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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

REFERENCES

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