controversies in melanoma prof ravi kant, dr ajay yadav, dr vivek gupta, dr vishal gupta, ms tanmya...
TRANSCRIPT
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Controversies in Melanoma
Prof Ravi Kant, Dr Ajay Yadav, Dr Vivek Gupta, Dr Vishal Gupta, Ms Tanmya Stuti Ravi
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Controversies in Melanoma
• Biology• Detection-Computer, USG, RT-PCR• Staging- AJCC 2000 +Prognosis• SLN Biopsy + ELND• Surgical margins• Adjuvant treatment + Vaccines• Summary
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Biology of melanoma
development and progression
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Biology of melanoma
1. Melanocytes →
2. Nevus →
3. Dysplastic nevus →
4. Radial growth phase →
5. Vertical growth phase →
6. Metastases.
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Melanoma & Nevi
• Class I = Precursor
• Class II = Intermediate
• Class III = VGP tumorigenic
VGP = vertical growth phase
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Cell cycle regulation in melanoma
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Expression of defined molecules in melanoma cell
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Express adhesions receptors,
Integrins, Adherine, and cellular
adhesions molecules
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• 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
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11B- catenin pathway
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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)
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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
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Naevi
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Nevus• Proliferative lesion of
melanocytes
• Scattered along basal layer
• Acquired - mostly
• congenital
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Naevi : types
1. Lentigo Flat
2. Junctional
3. Compound – slightly elevated
4. Intradermal – papillomatous
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Naevi: Lentigo simplex-1• Pigmented macule, <5mm, jet
black color
• In infants & children
• Melanocytic proliferation along basal layer
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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
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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
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Naevi: Compound
• Next stage of maturation of junctional naevi
• In children & adolescent
• Pale brown & papular
• Junctional + dermal component
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Naevi: Intradermal
• Last stage in maturation• Mostly after 30 years of age• Flesh colored papule with little
pigment• Melanocytes confined to
dermis only
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Blue naevi• Benign melanocytic naevi• Slate blue color• Two types : common & cellular
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Common Blue naeviMostly in scalp & dorsum of hand, feet1. Dermal collection of spindle
melanocytes2. F > M , max. in 4th decade
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Blue naevi: Cellular type
1. Uncommon
2. F > M
3. > 50% in sacrococcygeal area& buttock
4. < 1% under go malignancy
5. Rx : simple excision
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Nevus
• Common
• Atypical
• Congenital
• Spitz
• Familial
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Malignant Melanoma
• Arises from transformed melanocytes of epidermis
• Accounts for almost all deaths from skin cancer
• 4 fold increase in incidence in Australia
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Melanoma : Risk Factors-1
• Congenital naevi >5% BSA, 1000X
• Previous melanoma
• Family history
• 5 naevi > 5mm (Common nevi)
• 50 naevi > 2mm (Common nevi)
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Melanoma : Risk Factors-2
• Dysplastic nevi, Atypical= 2X for single; 12X for >10
• Family history Atypical =37-148X
• Dysplatic naevi syndrome
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Melanoma : Risk factors-3
• White race,• Red hair, • Blond hair, • Blue eyes• Poor tanning ability, • Sunburns during childhood• Albinism
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Melanoma : Risk factors-4
• Freckles
• Equatorial latitude
• Xeroderma pigmentosa
• Psoralen sunscreen
• Tanning salons
• Junctional naevi
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Melanoma : Risk factors-5
• Spitz Nevi= benign except when>10 y age+ulceration>1cmInvolve subcut fatMitotic activity >6/mm2
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Melanoma : Risk factors-6
• Familial syndromes
• B-K nevus syndromes
• Atypical nevus
• CDKN2A mutation
• CDK4 mutation
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DD
• Pigmented Basal cell CA
• Seborrheic keratitis
• Solar lentigines
• Atypical nevi
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MM: Clinical features
• Lentigo maligna : Hutchinson's freckle (7-15%)
• Superficial spreading : most common (60-70%)
• Nodular : 12-25%
• Acral lentiginous
• Amelanotic
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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
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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
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2. Nodular Melanoma
• Second most common 15-30 %
• Rapid onset
• ♂>♀
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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
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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
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4. Acral lentiginous-risk factor
• >50 y age
• >3mm width, variegated border
• Extension of pigment in to nail bed/ nail fold
• Dark complexioned patient
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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
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5. Amelanotic Melanoma
• Locally aggressive
• Known for local recurrences
• Stain ► S-100
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MM : spread
• Local extension
• Blood stream : lung, liver, brain, skin
• Lymphatic :
– embolisation, permeation
– satellite nodule
– in-transit nodule
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Controversies in Melanoma
• Biology• Detection-Computer, USG, RT-PCR• Staging- AJCC 2000 +Prognosis• SLN Biopsy + ELND• Surgical margins• Adjuvant treatment + Vaccines• Summary
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MM : Diagnosis
• Signs of transformation of mole in to MM
• Major
–Change in size, shape, color• Minor
–Inflammation, itching
–Crusting or bleeding
– > 5mm diameter
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MM: Diagnosis
• A : Asymmetry
• B : irregular border
• C : color variegation
• D : diameter > 5 mm
• E : enlargement or evolution
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Detection- Vision
• A = asymmetry
• B = border irregularity
• C = color variegation
• D =diameter > 6mm
• E = elevation, enlargement, evolutionary changes
• F= any funny change
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Detection- Vision
1. Change in size2. Change in shape3. Change in Color4. Inflammation5. Crusting / bleeding6. Sensory change7. > 7mm in size enlargement
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Detection- Digital Vision
• Epiluminescence microscopy
• Dermatoscopy
• Surface microscopy
• Incident light microscopy
• Can see the dermis, epidermo-dermal junction
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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
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Epiluminescence microscopy-good signs
• Axial symmetry of pigmentation
• Presence of one color only
• Sensitivity 92%
• Specificity 71%
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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
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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
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Screening
Dermatologist
or
non-Dermatologists?
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Screening
Dermatologist
• sensitivity 89% - 97%
• positive predictive value - 17-75%
• specificity - 97%
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PET vs CTSensitive
%
Specificity %
FDG PET 94-100 83 -94
CT 55-84 68-84
Holder
Ann Surg 1998
Rinne
Cancer 1998
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FDG PET >CT
• regional and mediastinum lymph nodes
• abdominal visceral and soft tissue metastasis
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Lung mets
87 vs 70 %
CT>PET
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MRI for brain
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A single whole body PET scan could replace all other imaging modalities in melanoma.
PET
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1. Cost
2. Limited availability
3. Lack of sufficient data
Limitations of PET
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Controversies in Melanoma
• Biology• Detection-Computer, USG, RT-PCR• Staging- AJCC 2000 + Prognosis• SLN Biopsy + ELND• Surgical margins• Adjuvant treatment + Vaccines• Summary
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Prognostic factors
Tumor thickness = Breslow
Vs
Level of invasion = Clark level
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Thickness vs. Level
54 multivariate analysis of
prognostic factors using data from 48 papers
Vollmer
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Thickness vs. Level
Tumor thickness significant
in 42 of 54 studies
Vollmer
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Thickness vs. Level
Level of invasion important
prognostic factor in only 8 of 48
Studies
Vollmer
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Thickness vs. Level
• Tumor thickness
• 1 , 2, & 4 mm
• Best for survival data
• Adopted in 2002 AJCCButtner
Buzaid
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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
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Ulceration: prognostic significance
Significant prognostic factor
Vollmer - multivariate analysis in
7 of 11 studies
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Ulceration: prognostic significance
strongest predictors of outcome
Balch - meta-analysis that
included 15,798 patients with
localized melanoma
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Ulceration: prognostic significance
• Ulceration has the most significant impact on survival.
• Buzaid : influence of ulceration according to the tumor thickness
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Ulceration
• Acantholysis
• Shows autocrine and paracrine pathways are active
• Adverse prognosis
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Ulceration: prognostic significance
• Independent prognostic factor
• Included in AJCC 2002 staging
• Upstage patients compared
with those having tumor of
same thickness
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Satellites vs. In-transit metastases
• In transit and satellite metastases
common manifestations of
intralymphatic metastasis
• associated with poor prognosis
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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
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Satellites vs. In-transit metastases
• Satellites =
• pT4b (1997) N2c / N3 (2002)
• Stage II stage III
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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
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Lymph node size vs. number-Prognostic value
Number of LN most consistent prognostic factor by multivariate analysis
Buzaid J Clin Oncol 1997
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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
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Lymph node number-Prognostic value
• number of positive nodes has replaced size of lymph node mass
Current 2002 AJCC staging system.
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Lymph node number-Prognostic value
N1 = 1 LN
N2 = 2 or 3 LNs
N3 = 4 LNs
AJCC 2002 staging
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Prognostic Value of Biochemical & serologic markers
Significant prognostic factor in melanoma
• LDH
• S-100-B
• melanoma inhibitory activity serum markers
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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
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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.
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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
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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
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Prognostic Markers-3
• MMP-2 ↑=☼• VEGF ↑=☼• Mitf=
Microphtalmia transcription factor ↑=☺
• CD 40 + =☼
• CD 40 L+ CD 40 = worse prognosis
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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
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MM : prognostic factors
• Depth of invasion (BRESLOW)
• Ulceration
• High mitotic rate
• Anatomic location
• Histologic type
• Lymphoid & dendritic cell infiltration
• regression
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Depth of invasion in mm: Breslow
I 1
II 1-2
III 2-4
IV >4
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Depth of invasion : Clark
• I : superficial to basement membrane
• II : papillary dermis
• III : papillary/reticular dermis junction
• IV : reticular dermis
• V : subcutaneous fat
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Controversies in Melanoma
• Biology• Detection-Computer, USG, RT-PCR• Staging- AJCC 2000 +Prognosis• SLN Biopsy + ELND• Surgical margins• Adjuvant treatment + Vaccines• Summary
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Elective LN dissection
Persistent area of controversy
Micro metastases in Clinically N-
= 14% -20%
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Arguments for Elective LN dissection
retrospective + prospective studies
GoldsmithMemorial hospital1552 patients5 yr survival 78% vs. 68%
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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
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Balch Cancer 1979
At 5 Year Distant Metastases
Survival
ELND 15% 83%
TLND 78% 37%
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Survival advantage ?
Positive nodes after ELND 16%
Slingluff Ann Surg 1994
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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
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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
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ELND
or
Sentinel LN biopsy ?
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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
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SLN biopsy
• 100% sensitive
• 97% specific
Pu Plast Reconstruct Surg 1999
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• No decrease in survival compared with patients undergoing ELND
• Therapeutically equivalent but prognostically more accurate than ELND
Essner Ann Surg Oncol 1999
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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)
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• Primary tumors between 1mm
and 4mm thickness
• up to 45% incidence of occult
nodal metastases
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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%)
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SLN: Contraindication-2
• FNAC + LN
• Prior wide excision of primary
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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
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SLN Micromets: Significance
Short term DFS ↑ : HE-, IH-, RT PCR+
Short term DFS ↓ : HE-, IH-, RT PCR+
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SLN
Method Success in %
Blue dye 70-82
Isotope 84-94
Both 96-98
False +
in %
False-
in %
0,5, 27
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Blue dye for SLN
• Patent blue V & Isosulfan blue
• Anaphylaxis in 3 / 406 cases
• Incidence with Isosulfan blue =1%
• Prepared for anaphylaxis treatment
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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
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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
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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
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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
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Controversies in Melanoma
• Biology• Detection-Computer, USG, RT-PCR• Staging- AJCC 2000 +Prognosis• SLN Biopsy + ELND• Surgical margins• Adjuvant treatment + Vaccines• Summary
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• 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
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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
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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
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Tumor thickness =1-2 mm
Margin 1cm or 3cm
OS same
Margin: WHO Melanoma group
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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
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Mohs Micrographically controlled Surgery
• In situ fixation- earlier by ZnO
• Now micrography-sectioned and inked and oriented=mapped
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Controversies in Melanoma
• Biology• Detection-Computer, USG, RT-PCR• Staging- AJCC 2000 +Prognosis• SLN Biopsy + ELND• Surgical margins• Adjuvant treatment + Vaccines• Summary
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No Role of prophylactic
(adjuvant)
Isolated Limb Perfusion
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EORTC
WHO
North American Perfusion Group
No improvement in survival
Isolated Limb Perfusion
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Therapeutic isolated limb perfusion
• Better DFS
• No significant change in OS
Hafstrom J Clin Oncol 1991
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Who are candidates for ILP?
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Therapeutic
Patients with in transit disease confined to a limb, with no
signs of distant metastases at presentation.
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Drugs for ILP
• DTIC + Others
• Melphalan +others
• TNF ά
• Interferon
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Palliative
Bulky regional disease with limited systemic metastases
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• identified by prognostic factors or
• identified by sentinel lymph node biopsy.
Clark : J Natl Cancer Inst 1989
Adjuvant Indications:↑risk for metastatic disease
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High risk melanoma: Interferon
• Thickness >4mm• Mitotic index• Location• Gender• Ulceration• +SLN• AP-2 index
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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
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• high dose interferon alpha 2b
• tamoxifen,
• cisplatin, and
• Vindesine
• GM CSF
• Levamisole.
Adjuvant ?
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• TNF• Interleukin-2• Biochemotherapy• Cytokines• Ab3• Peptide based vaccines• MAGE tumor specific shared ag
Adjuvant ?
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What are New Options
• Biochemotherapy
• DTIC or temozolomide+Nitrosureas
• Interferon = antiproliferative and immunomodulatory
• Interleukin-2 =Immunostimulatory cytokine ►NK cells
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Vaccines
• Vaccines-ganglioside GM2• MAGE Tumor specific antigens• Ab3 a cytokine• Antibody based vaccines• HLA based• Cell based vaccines• Peptide vaccines• Recombinant viruses
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Controversies in Melanoma
• Biology• Detection-Computer, USG, RT-PCR• Staging- AJCC 2000 +Prognosis• SLN Biopsy + ELND• Treatment margins• Adjuvant treatment + Vaccines• Summary
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Major changes in AJCC classification in 2002 -1
• √ Thickness
• X not levels
• √ Ulceration
• √ Number of LN
• X size of LN
• √ LDH
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Major changes in AJCC classification in 2002-2
• √ Upstaging with ulceration
• √ Merge micro satellite & in-transit mets into stage III
• √ Include SLN into staging
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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 +/-
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• In situ 5 mm
• <2mm 1cm
• >2mm 2cmSober AJ : J Am Acad Dermatol 2001
Current recommendations for surgical margins: primary
cutaneous melanoma
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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
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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
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MM :– management of lymph nodes
• Biopsy : FNAC preferred
• Elective dissection : for
1. Clinically involved nodes,
2. Satellitosis,
3. Lymphatic invasion
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Sentinel lymph node biopsy
• Detects micrometastasis in lymph nodes
• Inrtadermal injection of radioactive colloid around lesion
• Lymph node identified by gamma probe
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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.
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Thank You