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Controversies in Melanoma
Prof Ravi Kant, Dr Ajay Yadav, Dr Vivek Gupta, Dr Vishal Gupta, Ms Tanmya Stuti Ravi
2
Controversies in Melanoma
• Biology• Detection-Computer, USG, RT-PCR• Staging- AJCC 2000 +Prognosis• SLN Biopsy + ELND• Surgical margins• Adjuvant treatment + Vaccines• Summary
3
Biology of melanoma
development and progression
4
Biology of melanoma
1. Melanocytes →
2. Nevus →
3. Dysplastic nevus →
4. Radial growth phase →
5. Vertical growth phase →
6. Metastases.
5
Melanoma & Nevi
• Class I = Precursor
• Class II = Intermediate
• Class III = VGP tumorigenic
VGP = vertical growth phase
6
Cell cycle regulation in melanoma
7
Expression of defined molecules in melanoma cell
8
Express adhesions receptors,
Integrins, Adherine, and cellular
adhesions molecules
9
• melanoma cells express N-adherine instead of E-adherine.
• E-adherine allows melanocytes to adhere to keratinocytes, while melanoma cells can not adhere to keratinocytes
10
11B- catenin pathway
12
Biology- what is new?
• PTEN pathway = phosphatase and tensin deleted on chromosome 10 →
• IGF-1 → Akt / PKB (Oncogene)+PtdIns(3,4)P2→ P13 kinase →growth factor + adhesion receptor (integrin)
13
Biology – what is new?
• Ras pathway →Grb2/Sos →ras →Raf →MEK 1,2 →MAPK 1.2 →TCF/SRF/Elk-1 →Proliferation
• As apoptosis is blocked by depriving
• Bad & Caspase-9 from p13 kinase
• Apoptosis turned into growth
Naevi
15
Nevus• Proliferative lesion of
melanocytes
• Scattered along basal layer
• Acquired - mostly
• congenital
16
Naevi : types
1. Lentigo Flat
2. Junctional
3. Compound – slightly elevated
4. Intradermal – papillomatous
17
Naevi: Lentigo simplex-1• Pigmented macule, <5mm, jet
black color
• In infants & children
• Melanocytic proliferation along basal layer
18
Naevi: Lentigo simplex-2• Abundant melanocytes along
basal layer
• Associated with Peutz-Jegher syndrome
• P-J syndrome = hamartomatous polypes in GIT +naevi in oral & buccal mucosa
19
Naevi: Junctional • Next stage after lentigo• Macular lesions, < 7mm• Less deeply pigmented than
lentigo• Homogenous brown black areas• Melanocytic proliferation along
basal layer• Highest malignant potential
20
Naevi: Compound
• Next stage of maturation of junctional naevi
• In children & adolescent
• Pale brown & papular
• Junctional + dermal component
21
Naevi: Intradermal
• Last stage in maturation• Mostly after 30 years of age• Flesh colored papule with little
pigment• Melanocytes confined to
dermis only
22
Blue naevi• Benign melanocytic naevi• Slate blue color• Two types : common & cellular
23
Common Blue naeviMostly in scalp & dorsum of hand, feet1. Dermal collection of spindle
melanocytes2. F > M , max. in 4th decade
24
Blue naevi: Cellular type
1. Uncommon
2. F > M
3. > 50% in sacrococcygeal area& buttock
4. < 1% under go malignancy
5. Rx : simple excision
25
Nevus
• Common
• Atypical
• Congenital
• Spitz
• Familial
26
Malignant Melanoma
• Arises from transformed melanocytes of epidermis
• Accounts for almost all deaths from skin cancer
• 4 fold increase in incidence in Australia
27
Melanoma : Risk Factors-1
• Congenital naevi >5% BSA, 1000X
• Previous melanoma
• Family history
• 5 naevi > 5mm (Common nevi)
• 50 naevi > 2mm (Common nevi)
28
Melanoma : Risk Factors-2
• Dysplastic nevi, Atypical= 2X for single; 12X for >10
• Family history Atypical =37-148X
• Dysplatic naevi syndrome
29
Melanoma : Risk factors-3
• White race,• Red hair, • Blond hair, • Blue eyes• Poor tanning ability, • Sunburns during childhood• Albinism
30
Melanoma : Risk factors-4
• Freckles
• Equatorial latitude
• Xeroderma pigmentosa
• Psoralen sunscreen
• Tanning salons
• Junctional naevi
31
Melanoma : Risk factors-5
• Spitz Nevi= benign except when>10 y age+ulceration>1cmInvolve subcut fatMitotic activity >6/mm2
32
Melanoma : Risk factors-6
• Familial syndromes
• B-K nevus syndromes
• Atypical nevus
• CDKN2A mutation
• CDK4 mutation
33
DD
• Pigmented Basal cell CA
• Seborrheic keratitis
• Solar lentigines
• Atypical nevi
34
MM: Clinical features
• Lentigo maligna : Hutchinson's freckle (7-15%)
• Superficial spreading : most common (60-70%)
• Nodular : 12-25%
• Acral lentiginous
• Amelanotic
35
1. Superficial spreading Melanoma
• Most common type 70%
• Occur any where on skin except hands & feet
• Usually > 5 mm , flat
• Variegated color pattern
• Irregular edge with areas of regression
• Long radial growth phase
36
2. Nodular Melanoma
• Most malignant
• Younger age group
• Any part of the body
• raised and always palpable with sharp irregular border
• Blue, black or gray color
• Lack of radial growth phase
37
2. Nodular Melanoma
• Second most common 15-30 %
• Rapid onset
• ♂>♀
38
3. Lentigo maligna Melanoma
• Hutchinsons melanotic freckle
• Least common type 5%
• Most commonly on face of elderly
• Begins as irregularly pigmented ,flat, brown macule
• quite large at the time of diagnosis late invasive growth phase
• Good prognosis
39
4. Acral lentiginous
• Uncommon 1-3%
• Palm, sole, heel & subungual
• More common in dark skin persons
• Subungual –common in big toe or thumb
• Poor prognosis , 29%@20Y
• 70% ulcerate, 74% >1.5 mm
40
4. Acral lentiginous-risk factor
• >50 y age
• >3mm width, variegated border
• Extension of pigment in to nail bed/ nail fold
• Dark complexioned patient
41
5. Amelanotic Melanoma
• Desmoplastic, 1.7%
• H&N
• Pink, reveal some pigment on close inspection; Stain+ with S-100
• Worse prognosis
• Often present with regional lymph nodes metastases
42
5. Amelanotic Melanoma
• Locally aggressive
• Known for local recurrences
• Stain ► S-100
43
MM : spread
• Local extension
• Blood stream : lung, liver, brain, skin
• Lymphatic :
– embolisation, permeation
– satellite nodule
– in-transit nodule
44
Controversies in Melanoma
• Biology• Detection-Computer, USG, RT-PCR• Staging- AJCC 2000 +Prognosis• SLN Biopsy + ELND• Surgical margins• Adjuvant treatment + Vaccines• Summary
45
MM : Diagnosis
• Signs of transformation of mole in to MM
• Major
–Change in size, shape, color• Minor
–Inflammation, itching
–Crusting or bleeding
– > 5mm diameter
46
MM: Diagnosis
• A : Asymmetry
• B : irregular border
• C : color variegation
• D : diameter > 5 mm
• E : enlargement or evolution
47
Detection- Vision
• A = asymmetry
• B = border irregularity
• C = color variegation
• D =diameter > 6mm
• E = elevation, enlargement, evolutionary changes
• F= any funny change
48
Detection- Vision
1. Change in size2. Change in shape3. Change in Color4. Inflammation5. Crusting / bleeding6. Sensory change7. > 7mm in size enlargement
49
Detection- Digital Vision
• Epiluminescence microscopy
• Dermatoscopy
• Surface microscopy
• Incident light microscopy
• Can see the dermis, epidermo-dermal junction
50
Epiluminescence microscopy-ominous signs
• Melanin pigment network
• Black dots
• Globules
• Streaks
• Radial streaming
• Blue-white milky veils
• Pseudopods
• Pseudo network
• Structure less area
• Melanin reticulum
• Epidermo-dermal junction
• Multiple brown dots
51
Epiluminescence microscopy-good signs
• Axial symmetry of pigmentation
• Presence of one color only
• Sensitivity 92%
• Specificity 71%
52
Detection-digital vision
• Computer based Dermatoscopy
• Spectrophotometric image analysis
• Reflectance spectroscopy
• Computer aided image analysis Topodermatographic
• USG, MR and OCT = in vivo histology
• Virtual histology
53
USG for Regional LN
• 7.5-20 mhZ for LN : 20-100 for Virtual• USG B scan-LN• Vassallo index<2 (Long:Trans)• Hypoechoic central area• Color Doppler-peripheral perfusion• USG Guided FNAC +RT-PCR Tyro• USG guided anchor wire for mets
54
Screening
Dermatologist
or
non-Dermatologists?
55
Screening
Dermatologist
• sensitivity 89% - 97%
• positive predictive value - 17-75%
• specificity - 97%
56
PET vs CTSensitive
%
Specificity %
FDG PET 94-100 83 -94
CT 55-84 68-84
Holder
Ann Surg 1998
Rinne
Cancer 1998
57
FDG PET >CT
• regional and mediastinum lymph nodes
• abdominal visceral and soft tissue metastasis
58
Lung mets
87 vs 70 %
CT>PET
59
MRI for brain
60
A single whole body PET scan could replace all other imaging modalities in melanoma.
PET
61
1. Cost
2. Limited availability
3. Lack of sufficient data
Limitations of PET
62
Controversies in Melanoma
• Biology• Detection-Computer, USG, RT-PCR• Staging- AJCC 2000 + Prognosis• SLN Biopsy + ELND• Surgical margins• Adjuvant treatment + Vaccines• Summary
63
Prognostic factors
Tumor thickness = Breslow
Vs
Level of invasion = Clark level
64
Thickness vs. Level
54 multivariate analysis of
prognostic factors using data from 48 papers
Vollmer
65
Thickness vs. Level
Tumor thickness significant
in 42 of 54 studies
Vollmer
66
Thickness vs. Level
Level of invasion important
prognostic factor in only 8 of 48
Studies
Vollmer
67
Thickness vs. Level
• Tumor thickness
• 1 , 2, & 4 mm
• Best for survival data
• Adopted in 2002 AJCCButtner
Buzaid
68
Thickness vs. Level- conclusion• Clark level of invasion is a minor
prognostic factor
• cutoffs of tumor thickness such as 1mm, 2mm and 4mm provide better prognostic information
• 2002 AJCC staging of melanoma
69
Ulceration: prognostic significance
Significant prognostic factor
Vollmer - multivariate analysis in
7 of 11 studies
70
Ulceration: prognostic significance
strongest predictors of outcome
Balch - meta-analysis that
included 15,798 patients with
localized melanoma
71
Ulceration: prognostic significance
• Ulceration has the most significant impact on survival.
• Buzaid : influence of ulceration according to the tumor thickness
72
Ulceration
• Acantholysis
• Shows autocrine and paracrine pathways are active
• Adverse prognosis
73
Ulceration: prognostic significance
• Independent prognostic factor
• Included in AJCC 2002 staging
• Upstage patients compared
with those having tumor of
same thickness
74
Satellites vs. In-transit metastases
• In transit and satellite metastases
common manifestations of
intralymphatic metastasis
• associated with poor prognosis
75
Satellites vs. In-transit metastases
prognosis of patient with satellites is usually worse than that of patient with in-transit or nodal metastasis (stage III)
Buzaid J Clin Oncol 1997
Haffner Br J Cancer 1992
Cascinelli J Surg Oncol 1986
76
Satellites vs. In-transit metastases
• Satellites =
• pT4b (1997) N2c / N3 (2002)
• Stage II stage III
77
Lymph node size vs. number-Prognostic value
Size not a significant prognostic
factor even after stratification
according to cutoff size
Drepper Cancer 1993
Buzaid J Clin Oncol 1995
78
Lymph node size vs. number-Prognostic value
Number of LN most consistent prognostic factor by multivariate analysis
Buzaid J Clin Oncol 1997
79
Author Pt No OS %
Survival % by LN no
1 2-4 5 or ↑Buzaid 95 442 42 55 34 25Drepper
93112 39 47 31 20
Singletary
92264 NS 45 31
Balch 92 234 NS 40 28 18Coit 91 449 32 40 40 19
80
Lymph node number-Prognostic value
• number of positive nodes has replaced size of lymph node mass
Current 2002 AJCC staging system.
81
Lymph node number-Prognostic value
N1 = 1 LN
N2 = 2 or 3 LNs
N3 = 4 LNs
AJCC 2002 staging
82
Prognostic Value of Biochemical & serologic markers
Significant prognostic factor in melanoma
• LDH
• S-100-B
• melanoma inhibitory activity serum markers
83
Prognostic Value of Biochemical & serologic markers
After logistic regression analysis,
LDH is found to be the only
statistically significant marker
for progressive disease and the
most relevant overall parameter
84
Prognostic Value of Biochemical & serologic markers
• AJCC staging 2002 includes LDH
• Distant metastases + elevated serum LDH = M1c category
• Two or more reports = > 24 hrs apart.
85
Prognostic Markers-1
• Micro stage• Breslow 1,2,4• Clark levels• Ulceration• Mitotic figures• Inflammatory
regression• Micro satellites
• Vertical growth fraction
• Tumor infiltrating lymphocytes
• Molecular markers
• Micro staging approaches
86
Prognostic Markers-2
• S phase fraction• Mitotic index• Ulceration
• RT-PCR +• Tyrosinase or• MelanA or• MART1 m rna
• Integrins: β3 subunit of vitronectin-receptor for Vertical growth phase
• Β1integrin for LN mets
87
Prognostic Markers-3
• MMP-2 ↑=☼• VEGF ↑=☼• Mitf=
Microphtalmia transcription factor ↑=☺
• CD 40 + =☼
• CD 40 L+ CD 40 = worse prognosis
88
Prognostic Markers-4
• Mutation in Codon 12 or 61 of N-ras = ☼ = ↓ OS
• Mutation in Codon 18 of N-ras exon 1 = ☺
(No mets)
• Transcription factor = Activator Protein-2=AP-2
• Regulates gene in cell cycle and growth control
• ↓ AP-2= ↓ p21=
↓ RFS & ↓OS
89
MM : prognostic factors
• Depth of invasion (BRESLOW)
• Ulceration
• High mitotic rate
• Anatomic location
• Histologic type
• Lymphoid & dendritic cell infiltration
• regression
90
Depth of invasion in mm: Breslow
I 1
II 1-2
III 2-4
IV >4
91
Depth of invasion : Clark
• I : superficial to basement membrane
• II : papillary dermis
• III : papillary/reticular dermis junction
• IV : reticular dermis
• V : subcutaneous fat
92
Controversies in Melanoma
• Biology• Detection-Computer, USG, RT-PCR• Staging- AJCC 2000 +Prognosis• SLN Biopsy + ELND• Surgical margins• Adjuvant treatment + Vaccines• Summary
93
Elective LN dissection
Persistent area of controversy
Micro metastases in Clinically N-
= 14% -20%
94
Arguments for Elective LN dissection
retrospective + prospective studies
GoldsmithMemorial hospital1552 patients5 yr survival 78% vs. 68%
95
Melanoma Inter-group Trial 1996
• 700 patients
• Prospective study
• Significantly improved survival rates with ELND in a subgroup = <60 years, non-ulcerated 1-4 mm
Balch : Ann Surg 1996
96
Balch Cancer 1979
At 5 Year Distant Metastases
Survival
ELND 15% 83%
TLND 78% 37%
97
Survival advantage ?
Positive nodes after ELND 16%
Slingluff Ann Surg 1994
98
Elective LN dissection: no benefit
WHO 1998 Prospective
Intergroup Melanoma 1996
Prospective
Mayo Clinic, 1986 Prospective
WHO, 1977 Prospective
Sydney melanoma, 1995 Retrospective
Duke university, 1994 Retrospective
University of Pennsylvania,1985
Retrospective
99
Elective LN dissection: benefitRomple, 1995 Retrospective
Drepper, 1993 Retrospective
Sydney melanoma unit, 1985
Retrospective
Duke university, 1983
Retrospective
University of Alabama, 1982
Retrospective
Memorial, 1975 Retrospective
100
ELND
or
Sentinel LN biopsy ?
101
Sentinel Lymph Node Biopsy
Sensible approach
In view of low occult metastasis - 12-15% ; It allows upto 85% of patients with melanoma to be spared a formal lymph node dissection, thus avoiding complication associated with that procedure
102
SLN biopsy
• 100% sensitive
• 97% specific
Pu Plast Reconstruct Surg 1999
103
• No decrease in survival compared with patients undergoing ELND
• Therapeutically equivalent but prognostically more accurate than ELND
Essner Ann Surg Oncol 1999
104
SLN Indications:
• 5-10% risk of mets to Node
• Candidate for High dose interferon alfa-2b
• Melanoma < 1mm thickness but Clarke level III or ↑ (10% risk of recurrence)
105
• Primary tumors between 1mm
and 4mm thickness
• up to 45% incidence of occult
nodal metastases
106
SLN: Contraindication-1
1. < 1 mm thickness melanoma
(< 2% N or M)
2. > 4mm thickness melanoma,
Clinically N-
(as 60-70% N & occult M 70%)
107
SLN: Contraindication-2
• FNAC + LN
• Prior wide excision of primary
108
SLN Micromets: Significance
Gershenwald 1999 J Clin Oncol
+SLN= 23% rec rate; 16% death rate
- SLN=9% recurrence rate, 35% death
Clary 2001, Ann Surg 233:250-258
+SLN=40% recurrence, 58%DFS@3y
-SLN=14% recurrence, 75%DFS@3y
109
SLN Micromets: Significance
Short term DFS ↑ : HE-, IH-, RT PCR+
Short term DFS ↓ : HE-, IH-, RT PCR+
110
SLN
Method Success in %
Blue dye 70-82
Isotope 84-94
Both 96-98
False +
in %
False-
in %
0,5, 27
111
Blue dye for SLN
• Patent blue V & Isosulfan blue
• Anaphylaxis in 3 / 406 cases
• Incidence with Isosulfan blue =1%
• Prepared for anaphylaxis treatment
112
Blue dye for SLN
• 2-5 ml of 1% Isosulfan blue into the dermis (not sub cut) around the intact tumor + Exercise+ 5-15 minutes wait
• Clears from SLN within 45 minutes
113
Isotope
• Tc 99m labeled sulfur colloid• 100 μm filtered Tc 99m labeled sulfur
colloid- even better• 99m Tc DTPA mannosyl-dextran →
affinity for lymph node; avoid distal lymph node imaging
• 3 hours prior injection, intradermally around the tumor
114
Isotope
• Allows dissection down to the LN without need to create flaps
• Keep hand held array at an angle= avoid “Shine Through”
• If ↑ 3:1 resection bed : background ratio = search more SLN
115
SLN
• H/E stain
• Immunohistochemistry to S-100 protein, HMB-45 antigen,
• RT-PCR Tyrosinase, Mel A
• 14% are HE – and + by IH
• 20-30% are HE-, IH- but RT-PCR+
• Cell culture technique
116
Controversies in Melanoma
• Biology• Detection-Computer, USG, RT-PCR• Staging- AJCC 2000 +Prognosis• SLN Biopsy + ELND• Surgical margins• Adjuvant treatment + Vaccines• Summary
117
• In situ 5 mm
• <2mm 1cm
• >2mm 2cmSober AJ : J Am Acad Dermatol 2001
Current recommendations for surgical margins: primary
cutaneous melanoma : thickness based decision
118
Diameter, Location & Surgical Margins : Zitelli 1997
Location
►
Head & Neck, Hand
Trunk & Extremity
Size in cm ↓
Margin in cm ↓ Margin in cm ↓
< 2 1.5 1
>2 2.5 1.5
119
Surgical margins
No significant difference in survival for excision margin 2 cm or 4 cm for tumor between 1mm and 4mm
Balch Ann Surg 1993
120
Tumor thickness =1-2 mm
Margin 1cm or 3cm
OS same
Margin: WHO Melanoma group
121
No significant difference in survival for margins 2 or 5 cm for tumors between 0.6 mm to 2mm
Swedish melanoma group.
Cancer 1998
Margin 2 or 5 cm
122
Mohs Micrographically controlled Surgery
• In situ fixation- earlier by ZnO
• Now micrography-sectioned and inked and oriented=mapped
123
Controversies in Melanoma
• Biology• Detection-Computer, USG, RT-PCR• Staging- AJCC 2000 +Prognosis• SLN Biopsy + ELND• Surgical margins• Adjuvant treatment + Vaccines• Summary
124
No Role of prophylactic
(adjuvant)
Isolated Limb Perfusion
125
EORTC
WHO
North American Perfusion Group
No improvement in survival
Isolated Limb Perfusion
126
Therapeutic isolated limb perfusion
• Better DFS
• No significant change in OS
Hafstrom J Clin Oncol 1991
127
Who are candidates for ILP?
128
Therapeutic
Patients with in transit disease confined to a limb, with no
signs of distant metastases at presentation.
129
Drugs for ILP
• DTIC + Others
• Melphalan +others
• TNF ά
• Interferon
130
Palliative
Bulky regional disease with limited systemic metastases
131
• identified by prognostic factors or
• identified by sentinel lymph node biopsy.
Clark : J Natl Cancer Inst 1989
Adjuvant Indications:↑risk for metastatic disease
132
High risk melanoma: Interferon
• Thickness >4mm• Mitotic index• Location• Gender• Ulceration• +SLN• AP-2 index
133
Interferon 2b
• √ US FDA for high risk melanoma
• ↓Recurrence
• Interferon alpha2b ▲DFS , ▲ OS by EOCG HDI 1684, EOCG1690 and French LDI Grob 2000- in selected cases
134
• high dose interferon alpha 2b
• tamoxifen,
• cisplatin, and
• Vindesine
• GM CSF
• Levamisole.
Adjuvant ?
135
• TNF• Interleukin-2• Biochemotherapy• Cytokines• Ab3• Peptide based vaccines• MAGE tumor specific shared ag
Adjuvant ?
136
What are New Options
• Biochemotherapy
• DTIC or temozolomide+Nitrosureas
• Interferon = antiproliferative and immunomodulatory
• Interleukin-2 =Immunostimulatory cytokine ►NK cells
137
Vaccines
• Vaccines-ganglioside GM2• MAGE Tumor specific antigens• Ab3 a cytokine• Antibody based vaccines• HLA based• Cell based vaccines• Peptide vaccines• Recombinant viruses
138
Controversies in Melanoma
• Biology• Detection-Computer, USG, RT-PCR• Staging- AJCC 2000 +Prognosis• SLN Biopsy + ELND• Treatment margins• Adjuvant treatment + Vaccines• Summary
139
Major changes in AJCC classification in 2002 -1
• √ Thickness
• X not levels
• √ Ulceration
• √ Number of LN
• X size of LN
• √ LDH
140
Major changes in AJCC classification in 2002-2
• √ Upstaging with ulceration
• √ Merge micro satellite & in-transit mets into stage III
• √ Include SLN into staging
141
Major changes
• Ultrasound of LN
• RT-PCR Tyrosinase of SLN
• 1→ 106–109
• Detect 1 cancer cell out of 106 – 109
normal cells
• Thin margins
• Adjuvant interferon +/-
142
• In situ 5 mm
• <2mm 1cm
• >2mm 2cmSober AJ : J Am Acad Dermatol 2001
Current recommendations for surgical margins: primary
cutaneous melanoma
143
Summary
• No role of wide margins
• No role of ELND
• No role of Prophylactic ILP
• Role of SLN
• Interferon alpha2b ▲DFS , ▲ OS
→ EOCG HDI 1684, EOCG1690
& French LDI Grob 2000- in selected cases
144
Summary Rx
• Primary surgical
• Surgical principles
Complete surgical excision
Minimum margin 1.0 cm
Maximum margin 2.0 cm
Do not excise beyond deep fascia
145
MM :– management of lymph nodes
• Biopsy : FNAC preferred
• Elective dissection : for
1. Clinically involved nodes,
2. Satellitosis,
3. Lymphatic invasion
146
Sentinel lymph node biopsy
• Detects micrometastasis in lymph nodes
• Inrtadermal injection of radioactive colloid around lesion
• Lymph node identified by gamma probe
147
Sentinel lymph node biopsy
• Intraoperative identification by using patent blue dye
• Identify patients appropriate for elective dissection
• Identify patients among high risk for adjuvant interferon.
148
Thank You