Controversies in Melanoma

Prof Ravi Kant, Dr Ajay Yadav, Dr Vivek Gupta, Dr Vishal Gupta, Ms Tanmya Stuti Ravi

• Biology• Detection-Computer, USG, RT-PCR• Staging- AJCC 2000 +Prognosis• SLN Biopsy + ELND• Surgical margins• Adjuvant treatment + Vaccines• Summary

Biology of melanoma

development and progression

Biology of melanoma

1. Melanocytes →

2. Nevus →

3. Dysplastic nevus →

4. Radial growth phase →

5. Vertical growth phase →

6. Metastases.

Melanoma & Nevi

• Class I = Precursor

• Class II = Intermediate

• Class III = VGP tumorigenic

VGP = vertical growth phase

Cell cycle regulation in melanoma

Expression of defined molecules in melanoma cell

Express adhesions receptors,

Integrins, Adherine, and cellular

adhesions molecules

• 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

11B- catenin pathway

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)

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

Nevus• Proliferative lesion of

melanocytes

• Scattered along basal layer

• Acquired - mostly

• congenital

Naevi : types

1. Lentigo Flat

2. Junctional

3. Compound – slightly elevated

4. Intradermal – papillomatous

Naevi: Lentigo simplex-1• Pigmented macule, <5mm, jet

black color

• In infants & children

• Melanocytic proliferation along basal layer

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

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

Naevi: Compound

• Next stage of maturation of junctional naevi

• In children & adolescent

• Pale brown & papular

• Junctional + dermal component

Naevi: Intradermal

• Last stage in maturation• Mostly after 30 years of age• Flesh colored papule with little

pigment• Melanocytes confined to

dermis only

Blue naevi• Benign melanocytic naevi• Slate blue color• Two types : common & cellular

Common Blue naeviMostly in scalp & dorsum of hand, feet1. Dermal collection of spindle

melanocytes2. F > M , max. in 4th decade

Blue naevi: Cellular type

1. Uncommon

2. F > M

3. > 50% in sacrococcygeal area& buttock

4. < 1% under go malignancy

5. Rx : simple excision

• Common

• Atypical

• Congenital

• Spitz

• Familial

Malignant Melanoma

• Arises from transformed melanocytes of epidermis

• Accounts for almost all deaths from skin cancer

• 4 fold increase in incidence in Australia

Melanoma : Risk Factors-1

• Congenital naevi >5% BSA, 1000X

• Previous melanoma

• Family history

• 5 naevi > 5mm (Common nevi)

• 50 naevi > 2mm (Common nevi)

Melanoma : Risk Factors-2

• Dysplastic nevi, Atypical= 2X for single; 12X for >10

• Family history Atypical =37-148X

• Dysplatic naevi syndrome

Melanoma : Risk factors-3

• White race,• Red hair, • Blond hair, • Blue eyes• Poor tanning ability, • Sunburns during childhood• Albinism

• Freckles

• Equatorial latitude

• Xeroderma pigmentosa

• Psoralen sunscreen

• Tanning salons

• Junctional naevi

• Spitz Nevi= benign except when>10 y age+ulceration>1cmInvolve subcut fatMitotic activity >6/mm2

• Familial syndromes

• B-K nevus syndromes

• Atypical nevus

• CDKN2A mutation

• CDK4 mutation

• Pigmented Basal cell CA

• Seborrheic keratitis

• Solar lentigines

• Atypical nevi

MM: Clinical features

• Lentigo maligna : Hutchinson's freckle (7-15%)

• Superficial spreading : most common (60-70%)

• Nodular : 12-25%

• Acral lentiginous

• Amelanotic

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

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

2. Nodular Melanoma

• Second most common 15-30 %

• Rapid onset

• ♂>♀

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

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

4. Acral lentiginous-risk factor

• >50 y age

• >3mm width, variegated border

• Extension of pigment in to nail bed/ nail fold

• Dark complexioned patient

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

5. Amelanotic Melanoma

• Locally aggressive

• Known for local recurrences

• Stain ► S-100

MM : spread

• Local extension

• Blood stream : lung, liver, brain, skin

• Lymphatic :

– embolisation, permeation

– satellite nodule

– in-transit nodule

MM : Diagnosis

• Signs of transformation of mole in to MM

• Major

–Change in size, shape, color• Minor

–Inflammation, itching

–Crusting or bleeding

– > 5mm diameter

MM: Diagnosis

• A : Asymmetry

• B : irregular border

• C : color variegation

• D : diameter > 5 mm

• E : enlargement or evolution

Detection- Vision

• A = asymmetry

• B = border irregularity

• C = color variegation

• D =diameter > 6mm

• E = elevation, enlargement, evolutionary changes

• F= any funny change

Detection- Vision

1. Change in size2. Change in shape3. Change in Color4. Inflammation5. Crusting / bleeding6. Sensory change7. > 7mm in size enlargement

Detection- Digital Vision

• Epiluminescence microscopy

• Dermatoscopy

• Surface microscopy

• Incident light microscopy

• Can see the dermis, epidermo-dermal junction

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

Epiluminescence microscopy-good signs

• Axial symmetry of pigmentation

• Presence of one color only

• Sensitivity 92%

• Specificity 71%

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

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

Screening

Dermatologist

non-Dermatologists?

Screening

Dermatologist

• sensitivity 89% - 97%

• positive predictive value - 17-75%

• specificity - 97%

PET vs CTSensitive

Specificity %

FDG PET 94-100 83 -94

CT 55-84 68-84

Holder

Ann Surg 1998

Cancer 1998

FDG PET >CT

• regional and mediastinum lymph nodes

• abdominal visceral and soft tissue metastasis

Lung mets

87 vs 70 %

CT>PET

MRI for brain

A single whole body PET scan could replace all other imaging modalities in melanoma.

1. Cost

2. Limited availability

3. Lack of sufficient data

Limitations of PET

• Biology• Detection-Computer, USG, RT-PCR• Staging- AJCC 2000 + Prognosis• SLN Biopsy + ELND• Surgical margins• Adjuvant treatment + Vaccines• Summary

Prognostic factors

Tumor thickness = Breslow

Level of invasion = Clark level

Thickness vs. Level

54 multivariate analysis of

prognostic factors using data from 48 papers

Vollmer

Thickness vs. Level

Tumor thickness significant

in 42 of 54 studies

Vollmer

Thickness vs. Level

Level of invasion important

prognostic factor in only 8 of 48

Studies

Vollmer

Thickness vs. Level

• Tumor thickness

• 1 , 2, & 4 mm

• Best for survival data

• Adopted in 2002 AJCCButtner

Buzaid

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

Ulceration: prognostic significance

Significant prognostic factor

Vollmer - multivariate analysis in

7 of 11 studies

strongest predictors of outcome

Balch - meta-analysis that

included 15,798 patients with

localized melanoma

• Ulceration has the most significant impact on survival.

• Buzaid : influence of ulceration according to the tumor thickness

Ulceration

• Acantholysis

• Shows autocrine and paracrine pathways are active

• Adverse prognosis

• Independent prognostic factor

• Included in AJCC 2002 staging

• Upstage patients compared

with those having tumor of

same thickness

Satellites vs. In-transit metastases

• In transit and satellite metastases

common manifestations of

intralymphatic metastasis

• associated with poor prognosis

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

• Satellites =

• pT4b (1997) N2c / N3 (2002)

• Stage II stage III

Lymph node size vs. number-Prognostic value

Size not a significant prognostic

factor even after stratification

according to cutoff size

Drepper Cancer 1993

Lymph node size vs. number-Prognostic value

Number of LN most consistent prognostic factor by multivariate analysis

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

Lymph node number-Prognostic value

• number of positive nodes has replaced size of lymph node mass

Current 2002 AJCC staging system.

Lymph node number-Prognostic value

N1 = 1 LN

N2 = 2 or 3 LNs

N3 = 4 LNs

AJCC 2002 staging

Prognostic Value of Biochemical & serologic markers

Significant prognostic factor in melanoma

• LDH

• S-100-B

• melanoma inhibitory activity serum markers

After logistic regression analysis,

LDH is found to be the only

statistically significant marker

for progressive disease and the

most relevant overall parameter

• AJCC staging 2002 includes LDH

• Distant metastases + elevated serum LDH = M1c category

• Two or more reports = > 24 hrs apart.

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

• 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

• MMP-2 ↑=☼• VEGF ↑=☼• Mitf=

Microphtalmia transcription factor ↑=☺

• CD 40 + =☼

• CD 40 L+ CD 40 = worse prognosis

• 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

MM : prognostic factors

• Depth of invasion (BRESLOW)

• Ulceration

• High mitotic rate

• Anatomic location

• Histologic type

• Lymphoid & dendritic cell infiltration

• regression

Depth of invasion in mm: Breslow

II 1-2

III 2-4

Depth of invasion : Clark

• I : superficial to basement membrane

• II : papillary dermis

• III : papillary/reticular dermis junction

• IV : reticular dermis

• V : subcutaneous fat

Elective LN dissection

Persistent area of controversy

Micro metastases in Clinically N-

= 14% -20%

Arguments for Elective LN dissection

retrospective + prospective studies

GoldsmithMemorial hospital1552 patients5 yr survival 78% vs. 68%

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

Balch Cancer 1979

At 5 Year Distant Metastases

Survival

ELND 15% 83%

TLND 78% 37%

Survival advantage ?

Positive nodes after ELND 16%

Slingluff Ann Surg 1994

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

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

Sentinel LN biopsy ?

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

SLN biopsy

• 100% sensitive

• 97% specific

Pu Plast Reconstruct Surg 1999

• No decrease in survival compared with patients undergoing ELND

• Therapeutically equivalent but prognostically more accurate than ELND

Essner Ann Surg Oncol 1999

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)

• Primary tumors between 1mm

and 4mm thickness

• up to 45% incidence of occult

nodal metastases

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%)

SLN: Contraindication-2

• FNAC + LN

• Prior wide excision of primary

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

SLN Micromets: Significance

Short term DFS ↑ : HE-, IH-, RT PCR+

Short term DFS ↓ : HE-, IH-, RT PCR+

Method Success in %

Blue dye 70-82

Isotope 84-94

Both 96-98

False +

False-

0,5, 27

Blue dye for SLN

• Patent blue V & Isosulfan blue

• Anaphylaxis in 3 / 406 cases

• Incidence with Isosulfan blue =1%

• Prepared for anaphylaxis treatment

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

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

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

• 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

• 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

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

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

Tumor thickness =1-2 mm

Margin 1cm or 3cm

OS same

Margin: WHO Melanoma group

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

Mohs Micrographically controlled Surgery

• In situ fixation- earlier by ZnO

• Now micrography-sectioned and inked and oriented=mapped

No Role of prophylactic

(adjuvant)

Isolated Limb Perfusion

North American Perfusion Group

No improvement in survival

Isolated Limb Perfusion

Therapeutic isolated limb perfusion

• Better DFS

• No significant change in OS

Hafstrom J Clin Oncol 1991

Who are candidates for ILP?

Therapeutic

Patients with in transit disease confined to a limb, with no

signs of distant metastases at presentation.

Drugs for ILP

• DTIC + Others

• Melphalan +others

• TNF ά

• Interferon

Palliative

Bulky regional disease with limited systemic metastases

• identified by prognostic factors or

• identified by sentinel lymph node biopsy.

Clark : J Natl Cancer Inst 1989

Adjuvant Indications:↑risk for metastatic disease

High risk melanoma: Interferon

• Thickness >4mm• Mitotic index• Location• Gender• Ulceration• +SLN• AP-2 index

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

• high dose interferon alpha 2b

• tamoxifen,

• cisplatin, and

• Vindesine

• GM CSF

• Levamisole.

Adjuvant ?

• TNF• Interleukin-2• Biochemotherapy• Cytokines• Ab3• Peptide based vaccines• MAGE tumor specific shared ag

Adjuvant ?

What are New Options

• Biochemotherapy

• DTIC or temozolomide+Nitrosureas

• Interferon = antiproliferative and immunomodulatory

• Interleukin-2 =Immunostimulatory cytokine ►NK cells

Vaccines

• Vaccines-ganglioside GM2• MAGE Tumor specific antigens• Ab3 a cytokine• Antibody based vaccines• HLA based• Cell based vaccines• Peptide vaccines• Recombinant viruses

• Biology• Detection-Computer, USG, RT-PCR• Staging- AJCC 2000 +Prognosis• SLN Biopsy + ELND• Treatment margins• Adjuvant treatment + Vaccines• Summary

Major changes in AJCC classification in 2002 -1

• √ Thickness

• X not levels

• √ Ulceration

• √ Number of LN

• X size of LN

• √ LDH

Major changes in AJCC classification in 2002-2

• √ Upstaging with ulceration

• √ Merge micro satellite & in-transit mets into stage III

• √ Include SLN into staging

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 +/-

• In situ 5 mm

• <2mm 1cm

• >2mm 2cmSober AJ : J Am Acad Dermatol 2001

Current recommendations for surgical margins: primary

cutaneous melanoma

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

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

MM :– management of lymph nodes

• Biopsy : FNAC preferred

• Elective dissection : for

1. Clinically involved nodes,

2. Satellitosis,

3. Lymphatic invasion

Sentinel lymph node biopsy

• Detects micrometastasis in lymph nodes

• Inrtadermal injection of radioactive colloid around lesion

• Lymph node identified by gamma probe

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.

Thank You

Controversies in Melanoma

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