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Melanoma

Edward Buckingham, M.D.

Combined Plastics ConferenceSeptember 6, 2000

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Melanoma - Outline

General statistics and development Risk factors and patient assessement

Pathology and prognosis Work-up and staging

Surgical treatment

Lymph node controversy/sentinel node

Adjuvant therapy

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Melanoma - Data

Incidence increase fastest Mortality increase 2nd only to lung

5th most prevalent, incidence 7%/yearincrease

5% skin cancer, 75% skin cancer death

1/75 in 2000, 1/1500 in 1935

20% H&N, 51% facial, 26% scalp, 16%

neck, 9% ear

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Development of Nevi

Melanocytes dendritic, neural crest, basal cell layer

synthesis of melanin

1/10 to keratinocytes

hyperplasia- tanning/lentigines, increased ratio

Nevus transformation poorly understood

dendritic- rounded

no longer lentigionous pattern- nests

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Development of Nevi

Junctional nevi nests along dermal-epidermal junction

Compound nevi

invade dermis, first as nests then cords and

single cells

Dermal nevi junctional component lost

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Evolution of Nevi

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Melanocyte Hyperplasia

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Junctional Nevi

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Compound Nevi

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Dermal Nevi

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Developement of Melanoma

Questionable benign melanocytes

progressive hyperplasia/dysplasia

Radial growth

in epidermis, lines of radii, no expansive nests

or nodules slow unrestricted , no metastatic potential

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Development of Melanoma

Vertical growth vertically into dermis

expansive and coalescent nests and nodules

metastatic potential dermal lymphatic and

vascular invasion

Growth patterns biphasic- slow radial months to years- rapid

vertical growth

monophasic- rapid vertical growth only

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Evolution of Melanoma

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Dysplastic Nevi

border melanocytic nevi and malignantmelanoma

clinical resembles malignant melanoma

lentiginous compound nevus, prominent

bridging across rete ridges

aberrant in inter-rete spaces lamellar fibrosis of papillary dermis,

variable lymphoid response

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Dysplastic Nevi

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Dysplastic Nevi

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Types of Melanoma

Acral lentiginous Mucosal melanoma

Superfical spreading melanoma

Lentigo maligna melanoma

Nodular melanoma

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Superficial spreading

most common head and neck, 50% 4th to 5th decade

clinical mixture of brown/tan, pink/white

irregular borders, biphasic growth

irregular nests in epidermis

underlying lymphoid infiltrate

enlarged nests and single cells in all

epidermal layers

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Superficial spreading

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Lentigo maligna

20% of head and neck longest radial growth phase >15 yrs

elderly sun exposed areas

clinical dark, irregular ink spot

contiguous lintiginous proliferation,

dyshesive, variable shape, atrophicepidermis, infundibular basal cell layer of

hair follicles

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Lentigo maligna

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Nodular melanoma

30% of head and neck 5th decade

aggressive monophasic growth

sun-exposed and nonexposed areas

well circumscribed blue/black or nodular

with involution in irregular plaque

downward tumorigenic growth, expand

papillary dermis into reticular dermis

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Nodular melanoma

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Mucosal melanoma

8% head and neck histologic staging little use

local control predicts survival

neck dissection for clinical N+

XRT for histo N+

adjuvant interferon alpha 2-b

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Risk factors

Type I or II skin atypical and congenital nevi

actinic skin changes

history of melanoma

family history of melanoma, atypical nevi

history of significant sun exposure

(blistering)

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Clinical

early, increase in size, change in shape orcolor of pigmented lesion

most common symptom pruritis

late, tenderness, bleeding, ulceration

ABCDEs (asymmetry, border, color,

diameter, elevation, surrounding tissue) Epiluminescence microscopy (ELM)

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Biopsy

excisional biopsy or saucerization if small incisional if large

Depth of biopsy must be to sub-Q fat

if melanoma a second excision must be

performed

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Pathology

diagnosis, tumor thickness in millimeters,margins

histologic subtype, anatomic site, Clark

level, mitotic rate, growth phase, ulceration,regression, lymphocytes, angiolymphatic

spread, neurotropism, microsatellitosis,

precursor lesion

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Prognosis Breslow (thickness in millimeters) strongest

predictor

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Prognosis

Clark level less predictive, thin skin useful

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Prognosis

anatomic site, ulceration, gender, histologictype, nodal disease

head and neck- scalp worse

extremity better trunk

women better men

lymph node + Breslow thickness, ulceration, # pos. nodes

Cohen 10 yr survival # nodes positive

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Work-up

H&P

entire skin, inguinal, axillary, supraclavicular,

H&N nodes,especially primary drainage

brain, bone, GI, constitutional symptoms

palpable nodes FNA

Labs and imaging

vary, CXR to routine CT chest and LFT

H&N CT neck routine

If stage III(regional) or IV (distant) - CT head,

chest, abdomen, pelvis

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Work-up

FDG-PET some use in distant disease

sensitivity 17% in study with SLN biopsy

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Staging-Clark

Level I - in situ at basement membrane Level II - through basement membrane

into papillary dermis

Level III - spread to papillary/reticular

interface

Level IV - spread to reticular dermis Level V - sub-Q invasion

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Staging-Breslow

4.00 mm - thick

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Staging

CS/PS (I, II, III) AJCC- Stage I and II - local, III - regional

IV - distant

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AJCC Staging

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Surgical Treatment

Recommended margins vary Rule of thumb

4mm then 3 cm

All depths to underlying muscle fascia

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Nodal Disease

CS-II remove regional lymphaticsdepending on location of primary and

presence of distant metastasis

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CSI- The Debate

Balch study- nonrandomized 5 and 10 yr survival intermediate thickness

(0.76-3.99) doubled with ELND

5 and 10 yr survival for thin (4.0) no change with ELND

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Balch Study

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CSI - The Debate

Four prospective randomized trials Mayo clinic 3 groups stage I (ELND, delayed,

none) no survival difference, increased

complications if none, criticized not looking atsubgroups to benefit

WHO no survival benefit, criticized no

subgroups, largely extremity lesions in females

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CSI - The Debate

Four prospective randomized trials Balch - no overall 5 yr difference, improved in

patients , 60 yrs with ELND, 1-2 mm tumors,

no ulceration, or both benefited, WHO trunk 1.5 mm or more immediate or

delayed no significant survival benefit, however

was between ELND with occult metastasis andlater developers with delayed LND

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The Debate - PRO ELND

sequential dissemination theory 30% stage I & II occult disease

Once palpable 70-80% distant disease, 10 yr

survival 15-25%, 5 yr 1-2 nodes

micrometastasis 65%

Balchs non-randomized study

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The Debate - CON ELND

randomized trials 70% no occult disease

sequential dissemination only theory

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Balchs recommendations

Three groups local, local plus micro, local plus distant

Thin - 95% cure rate no benefit to ELND

Intermediate - 60% regional, 20% distant,

benefit ELND

Thick - >60% regional, >70% distant, nobenefit

Should consider other factors as well

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Sentinel Node Theory

Essence of debate to identify those withoccult metastasis

Morton- first node in group to receive flow

from tumor site

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SLN - procedure

isosulfan blue injection at tumor site, followchannels to node

studies with ELND 80% sensitivity, specificity

99% preoperative lymphscintigraphy, intra-

operative radiolymphoscintigrapy, and

isosulfan blue dye

69.5% SLN excised blue dye, 83.5% hot,

combined success 96%, location matters

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SLN - Utility

prognostic indicator - study SLN statusmost significant indicator of disease-free

and disease-specific survival

pathology H&E, S-100, HMB-45 limited by # sections

reverse transcription with polymerase chain

reaction (RT-PCR)- peripheral blood and

nodes, (mRNA tyrosinase) 29 ELND 38% path

positive, 66% RT-PCR positive

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Adjuvant Therapy

Radiation high dose (400-500 cGy) bulky, residual,

recurrent, unresectable, ill

lentigo maligna 5 yr cure 80% (disfiguring,debilitating location)

adjuvant- trend toward improved regional

control in N+ dissected necks palliate - especially bony mets

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Adjuvant Therapy

Chemotherapy response 25%, durable control 1%

consider in CSI with >1.5 mm, CSII with WLE,

TND no survival advantage demonstrated

single agent dacarbazine (DTIC)

multiple combinations carmustine, cisplatin,

DTIC, tamoxifen

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Adjuvant Therapy

Immunotherapy unusual behavior, no survival benefit

Interferon

ECOG 1684, >4mm or N+, 6.9 yrs high dose

IFN-alpha-2b, improved disease-free and

overall survival approx. 1 yr. 26% dropout rate

toxicity

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Summary

Incidence and deaths on rise Survival rates increasing due to detection

and thorough treatment

Depth and nodal status most important

prognostic indicators

ELND still debated SLD useful

Other modalities therapy further research