Melanoma

DEFINITION AND PATHOGENESIS

• May be metastatic to soft tissue (or bone) or a primary cutaneous malignancy
• Classification based on radial growth phase
  • Level I: confined to epidermis (in situ melanoma)
  • Level II: tumor cells extend from the epidermis to unexpanded papillary dermis (10% in vertical growth phase)
  • Level III: tumor nodule fills and expands the papillary dermis (usu >1mm thick)
  • Level IV: tumor cells infiltrate reticular dermis collagen fibers
    • (a): into superficial reticular dermis
    • (b): into deep reticular dermis
  • Level V: infiltration of tumor cells into subcutaneous fat (periosteum in subungual location)
• Histologic types
  • Superficial spreading melanoma
    • High incidence of precursor lesion (benign or dysplastic nevus)
    • Most common histologic type in hand locations, even in subungual location
  • Lentigo maligna melanoma
    • Prevalent in Australia as "Hutchinson's melanotic freckle", occurring in lentigo maligna
  • Acral and mucosal lentiginous melanoma
    • Subungual melanoma is a subset of acral-lentiginous melanoma (thumb and great toe most common)
    • "Hutchinsons' sign": pigmentation extends beyond cuticle involving skin (warrants prompt bx of nail bed)
  • Melanoma with unclassified radial growth phase
  • Nodular melanoma
• Other variants
  • Desmoplastic and desmoplastic neurotropic
• Vertical growth phase--formation of a nodule, into, and out of the skin, with statistical chance for distant metastases (90% adjacent to region of radial growth)

IMPORTANCE

• Rising incidence due to sun exposure with ? incidence in fair skinned individuals, those with multiple large nevi, and those with a family hx of skin cancer
• ?32,000 cases/?6,700 deaths/yr in the USA (most common cancer in F 25-29 yrs)
• About 5% of pts with melanoma have evident skeletal metastases, 50% at autopsy

CLINICAL FEATURES

• "ABCD(E)" criteria generally apply:
  • Asymmetry
  • Border irregularity
  • Color variegation
  • Diameter
  • (Elevation)
• >95% white, <5% black
• Median age 46 (58 in subungual location)
• Subungual melanoma: massive destruction of the uderlying phalanx may occur
• Subungual and plantar lesions associated with a high rate of misdiagnoses
• Thumb, then MF most commonly involved
• ? ulceration (29/38)(poor prognosticator)
• Most common location of foot/ankle lesions is plantar surface of the foot
• Foot/ankle lesions generally have a poorer prognosis due to advanced stage (delay in dx)(esp plantar location)
• Soft tissue musculoskeletal metastases may occur without evidence of a primary lesion
• Radial and vertical growth phases are clinically evident
• TNM staging: Stage I-IV (PT=primary tumor, N=regional LN, M=distant metastases)
  • Stage I: local disease
  • Stage II: local disease
  • Stage III: nodal/in-transit disease
  • Stage IV: distant visceral metastases

RADIOLOGIC FEATURES

• X-rays usually negative, except in subungual lesions which can reveal marked erosion of the distal phalanx
• Metastases: multiple bone lesions which are primarily lucent, although a solitary lesion may be present
• Lymphatic mapping using a lymphoscintigram to identify the sentinel lymph node
  • Low-dose radiolabelled sulfur colloid intradermally injected near the primary and a mark made over the skin
  • In the OR (the same day), isosulfan blue is injected intradermally or methylene blue topically near the primary and a cut down is performed at the previous mark to identify and remove the blue sentinel node (false - <1-2%)
  • A hand held gamma detector is used to help locate the "hot" node
  • Neoprobe (Neoprobe Corp, Dublin, OH)

GROSS PATHOLOGY

• Usually >6mm in size
• Vertical growth phase area is usually raised above adjacent radial growth phase area
• Friable lesion within bone in metastatic disease

HISTOLOGIC/MOLECULAR FEATURES

• Keratinocytes, lymphocytes, and melanocytes
• Thickness measured from top of the granular layer to the level of the deepest tumor cell
• Melanocytes uniform to pleomorphic, depending on morphology of tumor, arranged in a pagetoid pattern
• Histogenic types
• Acral lentiginous
  • ? desmoplasia
  • ? neurotropia
• Desmoplastic
  • ? neurotropia
• Nodular
  • Unclassified
• + S-100
• + HMB-45 antibodies
• CAM 5.2, 903, for keratin
• Other stains:
  • Common leukocyte antigen
  • Vimentin
• Karyotyping
  • Abnormalities on chromosomes 1, 6, 7, 9
• Loss of P-selectin adhesion receptors (in tumor microvasculature) for infiltrating WBCs (no inflammatory infiltrate/tumor regression)
• EM: melanosomes and ellipsoidal premelanosomes with cross striations

DIFFERENTIAL CLINICOPATHOLOGIC DIAGNOSIS

• Subungual lesions: infection, metastases (usu. squamous cell carcinoma of the lung), GCT of TS
• Lymphoma and spindle cell sarcomas in metastatic lesions to bone
• "Misdiagnoses"
  • Benign nevus
  • Subungual hematoma
  • Blister
  • Chronic paronychia
  • Verrucae vulgaris
  • Pyogenic granuloma
  • Eccrine paroma
  • Dermatofibroma
  • Cysts

DISEASE COURSE AND TREATMENT

• Punch (not shave) bx to preserve anatomic relationships for staging
• Survival ­ (to 70-80%) due to earlier dx, esp if tx is during the radial growth phase, when cure is almost certain with prompt resection
• Survival related to thickness of the lesion (Breslow):
  • <0.76mm thick lesions rarely metastasize (2% dead at 8 yrs) unless in the early vertical phase of growth (100% survival in radial growth phase lesions)
    • LN dissection with conflicting results, but possibly of benefit in higher thickness lesions
  • 0.77-1.50mm thick lesions have low-intermediate risk of LR/metastasis
  • 1.51-3.99mm thick lesions have high-intermediate risk of LR/metastasis
  • >4.00mm thick lesions have very high risk of LR/metastasis
• Level of invasion (more subjective)(Clark)
  • Level I: in situ melanoma, epidermal confinement
  • Level II: invasion of papillary dermis
  • Level III: invasion of papillary/reticular dermal junction
  • Level IV: invasion of reticular dermis
  • Level V: invasion of subcutaneous fat (periosteum in subungual lesions)
• Other favorable prognosticators (in order of relative weight of importance):
  • Low mitotic rate
  • Tumor-infiltrating lymphocytes
  • <1.70mm thick
  • Location on an extremity (excluding volar or subungual regions)
  • Female pts
  • Absence of regression in the radial growth phase
  • "Odds of survival" tables based on these factors
• Sentinel node mapping with techntium 99m-antimony sulfide colloid, blue dye mapping, and sentinel node bx (esp > 1.2mm thick lesions)
• LN resection if sentinel LN (based on lymphatic mapping) is + for tumor (on permanent sections--not on frozen)
• Tumors may regress spontaneously only to present as a metastasis later (with only a hx of a pigmented lesion)
• Resection margin 1-3cm based on thickness of tumor
  • <1mm = 1cm
  • 1-2mm = 1-2cm
  • 2-4mm = 2cm
  • >4mm = 3cm
• Amputation for digital lesions
  • Neck of proximal phalanx for the thumb
  • PIPJ level has been recommended for fingers
• LR may occur
• Lower rate of regional LN metastases at initial presentation for desmoplastic and desmoplastic neurotropic melanomas
• Loss of p27KipI protein expression in nodular (not superficial) melanomas a prognostic indicator of early relapse
• Skeletal involvement in 11-17% clinically detectable metastases, 23-49% of autopsy found metastases
• Isolated skeletal metastases (stage IV)
• Long latency indicates ­ prognosis and appendicular locations warrant aggressive management
• Intramuscular metastases have been reported
• ? signal intensity on T1-weighted and STIR images
• Stage IV disease general prognosis is poor
• 10% may not have hx of primary lesion (spontaneous regression prior to metastasis)
• Hyperthermic isolation perfusion with melphalan with complete responses reported
• Metastatic disease is slowly and progressively fatal
• Median survival from the 1st skeletal metastasis is 2-11 mos (1-yr survival after brain, liver, or brain metastases @ 10%
• Better prognosis for a solitary appendicular lesion after a long NED period (no pts with axial metastases survive)
• Appears to be a better prognosis for pts whose initial lesion was <2mm in thickness
• Surgical resection must be considered for solitary metastases ? chemotx/XRT
• Immunotherapy including vaccine tx undergoing trials

SPECIAL CONSIDERATIONS (variants)

• Neurotropic (Desmoplastic) Melanoma
  • Tend to migrate and spread along nerves, with desmoplastic properties, usually occurring in the head/neck region
  • Has been reported along the ulnar nerve first arising from a subungual tumor
  • Immunohistochemistry with + S-100 protein, + HMB-45, + nerve growth factor receptor

• Minimal deviation melanoma

• Malignant blue nevi and related lesions

• Unclassified vertical growth phase variants

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