage related andoverall survival figures reflect the stagemix within individual series.

Mckeowen popularised the concept ofsubtotal oesophagectomy in U.K. In thisoperation only a small proximal stumpis left behind and proximal tumourclearance is invariably complete forlesions as high as middle third. This waspopularized by Mckeowen in the 1970sand was associated with 5 years survivalof approximately 30% at a time when theaverage was 10-15%. Oesophago gastricanastomosis is above the level of theaortic arch.

Three f ield node dissection-Radical resection with methodicalclearance of regional lymphnodes andadjacent tissues. The ultimate lymphnodeclearance involves radical dissection inthe abdomen chest and neck (3 folddissection). This is widely practicised inJapan with a low postop mortality.Rationale for this procedure was therelatively unsatisfactorily outcome ofconventional oesophagectomy withlymphnode dissection in the middle andlower mediastinum.Japanese indicated 5years survival of 13.8%.Presently insome centres, if some cure seems possible,but there are significant operative riskfactors 3 field node dissection is done in2 stages. Oesophagectomy & mediastinaldissection is done first followed bycervico abdominal dissection andreconstruction three weeks later. In this


40

procedure, the nodes are dissected in thefollowing tissue zone i.e. internal jugularvein, supraclavicular, recurrentlaryngeal nerve, paratracheal, tracheal,bifurcation and pulmonary hilum,paraoesphageal, paraaortic, pulmonaryligament, superior & inferiordiaphragmatic, perigastric (Pericardial)lesser curvature of stomach, left gastic,common hepatic and coeliac axis. Theupper mediastinal nodes are dissected viaa right thoractomy and the recurrentlaryngeal nerves are taped the dissectionis carried up through the thoracic inlet asfar as possible.A collar incision is madein the neck and the dissection is carriedout to the level of omohyoid musclesuperiorly and external jugular veinlaterally.This denudes the trachea,Bronchi and the right bronchial artery ispreserved as far as possible to maintaintracheo bronchial circulation

Complications-After 3 field nodedissection pulmonary complicationsoccur in 16% cases. The dissectiondenerves the mediastinal trachea andmain stem bronchi. Because of this thereis impairment of cough reflex. Hence itis the practice to perform fibre-opticbronchoscopy once or twice a day forfirst 5 post op days. 30% patientsdeveloped recurrent laryngeal NDysfunction. Part of this was responsiblefor significant incidence of regurgitationand pneumonia late in the recoveryprocess.

Minimally invasive surgery-Thatis completely endoscopic resection of theoesophagus including gastricmobilization and anastomosis has beenperformed but it is an extraordinarilyprolonged procedure and is at presentimpractical for routine use. Some groupshave resected the oesophagus byThoracoscope while the stomach hasbeen mobilized at laparotomy. The

anastamosis has most cordially beenperformed in the neck. But intrathoracicstapled anastomosis has also beenperformed. Avoiding formal thoractomyseems rational but as yet surgicalmorbidity has not been reduced byendoscopic surgery and the procedureremains experimental. For the momenttechnique are still evolving and surgeonsare improving their skills. If a usefulmethod is developed it is vital thatminimal access oesphagectomy issubmitted for formal prospectiverandomized study.

In Osaka 138 patients underwent thisprocedure between 1980 – 1993.Hospital mortality was 5%. 5 yearssurvival was 42% (100% for TI Lesionand 34% in T4 lesion). Survival seemedmore dependent on lymphnode invasion.More important groups areparaoesphageal, perigastric and rec.laryngeal nerve group lymphnodes.

Japanese results are better in the wholeworld because of the reasons such as-Lesspressure on the operating theatre time inJapan. Allowing more time to be takento do job thoroughly well; Patients stayin hospital much longer (mean durationincluding chemotherapy – 11 weeks postoperative); Well trained assistants; Betterinteraction between surgeon,radiotherapist and chemotherapist;Good surgical techniques; Only done inhospital with adequate facilities;Resection is done in centre where at leastone oesophageal resection is done everymonth.

British authors feel that resection shouldnot be done if there is no chance of cureor only minimal chance while Japanesesurgeons have a strong feeling thatresection produces the best palliation butall agree that the concept of curativesurgery is an important one and that the

primary aim of surgical resection shouldbe cure whenever possible.

Lesions of cardia can be dealt withsub total oesophageal resection.Resection provided that the tumor in theproximal stomach can be clearledadequately and still leave enoughstomach for a satisfactory reconstruction.Deemester has suggested subtotaloesophagectomy and total gastrectomywith reconstruction by colonicinterposition in fit patients withpotentially curable disease. This is a verymajor undertaking and only suitable forvery carefully selected cases. Mortalityof oesophageal resection is related to -Age; Tumor size; Lung function (FEVI);Nutritional status and nutritionalsupport. Radical treatment foroesophageal cancer is hazardous and it istherefore particularly important to assessthe fitness of patients for any treatmentthat is proposed.

Nutritional status andnutritional support-Severemalnutrition indicates advanced cancer.If it occurs there is no point in attemptingrestoration to normal nutritional statusbefore resection as this takes too long tobe practical. Partial nutritionalrestoration has not shown to reduce therisk of oesophageal resection.

Mortality following surgicalresection has been significantlyreduced

• Methods of pall iation haveimproved

• Chemotherapy has a much morepredictable response rate

• This is not a disease that isuntreatable a great deal can be done.

• Achieving the best results requiresan experienced multidisciplinaryteam.


Adeno carcinoma of oesophagus is a moreaggressive disease than squamous cellcarcinoma

Other methods of treatment

Chemotherapy-This has improved inrecent years but is still not curative on itsown. Preoperative chemotherapy withF.L.E.P. followed by concurrentchemoradiotherapy is active againstlocally advanced oesophageal cancer. Inthis series the pathologic completeresponse rate was 33% amongst thosepatients who underwent surgery. Beforesurgery 90 patients who had L.A.E.C.received chemotherapy i.e. 3 course of 5FU. Leucovorin etoposide and cisplatini.e. F.L.E.P. followed by concurrentchemoradiotherapy i.e. one course ofcisplatin and etoposide combined with4000 R. 4 weeks after radiation transthoracic oesophagectomy was done

Radiotherapy -Survey of literaturesuggests that better cure rates are obtainedby resection than by irradiationprovided that operative mortality is low.Radiotherapy is presently the treatmentof choice for cancer of the cervicaloesophagus, it preserves voice andlaryngeal function. In theorycombination of surgery andradiotherapy should improve cure ratebecause each has different limitations intreating the primary lesion.

Preoperative radiotherapy-In eightrandomized studies has shown benefitfrom combined treatment

Post operative radiotherapy-Hasnot been shown to have any benefit, buttrials are few and lack statisticalpower.Non randomized studies havesuggested a deleterious effect.

Combined surgery andradiotherapy-The outcome appears to

be better than those associated withsurgery alone approximately doublingthe 3 years survival. Patients withchemoradiotherapy had longer diseasefree survival but there were higher postoperative complications. But given thefailure of combined therapy to prolongoverall survival we clearly need moreeffective less toxic regimes.

Palliation-Prevailing feeling is that ifradical treatment is unlikely to achieve acure, it is better to have swallowingrestored in the least traumatic manner sothat, if survival is short the remainingtime is not spent in recovering from a bigoperation.The decision to pursue apalliative course of action is thereforetaken in a greater proportion of cases andthe technology of palliation is a subjectof much interest. The methods availablefor palliation are- Dilation, Intubation,Laser, Bipolar diathermy, Alcoholinjection, Endoluminal radiotherapy orbrachy therapy, Expanding stents,Surgical palliation

Dilatation -Simple and relatively safebut gives only very temporary relief.Canbe useful for tiding a patient over a periodof assessment but is much less popular forpalliation now.

Intubation-Endolunimual tubes torestore swallowing have been used forgenerations, but in the last 20 years tubedesign and methods of insertion haveimproved sufficiently to maketechniques reasonably effective and safe.Tubes which need to be inserted duringsurgery are-Mouseeau barbin andCelestin tube. The tubes insertedendoscopically commonly used isAtkinson tube. It is used most widely. Itis relatively soft, funnel shaped and itgives reasonable palliation. But mostpatients are restricted to semi solid foodonly and there is significant perforation

rate (5-10%). Now are used selfexpanding endoluminal stents

LASER-Laser canalization is nowwidely used and many would consider thisas the current method of choice. Goodpalliation is obtained with littlemorbidity and comparative trials haveshown it to have small but significantadvantage over intubation

Disadvantages-Procedure needs to berepeated regularly. Equipment isexpensive and requires maintenance & isnot portable. Considerable investmentand time is required as lasers areexpensive. Access to the lesion is notalways ideal.

Procedure -Laser used is Nd Yag(YIttrium Aluminium Garnet). 90-100watt laser used for 2 sec at 1 cm distancefrom the tissue beams aimed at neoplastictumor closest to the tumor and treatmentprogresses to an increasing largerconcentric circles towards but not to thewall of the oesophagus. If not completedin one sitting treatment can be carriedout on subsequent sittings almost everyother day. At the beginning of each laserafter the first one the previously treatedneoplastic tissue that plugs the lumenmust be removed so that progressivecoring out of the tumor can be done.Indicated in patients who have beenrejected as surgical candidate even forpalliation due to location or local spreadof tumor or due to patients clinical status.

Advantages of LASER- It averts theneed for surgery. It diminishesconsiderably likelihood of systematicside effect. Can be performed underdirect vision. Unlike radiotherapy, thereis no maximum dose and so if tumorrecurs in same area re-treatment can begiven

Advancement in LASER use-


42

With the marriage of computer and lasertechnology. The selection of proper dosefor a given problem will be refined. Useof tissue sensitized agents to allow formore precise destruction of neoplastictissue with less damage to normal tissue.Progress in the development ofendoscopes and endoscopic accessorieswill render the target lesion betteraccessible to laser treatment.

Results & risks-In one series it gavesymptomatic improvement in 37 out of40 cases Endoscopic luminal diameter isimproved from nil to 11.5mm. There isrisk of perforation and T.O.Fistula

Bipolar diathermy-Bipolar tumorprobe diathermy has shown to producesimilar results to laser withcircumferential tumor. The equipmentis much less expensive than laser. But it isnot applicable to polypoidal tumors thatdo not encircle the oesophoagus. A probewith a 180 degree contract plate isavailable for polypoid lesions. But it isdifficult to use in practice.

Alcohol injection-Endoscopic tumornecrosis with 100% ethanol is simple andcheap and may have results similar tolaser and diathermy. A simple endoscopicinjection needle is used to inject smallaliquotos of alcohol in the tumorthroughout its length. Relief of dysphagiamay take a few days but good qualitypalliation can be produced. The periodof 48 hours between treatment generallyallows for maximal tissue necrosis and iswell olerated by patients

Endo luminal radiotherapy orbrachy therapy (E.R.)-E.R. with asource that produces little tissuepenetration (Brachy Therapy) is simpleand effective method of palliation with alow complication rate. In common withlaser the equipment is expensive but relief

of dysphagia can be prolonged.

Expanding stents -These are thelatest addition to the armamentarium.These are expensive but have theadvantage of producing excellent reliefof dysphagia with a single procedureCumulative hospital costs are lower asrepeated treatments are not required. Noserious complication. Prospective trialsare going to decide, which of the availabledesigns is best. Commonly used areultraflex and Z stents.

Surgical pall iation-Pall iativeresection gives excellent relief ofdysphagia but it is a major procedure withsignificant disadvantages, specially whenexpected survival is short. When cure isnot possible, surgical resection should bediscouraged

Endoscopic mucosal resection-Iflesion invades submucosa incidence oflymphnode metastasis is 40-60%.Lymphnode permeation is 70-80%.If lesion is confined to mucosa theincidence of lymphnode metastasis is 4-7%. If lesion is epitheial, no metastasisoccurs. Hence in recent years enthusiasmhas gone for the technique of endoscopicmucosal resection in very early cases i.e.epithelial or mucosal specially in elderlyor unfit patients. E.M.R. Involves raisingthe lesion by submucosal injection ofsaline and diathermy excision of theaffected portion.

At present E.M. is recommended

• if there are 5 or fewer lesions

• the lesion is smaller than 6 cm

• it does not occupy the wholecircumference of the oesophagus

Conclusion

• Treating cancer of the oesophagusremains a challenge

• Prevailing attitude is one of despairand results fall short of what onewould like to achieve.

• Considerable progress has however,been made in last three decades.

• If, diagnosis is made at an earlierstage then complications such asoesophago bronchial fistula are lesscommon

• In carcinoma of oesophaguslaparoscopy have resulted inacceptable resection and survivalrate. Endoscopic ultrasound helps toevaluate the extent of oesophagealwall involvement. Survival for thisdisease is st i l l largely stagedependant and earlier diagnosisprobably holds the key to improveddiagnosis.


10Reveiwarticle

Management of Cancer Urinary BladderLt. Gen. S. Mukherjee

Armed Forces Medical College, Pune

Approximately 70% to 80% ofpatients with newly diagnosedbladder cancer will present with

superficial bladder tumors (i.e., stage Ta,Tis, or T1). Those who do present withsuperficial, noninvasive bladder cancercan often be cured, and those with deeplyinvasive disease can sometimes be curedby surgery, radiation therapy, or acombination of modalities that includechemotherapy. 1 Studies havedemonstrated that some patients withdistant metastases have achieved long-term complete response followingtreatment with combinationchemotherapy regimens.

Prognostic factors

The major prognostic factors incarcinoma of the bladder are the depthof invasion into the bladder wall and thedegree of differentiation of the tumor.Most superficial tumors are welldifferentiated. Patients in whomsuperficial tumors are less differentiated,large, multiple, or associated withcarcinoma in situ (Tis) in other areas ofthe bladder mucosa are at greatest risk forrecurrence and the development ofinvasive cancer. Such patients may beconsidered to have the entire urothelialsurface at risk for the development ofcancer. Tis may exist for variabledurations. Adverse prognostic featuresassociated with a greater risk of diseaseprogression include the presence ofmultiple aneuploid cell lines, nuclearp53 overexpression, and expression ofthe Lewis-x blood group antigen.2-5

Patients with Tis who have a complete

response to bacillus Calmette-Guérinhave approximately a 20% risk of diseaseprogression at 5 years; patients withincomplete response have approximatelya 95% risk of disease progression.2 Severaltreatment methods (i.e., transurethralsurgery, intravesical medications, andcystectomy) have been used in themanagement of patients with superficialtumors, and each method can beassociated with 5-year survival in 55% to80% of patients treated.2,3,6

Invasive tumors that are confined to thebladder muscle on pathologic stagingafter radical cystectomy are associatedwith approximately a 75% 5-yearprogression-free survival rate. Patientswith more deeply invasive tumors, whichare also usually less well differentiated,and those with lymphovascular invasionexperience 5-year survival rates of 30%to 50% following radical cystectomy. 7When the patient presents with locallyextensive tumor that invades pelvicviscera or with metastases to lymph nodesor distant sites, 5-year survival isuncommon, but considerablesymptomatic palliation can still beachieved.8

Expression of the tumor suppressor genep53 also has been associated with anadverse prognosis for patients withinvasive bladder cancer. A retrospectivestudy of 243 patients treated by radicalcystectomy found that the presence ofnuclear p53 was an independent predictorfor recurrence among patients with stageT1, T2, or T3 tumors.9 Anotherretrospective study showed p53

expression to be of prognostic value whenconsidered with stage or labeling index.10

Tumour staging

The clinical staging of carcinoma of thebladder is determined by the depth ofinvasion of the bladder wall by the tumor.This determination requires acystoscopic examination that includes abiopsy, and examination under anesthesiato assess the size and mobility of palpablemasses, the degree of induration of thebladder wall, and the presence ofextravesical extension or invasion ofadjacent organs. Clinical staging, evenwhen computed tomographic and/ormagnetic resonance imaging scans andother imaging modalities are used, oftenunderestimates the extent of tumor,particularly in cancers that are lessdifferentiated and more deeplyinvasive.11

The American Joint Committee onCancer (AJCC) has designated staging byTNM classification to define bladdercancer.12

Primary tumor (T)

• TX: Primary tumor cannot beassessed

• T0: No evidence of primary tumor

• Ta: Noninvasive papil larycarcinoma

• Tis: Carcinoma in situ (i.e., flattumor)

• T1: Tumor invades subepithelialconnective tissue


44

• T2: Tumor invades muscle

• pT2a: Tumor invades superficialmuscle (inner half)

• pT2b: Tumor invades deep muscle(outer half)

• T3: Tumor invades perivesicaltissue

• pT3a: Microscopically

• pT3b: Macroscopically(extravesical mass)

• T4: Tumor invades any of thefollowing: prostate, uterus, vagina,pelvic wall, or abdominal wall

• T4a: Tumor invades the prostate,uterus, vagina

• T4b: Tumor invades the pelvic wall,abdominal wall

[Note: The suffix “m” should be addedto the appropriate T category to indicatemultiple lesions. The suffix “is” may beadded to any T to indicate the presenceof associated carcinoma in situ.]

Regional lymph nodes (N)

• NX: Regional lymph nodes cannotbe assessed

• N0: No regional lymph nodemetastasis

• N1: Metastasis in a single lymphnode, =2 cm in greatest dimension

• N2: Metastasis in a single lymphnode, >2 cm but =5 cm in greatestdimension; or multiple lymphnodes, =5 cm in greatest dimension

• N3: Metastasis in a lymph node, >5cm in greatest dimension

Distant metastasis (M)

• MX: Distant metastasis cannot beassessed

• M0: No distant metastasis

• M1: Distant metastasis

AJCC stage groupings

Stage 0a : Ta, N0, M0

Stage 0is : Tis, N0, M0

Stage I: T1, N0, M0

Stage II: T2a, N0, M0, T2b, N0, M0

Stage III: T3a, N0, M0, T3b, N0, M0, T4a,N0, M0

Stage IV: T4b, N0, Any T, N1/N2/N3M0

Treatment option overview

Prolonged survival in most patients withsuperficial cancers is achieved bytransurethral resection (TUR) with orwithout intravesical chemotherapy.Cure is not possible for the majority ofpatients with deeply invasive tumors andfor most patients with regional or distantmetastases. In North America, thestandard treatment of patients withinvasive bladder cancers is radicalcystectomy and urinary diversion. Othertreatment approaches include TUR andsegmental resection with or withoutradiation therapy, combinedchemotherapy-radiation therapy, oreither followed by salvage cystectomy,when needed, for local failure.13,14

Reconstructive techniques that fashionlow-pressure storage reservoirs from thereconfigured small and large boweleliminate the need for external drainagedevices and, in some male patients, allowvoiding per urethra. These techniques aredesigned to improve the quality of lifefor patients who require cystectomy.15

Stage- 0 bladder cancer

Patients with stage 0 bladder tumors canbe cured by a variety of treatments, eventhough the tendency for new tumor

formation is high. Patients at greatest riskof recurrent disease are those whosetumors are large, poorly differentiated,multiple, or associated with nuclear p53overexpression. In addition, patients withcarcinoma in situ (Tis) or dysplasia ofgrossly uninvolved bladder epitheliumare at greater risk of recurrence andprogression. Transurethral resection(TUR) and fulguration are the mostcommon and conservative forms ofmanagement. Careful surveillance ofsubsequent bladder tumor progression isimportant. Patients who require moreaggressive forms of treatment are thosewith extensive multifocal recurrentdisease and/or other unfavorableprognostic features. Segmentalcystectomy is applicable to only a smallminority of patients because of thetendency of bladder carcinoma toinvolve multiple regions of the bladdermucosa and to occur in areas that cannotbe segmentally resected.

Intravesical therapy with thiotepa,mitomycin, doxorubicin, or bacillusCalmette-Guérin (BCG) is most oftenused in patients with multiple tumors orrecurrent tumors or as a prophylacticmeasure in high-risk patients after TUR.Administration of intravesical BCGplus subcutaneous BCG following TURwas compared with TUR alone inpatients with Ta and T1 lesions.Treatment with BCG delayedprogression to muscle-invasive and/ormetastatic disease, improved bladderpreservation, and decreased the risk ofdeath from bladder cancer. Twononconsecutive 6-week treatmentcourses with BCG may be necessary toobtain optimal response.16 Patients witha T1 tumor at the 3-month evaluationafter a 6-week course of BCG and patientswith Tis that persists after a second 6-week BCG course have a high likelihood


of developing muscle-invasive diseaseand should be considered forcystectomy.17 Although BCG may notprolong overall survival for Tis disease,it appears to afford complete responserates of about 70%, thereby decreasingthe need for salvage cystectomy

Standard treatment options

• TUR with fulguration.17

• TUR with fulguration followed byintravesical BCG. BCG is thetreatment of choice for Tis.5,7,9,13,14

• TUR with fulguration followed byintravesical chemotherapy.2,11,17

• Radical cystectomy in selectedpatients with extensive or refractorysuperficial tumor.17,18

Stage- I bladder cancer

Patients with stage I bladder tumors canbe cured by a variety of treatments, eventhough the tendency for new tumorformation is high. In a series of patientswith Ta or T1 tumors who werefollowed for a minimum of 20 years oruntil death, the risk of bladder recurrencefollowing initial resection was 80%.18

Patients at greatest risk of recurrentdisease are those whose tumors are large,poorly differentiated, multiple, orassociated with dysplasia of grosslyuninvolved bladder epithelium.Transurethral resection (TUR) andfulguration are the most common andconservative forms of management.Careful surveillance of subsequentbladder tumor progression is important.Patients who require more aggressiveforms of treatment are those withextensive multifocal recurrent diseaseand/or other unfavorable prognosticfeatures. Segmental cystectomy isapplicable to only a small minority ofpatients because of the tendency of

bladder carcinoma to involve multipleregions of the bladder mucosa and tooccur in areas that cannot be segmentallyresected.

Intravesical therapy with thiotepa,mitomycin, doxorubicin, or bacillusCalmette Guérin (BCG) is most oftenused in patients with multiple tumors orrecurrent tumors or as a prophylacticmeasure in high-risk patients after TUR.

Standard treatment options

• TUR with fulguration.19

• TUR with fulguration followed byintravesical BCG.20

• TUR with fulguration followed byintravesical chemotherapy.20

• Radical cystectomy in selectedpatients with extensive or refractorysuperficial tumor

• Interstit ial implantation ofradioisotopes with or withoutexternal-beam radiation therapy

Stage- II bladder cancer

Stage II bladder cancer may be controlledin some patients by transurethralresection (TUR), but often moreaggressive forms of treatment are dictatedby recurrent tumor or by the large size,multiple foci, or undifferentiated gradeof the neoplasm. Segmental cystectomyis appropriate only in very selectedpatients. Radical cystectomy isconsidered standard treatment.

After radical cystectomy, however, anapproximate 50% risk of recurrence stillexists for patients with muscle-invasivedisease. The addition of preoperativeradiation therapy to radical cystectomydoes not result in any survival advantagewhen compared with radical cystectomyalone. Since the disease commonly recurswith distant metastases, systemic

chemotherapy administered before orafter cystectomy has been evaluated as ameans of improving outcome.Administration of chemotherapy beforecystectomy (i.e., neoadjuvant) may bepreferable to postoperative treatmentbecause tumor downstaging fromchemotherapy may enhanceresectability, occult metastatic diseasemay be treated as early as possible, andchemotherapy may be better tolerated.A meta-analysis of 10 randomized trialsof neoadjuvant chemotherapy, includingupdated data for 2,688 individualpatients, showed that platinum-basedcombination chemotherapy wasassociated with a significant 13% relativereduction in the risk of death andresulted in an improvement in 5-yearsurvival from 45% to 50% (P = .016).Neoadjuvant single-agent cisplatin wasnot associated with any such survivalbenefit in the meta-analysis.21 Based onthese findings, it is reasonable to offerneoadjuvant platinum-basedcombination chemotherapy prior tocystectomy in patients with muscle-invasive bladder cancer.

In patients who are not willing or able toundergo radical cystectomy, definitiveradiation therapy is an option that yieldsa 5-year survival of approximately 30%.22

Approximately 50% of patients havedysuria and urinary frequency duringtreatment, which resolves several weeksafter treatment, and 15% report acutetoxic effects of the bowel.

Systemic chemotherapy has beenincorporated with definitive radiationtherapy to develop a more effectivebladder-sparing approach for patientswith locally advanced disease. Theutility of this multimodality approachwas confirmed in a prospective,randomized comparison of radiationtherapy and chemoradiation therapy,


46

which reported an improved rate of localcontrol when cisplatin was given inconjunction with radiation therapy, eventhough there was no improvement in therate of distant metastases or overallsurvival.23 In a phase III study, theRadiation Therapy Oncology Groupevaluated the potential benefit of adding2 cycles of neoadjuvant methotrexate,cisplatin, and vinblastine prior toconcurrent cisplatin and radiationtherapy, but neoadjuvant chemotherapywas associated with increasedhematologic toxic effects and yielded noimprovement in response rate, freedomfrom distant metastases, or overallsurvival when compared withchemoradiation therapy alone.24 Becauseno randomized trials have directlycompared the bladder-preservingchemoradiation therapy approach withradical cystectomy, it is not clear if theformer is as effective as the latter. Choiceof treatment should be guided by apatient’s overall medical condition andby consideration of the adverse effects oftherapy.

Treatment options

• Radical cystectomy with or withoutpelvic lymph node dissection

• Neoadjuvant platinum-basedcombination chemotherapyfollowed by radical cystectomy

• TURBT / External-beam radiationtherapy / Chemotherapy alone inpatients with multiplecomorbidities and poor PS.

• TURBT followed by RT &concurrent Chemotherapy.

• Segmental cystectomy (solitarylesion).

Stage- III bladder cancer

For most patients, radical cystectomy is

considered standard treatment. Radicalcystectomy includes removal of thebladder, perivesical tissues, prostate, andseminal vesicles in men and the uterus,tubes, ovaries, anterior vaginal wall, andurethra in women and may or may not beaccompanied by pelvic lymph nodedissection

After radical cystectomy, however, anapproximate 50% risk of recurrence stillexists for patients with muscle-invasivedisease. A meta-analysis of 10randomized trials of neoadjuvantchemotherapy, including updated datafor 2,688 individual patients, showedthat platinum-based combinationchemotherapy was associated with asignificant 13% relative reduction in therisk of death and resulted in animprovement in 5-year survival from45% to 50% (P = .016). Neoadjuvantsingle-agent cisplatin was not associatedwith any such survival benefit in themeta-analysis.21 Based on these findings, itis reasonable to offer neoadjuvantplatinum-based combinationchemotherapy prior to cystectomy inpatients with muscle-invasive bladdercancer.

In patients who are not willing or able toundergo radical cystectomy, definitiveradiation therapy is an option that yieldsa 5-year survival of approximately 30%.Randomized trials, conducted from the1950s through the 1980s, of definitiveradiation therapy (with salvagecystectomy only for incomplete responseor failure) versus preoperative radiationtherapy followed by cystectomy havefound similar or worse survival inpatients who received definitiveradiation therapy. 23

Systemic chemotherapy has beenincorporated with definitive radiationtherapy to develop a more effective

bladder-sparing approach for patientswith locally advanced disease. Theutility of this multimodality approach issame as mentioned above for stage IIbladder cancer. In some nonrandomizedstudies, 50% or more of patients who hadbladder-preserving therapy (i.e., initialtransurethral resection of as much tumoras possible followed by concurrentchemoradiation therapy) were alive at 5years, and 75% of those survivors had anintact bladder.24 Because no randomizedtrials have directly compared thebladder-preserving chemoradiationtherapy approach with radicalcystectomy, it is not clear if the former isas effective as the latter. Choice oftreatment should be guided by a patient’soverall medical condition and byconsideration of the adverse effects oftherapy.

Treatment options

• Radical cystectomy with or withoutpelvic lymph node dissection.

• Neoadjuvant platinum-basedcombination chemotherapyfollowed by radical cystectomy

• External-beam radiation therapywith or without concurrentchemotherapy.(Organ preservation/ treatment for unfit patients)

Stage- IV bladder cancer

Currently, only a small fraction ofpatients with stage IV bladder carcinomacan be cured. These patients may undergoradical cystectomy with pelvic lymphnode dissection. The extent of lymphnode dissection during cystectomy iscontroversial 2 as there are no data fromprospective trials demonstratingimproved outcomes with lymph nodedissection. Definitive radiation therapywith or without concurrentchemotherapy, evaluated mainly in


patients with locally advanced (T2-T4)disease, appears to have minimal curativepotential in patients with regional lymphnode metastases.

The focus of care for many stage IVpatients is on palliation of symptomsfrom bladder tumor that is often massive.Urinary diversion may be indicated, notonly for palliation of urinary symptoms,but also for preservation of renalfunction in candidates for chemotherapy.Platinum-based combinationchemotherapy regimens are the standardof care. Gemcitabine has shown activityin phase II trials of patients withmetastatic bladder cancer.25 In amulticenter, randomized, phase III trialcomparing the combination ofgemcitabine/cisplatin (GC) with the M-VAC regimen in 405 patients withadvanced or metastatic bladder cancer,GC yielded similar response rates, time-to-progression, and overall survival(hazard ratio [HR] = 1.04; 95%confidence interval [CI], 0.82-1.32; P =.75) compared with M-VAC, but GC hada better safety profile and was bettertolerated than M-VAC. Although thisstudy was not designed to show theequivalence of the 2 regimens, thesimilar efficacy and reduced toxic effectsof GC make it a reasonable alternativein patients who may not tolerate the M-VAC regimen.26

For patients with T4b, N0, M0;Any T, N1, M0; Any T, N2, M0;Any T, N3, M0

Treatment options

• Radical cystectomy with pelviclymph node dissection.

• External-beam radiation therapy.

• Urinary diversion or cystectomy forpalliation.

• Chemotherapy as an adjunct to localtreatment.

For patients with Any T, AnyN, M1 disease

Treatment options

• Chemotherapy alone or as an adjunctto local treatment.3,4,9

• External-beam radiation therapy forpalliation.

• Urinary diversion or cystectomy forpalliation.

Recurrent bladder cancer

The prognosis for any patient withprogressive or recurrent invasivebladder cancer is generally poor.Management of recurrence depends onprior therapy, sites of recurrence, andindividual patient considerations.Recurrent or progressive disease indistant sites or after definitive localtherapy has an extremely poor prognosis,and clinical trials should be consideredwhenever possible.

In patients with recurrent transitionalcell carcinoma, combinationchemotherapy has produced goodresponse rates with occasional completeresponses seen. 27 Chemotherapy agentsthat have shown activity in metastaticbladder cancer include: paclitaxel,ifosfamide, and gemcitabine.28

References

1. American Cancer Society: CancerFacts and Figures 2006. Atlanta, Ga:American Cancer Society, 2006.

2. Hudson MA, Herr HW: Carcinomain situ of the bladder. J Urol.1995;153 (3 Pt 1): 564-72.

3. Torti FM, Lum BL: The biology andtreatment of superficial bladdercancer. J Clin Oncol, 1984; 2 (5):

505-31.

4. Lacombe L, Dalbagni G, Zhang ZF,et al.: Overexpression of p53 proteinin a high-risk population of patientswith superficial bladder cancerbefore and after bacillus Calmette-Guérin therapy: correlation toclinical outcome. J Clin Oncol.1996; 14 (10): 2646-52.

5. Stein JP, Grossfeld GD, GinsbergDA, et al.: Prognostic markers inbladder cancer: a contemporaryreview of the literature. J Urol.1998;160 (3 Pt 1): 645-59.

6. Witjes JA, Caris CT, Mungan NA,et al.: Results of a randomized phaseIII trial of sequential intravesicaltherapy with mitomycin C andbacillus Calmette-Guerin versusmitomycin C alone in patients withsuperficial bladder cancer. J Urol.1998; 160 (5): 1668-71; discussion1671-2.

7. Quek ML, Stein JP, Nichols PW, etal.: Prognostic significance oflymphovascular invasion of bladdercancer treated with radicalcystectomy. J Urol. 2005; 174 (1):103-6.

8. Thrasher JB, Crawford ED: Currentmanagement of invasive andmetastatic transit ional cel lcarcinoma of the bladder. J Urol.1993; 149 (5): 957-72.

9. Esrig D, Elmajian D, Groshen S, etal.: Accumulation of nuclear p53and tumor progression in bladdercancer. N Engl J Med. 1994; 331(19): 1259-64.

10. Lipponen PK: Over-expression ofp53 nuclear oncoprotein intransitional-cell bladder cancer andits prognostic value. Int J Cancer


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1993; 53 (3): 365-70.

11. Consensus conference. Magneticresonance imaging. JAMA 1988; 259(14): 2132-8.

12. Urinary bladder. In: American JointCommittee on Cancer. AJCCCancer Staging Manual. 6th ed. NewYork, NY: Springer, 2002, pp 335-340.

13. Kachnic LA, Kaufman DS, HeneyNM, et al.: Bladder preservation bycombined modality therapy forinvasive bladder cancer. J ClinOncol. 1997; 15 (3): 1022-9.

14. Sauer R, Birkenhake S, Kühn R, etal.: Efficacy of radiochemotherapywith platin derivatives compared toradiotherapy alone in organ-sparingtreatment of bladder cancer. Int JRadiat Oncol Biol Phys. 1998; 40(1): 121-7.

15. Hautmann RE, Miller K, Steiner U,et al.: The ileal neobladder: 6 yearsof experience with more than 200patients. J Urol. 1993; 150 (1): 40-5.

16. Coplen DE, Marcus MD, Myers JA,et al.: Long-term followup of patientstreated with 1 or 2, 6-week coursesof intravesical bacillus Calmette-Guerin: analysis of possiblepredictors of response free of tumor.J Urol. 1990; 144 (3): 652-7.

17. Malmström PU, Wijkström H,Lundholm C, et al.: 5-year followupof a randomized prospective studycomparing mitomycin C andbacillus Calmette-Guerin inpatients with superficial bladdercarcinoma. Swedish-NorwegianBladder Cancer Study Group. JUrol. 1999; 161 (4): 1124-7.

18. Holmäng S, Hedelin H, Anderström

C, et al.: The relationship amongmultiple recurrences, progressionand prognosis of patients with stagesTa and T1 transitional cell cancerof the bladder followed for at least20 years. J Urol. 1995; 153 (6): 1823-6.

19. Amling CL, Thrasher JB, FrazierHA, et al.: Radical cystectomy forstages Ta, Tis and T1 transitionalcell carcinoma of the bladder. JUrol. 1994; 151 (1): 31-5.

20. Witjes JA, Caris CT, Mungan NA,et al.: Results of a randomized phaseIII trial of sequential intravesicaltherapy with mitomycin C andbacillus Calmette-Guerin versusmitomycin C alone in patients withsuperficial bladder cancer. J Urol.1998; 160 (5): 1668-71.

21. Advanced Bladder Cancer Meta-analysis Collaboration.:Neoadjuvant chemotherapy ininvasive bladder cancer: a systematicreview and meta-analysis. Lancet2003;361 (9373): 1927-34.

22. Jahnson S, Pedersen J, Westman G:Bladder carcinoma—a 20-yearreview of radical irradiationtherapy. Radiother Oncol. 1991; 22(2): 111-7.

23. Shipley WU, Winter KA, KaufmanDS, et al.: Phase III trial ofneoadjuvant chemotherapy inpatients with invasive bladdercancer treated with selective bladderpreservation by combined radiationtherapy and chemotherapy: initialresults of Radiation TherapyOncology Group 89-03. J ClinOncol. 1998; 16 (11): 3576-83.

24. Rödel C, Grabenbauer GG, Kühn R,et al.: Combined-modality treatment

and selective organ preservation ininvasive bladder cancer: long-termresults. J Clin Oncol 20 (14): 3061-71, 2002.

25. Bajorin DF: Paclitaxel in thetreatment of advanced urothelialcancer. Oncology (Huntingt)2000;14 (1): 43-52, 57.

26. von der Maase H, Hansen SW,Roberts JT, et al.: Gemcitabine andcisplatin versus methotrexate,vinblastine, doxorubicin, andcisplatin in advanced or metastaticbladder cancer: results of a large,randomized, multinational,multicenter, phase III study. J ClinOncol. 2000; 18 (17): 3068-77.

27. Sternberg CN, Yagoda A, Scher HI,et al.: Methotrexate, vinblastine,doxorubicin, and cisplatin foradvanced transitional cel lcarcinoma of the urothelium.Efficacy and patterns of response andrelapse. Cancer 1989;64 (12): 2448-58.

28. Bajorin DF: Paclitaxel in thetreatment of advanced urothelialcancer. Oncology (Huntingt) 2000;14 (1): 43-52.


11Wound Healing

R.P. GuptaShanti Mukand Hospital, Delhi

Reviewarticle

The term Healing refers to thereplacement of destroyed tissueby living tissue.Healing Process

has two aspects Contraction - Amechanical reduction in the size of thedefect occurring in the first few weeks.Replacement of lost tissue- This isbrought about by-Migration of cells andby division of adjacent cells to provideextra time to fill the gap. This isaccomplished in two ways-Regeneration(Replacement of lost tissue by tissuesimilar in type due to the proliferationof surrounding undamaged specializedcells); Repair (The replacement of losttissue by granulation tissue, whichmatures to form scar tissue. This isinevitable when the surroundingspecialized cells do not posses thecapacity to proliferate eg. Muscles andneurons).

Wound healing is a complicated processinvolving:

• Movement of cells

• Division of cells

• Rearrangement of tissues

• Bio-chemical changes.

In healing the phases are as follows:-

• Lag phase : No marked changesare seen in the wound for few days.

• Rapid change in size due tocontraction : Bio-chemicalchanges are in the early period. OnMicroscopic examination there is anacute inflammatory reaction, ininitial period and rapid cell division

is more conspicuous later.

Basic things that happen inwould healing are

• Wound contraction

• Granulation tissue formation

• Bio-chemical changes

Wound contraction

• Lag phase : Initially for 2-3 daysfollowed by.

• Period of rapid contraction :Which is largely completed by 14th

Day. Wound is reduced byapproximately 80% of its originalsize Contraction of wound results inmuch faster healing as 1/4th to 1/3rd

amount of new tissues have to beformed.

Causes of wound contraction :No definite causes are known. Butaccepted ones are-removal of fluid bydrying; contraction of collagen (It issupposed that the contracting mechanismlies in the edge of the wound, the so called“picture frame area”. Interference withthis area delays contraction).

Factors which inhibit woundcontraction

• X-ray radiation or chemo-therapy.

• Corticosteroids

• Burns.

• Immediate skin grafting of the Rawwound prevents contraction.

Granulation tissue formation

Three phases are observed in this process.

Damaged cells set in motion thephenomenon of Acute Inflammation

• An exudation of f ibrin andpolymorphs develop.

• Hemorrhage also occurs and theblood clot contributes to fibrinformation.

• Ground substance undergoesdepolymerisation.

• Loss of granules happen in mast cells.

Phase of demolition

• Dead tissue cells liberate theirautolytic enzymes.

• Proteolytic enzymes come fromdisintegrating polymorphs.

• There is associated mononuclearinfiltration with large phagocyticmacrophages. These digest or removeparticulate matter.

• Fusion of macrophages leads toformation of foreign body giant cells.

In-growth of granulation tissue

It is formed by the proliferation andmigration of the surrounding connectivetissue elements. It is composed of, in thefirst instance, capillary loops andfibroblasts together with a variablenumber of inflammatory cells. It is thusa highly vascular tissue but with thepassage of time it develops into a vascularscar tissue. There are two stages-Stage ofvascularisation followed by stage ofdevascularisation


50

Stage of vascularisation- There isingrowth of capillary loops andfibroblasts so that the insoluble fibrinclot is converted into living vasculargranulation tissue and is knownorganization.Blood clot andinflammatory exudates is invaded bymacrophages followed by capillary loopsand fibroblasts.Formation of vasculararcades.Newly formed blood vessels leakproteins. Some of the newly formedblood vessels develop smooth muscle coatand form arterioles. Fibroblasts whichaccompany capillary loops are at firstlarge and plump but gradually collagenfibres from around them and the cellsbecame mature, elongated fibrocytes.Fibroblasts are responsiblefor the production of themucopolysachharide ground substance.

The nerve fibres and lymphatics areformed from the existing nerve fibres andlymphatics in the surrounding region.

Stage of devascularisation-Asfibroplasia proceeds, some blood vesselsundergo atrophy while others showendarteritis obliterans. Sometimes thisphase is followed by cicatrization andleads to contraction.

Factors affecting granulationtissue formation

Scurvy - Maturation of collagen doesnot occur in absence of vitamin C.

Cortisone administration-Decreases granulation tissue formation asseen in animals but in human beings thedose in which cortisone is given, does notinfluence wound healing.

Protein starvation - Lack of adequateproteins decrease wound healing

Bio-chemical considerations -

a. Early productive phase- In thisphase protein containing methionine

is accumulated. During this proteinand hexosamine content is increased.This indicates that good groundsubstance is being formed.

b. Collagen phase- Cystinecontaining proteins also accumulateat this time and hexosamine level ofwound gradually diminishes. Asfibroplasias proceeds.Hydroxyproline content of woundincreases.

Tensile strength- This is estimatedby the force necessary to disrupt thewound. This is related to granulationtissue and collagen formation. It isaffected by:-

Direction of the wound- Skinwounds made in the direction parallel tothe lines of LANGER heal faster thanthose made perpendicular to them. Thelines of LANGER are due to theorientation of collagen bundles indermis.Skin incision made across thelines of LANGER tend to gape andtheir healing is delayed.

Abdominal support - Abdominalbinders reduce the rate of gain of tensilestrength.

Effect of previous wounding -Resutrued wounds heal faster than thosesutured primarily because the reparativeprocess has already commenced.

Severe trauma -Delays woundhealing due to the adrenal corticalresponse to stress.

Complications of wound healing

• Infection

• Implantation of epidermoid cyst.

• Neoplasia (squamouns cellcarcinoma).

• Keloid formation.

• Pigmentary changes.

• Painful scar

• Weak scar

• Cicatrization

Factors influencing woundhealing

Local factors

• Poor blood supply – Delays woundhealing

• Exposure to ionising radiations eg.X-ray – delay wound healing.

• Adhesions to bony surfaces – delayswound healing

• Infection

• Movement delays wound healing

• Neoplasia

• Trauma

• Ultra-violet rays helps in woundhealing.

General factors

• Age – healing is faster in youngindividuals.

• Nutrition – In protein deficiencythere is delay in wound healing.

• Scurvy – In Deficiency of VitaminC there is presence of excessiveamount of poorly sulphated groundsubstance and lack of maturation ofcollagen fibres.

• Hormones

• Corticosteroids delay wound healingin animals. In human being chroniclong term use delays wound healing.

• Desoxy corticosterone acetate andanabolic steroids help in woundhealing.

• Temperature : Wounds healslowly in cold weather. Optimumtemp in 30oC.

}


• Oxygen - Collagen synthesis isincreased by raising theconcentration of inspired oxygen.

• Zinc – it helps in bio-synthesis ofcollagen.

• Metabolic disease – l ikediabetes, jaundice and uremia delaywound healing.

Wound healing - Wound healing isthe summation of number of processeswhich follow injury, including

• Coagulation

• Inflammation

• Matrix sunthesis and deposition

• Angiogenesis

• Fibroplasia

• Epithelisation Contraction

• Remodeling

• Scar maturation

Wound dehiscence

Suture failure plays an important role:

There is poor connective tissueformation in the scar. Causes are:-

• Local sepsis and intra abdominalcollection of pus or fluid.

• Mass of implanted dead tissue.

For repair – Use non absorbablemonofilament sutures. Wounddehiscence reflects an error of judgmenton the part of the Surgeon i.e. failure toassess the risk of break – down and adoptthe appropriate wound closure techniqueto prevent it.

• Avoid tying the sutures too tight; thiscompromises the perfusion of thewound.

• Interrupted sutures are more securethan continuous suture.

Intra abdominal infection - is thewell known risk factor for wound

dehiscence.

• Overall 44% of the patients withabdominal wound dehiscence hadintra abdominal infection and inthese patients mortality rate wasdouble.

• Surgical technique of closure isimportant.

• Type of closure, type of suture andsuture bites being taken 1 cm apartand 1 cm deep in facia are important.

• It is well established that age, obesity,infection and technique of closureinfluence the incidence of midlinewound complications.

Israelsson suggests that suture length towound length ratio i.e. SL : WL is alsoimportant. If SL : WL ratio is less than 4,the likelihood of abdominal walldehiscence increases.

Newer concepts in woundhealing

Hyperabaric Oxygen - Use of hyper-baric oxygen in wound healing ofischemic limbs.

Diabetes and wound healing –Recent studies have demonstrated theimportance of blood glucose control inthe wound healing process and the roleof insulin like growth factor in properwound repair, due the deficientproduction of growth factors locally.

Nitric oxide - is an automatic regulatorof wound fibroblast synthetic factor.Severe malnutrition and steroid use maydiminish nitric oxide production by localinflammatory cells and decrease woundhealing.

Vacuum assisted closure - Vacuumassisted closure or VAC techniqueproduces good results in patients withchronic or otherwise difficult wounds.The application of sub-atmospheric

pressure eliminates chronic oedema, thusincreasing localized blood flow. Theforce applied to the wound leads toenhanced formation of granulationtissue.The technique should be used toprepare the wound bed so that a lessersurgical procedure can be performed witha greater chance for successful woundclosure, minimizing the time to completewound closure and thus minimizing thecost, hospitalization and rehabilitation.

Electrical stimulation of woundedges- Stimulation with low dosecurrent with implanted electrodes orsurfaces electrodes has been shown toenhance wound healing in experimentalcases.

Trauma

Platelet Aggregation PDGF(Platlet Derived GrowthFactor Alpha)

TGFA(Transformign GrowthFactors)

Neutrophils TGFB(Transforming GrowthFactor Alpha + Beta)Interleukins

Macrophages TGFA/B(Transforming GrowthFactor A+B)

PDFG(Platlet Derived GrowthFactor Alpha)

FGF(Fibroblast Growth Factor)Interleukins

Fibroblasts Endothelia IGF(Interleukin Growth Factor)FGF(Fibroblast Growth Factor)Endothe Line

Collagen Deposition Wound Closure


52

12Surgical Management of Skeletal Tumours

G.D.Sundararaj, Vinoo Mathew CherianDepartment of Orthopaedics & Spinal Disorders Services,Christian Medical College, VelloreReview

article

The management strategies formusculoskeletal tumourscontinue to evolve. Disease-free

survival and functional outcome haveimproved with advances in diagnosticimaging, bioengineering, chemotherapyregimens, radiotherapeutic techniques,and surgical techniques including limb-sparing procedures1.

History & clinical examination-A detailed history followed bysystematic clinical examination isessential to reach a clinical diagnosis andto plan the investigations andmanagement.

Investigations- The following bloodinvestigations and imaging studies helpto reach a diagnosis, to consider thedifferential diagnoses and in themanagement of the tumour: CompleteBlood Count, Prothrombin Time,Activated Partial ThromboplastinTime,Blood sugar, Serum Creatinine,Electrolytes, Uric acid, Liver FunctionTests, Serum Calcium, Phosphorus andParathormone, Good qualityRadiographs of the involved part, ChestX-ray, Ultrasonogram of Abdomen, BoneScintigraphy, CT scans withreconstruction images, CT scan of Chest,Magnetic Resonance Imaging,Angiogram,Positron EmissionTomography.2

Biopsy-Biopsy is the final step in thediagnostic pathway. The biopsy shouldprovide sufficient tissue for grosspathological evaluation, histologicanalysis, immunohistochemistry, and, ifneeded, electron microscopy and

cytogenetic testing. Biopsy incisionsshould be placed such that it will notcompromise the definitive procedure.This is done by ensuring that the entireskin incision and biopsy track can beincorporated into the definitive surgicalfield and removed with the tumour, alongwith a cuff of normal tissue. Extremityincisions should be longitudinal to allowtheir incorporation at the time ofdefinitive local surgery. The biopsyshould avoid exposure andcontamination of essential neurovascularstructures and joints. Small, adequateincisions, meticulous haemostasis, andavoidance of creating skin or fascial flapscan help prevent local spread andcontamination. If infection is considered,lesions should be cultured prior to givingprophylactic antibiotics. For mostsurgeons a well planned and executedopen biopsy remains the gold standard,especially if there is no soft tissuecomponent to the tumour, because itprovides the best chance of obtainingrepresentative tissue. Fine needleaspiration and core biopsy can beperformed on most skeletal lesions. Imageguidance like computerised tomography,ultrasound and fluoroscopy andspecialised biopsy tools have led to anaccuracy rate of 85% to 90%.3 In futuremagnetic resonance imaging guidedbiopsies will enhance the accuracy of theprocedure by focusing on the most viablesection of the tumour. Biopsies donewithout proper planning, poorly placedincisions and complications of biopsylike non healing ulcers, sinus formationand tumour fungation can compromise

subsequent management of the tumourand lead to adverse prognosis.

Staging of tumours- Staging systemsattempt to predict the prognosis and toevaluate the effect of therapeuticintervention by stratifying similartumours according to various prognosticfactors like the surgical grade, size, andcompartmentalization of the tumour andthe presence or absence of metastases2.Musculoskeletal neoplasms may beintracompartmental or extracompart-mental. A compartment is defined as ananatomical space bounded by naturalbarriers namely bone, fascia, joint andmuscle. Intracompartmental tumours arebounded in all dimensions by thesenatural barriers to extension of thetumour. Extracompartmental tumoursare found in an extracompartmentallocation (eg: the popliteal space) or haveextended beyond the natural barrierseither by growth or by contaminationfrom fracture, haemorrhage, or anoperative procedure. Extracompart-mental extension may be an indicationof invasiveness2.

Staging of benign tumours ofbone Enneking was the first to describea system for the staging of benignmusculoskeletal tumours, and this systemis the one most commonly used (Table1). The system is based on the biologicalbehaviour of these tumours as suggestedby radiographic findings. Benign tumoursgrow in a centrifugal fashion and areactive capsule (in this case, bone) isformed as the response of the host to thetumour. The extent of the reactive


capsule reflects the rate at which thetumour is growing. Slowly growingtumours usually have a thick, welldefined zone of transition, whereas thosethat are growing rapidly have a poorlydefined or barely detectable zone.Because they lack histologicaluniformity, benign tumours of bone aregraded on the basis of radiographiccriteria. To distinguish them from thestages of malignant tumours, the stages ofbenign tumours are designated by Arabicnumerals.

Stage- 1 tumours are classified as latentbenign. Such tumours are usuallyasymptomatic and are commonlydiscovered as an incidental radiographicfinding. Thick, dense reactive bone ispresent on both plain radiographs and CTscans. These lesions remain dormant andheal spontaneously in many instances.Examples include fibrous corticaldefects, non-ossifying fibromas, andosteoid osteomas. Operative treatmentusually is not necessary.

Stage- 2 indicates an active benign bonetumour. These tumours are activelygrowing and enlarging and therefore maybe associated with physical signs andsymptoms. In some instances, destructionof the cortex leads to a pathologicalfracture. A stage-2 tumour has a thin rimof reactive bone but remainsintracompartmental. Examples includeslowly expanding aneurysmal bone cystsand chondroblastomas. Operativecurettage and bonegrafting arecommonly used procedures for suchtumours.

Stage- 3 benign bone tumour has littleassociated reactive bone and often breaksthrough the bone cortex. These lesionsare likely to be growing faster than areStage-1 or 2 lesions, and they are foundboth clinically and radiographically tobe more locally invasive.

Table- 1, Enneking Staging System for PrimaryBenign Tumours of Bone 2

Stage Definition Behaviour

1 Latent Remains static or heals spontaneously

2 Active Progressive growth but limited by natural barriers

3 Locally invasive Progressive growth, not limited by natural barrierCampanacci et al.4 described a gradingsystem for giant-cell tumours of bone thatis based solely on radiographicappearance. A Grade-I tumour is welldemarcated by a thin rim of reactivebone, with an intact or slightly thickenedcortex without deformation.

Grade-II giant-cell tumours haverelatively well defined margins but noradiopaque rim. The cortex is thin andexpanded but intact.

Grade-II lesions associated with afracture are considered separately.

Grade-III lesions demonstratepermeative growth in bone, withdestruction of bone cortex and anassociated soft-tissue mass.

Staging of malignant tumours ofbone

The initial staging system for bonesarcomas was described by Enneking etal and adopted by the MusculoskeletalTumour Society2,5,6. A surgical stagingsystem for musculoskeletal sarcomas isaccomplished by assessment of thesurgical grade (G), the local extent (T),and the presence or absence of regionalor distant metastases (M). The sarcomasfor which this system was designed arethose arising from the mesenchymalconnective tissue of the musculoskeletalsystem. Lesions derived from themarrow, reticuloendothelial tissuehoused within bone and mesenchymalsoft tissue, and the skull are not includedin this system because their natural

history, surgical management, andresponse to treatment are quite different.Thus leukemias, plasmacytomas,lymphomas, Ewing’s sarcoma,undifferentiated round-cell lesions, andmetastatic carcinomas are excluded

Table -2, Enneking StagingSystem for Primary Malignant

Tumours of Bone 5, 6

Stage Tumour Metastases Grade

IA T1 M0 G1

IB T2 M0 G1

IIA T1 M0 G2

IIB T2 M0 G2

III T1 or T2 M1 G1 or G2

Note—T1 = tumour is intracom-partmental, T2 = tumour is extracom-partmental, M0 = no regional or distantmetastasis, M1 = regional or distantmetastasis, G1= low grade, G2 = highgrade.

The American Joint Committee onCancer devised a staging system whichwas recently revised7, and for casesdiagnosed beginning January1, 2003, theextent (T) of the tumour now reflects thesize of the tumour rather than itstranscortical extension. Tumours 8 cmor less in the greatest dimension aredesignated T1, whereas those greater than8 cm are designated T2. Patients withsmall tumours generally have a betterprognosis than those with large tumours.


54

A new designation, T3, has been added toindicate skip metastases—that appear toconvey a better prognosis than osseous orhepatic metastases. This new AJCCstaging system is summarized in Table 3.Note that there is now a defined stage III,representing a tumour without regionalnodal (N0) or distant (M0) metastases, butwith a skip metastasis (T3) in the affectedbone. For high-grade tumours such asosteosarcoma, a skip lesion suggests a poorprognosis. This AJCC staging system doesnot apply to primary malignantlymphoma of bone or multiple myeloma,but is used for all other primarymalignant tumours of bone (e.g.,osteosarcoma, Ewing’s sarcoma).

Table-3, American JointCommittee on Cancer StagingSystem for Primary Malignant

Tumours of Bone for thoseTumours Diagnosed on orAafter January 1, 2003 5, 7

Stage Tumour Lymph Metas- GradeNode tases

IA T1 N0 M0 G1 or G2

IB T2 N0 M0 G1 or G2

IIA T1 N0 M0 G3 or G4

IIB T2 N0 M0 G3 or G4

III T3 N0 M0 Any G

IVA Any T N0 M1a Any G

IVB Any T N1 Any M Any G

IVB Any T Any N M1b Any G

Note—Tx = primary tumour cannot beassessed, T0 = no evidence of primarytumour, T1 = tumour 8 cm or less ingreatest dimension; T2 = tumour morethan 8 cm in greatest dimension, T3 =discontinuous tumours in the primarybone; Nx = regional lymph nodes notassessed, N0 = no regional lymph nodemetastases, N1 = regional lymph node

metastasis; Mx = distant metastasiscannot be assessed, M0 = no distantmetastasis, M1 = distant metastasis, M1a= lung, M1b = other distant sites; andGx = grade cannot be assessed, G1 = welldifferentiated (low grade), G2 =moderately differentiated (low grade),G3 = poorly differentiated (high grade),G4 = undifferentiated (high grade).

Operative margins according toEnneking 2, 6

Four types of margins based on therelationship of the surgical margin to theneoplasm and its pseudocapsular-reactivezone are recognised.

Table- 4, Surgical Margins

Type Plane of dissection Result

Intralesional Piecemeal debulkingmacroscopic or curettage Leavesdisease

Marginal Shell out en bloc through Mayeither pseudocapsule or reactive leave/“satellite” zone “skip”

lesions

Wide Intracompartmental en bloc Maylesions with cuff of normal tissue leave

Radical Extracompartmental en Nobloc entire compartmentresidual

lesion

Operative procedures- generalrecommendations

An intralesional procedure (curettage) isperformed for benign bone tumours ofall stages. However, for many stage-2 andall stage-3 benign bone tumours, themargins of excision within the lesion areextended by power curettage andadjuvants such as phenol,methylmethacrylate, or liquid nitrogen.Still, it must be assumed that microscopicdisease is left behind 2.

Table- 5, Operative proceduresaccording to the system of Enneking

et al6

Margin Local AmputationIntralesional Incisional biopsy Debulkingamputation

Curettage orDebulking excision

Marginal Marginal excision Marginalamputation

Excisional biopsy

Wide Wide excision Wideamputation

(intracompartmental) (throughbone)

Radical Radical resection Radicalamputation

(extracompartmental) (throughjoint)

Excision through the perilesionalreactive zone is indicated for recurrentstage-2 or stage-3 benign bone tumours,and possibly for some primary stage-3tumours. Also, such excisions are usedwith success in patients who have a highor low-grade bone or sarcoma that hasshown histological evidence of extensivenecrosis in response to preoperativechemotherapy and radiation therapy.However, a higher prevalence of localrecurrence can be expected in patientswho have an excision through theperilesional reactive zone when noeffective adjuvant treatment wasadministered.

Wide margins are desirable for a fewrecurrent stage-3 benign bone tumoursand for most bone and soft tissue sarcomaswhen the margins have been adequatelydefined by contemporary stagingtechniques, such as magnetic resonanceimaging or computed tomography.Before the introduction of adequateimaging techniques and adjuvant


treatments, wide margins often wereassociated with a high rate of recurrencebecause of poor preoperative definitionof the location and histological extensionof the tumour. Radical resections,formerly the procedure of choice formost high-grade sarcomas, are nowreserved for recurrent sarcomas after apathological fracture through the bonesarcoma or when the margins cannot bedefined accurately. Radical resectionstherefore are infrequently used formusculoskeletal sarcomas at the presenttime 2, 8

Limb-sparing surgery forpatients with sarcomas

Limb-sparing surgery for patients withprimary malignant sarcomas of theextremities is now well established. MRIand CT now provide accurate tumourdefinition and enhance the possibility ofachieving safe surgical margins. The firstobjective of this type of tumour surgeryis to avoid local recurrence, which almostalways leads to death. The secondobjective is to preserve as much functionas possible. Amputation may be the onlysafe surgical option in some patients withextensive skin or neurovascularinvolvement: a 10% to 15% amputationrate is common. 8 Bony defects created bylimb-sparing procedures may bereconstructed by any of a variety ofmethods. The options for reconstructionof large defects may be classified asbiological, non- biological or combined.Biologic reconstructions using allograftsor vascularised / non-vascularisedautogenous grafts have given good resultsin diaphyseal defects. Osteoarticularreconstruction using allograft has beenless successful. Large osteoarticulardefects can be replaced by custom-madeprostheses with mobile joints. Thecombination of allograft and prosthesis

as a composite is an option and its resultsare similar to that of endoprostheticreplacement. In some situations,arthrodesis using large spanning bonegrafts may be appropriate. Intercalarysegments of long bones may be filled withautograft (vascularised or non-vascularised), allograft or with custom-made implants. Distractionosteosynthesis may be considered whenpossible. Said and El-Sherif from Egyptreported a method of shortening anddistraction for bridging bony defectscreated by en-bloc resection for twopatients with tumours of the distal femur[8-10].

In growing children, limb-sparingsurgery needs special consideration toavoid later limb-length discrepancy, andexpandable prostheses have beendeveloped to anticipate this problem. Itis often necessary to sacrifice a majorphysis when the tumour is excised and theseverity of limb-length discrepancy afterexcision of a major growth plate dependson the patient’s bone age. Extendableprostheses are required when theestimated leg-length discrepancy atskeletal maturity is more than 3 cm orwhen the arm-length discrepancy is morethan 5 cm. When the estimateddiscrepancy is less these patients can betreated with conventional “adult-type”prostheses made longer by up to 1.5 cmin the lower limb and 2 to 3 cm in thehumerus. Complications includeinfection, local recurrence, asepticloosening, joint stiffness, subluxation,periprosthetic fracture, and outgrowingthe prosthesis. The introduction of non-invasive extendable prostheses isexpected to significantly reduce theproblems associated with multipleoperations and infection11

A realistic estimate of the expected

function after a proposed limb-sparingprocedure must be given preoperativelyto patients and their relatives. All currentmethods have advantages anddisadvantages. Allografts may beprogressively incorporated by the host.Disadvantages include bone graftfractures and resorption, cartilagedegeneration, joint instability, delayedunion or non-union and the incidences aredirectly related to the size of the graft andthe use of chemotherapy. Another majorconcern is the possibility of diseasetransmission. Prosthetic replacement hasthe advantages of allowing early weightbearing, having predictable function,having low risks of early complicationsand being readily available. Theprostheses are expensive andcomplications are expected to increasewith time. An arthrodesis is lessattractive initially, but once it is achievedit provides a stable limb and avoids thecomplications associated with prostheticreplacement such as fracture, looseningand infection. The choice ofreconstruction after distal femoralresection depends on the surgeon’spersonal experience and the availabilityof various techniques. 8-10 The evaluationand cornparison of the various types oflimb-sparing procedures are difficult, butEnneking’s surgical staging system allowsstandardised preoperative evaluation,analysis and end-result reporting. Thekey to appropriate management ofskeletal tumours lies in early detection,diagnosis, accurate staging and amultidisciplinary approach with surgicalexcision, (providing adequate tumourfree margins) being the cornerstone.

References1. Weber KL. What’s New in

Musculoskeletal Oncology. J BoneJoint


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2. Surg Am. 2004; 86-A (5): 1104-9.3. Peabody TD, Gibbs CP Jr, Simon

MA. Evaluation and Staging ofMusculoskeletal Neoplasms. J BoneJoint Surg Am. 1998; 80-A: 1204–12189.

4. Sabharwal T, Salter R, Adam A,Gangi A. Image-Guided Therapies inOrthopaedic Oncology. OrthopClin N Am 2006; 37:105-112.

5. Campanacci, M., Baldini, N,Boriani, S, and Sudanese, A. Giant-cell Tumour of bone. J. Bone andJoint Surg Am. 1987; 69-A: 106-114.

6. Stacy GS, Mahal RS, Peabody TD.Staging of Bone Tumours: A Reviewwith Illustrative Examples. AJR2006; 186:967-76

7. Enneking WF, Spanier SS,Goodman MA. A System for theSurgical Staging of MusculoskeletalSarcoma. Clin Orthop 1980;153:106–120

8. American Joint Committee onCancer. Bone. In: Greene FL, PageDL, Fleming ID, et al., eds. AJCCCancer Staging Manual. New York,NY: Springer-Verlag, 2002:213–21914.

9. Hurson.B.J. Limb- sparing surgeryfor Patients with Sarcomas. J BoneJoint Surg Br. 1995; 77- B: 173-4.

10. Hornicek FJ, Gebhardt MC, SorgerJI, Mankin HJ. TumourReconstruction. Orthop Clin N Am1999; 30:673-84.

11. D.Luis Muscolo, Miguel A. Ayerza,Luis A. Aponte-Tinao. MassiveAllograft Use in OrthopaedicOncology. Orthop Clin N Am 2006;37:65-74.

12. Abudu A, Grimer R, Tillman R,Carter S. The Use of Prosthesis inSkeletally Immature Patients.Orthop Clin N Am 2006; 37:75-84.

Brain surgery

Brain surgery is perhaps theoldest of the practiced medicalarts. No hard evidence exists

suggesting a beginning to the practiceof other facets of medicine such aspharmacology- using drugs, chemicaland natural ingredients to help afellow human being. There is ampleevidence, however, of brain surgery,dating back to the Neolithic (lateStone Age) period. Unearthedremains of successful brainoperations, as well as surgicalimplements, were found in France—at one of Europe’s notedarcheological digs. And, the successrate was remarkable, even circa 7,000B.C. But, pre-historic evidence ofbrain surgery was not limited toEurope. Pre-Incan civilization usedbrain surgery as an extensive practiceas early as 2,000 B.C. In Paracas, Peru,a desert s tr ip south of Lima,archeologic evidence indicates thatbrain surgery was used extensively.Here, too, an inordinate success ratewas noted as patients were restoredto health. The treatment was used formental illnesses, epilepsy, headaches,organic diseases, osteomylitis, as wellas head injuries. Brain surgery wasalso used for both spiritual andmagical reasons; often, the practicewas limited to kings, priests and thenobility. Surgical tools in SouthAmerica were made of both bronzeand man-shaped obsidian (a hard,sharp-edged volcanic rock).

Africa showed evidence of brainsurgery as early as 3,000 B.C. inpapyrus writings found in Egypt.“Brain,” the actual word itself, is usedhere for the first time in any language.Egyptian knowledge of anatomy mayhave been rudimentary, but theancient civilization did contributeimportant notations on the nervoussystem. Hippocrates, the father of

modern medical ethics, left manytexts on brain surgery. Born on theAegean Island of Cos in 470 B.C.,Hippocrates was quite familiar withthe clinical signs of head injuries. Healso described seizures accurately, aswell as spasms and classified headcontusions, fractures and depressions.Many concepts found in his textswere still in good stead two thousandyears after his death in 360 B.C.

Ancient Rome in the first centuryA.D. had its brain surgeon star, AulusCornelius Celsus. Hippocrates didnot operate on depressed skullfractures; Celsus often did. Celsus alsodescribed the symptoms of braininjury in great detail. Asia was hometo many talented brain surgeons:Galenus of Pergamon, born inTurkey, and the physicians ofByzance such as Oribasius (4thcentury) and Paul of Aegina. AnIslamic school of brain surgery alsoflourished from 800 to 1200 A.D., theheight of Islamic influence in theworld. Abu Bekr Muhammed el Razi,who lived from 852 to 932 in theCommon Era, was perhaps thegreatest of Islamic brain srugeons. Asecond Islamic brain surgeon, Abul’Qluasim Khalaf , l ived andpracticed in Cordoba, Spain, and wasone of the great influences on westernbrain surgery.

The Christian surgeons of the MiddleAges were clerics, well educated,knowledgeable in Latin, and familiarwith the realm of medical literature.Despite the church’s ban on study ofanatomy, many churchmen of greatrenown (advisors and confessors to asuccession of Popes) were outstandingphysicians and surgeons. LeonardoDavinci’s portfolio containinghundreds of accurate anatomicalsketches indicates the intenseintellectual interest in the workingsof the human body despite theChurch’s ban.


13Gastric Cancer

M.L. DathanDepartment of Surgery, Jubilee Mission Medical College & Research Institute, Thrissur, Kerala

Reviewarticle

The gloomy view mentioned in= the title of this article still

prevails in most parts of theworld. However in the past few decades,a lot of changes in our understanding ofthis cancer have taken place. These

changes include the epidemiologicalaspects, the role of Helicobacter pylorias a carcinogen, the developments ofmolecular biology of the cancer, thevalue of early detection and realisationof the importance of staging andaggressive surgical management. All theseaspects are highlighted in this article.

Epidemiology

Gastric cancer is the second commonestcause of cancer mortality in the male

throughout the world. There are largedifferences in the incidence of this cancerin different parts of the world (fig. 1).Japan, chile, Costa Rica, Ireland and eastEuropean countries record a highincidence rate whereas North America,

Western Europe andAustralia are region oflow incidence. Indiancities like Chennai andBangalore record a highincidence (20-30/100,000 males) whereasin other cit ies l ikeMumbai, Delhi andBhopal, the incidence ismuch lower (fig. 2). FromThrissur and northernparts of Kerala, highernumber of cases isreported annually in thehospital statistics.

Age and sex

Maximum incidence is inthe f i fth and sixthdecades. Male to femalesex ratio is 2:1 throughout

the world. In younger age the ratioapproaches unity. Of the histologicaltypes, the diffuse type is more commonin younger age group.

Trends

Throughout the world during the secondhalf of last century, there was a decliningtendency of gastric cancer mortality, themaximum being noticed at NorthAmerica, where there is a reduction of40 – 50 %. In Japan, there was a decline of

only 8-12%, that too due to the earlydetection and treatment of gastriccarcinoma (fig.3). The decliningtendency throughout the world is for the

distal gastric cancer, but the proximalgastric cancer seems to be increasingespecially in the west.

Migrant studies

Studies of Japanese migrants to USAshowed a relatively slow fall in mortalityfrom gastric cancer in the firstgeneration, but the rate drops sharply inthe Japanese offspring’s born in USA.

( F i g .1 )

( F i g .2 )

( F i g .

( F i g .


58

This data support two conclusions.Firstly, the influence of environmentmust be significant in the reduction ofincidence in the second generation.Secondly, the risk is determined bypatterns of exposure of environmentalfactors occurring early in life, asevidenced by stability of rates occurringamong the first generation of Japanesemigrants to USA.

Dietary factors

Stomach being the organ of constantcontact with contents of the diet, allepidemiological studies has been directedto find out the association of various foodcontents and risk of gastric carcinoma.The diet contents might act as a directcarcinogen, a promoter and even as aninhibitor. The association of nitrates andnitrites in the diet and water has beenextensively investigated and found to bea significant risk factor. Nitrosamine isformed inside the stomach from nitritesand nitrates by bacteria. Nitrosamines arepotent carcinogenic agents. Formation ofnitrosamine in the stomach is inhibitedby ascorbic acid and perhaps by otherantioxidants. Other dietary factors likehigh salt intake, Smoked food, lowprotein intake and low consumption offruits and vegetables, consumption oflarge quantity of spices are incriminatedas etiological factors. The high riskfactors observed from our own dietarysurvey include high consumption of drysalted fish, low intake of leafy vegetablesand fruits and high intake of chilly.Strangely enough pan-chewing has beennoticed as a high risk factor in our study1

Helicobacter pylori (H.Pylori)

During the last two decades it has beenestablished that H.pylori has a definiterole in the pathogenesis of gastricadenocarcinoma and lymphoma.

Eurogast study group examined therelationship between the organism andgastric cancer in 17 populations from 13countries. This showed a statisticallysignificant relationship betweenseropositivity for H. pylori andcumulative incidence of gastric cancer inthese populations. There wasapproximately six fold increase of gastriccarcinoma in this population withH.pylori infections2. Forman et al haveshown significant correlation betweenH.pylori infection and gastric cancermortality in china3. Naomi Uemura et alin their recent prospective study of 1526Japanese patients showed that gastriccancers developed in 36 (2.9%) of the H.Pylori infected and none of theuninfected patients4. Those withhistological findings of severe gastricatrophy, corpus predominant gastritis orintestinal metaplasia are at increased risk.In 1994 the World Health Organizationand International Agency for cancerconsensus groups have accepted that therewas sufficient epidemiological andhistological evidence to classify H.pylorias a definite carcinogen5.

H.Pylori is a gram negative spiral shaped,microaerophilic, urease positive bacillussurviving in one of harshestenvironments of the human body, vizgastric acidity. It chronically infects thestomach over half of world’s population.The infection is acquired duringchildhood via oral or faecal route and ifnot treated with antibiotics, it will persistthroughout life.

H.Pylori infection results in threephenotypes of gastritis

• Mild pan gastritis- commonest andnot associated with human disease.

• Corpus predominant gastritis whichlead on to gastric atrophy and

intestinal metaplasia and gastriccancer.

• Antral predominant gastritisassociated with increased gastric acidand duodenal ulcer. These patientswill have an increased parietal cellmass. Probably the genotype ofH.pylori which produces this typeof gastritis is different from thatproducing gastric cancer.

Recently it has been demonstrated thatthe genotypes, H.Pylori Cag A +, Vac Aare associated with gastric atrophy andintestinal metaplasia 6, 7.

Intestinal metaplasia (IM)

There are three subdivisions of intestinalmetaplasia. Type I or complete IM ischaracterized by the presence ofabsorptive cells, paneth cells and gobletcells secreting sialomucins (smallintestinal type). Type II and type III arecharacterized by the presence of varyingamount of columnar and goblet cellssecreting sialomucin and/ orsulphomucins.

Type II secretes neutral and acidsialomucin

Type III secretes sulphomucins (ColonicIM)

Type III IM is associated with a four foldincreased risk of gastric cancer. It isdifficult to differentiate between thesetypes of IM from endoscopic biopsies.Overall risk of gastric cancer in peoplewith all types of IM is 10 fold. IM of thelesser curvature extending from thecardia to the pylorus or entire stomach isassociated with a higher risk of gastriccancer.

Other precursor conditions ofgastric carcinogens

Prior gastric surgery- Balfour first


reported a correlation between priorgastric surgery for benign disease andsubsequent development of gastric cancerin 1922. However the risk is observedonly after a latency of 15 years and thattoo following partial gastrectomy forbenign conditions

Pernicious anaemia- Patients withpernicious Anaemia are also at increasedrisk for developing gastric cancer. It is anauto immune disease associated withatrophic gastritis and subsequent IM. Therelative risk for a patient with perniciousAnaemia developinggastric cancer isapproximately 2.1 to 5.6

Gastric polyps- Thepresences of gastricpolyps can increase apatient’s risk of gastriccancer. Adenomatouspolyps carry a definiterisk for development ofmalignancy as in the caseof colonic adenomatouspolyps. The risk isapproximately 10 to 20% and increases withincreasing size of thepolyp. Endoscopicremoval is indicated forpedunculated lesion andis sufficient if polyp iscompletely removed andif there are no foci ofinvasive cancer onhistologic examination.If the polyp is larger than2 cm or sessile or has aproven focus of invasivecarcinoma, thenoperative excision iswarranted.

Hyperplastic polyps arevery common and are

considered as benign. However, theirpresence is associated with an increasedrisk of gastric cancer, because they formin stomachs with established gastritis, aknown risk factor for carcinoma.

Familial factors

There is a two to four fold increase ofgastric cancer among the first degreerelatives of the affected. Persons withblood group A have an approximate 20%relative risk of developing gastric cancer.Hanzel et al observed that this increasedrisk with blood group A is seen in diffuse

histology type 8.

The Molecular biology of gastriccancer

In contrast to colorectal cancer, themolecular biology of gastric cancer is lesswell worked out. The genetic alterationassociated with gastric carcinoma can beclassif ied as over expression /amplification of oncogenes and growthfactor, inactivation of the Tumoursuppressor genes, the reduction ofcellular adhesion, and the reactivation ofthe telomerase and the presence of

m i c r o s a t e l l i t einstability.

The over expressed/amplified oncogenesinclude c-Met, k-sam andc-erbB2. Similarlyseveral growth factorsl ike transforminggrowth factor alpha(TGF - á), the epidermalgrowth factor (EGF) andvascular endothelialgrowth factor (VGEF)are over expressed.

The inactivation of theTumour suppressorgenes P53 and P16 havebeen reported in bothdiffuse and intestinaltype cancers, whereasadenomatous polyposiscoli (APC) gene and beta-catenin gene mutationsare frequent in intestinaltype cancers.

Reduced celladhesiveness isconsidered indispensablefor both early and latecarcinogenic steps. E –Cadherin (120kDa,The multistep gastric carcinogenesis pathway


60

chromosome 16q) is a key functionalcomponent of adherence junctionbetween epithelial cells. E- cadherin isbound via series of undercoat proteins,the catenins to the cytoskeleton. An intactE- cadherin – catenin complex is requiredfor normal intercellular adhesion. Thereduction of E- cadherin expression isfound in approximately 50% of diffusegastric cancers. The E–cadherin gene(CDHI) has been categorized as a tumorsuppressor gene. Mutation of this gene hasbeen implicated in diffuse gastric cancer.

Microsatellite instability- The humangenome is punctuated with repetitive di,tri or tetranucleotide sequences termedmicrosatellites. Slippage during DNAreplication is normally corrected bymismatch repair system. Deficiencies inthis mismatch repair system results inmicrosatellite instability which is seen inapproximately, 20 – 30 % of intestinaltype of sporadic gastric cancer. Thismicrosatellite instability is seen invirtually all hereditary non polyposiscolo- rectal cancers

Correa and colleagues proposed a modelfor pathogenesis of intestinal type ofgastric carcinoma as early as 1975 whichis based on progression from gastritis tocarcinoma over the course of severaldecades9. Recent evidences of role ofH.pylori and advances in molecularbiology highlights the role of thesefactors in the multistep wise progressionof carcinogenesis apart from role ofenvironmental factors like diet10.

The multistep gastric carcinogenesispathway

Pathology

Ninety five percent of gastric neoplasmsare adenocarcinomas.

Macroscopic Appearance of advancedCarcinoma

The Borrman’s classification system (fig-4)

Type I Polypoid or fungating lesions

Type II Ulcerating lesions surroundedby elevated borders

Type III Ulcerating lesion infiltratinginto the gastric wall

Type IV Diffusely infiltrating lesions

Type V Unclassified

Histology

Many histological classifications ofgastric adenocarcinomas have beenproposed. The most popular and usefulsystem is proposed by Lauren10 in 1965.This classification separates gastriccancer into intestinal and diffuse typeswith different pathology, epidemiology,pathogenesis and prognosis. The Correahypothesis of gastric carcinogenesis isproposed for the intestinal type whicharises from the precancerous condition

gastric atrophy and intestinal metaplasia.

Distinctive features of the twohistological types of Lauren’sclassification are as follows:

Intestinal Diffuse

Environmental Familial Blood group AGastric atrophyIntestinal metaplasiaMen>Women Women>Menolder age group younger age groupGland formation Poorly differentiated,(well differentiated) signet ring cellsHaematogenous Transmural/Lymphatic

spread spreadMicro satellite Reduction of E.cadherininstability expressionAPC gene mutationP53, P16 P53, P16 inactivationinactivation


WHO classification

In 1990 the world Health Organizationrecommended another classificationsystem for gastric cancers. According tothis system, carcinoma of the stomach isdivided into adenocarcinoma,adenosquamous carcinoma, squamouscelled carcinoma, undifferentiatedcarcinoma and unclassified carcinoma,Adenocarcinomas are further dividedinto: papillary, tubular, mucinous andsignet ring. Each type is furthersubdivided by degree of differentiation

Diagnosis and staging of gastriccancer

The early diagnosis of gastric carcinomais difficult in most countries except inJapan where screening investigationsdetect more than 50% of early gastriccancers. Gastric adenocarcinoma lacksspecific symptoms early in the course ofthe disease. Dyspeptic symptoms likevague epigastric discomfort andindigestion are mistaken for gastritis orulcer disease and resort to symptomatictreatment without diagnosticinvestigations for a variable period.Typically the pain is constant, nonradiating and unrelieved by foodingestion. More advanced disease maypresent with weight loss, anorexia, fatigueor vomiting. Proximal tumors oftenpresents with dysphagea, whereas distalantral tumors present with gastric outletobstruction. Diffuse mural involvementby Tumour, as occurs in linitis plastica,leads to decreased distensibility of thestomach and early satiety. 15% maypresent with haematemesis and 40% areanemic at the time of presentation. Verylarge tumors may erode into transversecolon presenting with large bowelobstruction.

Physical signs include palpable epigastric

mass, palpable supraclavicular(Virchow’s) or periumblical (SisterMary Joseph’s) lymph nodes, peritonealmetastasis palpable by rectalexamination (Blumer’s shelf) or palpableovarian mass (Krukenberg’s Tumour). Asthe disease progress, patients maydevelop hepatomegaly secondary tometastasis, jaundice, ascites and cachexia.

Investigation

1. Flexible Upper GI endoscopy &biopsy is preferable to upper GIradiology with double contrast barium.The addition of direct brush cytology tomultiple biopsies increases the diagnosticaccuracy.2. Endoscopic ultra sonography ( EUS)assists in the staging of the disease vizextent of gastric wall invasion as well asnodal station3. Complete Blood count, serumchemistries including liver function tests,coagulation studies, chest X-ray and CTscan of abdomen & pelvis, CT scan ofchest for proximal gastric cancer areneeded for staging and furthermanagement4. Laparoscopy: Laparoscopy can detectmetastatic diseases of smaller size notdetected by CT scan in 23% to 37% ofpatients

Cytological analysis of peritoneal fluidor fluid obtained by peritoneal lavagemay reveal the presence of freeintraperitoneal gastric cancer cells.Patients with positive findings onperitoneal cytology have a poorprognosis, similar to macroscopic stageIV disease.

Staging of gastric carcinoma

Two major staging systems are TNMstaging system & JRSGC staging systemof Japanese Research Society.

TNM Staging (1997)

A major revision occurred in 1997 whennodal status stratification was changed inthe fifth edition of TNM classification.In this staging system, a minimum of 15lymph nodes must be evaluated foraccurate stage

T. Primary tumour

To - No evidence of primary TumourTis – Tumour limited to mucosa, nopenetration of the basement membraneT1a – Limited to mucosa with invasionof lamina propriaT1b – Tumour invades submucosaT2 a –Tumour invades muscularispropriaT2b – Tumour invades subserosaT3 – Penetration of serosa withoutinvasion of adjacent tissuesT4 – Invades adjacent tissues and / organ

N.Category

In 1997 staging, nodal status is based onthe histopathologically involved nodes

P No : No metastatic lymph nodesP N1 : Involvement of 1- 6 metastatic

nodesP N2 : Involvement of 7 – 15 meta-

static nodesP N3 : Involvement of > 15 metastatic

nodes

The definition of “regional nodes”includes perigastric nodes and nodesalong the left gastric, common hepatic,splenic and coeliac arteries andhepatoduodenal l igament (1-12according to JRSGC). The involvementof other nodes such as retro pancreatic,mesenteric and Para aortic nodes (13-16,according to JRGSGC) is classified asdistant metastasis (M1)


62

M - Category

Mo – No metastasis to distant organs

M1 – Distant metastasis present. Alsometastasis to the distant lymph nodes asmentioned above and peritonealmetastasis

Mx – Distant metastasis cannot beassessed

Stage grouping according toTNM staging

Stage : Tis No MoStage Ia : T1No MoStage Ib : T1N1Mo, T2 No MoStage II : T1 N2 Mo, T2 N1 Mo, T3

No MoStage IIIa : T2 N2 Mo, T3 N1 Mo, T4

No MoStage IIIb : T3 N2 Mo, T4 N1 MoStage IV : T4 N2 Mo, Any T, Any N,

M1

Japanese Research Society forGasric Cancer (JRSGC)classif ication system (13th

Edition)11

The principles of JRSGC staging dependon

1. Clinical findings (c)2. Surgical findings (s)3. Pathological findings (p)4. Final findings (f)

Clinical findings- Any findingsduring diagnostic evaluation, includinglaparoscopy, are defined as clinicalfindings. These are recorded as Ct2, cN1,cM0, c stage II

Surgical findings- Any findingsduring surgery including frozen sections,cytology and macroscopic examinationof the resected specimens are defined as

surgical findings Results of therapeuticlaparoscopy are included in surgicalfindings.

Pathological findings- Any findingsbased on microscopic examination ofmaterials obtained by endoscopic,laparoscopic or surgical resection aredefined as pathological findings.

Final findings - Comprehensivefindings based on clinical, surgical andpathological findings are defined as finalfindings. When there is conflict betweensurgical and pathological findings, thepathological findings take precedence.

A. Primary lesions

1. Number and size of lesion – two largestdimensions should be recorded for eachlesion.

2. Tumour locationU- Upper thirdM- Middle third 3 portions of theL – Lower third stomach

E – Esophagus TumourD – Duodenum extension

Four equal parts of the circumference –

Less: - lesser curvature,Gre: - Greater curvatureAnt: - Anterior wallPost: - Posterior wall

3. Macroscopic types

Type 0 - Early gastric cancer (T1 ofTNM)

Sub classified into

Type 0I : Protruded typeType 0II a : Superficial elevated typeType 0IIb : Flat typeType 0IIc : Superficial depressed typeType 0III : Excavated type

Type I- : Polypoids, Sharplydemarcated from the surroundingmucosa, usually attached on a wide base.Type 2 : Ulcerated carcinomas withsharply demarcated and raised marginsType 3 : Ulcerated carcinomaswithout definite limits, infiltrating intothe surrounding wallType 4 : Diffusely infiltratingcarcinoma in which ulceration is usuallynot a marked featuresType 5 : Non- classifiable carcinomathat cannot be classified into any of theabove types.

Type 1 to 5 is similar to Borrman’sclassification

4. Depth of tumor invasion (T)

T1 : Tumor invasion of mucosa and/or muscularis mucosa (M) or submucosa(SM)

T2 : Tumor invasion of muscularispropria (MP) or subserosa (SS)

T3 : Tumor penetration of Serosa(SE)

T4 : Tumor invasion of adjacents t r u c t u r e s ( S I )

Tx : Unknown

B. Metastatic lesions

1. Lymph node Metastasis

Regional lymph nodes are numbered byJRSGC as follows

No.1 Right Paracardial lymph nodes(LN)

No 2 Left Paracardial LN

No 3 LN along the lesser curvature

No 4sa LN along the short gastricvessel

No 4sb LN along the rightgastroepiploic vessels

}}


No 5 Suprapyloric LN

No 6 Infrapyloric LN

No 7 LN along the left gastric artery

No 8a LN along the common hepaticartery (antero superior group)

No 8p LN along the common hepaticartery (posterior group)

No 9 LN around the celiac artery

No 10 LN at the splenic hilum

No 11p LN along the proximal splenicartery

No 11d LN along the distal splenicartery

No 12a LN in the hepatoduodenal liga-ment (along the hepatic artery)

No 12b LN in the hepaoto duodenalligament (along the bile duct)

No 12p LN in the hepatoduodnal liga-ment (behind the portal vein)

No 13 LN on the Posterior surface ofthe pancreatic bed

No 14v LN along the superiormesenteric vein

No 14a– LN along the superiormesenteric artery

No 15 LN along the middle colicvessels

No 16a1 LN around the aortic hiatus

No 16a2 LN around the abdominal aorta(from the upper margin of theceliac trunk to the lower marginof the left renal vein)

No 16 b1 LN around the abdominalaorta (from the lower marginof the left renal vein to theupper margin of the inferiormesenteric artery)

No 16b2LN around the abdominalaorta (from the upper marginof inferior mesenteric artery tothe aortic bifurcation)

No 17 LN on the anterior surface ofthe pancreatic head

No 18 LN on the inferior margin ofthe pancreas

No 19 Infradiaphragmatic lymphnodes

No 20 LN in the esophageal hiatus ofthe diaphragm

No 110 Para esophageal LN in the lowerthorax

No 111 Supradiaphragmatic LN

No 112 Posterior mediastinal LN.

The detailed classification of the lymphnodes depending on the location of theTumour is available JRSGCclassification – 13th edition. N4 group hasbeen classified as metastatic disease in the13th edition

2. Liver metastasis (H)

Ho – No liver metastasisH1 – liver metastasisHx – unknown

3. Peritoneal metastasis (P)

Po, P1, PX

1. Peritoneal cytology ( Cy)

CY0, CYI CYX

2. Other distant metastasis( M)

Mo, MI, Mx

MI should be categorized according to thefollowing notation.

LYM – Lymph nodesPUL – PulmonaryPLE – Pleura

MAR – Bone MarrowOSS – OsseousBRA – BrainMEN – MeningesOTH – Others

C. stage grouping

No N1 N2N3

T1 IA IB II

T2 IB II IIIA

T3 II IIIA IIIBIV

T4 IIIA IIIB IV

H1,P1,Cy1,M1 IV

Surgical treatment

Early gastric carcinoma (EGC)

EGC is a unique form of gastriccarcinoma confined to mucosa andsubmucosa (TNM – T1, JRSGC Type 0)irrespective of the involvement of lymphnodes. It has an excellent prognosis.Aggressive screening practice in Japanresulted in detection of EGC in morethan 50% cases of total number of cases.Node positive patients with EGC have asignificantly poorer survival rate thannode negative patients. The overallincidence of metastasis in lymph nodesin EGC is 5.7% to 13%; for mucosalcarcinomas – 1.2 to 2.6 % and submucosalcarcinomas – 16.5 % to 23.8%. Youngerage group, macroscopic depressed type,large tumor size (> 30mm),undifferentiated histologic type,histologic ulceration of carcinoma andlymphatic vessel invasion have asignificant association with regionallymph node metastasis.

Surgical decision making in EGC(Recommendations of Japanese Gastriccancer Association March 2001)12


64

Mucosal Cancer (M)- No

Differentiated - _ < = 2cmEndoscopic mucosal

Resection (EMR)

Not differentiated – ModifiedGastrectomy A (MGA)

(MGA = 2/3 gastrectomy + D1- N1 nodedissection + No.7 node dissection)

Submucosal (SM)-No

Differentiated < 1.5 cm.- MGA

Not differentiated –MGB (2/3gastrectomy + D1 + No.7, 8a & 9 – nodedissection)

Modified Gastrectomy could be vaguspreserving, pylorus preserving orlaparoscopic

Surgical treatment of more advancedstage of gastric cancer as recommendedby Japanese Gastric Cancer Association– March 2001Stage IB – T1 N1 (EGC), T2 NOT1 (M, SM) < 2 cm N1 – ModifiedGastrectomy B (MGB)T1 (M, SM) > 2 cm N1 – Standard D2T2 (MP, SS) No – Standard D2D2 dissection means dissection of groupN1 & N2 lymph nodes (as Per JRSGC)Stage IIT1 N2, T2 N1, T3 N0 – standard D2Stage III AT2 N2 T3 N1 – Standard D2T4 No – Extended resection includinginvolved adjacent organs + Adjuvant orneoadjuvant chemotherapy, because ofthe chance of R1 surgery (R1 =microscopic Residual tumor present)Stage IIIBT3 N2 – Standard D2 or D3T4 N1 – Extended ResectionAdjuvant chemotherapy, neoadjuvantchemotherapy and adjuvant radiotherapy

should be given in the setting ofrandomized control trial.

Stage IV

Most cases of stage IV cancer cannot becuratively treated with surgery alone. IfN3 is the only determinant factor forstage IV, D3 surgery may have a potentialfor R0 dissection.

D3 dissection means dissection of thegroups N1, N2 and N3 lymph nodes

R0 surgery means no microscopicresidual Tumour after dissection.

In patient with M1 lesion, but with goodperformance status, chemotherapy and /or radiotherapy with palliative resectiongive the best supportive care.

The palliative surgery such as resection,bypass, gastrostomy or jejunostomy maybe indicated in patients with urgentsymptoms like bleeding, stenosis andmalnutrition.

Surgical approachesIntraluminal endoscopy (formucosectomy)Laparoscopy / combined laparoscopyand Intra luminal endoscopyLaparotomyThoraco- laparotomyOperative procedureMucosectomyWedge resectionSegmental resectionProximal gastrectomyPylorus preserving gastrectomyDistal gastrectomyTotal gastrectomyControversy regarding theradical lymphadenectomy

It has always been a question whyJapanese results of surgical treatment ofgastric carcinoma are better. There are

different explanations for this question1) it is due to early pick up of the disease2) Japanese gastric cancer is biologicallydifferent disease 3) In Japan, a higherproportion of patients with goodprognostic features are seen than in thewest .There is no definite evidence tosupport these arguments.

In all stage of gastric carcinoma theJapanese results are much superior to thewestern results .In carcinoma stomachstage II, survival in USA is 29% - 30 %, inGermany 43.7% - 45% while in Japan itis 71.7 % - 75%, for stage IIIA survival is15% in USA, 28.6 – 30% in Germanyand 47.7.- 60% in Japan. A combinationof differences in staging and a higherstandard of surgery in Japan probablyaccounts for the differences. Staging iscrucial when survival figures arecompared. The more thorough thestaging, the higher stage is likely to be,and therefore, stage for stage, theoutcome seems better in patients who areadequately staged pathologically. Thisphenomenon is called ‘stage migration’(Will Roger’s phenomenon). Thepathologist wil l have diff icultyorientating a fixed specimen, henceoptimal approach is for the surgeon todissect the lymph nodes and label beforesending to the pathologists . This practiceis being followed in Japan.

However, the better survival benefits ofD2 dissection for early stage carcinomascould not be reproduced by therandomized control studies of the west,especially the MRC trial of UK andDutch gastric cancer group study 13, 14.There was no survival benefit for D2dissection by these studies and wasassociated with increased rate ofmorbidity and mortality. But otherwestern studies report less morbidity andmortality with D2 dissection 15,16,17. Theincreased morbidity and mortalityassociated with D2 surgery is considered


to be due to the complications of distalpancreatectomy and splenectomy. Hencethe recent trend even by Japanese doyenslike Maruyama is to preserve tail ofpancreas and spleen during D2 dissection,unless these structures are infiltrated bythe tumor 18,19. That is why in the 13th

edition, a more tailored approach to thesurgical treatment of gastric cancer wasrecommend by JRSGC

Conclusion

• Gastric cancer is one of the mostlethal and common cancers of theworld. Except in Japan wherepopulation based screeningprogramme is available, this canceris detected in an advanced stage andhence prognosis is dismal for thiscancer. Therefore it is known as thecaptain of men of death.

• There is a declining trend of distalgastric cancer all over the world, butthe proximal gastric cancer seems tobe increasing.

• A multistep process of oncogenesisinvolving dietary factors,Helicobacter pylori and geneticfactors has been proposed.Modulation of this multifactorialprocess might result in the controland therapy of this disease in future.

• The staging system proposed byJRSGC is exhaustive, butmeticulous in planning treatmentstrategies

• Although western surgeons do notadvocate radical lymphadenectomy,the Japanese surgeons, with theirextensive experience in this form oflymphadecectomy and consequentimproved survival of gastriccarcinoma patients, believe that arandomized controlled trial (RCT)of D2 dissection is unethical.

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14. Bonenkamp JJ, Hermans J, SasakuM et al, extended lymph nodedissection for gastric cancer. Dutchgastric Cancer Group. N Engl. J.Med 1999; 340: 908 – 914.

15. Smith JW, Shin MH, Kelsey L et al.Morbidity of radicallymphadenectomy in curativeresection of gastric carcinoma. Arch.Surgery 1991; 126: 1469-73.

16. Sue – Ling HM, Johnston D. D1 vsD2 dissection for gastric cancer.Lancet 1995; 345:1515-16

17. Siewert JR, Bottcher K, Roder JDet al. German Gastric study group.Prognostic s ignif icance ofsystematic lymph node dissection ingastric carcinoma Br.J.Surg 1993;80: 1015-18.

18. Maruyama K., Sasako M, Kinoshilha


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T. et al – Pancreas preserving totalgastrectomy for proximal gastriccancer. World J Surg. 1995; vol 19:532-536.

19. Kasakura.Y.Fujii.M., Mochizuk F etal. Is there a benefit of pancreatosplenectomy with gastrectomy foradvanced gastric cancer? Am.J.ofSurgery 2000 March; 179: 3, 237 –342.

History of Surgery

The first surgical procedures wereperformed in the Neolithic Age(about 10,000 to 6000 BC).Trepanning, a procedure in which ahole is drilled in the skull to relievepressure on the brain, may have beenperformed as early as 8000 BC. InEgypt, carvings dating to 2500 BCdescribe surgical circumcision—theremoval of foreskin from the penisand the clitoris from female genitalia.Ancient Egyptian medical texts havebeen found that provide instructionsfor many surgical proceduresincluding repairing a broken boneand mending a serious wound. Inancient India, the Hindus surgicallytreated bone fractures and removedbladder stones, tumors, and infectedtonsils. They developed plasticsurgery in 2000 BC. Using skin flapsfrom the forehead, Hindu surgeonsshaped new noses and ears for thepunished criminals. In the 4thcentury BC, the Greek physicianHippocrates published descriptionsof various surgical procedures, suchas the treatment of fractures and skullinjuries.

During most of the Middle Ages (5thto 14th century AD), the practice ofsurgery declined and its practice wasleft to barbers who traveled fromtown to town cutting hair, removingtumors, pulling teeth, stitchingwounds, and bloodletting, the

practice of draining blood from thebody, then thought to cure illness.

In 1316 the French surgeon Guy deChauliac published Chirurgiamagna (Great Surgery). The texthelped surgery gain respect as aserious science. At this time a neworder of surgeons arose in France.They were called surgeons of the longrobe, distinguished from the barbersurgeons who were known as surgeonsof the short robe. The barbersurgeons had little medical training,while the surgeons of the long robewere studied physicians andconsidered such practices asbloodlett ing primitive.Corporations, or guilds, of surgeonsof the long robe were formed inseveral countries.

During the 16th, 17th, and 18thcenturies Much credit belongs to theFrench surgeon Ambroise Paré,often called the father of modernsurgery. Paré successfully employedthe method of ligating, or tying off,arteries to control bleeding, thuseliminating the old method ofcauterizing, or searing, the bleedingpart with a red-hot iron or boilingoil. The English physician andanatomist Will iam Harveydiscovered the process of bloodcirculation and Italian anatomistMarcello Malpighi identified theexistence of tiny blood vessels calledcapillaries that carry blood from themajor blood vessels to the cells of thebody. John Hunter, a Britishanatomist and surgeon, performedmany experimental operations thatadvanced the practice of surgery.

In 1846 anesthesia was used as a wayto mask pain during surgery byAmerican dentist William Morton.Although Morton is often creditedwith the discovery of surgicalanesthesia, American surgeonCrawford Long used anesthesia in

1842 during the removal of tumorsbut did not publish his results until1849.

Post-surgical infections remained aserious complication of surgery untilthe mid-19th century when theFrench chemist Louis Pasteurdiscovered that fermentation orputrefaction, the decay and death ofbody tissue, is caused by bacteria inthe air. In 1865 the British surgeonJoseph Lister applied Pasteur’s workto surgery, developing antiseptic(germ-killing) techniques includingthe use of a carbolic acid spray to killgerms in the operating room beforesurgery. These antiseptic procedureshelped eliminate postoperativeinfection. Other physicians,including Austrian IgnazSemmelweiss and American OliverWendell Holmes, determined thatbacteria are also carried on the handsand clothing and transferred frompatient to patient as a physicianattends one after another. Thesephysicians pioneered techniques suchas washing hands and changing intoclean clothing before surgery thatprevent wounds from beingcontaminated during surgery.

At the turn of the 20th century,improved diagnostic abilities andmethods of treatment helped surgerybecome even more effective. Whenthe German physicist WilhelmConrad Roentgen invented X ray in1895 to “photograph” the inside ofthe body he changed the way surgerywas performed. The discovery of theblood groups A, B, and O by Austrianpathologist Karl Landsteiner enabledsurgeons to give patients transfusionsof their own blood type to ensuresurvival during surgery.

The introduction of antibiotics inthe 1940s further minimized the riskof postoperative infection.


14Reveiwarticle

Hepato Cellular CarcinomaJ. R. Daniel

Department of Radiology Imaging & Intervention,Pondicherry Institute of Medical Sciences, Pondicherry

Hepato cellular cancer is one ofthe most deadly and commoncancers in the world. Its survival

rate is miserably low, only 5% survivingin 5-year period. Incidence of the diseaseworldwide is increasing, so anImageologist should have a knowledgeabout the pathogenesis, natural course ofthe disease, recent advances in earlydetection, when the tumor is at a treatablestage. The Imageolotist should also haveknowledge of treatment and therecurrence rate in the management ofhepato cellular carcinoma

Aetio -pathogenesis

The chronic inflammatory disease of anycause can potentially induce hepatocellular carcinoma. These diseases leadto cirrhosis, which ultimately is theprecursor in 80% of the cases. Howevernon-cirrhotic, non-viral causes can alsoinduce hepato cellular carcinoma. Testfor Hepatitis – B and Hepatitits C ismandatory at the diagnosis of hepatocellular carcinoma. Other causes havealso to be kept in mind like alcohol,industrial pollutant, pharmaceutical,synthetic agents, aflatoxin, vinylchloride, estrogens, androgens, anabolicsteroids, hemochromatosis, alpha-antitrypsin, which can potentiallyinduce the cancer. The male female ratiois 4 : 1

Patient presentation

Patients usually present in the advancedstage of disease in India. As the disease isclinically silent until the tumor exceeds10cms. or when there is a diffused

involvement and sudden decompensationof the liver. Most of the patients presentwith a paraneoplastic picture likeerythrocytosis, hypoglycemia, hypercholesterolemia, carcinoid like picture

Effective screening programs will detectsmall tumors less than 2cms in diameter,failing which the detection is often late.Since there is no effective screeningprocedure in India and the natural courseof the disease is clinically silent andmanifest when tumor exceeds 10cm indiameter in India most of the patientspresent in the stage when there is diffuseinvolvement, or multicentricinvolvement with suddendecompensation.

Diagnostic imaging appearances

These may be classified as early tumordetection i.e., screening method, imaging,staging after the clinical presentation ofthe late or an advanced stage of the diseaseprocess. Supportive laboratory testinclude blood cell count, bloodchemistry, serum transaminase, albuminlevel, prothombin time, alpha –fetoprotein level that is mandatory in thediagnosis. Paracentesis and analysis of theaspirate is essential when ascites ispresent.

Screening methods adopted in west andJapan are different. The methodsavailable are alpha fetoprotein levels,high-resolution ultrasound infusionhepatic angiography, Lipiodol CT scansome of the methods like. Infusionhepatic angiography is not used in thepresent day because of its invasive and is

replaced by multislice CT. Multiphaseabdominal CT scan, which is now theimaging procedure of choice despite thehigh cost involved and availability inlarge cities only. An AFP level withultrasound have a higher specificity andsensitivity and is able to detected at highrate of 80% and above. The variabilityin detection depends as it is operatordependent and local factors like obesity,gas in abdomen etc when the procedurehave to be repeated to achieve greatersensitivity.

MRI plays a limited role and is lesssensitive than angiographic assistedmultiphase multi slice CT

Application and Limitation of ImagingTechniques

Plain X-ray is nonspecific may showenlarged liver if the mass is large and ispalpable, calcification is rare in HCC,contrast deposition in liver and lymphnodes seen if prior exposure to thecontrast material exists.

Nuclear medicine: Is non-specific andshows a cold defects if sulphur colloid isused and may show uptake in the mass ifbile secreting with gallium. It shows apositive scan in 90% of the case.

CT appearance: Depends on thetumor size, multi centricity anddiffuseness and the phase in which it istaken. In the unenhanced CT it is isodenseif the mass is large central areas ofnecrosis may be seen. In the arterial phaseit is hyper dense. In the portal venousphase it becomes isodense or hypo dense,delayed phase may show a capsule a more


68

specific sign of HCC. CT also helps indetecting portal venous involvementHepatic vein involvement and bleedingwithin the tumour. In the scenario of alarge tumor with the positive AFP levelit suggest HCC, reliability suffers in smallHCC as it can be confused with hepaticnodules. Lipiodol CT helps in detectingsatellite nodules as Lipiodol accumulateswithin the tumor due to a macro leak afact that is useful in targeting chemoembolic mixture in HCC

MRI: HCC appears as iso intense, hypointense or hyper intense relative to thenormal liver in T1 weighted images, Incontrast, at T2 weighted,it appears hyperintense.

Ultrasound: the appearance dependsupon the operator and is variable, smallHCC may be difficult to detect if carefulscreening is not performed. Small HCC’sare hyper echoic and mimic hemongiomaas fat is present in large amount withinthe tumor, if correlated with AFP levelit has high degree of sensitivity, incombination with the Doppler it isuseful in detecting associated vascularabnormalit ies l ike portal veininvolvement which is common in HCC,hepatic vein involvement is a morespecific sign of HCC

Interventional radiology : Anumber of ablative procedures areavailable in the treatment of HCC,alcohol injection, acetic acid injection,interstitial laser, radio frequencyablation, micro wave therapy,cyroablation. Their usefulness dependsupon the size, and proximity of thetumor to the vessels. The embolisationprocedure, like chemoembolisation i.e.,regional chemotherapy, blandembolisation of HCC by reducing itsblood supply, and devascularisationwhich is helpful in symptomatic

improvement, but in no way effective inthe improvement of long term survival.It can improve survival to a three yearsurvival rate if detected early in size lessthan 3cm and especially if Ethanol orother ablative procedure are used whichis cost effective and now can be widelypracticed.

Local ablation strategies: Radiofrequency ablation is a technique that usesheat to thermally ablate tumors. A thinprobe (18 gauge) is inserted into themiddle of the tumor, then needleelectrodes are deployed to adjustabledistances. An alternating electricalcurrent (400 to 500 kHz) is deliveredthrough the electrodes. The currentcauses agitation of the particles of thesurrounding tissues, generating frictionalheat. The heat leads to a reliable sphereof necrosis. The size of the sphere dependson the length of deployment of theelectrodes. Currently, the maximum sizeof the probe arrays allows for a 7-cm zoneof necrosis. This would be adequate for a5-cm tumor. The heat reliably kills cellswithin the zone of necrosis. The lack ofuniform success is due to the difficulty ofpositioning the probe accurately in threedimensions using ultrasonographic orCT guidance. Also, large blood vesselsmay act as heat sinks, preventing adequatecytodestruction of cells adjacent to thesestructures. Finally, treatment of tumorsclose to the main portal pedicles can leadto bile duct injury and obstruction. Thislimits the location of tumors that areoptimally suited for this technique. Inseries examining the results of treatmentof HCC with radio frequency ablation,the data suggest a uniformly excellentresponse, with a local recurrence rate (atthe site of ablation) of between 5% and20%. The treatment can be performedpercutaneously with CT orultrasonographic guidance, or at the time

of laparoscopy with ultrasonographicguidance. The disadvantage of thelaparoscopic approach is therequirement for general anesthesia, butsome have suggested better results withthis approach. Use of the percutaneousapproach may also be limited by thepresence of structures at risk for injuryaround the tumor, such as the diaphragm,colon, or gallbladder. These structurescan be retracted free in a laparoscopicapproach. In general, radio frequencyablation is reliable as a single treatment.A single ablation can take up to 20minutes for a 7-cm ablation. Theprocedure is well tolerated and can beperformed on an outpatient basis. It canbe repeated numerous times andfrequently, especially if performedpercutaneously. This technique is best-suited overall for small tumors (less than3 cm) deep within the hepaticparenchyma and away from the hepatichilum. Complete preservation of hepaticparenchyma is possible with reliabletumor killing. A theoretical risk ofneedle tract tumor seeding exists. Thetract can be thermally ablated whileretracting the needle, which decreasesthis risk.

Local injection therapy: Numerousagents have been used for local injectioninto tumors, but the most commonlyused agent has been ethanol. Ethanolinjection into HCC is the most widelyused therapy worldwide. The relativelysoft HCC within the hard backgroundcirrhotic liver allows injection of largevolumes of ethanol into the tumorwithout diffusion into the hepaticparenchyma or leakage out of the liver.Ethanol causes a direct destruction ofcancer cells, but it is in no way selectivefor cancer and will destroy normal cellsin the vicinity. The key to success is theaccuracy of the injection. This technique


is associated with a 15% risk ofrecurrence at the site of treatment. It hasthe advantage of being minimallyinvasive, because a very small needle canbe used for injection, and it is quiteinexpensive. The disadvantage is that aresponse usually requires multipleinjections (average of three). Themaximum size of tumor that can bereliably treated is 3 cm, even withmultiple injections. For this reason,radio frequency ablation is preferable tomost clinicians. Nevertheless, the cost ofradio frequency ablation may beprohibitive in many places. Acetic acidis another agent with established successas a local injection for HCC. Arandomized trial suggested that localrecurrence is lower with acetic acid thanwith ethanol.

Regional chemotherapy: Althoughthe results of systemic chemotherapy foreither regional or metastatic HCC aredismal, a large number of encouragingreports have appeared concerning avariety of regional chemotherapies forHCC confined to the liver. Despite thefact that increased hepatic extraction ofchemotherapy has been shown for veryfew drugs, some drugs such as cisplatin,doxorubicin, mitomycin C, and possiblyneocarzinostatin have been found toproduce substantial objective responseswhen administered regionally. Incontrast to the Western experience formetastatic colon cancer to the liver, fewdata are available regarding continuoushepatic arterial infusion for HCC,although pilot studies are suggestive.Almost all studies have been done usingbolus administration. Many but not allof the studies on regional intrahepaticarterial chemotherapy also use anembolizing agent such as Lipiodol,gelatin (Gelfoam), starch (Spherex),microspheres, or polyvinyl alcohol

(Ivalon). The last is rarely used now, dueto increased hepatotoxicity. Two newproducts have now come to market usingmicrospheres of defined size ranges. Theyare Embosphere (BioSphere) andContour SE (Boston Scientific). Theoptimal diameter of the particles fortranscatheter arterialchemoembolisation (TACE) has yet to bedefined. Consistently higher objectiveresponse rates are reported for arterialadministration of drugs together withsome form of hepatic artery occlusionthan for any form of systemicchemotherapy to date.

Cholangiocarcinoma

Cancers of the bile ducts are rare tumors.Because of the proximity of the bile ductto the liver, the pancreas, and majorvascular structures, surgical excision ofthese tumors usually requires a majorhepatic or pancreatic resection or both.Major vascular reconstructions may alsobe necessary. The technical demands ofsuch resections and the lack of effectivealternative therapies forcholangiocarcinomas explain thenihilistic attitude that generallysurrounds this disease. Advances inimaging over the last two decades nowallow for earlier diagnosis of bile ductcancer and better surgical planning.

Epidemiology and Etiology

Cholangiocarcinoma is a disease of theelderly, with the majority of such lesionsoccurring in patients older than 65 yearsand the peak incidence occurring in theeighth decade of life. Untreated, bile ductcancers are rapidly fatal diseases, and themajority of patients will die within 6months to a year of diagnosis. Deathusually results from liver failure orbiliary sepsis. Long-term survival ishighly dependent on the effectiveness ofsurgical therapy. A number of are

associated with an increased incidence ofcholangiocarcinomas, including PSC,choledochal cysts or Caroli’s disease, andpyogenic cholangiohepatitis and otherhepatic infections. In addition,environmental agents may influence theincidence of cholangiocarcinomas.

Distal bile duct cancers

USG will demonstrate a dilated extrahepatic and intrahepatic biliary tree.Cross-sectional imaging by CT scanningwill usually then demonstrate a mass inthe region of the head of the pancreas.

Treatment options

Complete resection is the only effectiveand potentially curative therapy forcancers of the lower bile duct. In patientswith nonresectable cancers, palliationfor biliary obstruction can be achievedwith a surgical bypass or biliaryendoprostheses. Endoprostheses fordistal biliary obstruction are usuallyplaced endoscopically and provide moredurable palliation than does anendoprostheses placed for hilarobstruction. Surgical bypasses alsoprovide excellent relief of jaundice andcan be achieved with an acceptably lowmorbidity and mortality. All otherpatients are treated with biliaryendoprostheses. Chemotherapy orradiotherapy or both have offeredgenerally poor results as palliativetreatment for unresectable cases.Survival beyond 1 year is uncommon inpatients subjected to palliative therapies.

Proximal or hilarcholangiocarcinoma

Proximal or hilar cholangiocarcinomasrepresent the greatest diagnostic andtherapeutic challenge because of the vastnumber of vital structures that can beinvolved by even a small hilarcholangiocarcinoma. Proximal or hilar


70

cholangiocarcinomas require the mostextensive of liver resections and vascularreconstruction for extirpation.

Radiographic evaluation

Radiological imaging is central to thediagnosis and treatment planning forpatients with cholangiocarcinomas. Theimportance of imaging studies resultsfrom the difficulties in obtaining apositive tissue diagnosis by biopsy,particularly when the tumors are smalland in the potentially curable stages.Relying on the results of percutaneousneedle biopsy or biliary brush cytologyis dangerous, as the results of these testsare often misleading and one may missthe opportunity to resect an early cancer.Therefore, the preoperative and, often,operative diagnosis are based mainly onthe history and radiologic appearance ofthe tumors.

Beyond diagnosis, the radiologicevaluation is aimed at determiningresectability, as surgical resection is themost effective and only potentiallycurative therapy. Imaging may locateoccult distant metastases and therebyspare patients from nontherapeuticsurgery. In defining the degree ofinvasion of adjacent organs andvasculature, imaging is also essential forplanning the surgical procedure anddirecting major vascular reconstructionswhen necessary. USG is usually the firstinvestigation performed because it isreadily available, and providesimportant diagnostic informationregarding the jaundiced patient.

Generally, intrahepatic bil iarydilatation will be seen without evidenceof extra hepatic bile duct abnormalityand without evidence of stones. Inexperienced hands, the tumor will oftenbe clearly defined by US, as will

information important for planning ofsurgery such as delineation of the biliaryextent of disease, vascular involvement,presence of lymph node metastases in theporta hepatis , and presence ofnoncontiguous liver metastases. USG notonly may demonstrate the level ofbiliary ductal obstruction but can alsoprovide information regarding tumorextension within the bile duct and in theperiductal tissues In centers specializingin treatment of cholangiocarcinomas, agood Doppler USG may indeed providediagnostic information equivalent to thatprovided by a combination ofangiography and CT and is highlyaccurate in predicting resectability. CTremains an important study forevaluating patients Importantinformation regarding level of biliaryobstruction, vascular involvement, andpresence of nodal or noncontiguousmetastases can be assessed. One of themost important findings to be gleanedfrom a CT scan, however, is the presenceof hepatic lobar atrophy, which is usuallyindicative of portal venous occlusionRecently, however, MRCP has emergedas a noninvasive substitute for directcholangiography. MRCP not only mayidentify the tumor and the level of biliaryobstruction but also may revealobstructed and isolated ducts notappreciated at endoscopic orpercutaneous study.

For patients presenting with proximalcholangiocarcinomas, a Doppler USG,helical CT, and chest radiograph maysuffice as preoperative radiologicevaluation. In patients in whom furtherdelineation of biliary or vascularinvolvement may be necessary, MRCPand MRA are the next tests of choice. Thisnoninvasive approach prevents biliaryinstrumentation and bacterbilia and theassociated increased perioperative

morbidity.

Biliary drainage

The important concept in the preventionof biliary sepsis is the understanding thatjaundice alone is not necessarily anindication for biliary decompression.Unlike biliary obstruction in the lowerbile duct, where a single stent usuallyeffectively rel ieves the bil iaryobstruction, biliary obstruction near thehilus is much more difficult to relieve.Even with a small tumor, a single stentlikely will drain only one-half of theliver. When the tumors are large andinvolve second- or third-order bile ducts,many stents may be required to provideeffective biliary decompression; it is alsopossible that effective bil iarydecompression cannot be achieved in suchcases.

Biliary drainage can be accomplishednonsurgically or surgically. Nonsurgicaldrainage is preferred if the patient hassignificant co morbid conditions or if thetumor as evaluated by preoperativeimaging is clearly not resectable for cure.Though biliary decompression cantheoretically be accomplished either bypercutaneous transhepatic puncture or byendoscopic stent placement, hilar tumorsare notoriously difficult to traverse withthe endoscopic technique.

Moreover, the failure rates and incidenceof subsequent cholangitis are high. Thus,most patients with unresectable hilartumors are not candidates for endoscopicbil iary drainage. Percutaneoustranshepatic biliary drainage andsubsequent placement of a self-expandable metallic endoprosthesis(Wallstent, Cook Medical Devices IndiaLtd.) is the palliative procedure of choicefor these patients.


Gallbladder cancer

Gallbladder cancer affects women two tosix times more often than it does men.The incidence steadily increases with age;reaching its maximum in the seventhdecade of life Seventy-five to ninety-eightpercent of all patients with carcinoma ofthe gallbladder have cholelithiasis.

Gallbladder cancer is usually associatedwith cholesterol-type gallstones. Otherrisk factors include the presence of ananomalous pancreaticobiliary ductjunction, chronic typhoid infection, andinflammatory bowel disease.

Calcification of the gallbladder(porcelain gallbladder), signifying long-standing inflammation, is associated withgallbladder cancer in 10% to 25% of cases.These conditions suggest that chronicinflammation may play an importantrole in the development of gallbladdercancer. Though reports of family clustersof gallbladder cancer exist in theliterature, congenital predisposition isnot believed to play a major role in thedevelopment of this cancer.

Radiologic evaluation

Before the routine use of CT and USG,the preoperative diagnosis rate forgallbladder carcinoma was generally lessthan 10%, which, in part, explains thedismal outcomes of surgical therapy inthe era prior to sophisticated cross-sectional imaging, as many patients withincurable disease were subjected toexploration. With the routine use of CTscanning and real-time US in the 1980s;preoperative diagnosis was achieved in75% to 88% of patients. Beyonddiagnosis, the goals of imaging alsoinclude accurate staging. The goal ofimaging is to determine extent of liverinvasion, invasion of other adjacentorgans, vascular involvement, extent of

biliary involvement, presence of nodalmetastases, and presence of peritonealmetastases.

Because the majority of patients willpresent with symptoms suggestive ofbiliary colic or chronic cholecystitis, thediagnostic workup will usually beginwith abdominal USG. Discontinuousgallbladder mucosa, echogenic mucosa,submucosal echolucency, or a massgreater than 1 cm should arousesuspicion of gallbladder cancer. Thefinding most convincing of a gallbladdermalignancy is an inhomogeneous massreplacing all or part of the gallbladder.The index of suspicion should be high forelderly patients, patients with atypicalsymptoms, and patients with suspiciouslaboratory findings such as anemia,hypoalbuminemia, and abnormal liverfunction tests. USG can also delineate thedegree of biliary involvement and candefine the presence of arterial or portalvenous involvement by tumor. Inexperienced hands, USG will providediagnostic information equivalent to thatprovided by much more expensive cross-sectional imaging.

CT scanning is usually the next imagingexamination performed because of itswide availability, low cost, low risk, andhigh yield. On CT, gallbladder cancercan appear as a mass almost filling thegallbladder lumen in 42% of cases, apolypoid mass in 26%, and diffuse wallthickening in 6% of gallbladder cancerpatients. CT is better than USG indemonstrating liver atrophy, whichusually is indicative of ipsilateral portalvein involvement by tumor. CT is alsobetter at detecting lymphadenopathy,particularly for retropancreatic nodaldisease, which would rule out thepotential for cure, though CT scanidentified only 38% of pathologicallypositive nodes preoperatively.

Angiography was another common testfor assessing vascular invasion when themass encroached on the porta hepatis, butthis invasive method of examinationcarries finite risks. Cholangiography andangiography remain important tests incertain settings, but Doppler USG,magnetic resonance Cholangiography,and MRA have largely replaced theseinvasive procedures in the majority ofcases.

Magnetic resonance procedures havelong been accepted as invaluable forcharacterizing hepatic tumors. Suchprocedures may also identify andcharacterize lymph node metastases withgreater precision than can other cross-sectional imaging techniques. Withrecent advances in hardware andsoftware, the extent of bil iaryinvolvement can now be determinedthrough MRCP. MRA allows forassessment of vascular invasion todetermine resectability and candemonstrate anomalous anatomicfindings to assist in surgical planning.

Conclusion

Imaging allows early detecting of thetumor in the background of an effectivescreening procedure and allowsidentification at a treatable stage. In largetumors > 10 cm in size or diffuse carriesa very poor prognosis at the time ofdetection with a survival of less that 1-year period. Preventive methods aremost essential as they are supposed toreduce, the incidence of hepatocellularcarcinoma. Once tumor is formedscreening procedures has is ownlimitation and is not 100% effective butscreening is well adapted and standard inthe west where the persons are screenedevery 6 months with AFP plus multislice,multiphase CT and abdominal highresolution ultrasound in the hope ofearly detection and improving survival.


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15Correspondence

Case Report ofEmbryonic Cell

Carcinoma Testis

A 54 years old male came tosurgery department withcomplaint of heaviness in right

testis and history of minor trauma. Onexamination, scrotal skin was normal.However right testicle showed a distinctsmall lump on superomedial aspect.Scrotal USG was done using 7.5 Mhzlinear transducer. Right testis showed adistinct hypoechoic mass lesion with fewcystic areas and no evidence of anycalcification on superomedial side.Doppler USG revealed increasedvascularity. Histopathology proved masslesion as Embryonal cell carcinomatestis (ECCT). There was no evidence oflymphadenopathy on transabdominalUSG. Chest radiograph of the patientwas normal. So the patient was staged asstage I non-seminomatous germ celltumor (NSGCT) testis according toRoyal Marsden Staging System fortesticular cancer. Patient wassubsequently treated by right sidedorchidectomy.

Discussion

Testicular neoplasms account for 1% to2% of all malignant neoplasms in men andare the fifth most frequent cause of deathin men aged 15 to 34 years1.Approximately 65% to 94% of patientswith testicular neoplasms present withunilateral testicular masses or diffusetesticular enlargement, and 4% to 14%present with symptoms of metastatic

disease2.Most primary testicular tumorsare of germ cell origin and are generallyhighly malignant. Only 60% of testiculargerm cell tumors are of one histologicsubtype, and the remainder are of two or

more histologic subtypes. Although thereare potentially several histologicsubtypes of germ cell tumor, clinically itis important to recognize only two basictumor types : seminomas and NSGCT.This is because seminomas and NSGCTbehave differently biologically andtherefore, have different therapeutic andprognostic implications.Pure ECCT is arare tumor accounting for only 2% to 3%of testicular germ cell neoplasms. It oftenoccurs in combination with otherneoplastic germ cell elements,particularly yolk sac tumors andteratoma. Like other NSGCT, thesetumors occur in younger age group thando seminomas, with a peak incidenceduring the latter part of the second andthird decade3. The typical ECCT is lesshomogeneous and well defined whileteratomas are heterogenous and morelikely than seminomas to contain cysticspaces and calcifications. Seventy percentof stage I NSGCT patients are cured byorchidectomy alone : 30% however willdemonstrate subsequent metastaticdisease. This can be almost entirelyprevented by retroperitoneal lymphnode dissection at the time of staging.Alternatively, close radiologicalsurveillance can be instituted to allowearly detection of metastatic disease withchemotherapy.

Around 25% of NSGCT patients havemetastasis (Stage II-IV) at presentationand these are also treated withchemotherapy which is usually associatedwith complete response. Around 25%however will demonstrate persitent

Doppler USG Scrotum showing a welldefined, hypoechoic mass lesion

(containing few cystic areas) withincreased vascularity and no evidenceof any calcification on superomedialside of right testis. Histopathology

report revealed Embryonal cellcarcinoma testis.


lymph node mass followingchemotherapy. No imaging modality iscurrently completely reliable indetermining which masses containsignificant disease and generally these aretreated with surgical excision(retroperitoneal lymph node dissection)4.

References

1. Granthem JG, Charboneou JW,James EM,et al . Testicularneoplasms: 29 tumors studied byhigh-resolution ultrasound.Radiology, 1985; 775- 780.

2. Krone KD, Caroll BA. Scrotalultrasound. Rad Clin North Am.1985; 23: 121-139.

3. Dambro TJ, Stewart RR, Caroll BA.The Scrotum. In : Diagnosticultrasound, 3rd ed. Elsevier Mosby.2005: 853-61.

4. Kabala JE. The male genitalia andurethra. In : Textbook of Radiologyand Imaging, 7th ed. ElsevierChurchill Livingstone. 2005; 1028-1032.

Pankaj SharmaDepartment of Radiology

Lady Harding Medical CollegeNew Delhi

Case Report ofMulticystic Dysplastic

Kidney with Pregnancy

A 26 years old primigravida withno history of any illness or drugintake during pregnancy came for

routine obstretic ultrasound.Sonography demonstrated a single liveintrauterine pregnancy of about 33 weeks

gestation age. Placenta was in the anteriorand superior segment. Fetal head wasenlarged with dilated bilateral sidelateral ventricles (atria measured approx26 mm). Fetal right side kidney appearedenlarged and showed non-communicatingcysts of variable sizes alongwithnonvisualised normal renal parenchyma.Fetal left side kidney and urinary bladderappeared normal. Liquor amnii wasnormal. USG findings were suggestive ofright side multicystic dysplastic kidney(MCDK) with hydrocephalus. Patientunderwent caesarian section and findingswere confirmed.

Discussion

Unilateral MCDK is the second mostcommon urinary tract abnormalitydiagnosed antenatally. Simple MCDK isdefined as unilateral renal dysplasiawithout additional genitourinary (GU)abnormalities. Complex MCDKincludes patients with bilateral renaldysplasia or unilateral renal dysplasiawith other GU abnormalities. The finaloutcome for patients with simple MCDKis quite good, with normal renal functionand compensatory hypertrophy of thecontralateral kidney in all patients. Incontrast, patients with bilateral diseaseor associated GU anomalies have a higherincidence of UTI and progression to renalfailure 1.Patients with antenatally orneonatally detected multicysticdysplastic kidney can primarily befollowed up conservatively. Involutionoccurs in approximately one fourth ofthe cases, usually within about 14 months.No significant involution can beexpected to occur after 18 months. Ifsurgery is decided on, we recommend anage of about 2 years. Late complications(e.g., Wilm’s tumor and renovascularhypertension) are rare 2.The termventriculomegaly (VM) describes large

1. USG Skull showing bilateral dilated lateralventricles with thin cortical parenchyma

suggestive of hydrocephalus.

2. USG abdomen showing right kidney replacedby non-communicating cysts of variable sizessuggestive of multicystic dysplastic kidney.

3. USG Skull and USG Abdomen showing rightmulticystic dysplastic kidney with

hydrocephalus.


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ventricles. Hydrocephalus (HC) refers toenlarged ventricles associated withincreased intracranial pressure and / orhead enlargement. VM is the mostcommon cranial abnormality. Theatrium of the lateral ventricle is the siteof confluence of the bodies, occipitalhorns, and temporal horns. Cordozareports that between 14 and 38 menstrualweeks, the transverse atrial measurementis constant at 7.6 mm (standard deviation0.6 mm). Measurement above 10 mmsuggests VM with a low false-positive rate.Borderline VM indicates measurements10 to 15 mm, and marked VM indicatesmeasurements above 15 mm 3.

Once enlarged ventricles are discovered,it is important to search for the etiologyand any associated abnormalities becausethey determine the prognosis. Actualventricle size is less prognostic4. VMgenerally stays stable or increases slightly(about 85%) but a small proportion mayresolve and become normal (about 15%).Aneuploidy is found in about 3% to12.6% of all VM fetuses and 4% withisolated VM, most commonly trisomy 21and trisomy 18.

References

1. Feldenberg LR, Siegel NJ. Clinicalcourse and outcome for childrenwith multicystic dysplastic kidney.Pediatr Nephrol. 2000 Oct; 14(12):1098- 1101.

2. Ylien E, Ahonen S, et al .Nephrectomy for multicysticdysplastic kidney : if and when?Urology, 2004 Apr; 63(4): 768-771;discussion 771-772.

3. Cordoza JD, Goldstein RB, FillyRA. Exclusion of foetal ventri-culomegaly with a singlemeasurement : The width of thelateral ventricular atrium.

Radiology. 1988; 169: 711-714.

4. Nyberg DA, Mock LA, Hirsch J,et al.Foetal hydrocephalus.Sonography detection and clinicalsignificance of associatedanomalies. Radioloy. 1987; 163:187-191.



Vitelline Duct Anomaly -a Case Report

Vitelline duct is a remnant of yolkstalk which connects yolk sac tothe midgut in developing

embryo1. A number of anomalies arefound to be associated with its partial orcomplete persistence. Herewith, wepresent a rare case of complete

persistence of Vitelline duct (Meckel’sdiverticulum) which was connectingileum to the umbilicus.

3 yrs old male child was presented withH/o reddish discolouration and

Fig- 1Umbilical

Granuloma

Fig- 2Onultrasoundexaminationof theabdomen,there washypo

intermittent mucoid discharge throughthe umbilicus since birth. There was nohistory of faecal discharge. On clinicalexamination a chestnut size tumour wasseen at the umbilicus, dischargingmucoid secretions. (Fig.1) Diagnosis ofumbilical granuloma with Vitelline ductanomaly was made.

On ultrasound examination of theabdomen, there was hypoechoic tubularstructure with central hyperechoic linehaving the gut signature2 with ‘L’ shape,seen connecting the umbilicus to thesmall bowel. The vertical limb wasmeasuring 2 cms and horizontal segmentwas measuring 5 cms. Colour Dopplershowed increased vascularity in thehypoechoic muscular portion. Noassociated kidney or urinary bladderanomalies were seen.

Sinogram using water soluble contrast(Angiograffin 65%) was done with 8Fcannula. Contrast was injected with gentlepressure. Contrast was seen going into thetract through the umbilicus, althoughintestinal communication was notdemonstrated, faint visualization of theintestine was seen.

Patient’s CBC, renal function tests andurine examination were normal.

Patient was operated upon. There was along tubular structure seen connectingthe umbilicus to the ileum. The lumen


Fig- 3Hypoechoic Tract Showing Gut

Fig- 5Ileal Sutures after Resection

Fig- 4Umbitical Granuloma with Meckel’sDiverticulum in connection with the

Ileum

was patent. The site of the diverticulumwas proximal to the ileo-caecal junctionon antimesenteric border ofthe ileum. Catheter could benegotiated into thediverticulum through theumbilicus. It went down intothe lumen of the intestine.The tract was clamped at thebase after dividing themesentery. Thediverticulum was resectedwith the umbilicalgranuloma in continuity.The rent in the small bowelwas repaired. Abdominalwall was sutured in layers.There was no other anomalyfound.

Histopath examination showed a fibroustract lined by stratified squamousepithelium alongwith intestinal mucosa.Mucosa showed finger like villi withdysplastic epithelium with intactbasement membrane. Findings suggestiveof Meckel’s diverticulitis with organizedgranuloma at the umbilicus. There wasno evidence of ectopic gastric orpancreatic tissue seen in the Meckel’sdiverticulum.

Discussion

Meckel’s diverticulum has an incidenceof 2% and is formed by persistence ofVitelline duct which arises from 1-2 feet

proximal to ileocaecaljunction. Differenttypes of anomalies maybe seen with the partialor complete persistenceof Vitelline duct3. Therecan be a sinus tract orfistula or atretic tract.Complications includediverticulitis, bleeding,ulceration, perforation,

intestinal obstruction, volvulus organgrene1.

Radiologically small bowel enema orBarium meal followthrough can demonstrateblind ending sac arisingfrom antimesentericborder of i leum 4.Sometimes a triradiatepattern of mucosal folds isseen at the base1. When it isinverted, a filling defect isseen similar to polyp. Themethod is cumbersomeand not very informative.

USG shows hypoechoictubular structure with agut signature which canmimick appendicitis. This

can be a good diagnostic tool to know theanatomical details. Surgery can beplanned accordingly.

Radionuclide imaging with 99 TCpertechnate shows increased uptake, ifthere is presence of ectopic gastric orpancreatic tissue1.

Angiography will show extravasations ofcontrast medium into diverticulum incase, there is active bleeding.

Thus imaging study specially USG andcontrast study can play a vital role in

diagnosis and surgery can beplanned or modifiedaccordingly.

References

1. Margulis andBurhenne. AlimentaryTract Radiology, 4thed, Vol1. C.V. Mosby Company, StLouis, Missouri USA, 1989: 218-226

2. Rumack, Wilsonand Charboneau. DiagnosticUltrasound, 2nded. Mosby,Year Book, St. Louis,Missouri, 1988


76

Fig. 2USG Scrotum showing scrotal calculus inrelation to left testis.

3. S. Patankar, A Banglore, RJahagirdar, S. Patankar. Prolapse ofpatent omphalomesceteric Duct.Bombay Hospital J. 2006;4804:649- 651

4. Grainger & Allison’s. DiagnosticRadiology, 4thed, Vol. 2, ChurchillLivingstone 2001;1052

Aruna M. Deodhar,Atul P. Deshmukh,

Rajlaxmi M. Chopade,Shubhangi J. Gulve,

Department of Radiology, VivekanandHospital, Signal Camp, Vidhya Nagar,

Latur, Maharashtra

Case Report of ScrotalCalculus

A 75 year old male came to surgerydepartment with history of feverfor five days and complaint of

pain lower abdomen alongwith inabilityto extend left hip. USG abdomen using3.5 Mhz sector transducer was found tobe normal. Further USG of bilateralinguinal and scrotal region was doneusing 7.5 Mhz linear transducer. Testesand epididymis of both sides showednormal size and echotexture. Right sidedscrotal sac revealed fluid with thickinternal echoes suggestive of right sidepyocoele. Left side scrotal sac revealedfluid with no internal echoes. A 11 mmmobile echogenic focus with distalacoustic shadowing was also seen in leftside scrotal sac. Findings were suggestiveof left side scrotal calculus alongwith leftsided hydrocoele.

Discussion

Scrotal calculus, also known as fibrinoidloose body or scrotal pearl, is a benignnonneoplastic extratesticular mass, firstdescribed by Kickham in 19351. Thecalcified loose body arises from the tunicavaginalis and may break free to become aloose body between the two membranesof the tunica vaginalis testes.

Grossly, these calculi appear as round,pearly white, rubbery masses.Histologically, scrotal pearls arecomposed of a central nidus ofhydroxyapatite around which fibrinoidmaterial is deposited. Thought fromhematomas, or from inflammationof the tunica vaginalis testes, thesecalcifications may present as eitherpainful or nontender free floating ordependent scrotal masses2. Because oftheir association with inflammatoryscrotal processes, hydrocoele is acommon secondary finding. Thepresence of a hydrocoele may makethe calculus more conspicuous andconversely, the absence of anassociated hydrocoele may renderidentification of a calculus morechallenging 1,2. The presence of calculusin a hydrocoele does not change theprognosis or treatment of this condition,although some doubts may arise duringsonographic assessment if it is attachedto the parietal portion of the tunicavaginalis 3.

References

1. Linkowski GD, Avellone A,Gooding GAW. Scrotal calculi :Sonographic detection. Radiology.1985; 156: 484.

2. Dambro TJ, Stewart RR, CarollBA. The Scrotum. In : DiagnosticUltrasound, 2nd ed. Mosby : St.Louis. 1998: 808.

3. Valero PJA, Medina PM, et al.Differential diagnosis of intrascrotalcalcification : lithiasis attached tohydrocoele wall. Arch Esp Urol.2000 May; 53(4): 370-372.

4. Spence LD, Moran V. Ultrasound ofintrascrotal calculi. Eur J Radiol.1995 Sep; 20(3): 210-211.



Fig. 1- USG Scrotum showingleft side hydrocoele alongwith

left side scrotal calculus.


Echogenic lesions with thin stalk and noposterior acoustic shadowing distendinginto gallbladder lumen from non-dependent gallbladder wall suggestive ofgallbladder polyps.

Fig 1

Fig 2

Case Report of GallBladder Polyp

A 33 years old male presentedwith complaint of pain in righthypochondrium. On trans-

abdominal USG, gallbladder wasdistended and showed multiple echogenicfoci (of sizes varying from 5 to 9 mm)with no posterior acoustic shadowing,protruding from the wall of thegallbladder into the gallbladder lumen.Thus the imaging findings revealed thediagnosis of gallbladder polyps. Patientwas advised cholecystectomy for

symptomatic gallbladder polyps. Patientrefused surgical treatment and wasmanaged conservatively.

Discussion

Gallbladder polyps affect approximately5% of the adult population1. Polypoidlesions of the gallbladder (PLG) includebenign pseudotumors (cholestrol polyps,adenomyomatosis), benign (adenoma)and malignant (adenocarcinoma)neoplasms. Cholestrol polyps are themost common PLG and are usually lessthan 10 mm in size. Cholestrol polypshave a characteristic pedunculated

appearance on USG and areoften multiple (30% of cases).Adenomyomatosis appears as asessile polyp with characteristicmicrocysts on USG and is mostoften larger than 10 mm.Adenoma and adenocarcinomamay be sessile or pedunculatedand are usually larger than 10mm. In the absence oftransmural invasion, it isdiff icult to differentiatesonographically between

adenoma and adenocarcinoma 2.B-ultrasonography is the most effectivediagnostic method for detecting PLG3.Endoscopic USG may be more sensitiveand specific than transabdominal USGin differentiating among PLGs.

Endoscopic USG and positronemission tomography mayprove to be useful in assessing themalignant potential of largegallbladder polyps. Most smallPLG are benign and remainstatic for years. Age more than50 years and size of polyp morethan 10 mm are the two mostimportant factors predictingmalignancy in polypoid lesionsof the gallbladder. Other risk

factors include concurrent gallstones,solitary polyp, and symptomatic polyp4.Patients who have biliary pain and smallgallbladder polyps without gallstonespresent a difficult management decisionfor the clinician. If the clinician isconfident that the polyps are the sourceof the pain, patient should be reffered forcholecystectomy. Laparoscopiccholecystectomy is the treatment ofchoice unless the suspicion of malignancyis high, in which case it is advisable tohave open exploration, intraoperativefrozen section, and preparation forextended resection4.

References

1. Myers RP, Shaffer EA, Beck PL.Gallbladder polyps : Epidemiology,natural history and management.Can J Gastroenterol. 2002 Mar;16(3): 187-194.

2. Ahrendt SA, Pitt HA. Biliary Tract.In : Textbook of Surgery, 17th ed.Philadelphia : WB Saunders. 2004;1622.

3. Sun XJ, Shi JS, et al. Diagnosis andtreatment of polypoid lesions of thegallbladder : report of 194 cases.Hepatobiliary Pancreatic Dis Int.2004 Nov; 3(4): 591-594.

4. Lee KF, Wong J, Li JC, et al.Polypoid lesions of the gallbladder.Am J Surg. 2004 Aug; 188(2): 186-190.




78

Case Report of SpleenicHydatidosis

A 38 year old female presented tosurgery department withcomplaint of pain in left

hypochondrium. X Ray abdomenrevealed diffuse soft tissue haze in lefthypochondrium displacing the splenicflexure of colon inferiorly. USGabdomen revealed a single, well defined,multicystic mass in spleen suggestive ofhydatid cyst with multiple daughter cysts.Contrast enhanced CT abdomen revealeda well defined, single hydatid cyst withmultiple daughter cysts in spleen. So finaldiagnosis of splenic hydatidosis was madeand patient was advised surgery. Patientunderwent splenectomy thereafter and isdoing well on follow up.

Discussion

Hydatid disease commonly affects liverand lungs. Incidence of extra-hepatichydatid varies from 14% to 19% 1,2.Splenic hydatidosis is rarely encounteredin clinical practice ocuring in 1.5%-4%of patients with echinococcus granulosusinfestation3. Primary splenic hydatidosisdevelops when the parasite escapes to thehepatic and pulmonary filters whereassecondary disease is related to rupturedintra-abdominal cysts. Intra-abdominalrupture is a typical complication ofsplenic hydatidosis.

Hydatid cyst consists of three layers:

• an adventitia formed of compressedhost tissue

• a middle layer of friable ectocyst

• an inner germinal layer from whichis produced large number of scoliceswhich are the heads of developingworms.

The diagnosis of uncomplicated hydatid

cyst depends on high index of suspicion.Various biochemical, serological andimaging techniques can be used. Thecasoni’s test has poor sensitivity and ahigh rate of false positives. ELISA ispositive in more than 90%. Though therisk of parasite diffusion is high, FNACcan greatly increase the chance ofdefinitive diagnosis of hydatidosis byfinding protoscolices or antigen 5.

USG is a sensitive and cost-effectiveimaging technique. USG is helpful indefining the internal structures, numberand location of the cysts andcomplications. The specificity is around90%. CT yields better informationabout the location, number and presenceof daughter cysts. Splenectomy remainsthe therapeutic procedure of choice forsplenic hydatidosis. Hypertonic salinesolution is widely used in surgery forintra-abdominal or intra-thoracicechinococcosis for its supposedantiparasitic action 3.

References

1. Amir - Jahed AK, Fardin R, FarzadA, Bakshandeh K. ClinicalEchinococcosis. Ann Surg. 1975;182: 541-546.

2. Karavias DD, Vaganas CE, KakkasSK, Panagoupolas CM, AndroulakisLA. Peritoneal Echinococcosis.World J Surg. 1996; 20: 337-340.

3. Venissac N, Alifano M, Mouroux J.Splenic Hydatidosis complicated bya Splenothoracic Fistula : Report ofa case. Surg Today. 2002; 32: 1023-1025.

4. Khanna AK, Prasanna GV, KhannaR, Khanna A. Unusual sites ofHydatid Cysts in India. Trop Doct.2005 Oct; 35(4): 233-235.

5. Husen YA, Nadeem N, Aslam F,

Bhaila I. Primary Splenic HydatidCyst : a case report withcharacteristic imaging appearance. JPak Med Assoc. 2005 May; 55(5):219-221.

6. Kalinova K, Stefanova P, BoshevaM. Surgery in children with Hydatiddisease of the Spleen. J Pediatric Surg.2006 July; 41(7): 1264-1266.

Pankaj SharmaDepartment of Radiology,

Lady Harding medical College,New Delhi


16Breast Pathology- Recent Advances

Rajeev Sen, Sunita Singh, Monika Gupta Department of Pathology, Medical College, Rohtak Recent

Advances

Approximately 75000 new casesof breast cancer are estimated tooccur in Indian women every

year. The breast cancer is the second mostcommon cancer after cervix uteri1.Increasing awareness, promotion of self-palpation, increasing use ofmammographic and imaging techniquesare bringing out more and more patientswith palpable and non-palpable lesions tomedical attention. Mammography,ultrasonography and contrast enhancingnuclear magnetic resonance have beenuseful tools in clinical evaluation2.Application of microarray technologyfor evaluation of expression of thousandsof genes may isolate, in future, the womenwith high risk for developing carcinomaof breast. Even then, till date, themanagement of breast lesion remainslargely dependent on crit icalmicroscopic examination of tissue / cellsobtained from the lesion.

Techniques

Aspiration vs surgical biopsies,frozen section, sentinal lymphnode-Techniques for pathologicalevaluation include Fine NeedleAspiration Cytology (FNAC), NeedleCore Biopsy (NCB), Stereotactic CoreBiopsy and Frozen Section .The adventof FNAC has brought down a decrease inthe number of open biopsies. The harvestof tumor cells obtained provides a costeffective assessment of morphology andcan be subjected toimmunohistochemistry, hormonestudies, cell kinetics and DNA analysis3,

4. Cell blocks can be prepared by

collecting aspirated material in 5 ml of50% ethanol / 10% formalin, andcentrifuged deposits or cell pallets afterfiltration are subjected to routine tissueprocessing.

Cytology of nipple discharge and scrapepreparation from nipple and skin lesionsare non-invasive tools providing usefulinformation in mastitis and intraductalpapillary lesion. Since needle core biopsy(NCB) provides information aboutarchitectural pattern, they are generallypreferred over FNAC. In non-palpableand gray zone diagnoses of breast lesions[like Phyllodes tumor, Lobularcarcinoma, Ductal Carcinoma In Situ(DCIS)], a definitive diagnosis isrendered in over 90% of cases byNCB5.Stereotactic core biopsy is areliable alternative to excision biopsy indiagnosis of non-palpable suspiciouslesions or microcalcifications detectedon mammography. Two X-ray images ofbreast lesions are taken at differentangles. A computer uses the images tolocate the abnormality and calculateprecise coordinates to guide the physicianin placing a needle at the target. Studieshave revealed 96% concordance betweenstereotactic core biopsy and excisionbiopsy for the invasive and in situ cancerand 78% concordance for type of cancer.Excision biopsy has to be performed ifthe lesion is diagnosed Atypical DuctalHyperplasia (ADH) to rule out DCIS andif the pathology findings do not correlatewith mammography6,7.

Frozen section is still useful in evaluatingre- excision lumpectomy margins. It

should not be attempted in lesions lessthan 1.0 cm, papillary lesions and non-palpable lesions screened positive formicrocalcification on mammography.Although highly accurate with falsepositivity rate of zero and false negativerate less than 1%, the technique has beenlargely substituted by pre operativeneedle aspirations and biopsies except forassessment of margins and intra operativeassessment of sentinel lymph node8.

The sentinel lymph nodes are identifiedby the surgeon during operativeprocedure, after injecting dye orradiolabelled tracer material. If negativeon frozen section, the lymph node is stepsectioned at three levels on paraffinembedding, to be stained withhaematoxylin and eosin (H& E) and atleast one section immunostained forKeratin cocktail (AE1/AE3)9. Presenceof single cells is reported as isolated tumorcell metastasis and cluster of cells notmore than 2 mm as micro metastasis.Other keratin positive cells includingreticulum cells, mesothelial cellinclusions, ectopic breast tissue andtraumatic displacement of breastepithelium induced by biopsy procedureresult in false positivity. If sentinel nodeis negative, it is presumed that the othernodes of group will be negative. Thereare one-third chances of other nodesbeing positive if sentinel lymph node ispositive10.

A basic surgical pathology report on amastectomy specimen should includediagnosis with histological type andgrade – nuclear grade, tubule formation,


80

mitotic count and composite histologicgrade; maximum diameter of invasivetumor, site and extend of in-situcomponent if present, vascular invasion,margins, nipple and any other significantfeatures. Report of lymphnodes shouldbe formulated informing total numberof nodes, involved nodes (number) anddeposits more than 2 cm(macrometastasis), extracapsularinvasion and tumor emboli in perinodallymphatics. Many laboratories are nowroutinely reporting steroid hormonereceptors status and HER- 2 / neu (c-erbB-2) expression in tumors11.

Diagnostic gray zone

(Inflamatory lesions,hyperplasias vs atypicalproliferative lesions vs in situcarcinomams)

FNAC

Overdiagnosis of cancer on FNAC mayoccur in fibroadenoma, fibrocysticdisease with florid or atypical ductalhyperplasia, fat necrosis with reparativeinflammatory atypia and lactationadenoma. Although presence ofmyoepithelial cells, bipolar bare nucleiand stromal fragments favor benignpathology; the high cellularity andnuclear atypia may be misleading12.Papillary lesions are difficult ones onaspiration and nipple discharge cytologyin the absence of obvious malignantfeatures and are reported as papillarylesions requiring histopathology forfurther categorization (papillaryhyperplasia, papilloma and paplliarycarcinoma). Irregular and palisadedarrangment,tall columnar singlecells,nuclear moulding and mitoticfigures in the absence of myoepithelialcells favor malignancy13. Helpful clues indifferentiating phyllodes tumor ofborderline and low-grade malignancy

from fibroadenoma are hypercellularstromal fragments with mitotic activityin the aspiration cytology smears14. Lowcellularity with minimal cytologicalatypia may results in false negativity inlow grade DCIS,lobular carcinoma andtubular carcinoma . Experience andacumen of cytopathologist are of utmostimportance in such cases13. Some lesionslike fat necrosis, chronic granulomatousinflammation, periductal mastitis andlymphocytic mastopathy may bemisdiagnosed on clinical assessment,mammography and even on aspirationcytology; generally because of eitheratypical looking histiocytes orregenerative epithelium and stromalreaction. Variable sized atypicalmacrophages and histiocytic giant cellsin fat necrosis may be misinterpreted byuninitiated. However, background ofgranular debris, fat and fragments ofadipose tissue, chronic inflammatorycells and absence of epithelial cells arehelpful features15. A cavity developing infew long-standing cases with fibrosis andcalcification in the wall has been termedmembranous fat necrosis16.

Inflammatory lesions

Chronic granulomatous inflammation inthe breast may be observed because ofdiverse etiology, and at times, it becomesextremely difficult to correctly identifythe cause on morphological examinationalone. Caseating granulomas,demonstration of acid fast bacilli, highlyreactive tuberculin test or serologyagainst mycobacteria, evidence ofinfection elsewhere in body and PCRestablish tuberculous etiology.Interferon Y tests, demonstratingproduction of Y interferon andquantif ication of activated Tlymphocytes obtained from the patientand challenged with Early SecretoryTarget (ESAT)-6 and Culture Filter

Protein (CFP)-10, are supposed to bespecific for tuberculosis and differentiateit from non tuberculous mycobacteriaand BCG induced positive serology17.

Naked or healing granulomas, with orwith out presence of Schaumann orAsteroid bodies, but without caseation,increased serum levels of angiotensinconverting enzyme (ACE), calcium andnegative tuberculin test suggestpossibility of sarcoidosis. Biopsy fromasymptomatic gastronemius muscle maybe a helpful clue. Suppurativegranulomas may be observed in atypicalmycobacteriosis as well as in fungalinfections; to be differentiated bydemonstration of microorganism on acidfast staining, Periodic Acid Schiffreaction, silver methanimine andappropriate culture18.

If all causes have been excluded,necrotizing suppurative granulomas,sometimes with formation of abscess andeven sinuses, mostly confined to lobules,may be because of idiopathic chronicgranulomatous mastits, also termed asPerilobular Mastitis. Autoimmuneetiopathogenesis appears to be themechanism, and early recognition andinitiation of steroid hormone, results incomplete remission of the disease19.Nipple retraction and discharge maymimic carcinoma in periductal mastitis(Duct Ectasia ). Smears from nippledischarge mostly reveal macrophageswith few benign epithelial cells20. Densefibrosis, lobular atrophy, lymphocyticinfiltration in perivascular andperilobular distribution on biopsyFrom Painful palpable or non palablemass in young to middle aged women,often in association with Type 1 diabetesare diagnostic of lymphocyticmastopathy / lymphocytic lobulitis.Prominent atypical change in stromalcells with granular cytoplasm observed


in the lesion should not be confused withgranulomatous inflammation andcarcinoma, as most of these lesionseventually show resolution ofinflammation21. The most commoncomplications reported after siliconimplants include; capsular contraction,an exaggerated and normal response toforeign material: which microscopicallyis seen as increase in dense collagen,synovium like metaplasia of wall,foreign body reaction around theimplant. Silicon gel leakage may produceoval cystic spaces sometimes filled withamorphous but non bifrengent material.The foreign body reaction may mimicmalignancy clinically and onhistopathology22.

Proliferative lesions

Morphological assessment may bedifficult in differentiating some benignlesions from malignant ones such asSclerosing Adenosis, Radical Scar /Complex Sclerosing Lesion (RS / CSL ),Microglandular Adenosis (MGA) fromtubular carcinoma and theirdifferentiation from each other, both onaspiration cytology and needle biopsy23-

26. Low power magnification observationsare of extreme importance in identifyingand differentiating RS/CSL, sclerosingadenosis, microgladular adenosis andtubular carcinoma from each other.Radical scars / complex sclerosinglesions are distinctive stellate lesionscharacterized by scleroelastotic centerhaving a glandular distribution and overall appaerence like the head of flower onlow power magnification. The lesionsmeasuring 1-9 mm are designated radicalscar and those, which are 10 mm, or moreshould be termed complex sclerosinglesion25. In sclerosing adenosis, there is anumeric increase in glandular elementsaccompanied by stromal proliferation,which produces glandular compression

and distortion. Low power examinationreveals multiple nodular areas withretention of over all lobular architecture.Microgladular adenosis is rare benignlesion with proliferation of smallductular or acinar structure in which ruleof two cells type is broken23,24.

Preservation of myoepithelial cell layerin flattened ducts, entrapped in denserelatively acellular stroma, is observedin radial scar. Disordered proliferationof microtubules lined by epithelial andmyoepithelial cells [the latter at timesextremely difficult to precieve and mayrequire identif ication byimmunostaining for anti Smooth MuscleActin(SMA)], arranged in lobulocentricconfiguration, supports diagnosis ofsclerosing adenosis23. Myoepithelial cellsare missing from tubules ofmicrogladular adenosis and tubularcarcinoma. Rounded glands, at placeslined by multilayered epithelium alongwith PAS positive secretion in the lumenand abnormally distributed in mammarystroma and fat are diagnostic of MGA.The glandular structure in tubularcarcinoma is angulated with branching insome, and is lined by large cells withabundant eosinophilic cytoplasm andapical snouts. The stroma is desmoplasticwith variable fibrosis and elastosis andshows characteristic metachromasia24,25.

Diagnosing and typing of in-situcarcinoma (DCIS) and differentiating itfrom Atypical Ductal Hyperplasia(ADH) on one hand and invasivecarcinoma on the other may betroublesome. It may require extensivesampling and sectioning as well ascompetence of the pathologist .Interpretation of papillary lesions alsofalls in gray zone even on histopathology.Whereas presence of mixed cellpopulation of ductal epithelial andmyoepithelial cells growing in streaming

and flip flap fashion, arrangement inthree dimensional sheets revealing slitl ike fenestrated, irregular andinterconnected spaces favor ADH, singlecell population with out spindle cellcomponent, nuclei oriented towards thelumen and punched out sieve like spacesare the features suggestive of cribrifromDCIS27. Variable distention of TerminalDuct Lobular Unit (TDLU) byproliferating acinar cells on lowermagnification is observed in lobularhyperplasia, as well as in lobularcarcinoma, with overlapping featuresdescribed in Atypical LobularHyperplasia (ALH) vs. in-situ LobularCarcinoma (LCIS). Lobular hyperplasiais called atypical when less monotonous,variable sized, cohesive cellsincompletely fill the TDLU withsomewhat irregular spaces. In LCIS, thereis greater distension of acini comparedto ALH, the cells are monotonous but lesscohesive and fill the TDLU completely28.DCIS is differentiated from LCIS withthe presence of cohesive cell groupswithout intracytoplasmic lumina, andwith variable nuclear and cytoplasmicatypia arranged in variable sized glands,rosettes, papillae or solid areas in theformer and poorly cohesive, monotonousevenly distributed cells withintracytoplasmic mucin, highnuclearcytoplasmic ratio,hyperchromatic nuclei withinconspicuous nuclei, completely fillingthe acini in later29. All forms of DCIS canextend to involve the acinar units ofTDLU. Similar morphologicalappearance of the cells in acini and ductspaces differentiate if from LCIS andALH, which are lobulocentric andextend in the ducts in a pagetoid fashion.Lobular neoplasm has discohesive cellsdue to loss of E- cadherin (specific markerfor lobular epithelial lesions of breast)30,31.


82

Presence of fibrovascular core coveredby epithelium distinguishes papillaryneoplasm from papil lomatosis .Papilloma may not be differentiatedfrom papillary carcinoma on frozensection. A well-developed fibrovascularcore lined by epithelial cells revealingbenign nuclei and mixed withmyoepithelial cells, with or with outpresence of apocrine cells, indicatesbenign tumor. Poorly developed ordelicate fibrovascular core, absence ofmyoepithelial cells, epithelial cells withatypical nuclei lined perpendicular tocentral core and sheets of variablethickness favour papillary carcinoma32.

Uncommon carcinomas

Malignancies other than adeno-carcinomas (squamous cell carcinoma,phyllodes tumor, sarcoma andlymphoma) make up fewer than 5% ofall the breast malignancies. In-situcarcinoma and invasive carcinoma aredifferentiated on the basis of malignantcells crossing the basement membraneinto the stroma in later with a potentialto invade the vasculature and metastasizeinto regional lymphnodes and distantsites. In-situ carcinomas, however, canextend to the overlying skin through theductal system as Paget’s disease. Althoughmorphologically classified as ductal orlobular on the basis of resemblance tothese structures, all carcinomas arethought to arise from TDLU and do notimply a site or cell type of origin. Ductalcarcinoma in-situ (DCIS), most often nonpalpable or vaguely palpable mass(earlier diagnosed as incidental findingin a biopsy for other lesions), are beingdetected with increasing frequency onmammographic screening asmicrocalcification or less often asdensity. It involves only a single ductalsystem or spread through out ducts and

lobules involving an entire sector ofbreast. In contrast to LCIS, these aregenerally monofocal lesions without skiplesions beyond 10mm and may be treatedwith complete excision ensuring a clearmargin of 10mm33.

Historically five architectural subtypesComedocarcinoma (high grade withcentral necrosis), Solid (high grade,completely filling the ducts), Cribriform(low to high grade), Papillary withfibrovascular core and Micropapillaryhaving bulbous protrusions without afibrovascular core (intermideate grade)have been described. Interestingly,mammographic calcifications are moreoften-calcified intraluminal secretionthan central necrosis. Uncommonvariants have been reported34. Small cellssolid DCIS made up of uniformpopulation of cells extending to TDLUmay be indistinguishable fromLCIS.Discohesion of cells favours later.Apocrine DCIS should be differentiatedfrom apocrine metaplasia and atypicalapocrine hyperplasia on the basis ofcharacteristic cytoarchitectural featuresand extent of lesion occupying the space(discussed in biopsy interpretation). It isfurther categorized, on the basis of cellcytology, in low grade (non necrotic) andhigh grade (necrotic) apocrine DCIS35.Neuroendocrine DCIS, usually seen inelderly women and presenting withnipple discharge, may be misdiagnosed asbenign lesions. Arranged in papillary orsolid pattern, the cells are polygonal,oval or spindle with high N/C ratio andgranular cytoplasm. Mucin is present inthe lumen and cells show negativeargentaffin and positive argyrophilicreaction. Clinging pattern refers to scantytumor cells attached to the duct liningepithelial layer irrespective of nucleargrade .It is possibly not a distinct entitybut a variant of ADH, micropapillary

DCIS or large cell DCIS. An interestingvariant is cystic hypersecretory DCIS.Cells line the ducts with more abundantcytoplasm revealing a secretory change,forming large distended cystic spacesfilled with colloid like material. Signetring cells DCIS has also been described;though signet ring cell pattern is rathercharacteristic of LCIS36,37,38.

It must be borne in mind that all thoughthere are many histomorphologicmarvels giving delight to thehistopathologist, pure forms areuncommon and different entities maysimply be variants of common forms.Invasive carcinoma may be a firmpalpable mass fixed to skin withretraction of nipple, and at times manifestas enlarged erythematous breast due toextensive involvement of dermallymphatics known as inflammatorycarcinoma, mimicking inflammatoryconditions on clinical examination,causing delay in diagnosis. Rarely, theprimary can be small or obscured bydense breast tissue manifesting asmetastasis in axillary nodes and distantsites with occult primary39 .The commonhistologic types include Invasive DuctCarcinoma (IDC), No Special Type(NST), lobular carcinoma, tubular,mucinous (colloid), cribriform,medullary and papillary carcinomas40.Carcinoma associated with large amountof DCIS requires wide excision to reducelocal recurrences.

Lobular carcinoma, in one fourth of thecases, has a diffuse pattern of invasionwithout prominent desmoplasia;producing only a vaguely thickened areaand subtle architectural changes onmammography. Greater incidence ofbilaterality of this tumour is beingquestioned, due to bias for performingcontralateral surgery in such patients.Hormone replacement therapy, in post


menopausal patients, may be responsiblefor increased incidence reported in thisage group. Most lobular carcinomas showloss of a region on chromosome 16(16q.22.1) including a cluster of gene forcell adhesion molecule (E Cadherin andb Catenin). Metastases to peritoneum,retroperitoneum, the leptomeninges,GIT, and the ovaries and uterus areobserved more frequently as comparedto other carcinomas 30,41. Althoughcomprising less than 2% of invasivecarcinomas, identifying special type ofcarcinoma is important because in a givenclinical context, adjuvant treatment willbe spared in tumors with good prognosisand vice versa and aggressive tumor willbe treated vigourously.Considered to beof poor prognosis , invasivemicropapil lary carcinoma ischaracterized by clusters of cells inmicropapillary (apical surfaces of thecells polarized insideout, without afibrovascular core.) or tubuloalveolararrangement suspended in a clear space/mucinous or aqueous fluid mimickingserous papillary carcinoma of the ovary.Vascular or lymphatic invasion may beextensive. Expression of ER/PR,HER2/neu, P53 and bcl2 has beenreported in a variable but significantproportion of cases 42,43.

Histologically identical to itscounterpart in salivary glands, adenoidcystic carcinoma is differentiated fromcribriform carcinoma by the presence oftwo cell population of epithelial andmyoepithelial cells, alcian blue positivemucin in large and PAS positive granulesin small cystic spaces and usually negativestaining for hormone receptors44.Occasional case reports include;mucoepidermoid carcinoma, clear cellhideradenoma and eccrinespiraadenoma(originating in breast away fromoverlying skin). Pleomorphic adenoma

and syringomatous tumor in the regionof nipple have also been reported11.Signet ring cell appearance, in a variablepopulation of cells has been observed inlobular carcinoma (otherwise showingcharacteristic discohesive monotonouscell population), ductal carcinoma andmetastasis. A poor prognostic variant,ductal signet ring cell carcinoma isdiagnosed on finding more than 20% ofneoplastic cells having discretemucicarmine positive/ diastase resistantPAS positive vacuoles in contrast toconfluent vacuoles pushing the nucleus toone side in metastasis from other organs.Unusual propensity to involve GIT,serosal and submucosal surfaces ofbladder and stomach have beenreported45.

A carcinoma first described in childrenwith a favourable prognosis manifestingas a well defined nodule due toperipheral fibrosis is juvenile /sclerosing carcinoma. The tumor showsa clear cell pattern due to presence ofintra and extracellular Alcian blue anddiastase labile PAS stain. Similar tumorobserved in adult patients carries poorprognosis46. A poorly differentiatedtumor with nuclear irregularity has beendescribed with cytoplasmic vacuoles oflipids positive with oil –red O47.Neuroendocrine differentiation hasbeen described in lobular carcinoma,ductal and mucinous carcinomas. Lessthan 0.5% of all mammary carcinomamay be composed predominantly, orentirely, of apocrine cells and arereferred to as apocrine carcinoma,behaving prognostically like IDC ofsimilar grade48,49. Epithelial ,myoepithelial tumors are unusualtumors of breast . Inadenomyoepitheliomas, nodules ofspindly myoepithelial cells resemblingsmooth muscle cells surround glandular

element. Any one of the components mayturn malignant with recurrence andmetastasis. Biological behaviour isunpredictable and does not correlate wellwith histology50. Squamous cellcarcinoma and heterologousdifferentiation such as cartilage, bone,myxoid stroma and poorlydifferentiated spindle cell component inan adenocarcinoma is referred to asmetaplastic carcinoma accounting forless than 0.2% of invasive carcinomas.Pleomorphic spindle cell producingappearance of a high-grade sarcoma withpoor prognosis is the most commonmetaplastic element51. A tumor,predominantly composed of bipolarspindle cells of relatively blandappearance arranged in interlacingbundles termed as spindle cell carcinoma,may be difficult to differentiate frombenign spindle cell proliferation offibromatosis52. Abrupt transition fromcarcinoma to an osseous or cartilaginousmatrix with out zone of transition hasbeen termed as matrix producingcarcinoma53. Low-grade adenosquamouscarcinoma may look like syringmatoustumor of minor salivary gland,microcystic adnexal carcinoma of skin inthe region of lip and syringomatousadenoma of nipple. Its association hasbeen reported with sclerosing adenosis,radical scar, ductal adenoma, papillomaand adenomyoepithelioma suggestingprobability of all these entities belongingto a broad spectrum ofadenomyoepithelial lesions54. Puresquamous cell carcinoma of breast is rare,and must be diagnosed only afterthorough sampling does not reveal anyarea of adenocarcinoma. Squamousdifferentiation is not uncommon inIDC55.


84

Prognostic factors in breastcancer

Increasing choice of therapeuticmodalities is available today for breastcarcinoma including surgical excisionvarying from conservative approach toradical dissection, various types ofchemotherapeutic regimes andradiotherapy. Prognostic and predictivefactors help in choosing the mostappropriate modality. Prognostic factorsprovide information useful in assessingthe outcome at the time of diagnosiswhereas predictive factors provideinformation about likelihood of responseto a given therapy. The degree ofepithelial proliferation in the breastlesions correlates with the magnitude ofrisk of developing invasive carcinoma.Patients with no or mild hyperplasiahave no increased risk for subsequentinvasive carcinoma; whereas moderate orflorid hyperplasia increases the risk 1.5to 2 times. The risk becomes five foldswith ADH or ALH and eight to ten foldwith DCIS or LCIS56.

The prognostic factors can be broadlyclassified as conventional and molecular.Amongst conventional prognosticfactors, age less than 50 years and earlydiagnosis of asymptomatic breastcarcinoma are considered goodprognostic factors57. Carcinomasmanifesting during pregnancy orlactation are poor prognostic with lowerexpression of hormonal receptors andhigh expression of HER 2/neu. Oralcontraceptive does not bear anyprognostic relationship58,59. Size of thetumor remains one of the strongestpredictors of dissemination and rate ofrelapse in node negative disease.“Minimal breast cancer” includes alltypes of in-situ carcinomas together withinvasive carcinomas with maximum

diameter of 1cm on subserial slicing ofwhole breast and mammography. It isrecommended that the size of tumorshould be measured to the nearestmillimeter in fresh state and afterfixation. On histologic section of thetumors measuring up to 1cm and/ orwith in-situ component, the stagemicrometer should be used60.Multicentric tumors are poor prognosticdiseases. Chances of involvement ofcontra lateral breast are five times inpatients suffering with carcinoma of onebreast as compared to general population61.

Histologically, tubular, cribriform,mucinous and tubuloalveolar carcinomasare included in the excellent prognosticgroup; where as tubular mixed, mixedductal NST, and classical lobularcarcinomas are good prognostic. Theaverage prognostic group includes mixedlobular, medullary and atypicalmedullary carcinomas and the poorprognostic group; ductal NST, mixedductal and lobular and solid lobularcarcinomas. Signet ring cell carcinomasand the ones clinically manifesting asinflammatory carcinomas haveextremely bad prognosis. Squamous cellcarcinoma, metaplastic carcinoma andcarcinoma with neuroendocrinedifferentiation are said to be aggressiveneoplasm but with little difference fromIDC in survival rate62. A number ofgrading systems have been devised tocorrelate morphology with prognosis.With all grading systems, wide samplingis important because grading may varyin different areas and there may be mixingof patterns. The most widely used gradingmethod for breast cancer is BloomRichardson system modified by Ellistonand Ellis, conceived for invasive ductalcarcinoma. It can be applied to its specialtypes and lobular carcinoma as well. In

this scheme, the grade is obtained byadding up the score of tubule formation,nuclear pleomorphism and mitoticcount. Each is assigned a score from 1-3points. The tumor is graded as- Grade 1(3-5 points); Grade 2(6-7 points); and Grade3(8-9 points)63.

Extensive necrosis and inflammatoryreaction at the periphery of the tumor(except in medullary carcinoma) may beassociated with an increased incidence oflymph node metastasis and decreasedsurvival rate. Stromal fibrosis andperiductal and diffuse elastosis have notbeen found prognostic factorsindependent of histological type oftumor64-66. Assessment of in-situcomponent, particularly at the excisionmargin of the specimen removed forIDC, is becoming important in thecontext of conservative breast surgery.Extensive in-situ component left behind,may be the source of relapse67.

Careful examination of lymph nodessubmitted from axillary chain, internalmammary chain (for medially locatedtumor) and sentinel lymph nodes is ofcritical importance. Lymph nodesmeasuring less than 5 mm may beprocessed in groups, sliced at two levels.Larger nodes should be sliced at rightangles to long axis with a maximum offour lymph nodes per block.Immunostaining should be carried out innegative nodes with suspiciousmorphology. Over all, ten-year survivalis reduced from 75% for node negativepatients to 25-35%for nodes positivepatients. The lymph node stage has beendivided into three categories, stage A- nolymph node involvement; stage B- upto 3axillary or single internal mammarynode and stage C- 4 or more axillarynodes. Extracapsular infiltration of thenodal metastasis is poor prognostic andmay warrant postoperative axillary


radiation68. Lymphovascular invasionshould be called positive only whentumor cells are present in spaces having aclear lining of endothelial cells in thetissue adjoining the tumor and notwithin. Vascular invasion is one of themost important predictors ofrecurrences following conservativesurgery and in f laps followingmastectomy69.

The three most powerful prognosticdeterminants: lymph node stage, tumorsize and histologic grade have been takeninto consideration for calculatingNottingham’sPrognostic Index(NPI).

NPI- [size (cm) x 0.2]+[lymph node stage(1-3)]+[grade (1-3)]

Score of less than 3.4 is good prognosticwith 15 years survival compared to anage matched control population being80%; score of 3.4-5.4, moderate groupwith 15 years survival 42% and scoreover 5.4, poor group with 15 yearssurvival of 13%68.

Molecular prognostic/ predictive factorsin use include hormone receptors,HER2/neu (c-erbb2). Immuno-histochemistry, although less readilyquantifiable, has substituted biochemicalassay on fresh tumor tissue for estrogen/progesterone receptors (ER/PR)analysis; as the former can be carried outon small samples including fine needleaspirates and avoids sampling error. Anattempt has been made to calculate ascore (H- score) taking in to considerationnumber of the tumor cell nuclei stainedand intensity of reaction; each assignedgrade 0-4. Adding up the two scores, thescoring of two or less may be consideredER/PR negative with negligible chanceof response to adjuvant hormonetherapy70.

Hormone receptors positivity bearspoor correlation with cytoarchitecturaltype; however the correlation of thereceptors has been found lower in thetumors from premenopausal groupcompared to postmenopausal women.Estrogen receptors positivity correlatessignificantly with high nuclear and lowhistologic grades, absence of tumornecrosis, presence of marked tumorelastosis, older patient age group, absenceof p53 mutation and absence of epidermalgrowth factor receptors70.

HER-2/neu is an oncogene that encodesa transmembrane glycoprotein withtyrosine kinase activity known as p185,which belongs to the family of growthfactor receptors. Its overexpression canbe measured by immunochemistry orFISH technique. It’s over expressioncorrelates with Herceptin therapy but isnot good predictor of response tochemotherapy or survival rates71.

Future predictive markers

It is widely accepted that tumors, with avery high proliferation rate, such as acuteleukemias, high grade lymphomas andgerm cell tumors, can responddramatically to chemotherapy. Similar,though less dramatic behaviour, has beenreported in breast cancers. Thusparameters of cell proliferation activityand DNA ploidy, whether measured byold fashioned mitotic count, by MIB-1(ki-67) or analog immunostain ordetermination of S phase fraction byflow cytometery have emerged as veryimportant prognostic determinants. Inone study tumor with a low S phasefraction (SPF<5%) had a response rateof 46% and with an intermediate SPF (5-10%) of 84%. All patients with a highSPF (>10%) responded tochemotherapy72. Presence of predictorsof invasion and metastasis at the

advancing edge of tumor has a bearing onthe invasive and metastatic ability of thetumor. Elevated levels of plasminogenactivators and inhibitors, such asurokinase type plasminogen activator(uPA) and plasminogen activatorinhibitor 1(PAI-1), are independentpredictors of shortened relapse freesurvival and over all survival. Patientswith uPA negative tumors have a betterresponse to tamoxifen treatment thanthose with uPA positive tumors73.Cathepsin D is a lysosomal protein thatis likely to have a role in tumor invasionand metastasis. The level of cathepsin Din normal breast is lower than 8 units/dl. This protease is overexpressed andsecreted by breast cancer cells. In nodenegative patients, cathepsin Doverexpression has been shown to be animportant predictor of poor survival andrecurrences74. Over expression of cellcycle regulator, cyclinD1 (required fortransition from G1to S phase of cycle)has not been found an independentprognostic marker in breast cancer75. P53gene is involved in the control of cellgrowth by keeping a check on the entryof cell into S phase. Mutation in p53 genecorrelates with aneuploidy, absence ofhormone receptors, a high tumor grade,a high S phase fraction, postmenopausalstatus and reduced patient survival76. Thenm23 gene has been associated withmetastatic suppressive ability. In breastcancer, reduced nm23H-1 expressioncorrelates with high metastaticpotential77.

E-cadherin and its down streammolecular alpha catenin are involved inhemotypic cell interactors. Loss ofexpression of these molecules correlateswith metastasis78. A gain in expression ofalpha-6-integrin is associated withreduced survival, which facilitates theadhesion of tumor cells to the vascular


86

endothelium. CD44 is a transmembraneglycoprotein occurring in severalisoforms. In breast cancer, expression ofCD44V6 has been shown to beindependent predictor of overall poorsurvival80. Expression of vascularendothelial factor (VEGF) and plateletderived growth factor(PDGF) as studiedby immunostain and RT-PCR methods,correlates with microvessel counts ortumor angiogenesis. This is a potent andindependent prognostic indicator,especially in early stage of cancer81.

Genetic predisposition

Identif ication of breast cancersusceptibility genes namely- BRCA-1 andBRCA-2 and ATM has revolutionizedthe breast cancer research. BRCA-1 is atumor suppressor gene and women withmutation in this gene are at high risk ofdevolping early onset breast and ovariancancers. Genetic mutations are inheritedin an autosomal dominant manner andmutations in BRCA-1 account for 50%of inherited breast cancer. The other geneassociated with familial early onset breastcancer is BRCA-2 localized onchromosome 13q12-13. About 70% ofbreast cancer families, which do notharbour mutation in BRCA-1, havemutations in BRCA-2 gene. Patients ofataxia-telengectasia(homozygous state)carry a risk of cancer 60-180 times abovegeneral population82.There are greathopes that evaluation of expression ofthousands of genes through microarraytechnology, that allows a much sharperseparation of prognostic groups than iscurrently possible, and markers ofresponse to specific treatment, will beidentified so that patients can get the mostsuitable treatment for the individualtumor without delay.

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Know about CSF

Formation 0.5ml/min. 60% bychoroid plexus in lateralventricles and 40% by exposed

vessels on verthicular walls.

Composition:

150 ml (Roughly)Clear, colourlessNo red blood cellsProteins 20 mg%Glucose 50% of Plasma

Calcium, cholestrol, urea are lowerthan plasma. Chloride, creatinine arehigher than plasma.

Pressure : 10-13 cm of water

Functions supports brain tissueRegulates brain ECF ProvidesProtein transport

Foot

• 26 Bones

• 29 Joints

• 42 Intrinsic muscles

• Numerous ligaments

• Increased vascularity

Human being walks 4,500 - 6,000 stepsper day, on an average. He/she walks1,85,000 km in his/her life timewhich amounts to going through theworld four times.

= Diabetic Foot

In diabetic foot the rule of 15 is asfollows:

15% of diabetic patients have footproblems

of these 15% are diagnosed

of these 15% are treated

of these 15% are amputed


90

Guidelines for the ContributorsSubmission of manuscript: All manuscripts submitted for publication to the NBE Journal of Post graduate Medical Education,Training & Research should include the following:1. Covering letter: One of the authors could be identified as the corresponding author of the paper, who would be responsiblefor the correspondence with the editor.2. Manuscript: Manuscripts can be submitted in a CD (compact disc) in MS Word (in addition to one hard copy). Typescriptshould be sent to the Editor, NBE Journal of Post graduate Medical Education, Training & Research, National Board ofExaminations, Ring Road, Ansari Nagar, New Delhi- 110 029 (India).Manuscripts should be presented in as concise a form as possible, typewritten in double space on one side of a good quality bondpaper (21.0 x 29.7 cms). Pages should be numbered consecutively and the contents arranged in the following order:- Title; Name(s)of the author(s); Department(s) and Institution (s); Abstract; Key words; Introduction; Material & Methods; Results; Discussion;Acknowledgement; and References. Abstract, Tables and Legends for Figures should be typed on separate sheets and not incontinuation of the main text.Title: Title of the article should be short, continuous (broken or hyphenated titles are not acceptable) and yet sufficiently descriptiveand informative so as to be useful in indexing and information retrieval.Abstract: Abstract should be brief (250 words) and indicate the scope and significant results of the paper. It should only highlightthe principal findings and conclusions so that it can be used by abstracting services without modification. Conclusions andrecommendations not found in the text of the articles should not be inserted in the Abstract. A set of suitable key words arrangedalphabetically may be provided.Introduction: Introduction should be brief and state precisely the scope of the paper. Review of the literature should be restrictedto reasons for undertaking the present study and provide only the most essentials background. This should cover the study area,study population, sample size, sampling techniques and the data collection techniques and tools, data analyses and statistical analyses.Results: Only such data as are essential for understanding the discussion and main conclusions emerging from the study shouldbe included. The data should be arranged in unified and coherent sequence. Data presented in tables and figures should not berepeated in the text. Only important observations need to be emphasized or summarised.Discussion: The discussion should deal with the interpretation of results without repeating information already presented underResults. It should relate new findings to the known ones and include logical deductions. It should also mention any weaknesses ofthe study. The conclusions can be linked with the goals of the study. All hypotheses should, if warranted, clearly be identified as such;recommendations may be included as part of Discussion, only when considered absolutely necessary and relevant.Acknowledgment: Acknowledgment should be brief and made for specific/technical assistance and financial support only andnot for providing routine departmental facilities and encouragement or for help in the preparation of the manuscripts (includingtyping or secretarial assistance).References: The total number of References should normally be restricted to a maximum of 30.References to literature cited should be numbered consecutively and placed at the end of the manuscript. In the text they should beindicated above the line (superior). As far as possible mentioning names of author(s) under references should be avoided in text.These should be written in vancouver style.1. Standard journal article- Sharma AK, Singh S, Organ transplantation in HIV infected patients. N. Engl. J. Med. 2002; 347:

284-72. Books and Monograph- Murray RR, Rusenthal KS. Medical Microbiology. 4th ed. St. Lovis: Mosby; 2002.3. Chapter in a book- Meltzen PS, Trent JM. Chromosome alternations in human solid tumors. In : Vogelstein B,

editor. The Genetic basis of human cancer, Newyork: MC GrawHill; 2002. p. 93-1134. Conference proceedings- Handen P, Jones W D, Editors. Germ cell Tumors. Proceedings of the 5th Germ cell tumor

conference; 2001 Sept 13-15; Leads, U/C. Newyork: Springer; 2002.5. Dissertation- Singh AK. Prevalence of hypertension in school children. Maulana Azad Medical College; 2003.6. Internet article- Abood S. Quality improvement initiatives in running homes Am J Nurs, 2002 Jun; 102 (6),

available from: http//www.muningworld.org/AJN/2002.nurseswatch.com


Undertaking by authorsWe, the undersigned, give an undertaking to the following effect with regard to our article entitled” . . . . . . . . . . . . . . . . . . . . .. . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Submitted for publication in the NBE Journal of Post Graduate Medical Education, Training & ResearchThe article mentioned above has not been published or submitted to or accepted for publication any form, in any other journal.

We also vouchsafe that the authorship of this article will not be contested by anyone whose name(s) is/are not listed by us here. I/We declare that I/We contributed significantly towards the research study i.e., (a) conception, design and/or analysis and interpretationof data and to (b) drafting the article or revision it critically for important intellectual content and on (c) final approval of theversion to be published. I/We also agree to the authorship of the article in the following sequence:

Authors’ names (in Sequence) Signature of authors

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ImportantAll the authors are required to sign independently in this form in the sequence given above. In case an author has left the

institution/country and whose whereabouts are not known, the senior author may sign on his/her behalf taking the responsibility.Addition/deletion/or any Change in the sequence of the authorship will be permissible at a later stage, without valid reasonsand permission of the Editor. If the authorship is contested at any stage, the article will be either returned orwill not be processed for publication till the issue is solved.

Copyright transfer agreementThe NBE Journal of Post Graduate Medical Education, Training & Research is published by the National Board of Examinations,Ansari Nagar, New Delhi- 110 029.The NBE Journal of Post Graduate Medical Education, Training & Research and Authorshereby agree as follows: In consideration of NBE Journal of Post graduate Medical Education, Training & Research reviewing andediting the following described work for first publication on an exclusive basis: Title of manuscript : . . . . . . . . . . . . . . . . . . . . .. . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

The undersigned author(s) hereby assigns, conveys, and otherwise transfers all rights, title, interest and copyright ownership of saidwork for publication. Work includes the material submitted for publication and any other related material submitted to NBEJournal of Post Graduate Medical Education, Training & Research. In the event that NBE Journal of Post Graduate MedicalEducation, Training & Research does not publish said work, the author(s) will be so notified and all rights assigned hereunder willrevert to the author(s).The assignment of rights to NBE Journal of Post Graduate Medical Education, Training & Research includes but is not expresslylimited to rights to edit, publish, reproduce, distribute copies, include in indexes or search databases in print, electronic, or othermedia, whether or not in use at the time of execution of this agreement, and claim copyright in said work throughout the world forthe full duration of the copyright and any renewals or extensions thereof.All accepted works become the property of NBE Journal of Post Graduate Medical Education, Training & Research and may notbe published elsewhere without prior written permission form NBE Journal of Post Graduate Medical Education, Training &Research. The author(s) hereby represents and warrants that they are sole author(s) of the work, that all authors have participatedin and agree with the content and conclusions of the work, that the work is original, and does not infringe upon any copyright,propriety, or personal right of any third part and that no part of it nor any work based on substantially similar data has beensubmitted to another publication.

Authors’ names (in sequence) Signature of authors

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