Melanoma

Key Points

Disseminated melanoma is not generally responsive to traditional chemotherapy or radiotherapy. With the advent of targeted therapy, molecular testing in melanoma has gained importance.

• Mutations by biology and targeted therapy (see table below)

Diagnosis

Indications for Testing

• Atypical melanocytic lesion (mole) requires histologic evaluation

Laboratory Testing

• Refer to Key Points

Histology

• Gold standard for diagnosis
  • Immunohistochemistry may be required to distinguish poorly differentiated lesions of carcinoma, sarcoma, or lymphoma (B-cell or T-cell) from melanoma
  • Stains to consider include cytokeratin 8,18 low molecular weight (CAM 5.2); melanoma antibody, HMB45; Ki-67 (Mib-1); melan A; p21 (Waf1/Cip 1); S-100 protein; and vimentin
• Architectural and cytologic features of biopsy are interpreted in the context of clinical information
  • Architecture – large, asymmetric, poorly circumscribed lesion; pagetoid spread of melanocytes; effaced rete ridges and underlying dermal architecture; perineural invasion
  • Cytology – large nuclei with prominent nucleoli; atypical mitoses (especially in dermis); lack of melanocyte maturation in deep portion of lesion
• Metaplastic differentiation (nonmelanocytic cells or tissues) may be identified that may not be melanoma

Imaging Studies

• Routine cross-sectional imaging (CT, PET, MRI) is not recommended  in patients with localized melanoma due to low yield

Prognosis

• Depth of tumor invasion – used to determine prognosis
  • Breslow thickness – most important factor contributing to T status in tumor, nodes and metastases staging
    • Measured from top of epidermal granular cell layer to deepest malignant melanocyte
    • 5-year survival – 95.3% with Breslow thickness ≤1.0 mm (corresponds to T1 lesion), 45.1% with Breslow thickness >4.0 mm
  • Clark level – important in T1 lesions (<1 mm thick) (corresponds to 95% or better survival)
    • Clark I – melanoma in situ; does not cross basement membrane
    • Clark II – invasion of papillary dermis
    • Clark III – expansion of papillary dermis
    • Clark IV – invasion of reticular dermis
    • Clark V – invasion of subcutaneous fat
• Additional histologic features used to determine prognosis
  • Involvement of regional lymph nodes (regional nodal dissection or sentinel node testing)
  • Metastases
  • Growth phase
  • Mitotic count
  • Regression
  • Ulceration
• Additional serum testing
  • Lactate dehydrogenase – prognostic factor in late-stage melanoma
    • Elevated levels may indicate metastases
  • S-100B, serum – elevated level associated with poor prognosis

Differential Diagnosis

• Clinical – melanocytic nevi
• Histologic
  • Well differentiated – melanocytic nevi
  • Poorly differentiated – carcinoma, sarcoma, lymphoma (T-cell, B-cell)

Screening

Monitoring

Clinical Background

Melanoma is a malignancy of the melanocytes. This disease is experiencing a rising incidence worldwide, ranking second to adult leukemia in loss of years of potential life per death.

Epidemiology

• Incidence – 18/100,000
  • Estimated 76,250 new melanomas and 9,180 deaths in U.S. in 2012 (American Cancer Society, 2012)
  • Tripled over the last 20 years
  • Highest incidence worldwide is in Australia
• Age – median is 57 years; rare in children
• Sex – M>F, 1.5:1
• Ethnic – tenfold increased incidence in Caucasians
  • Acral lentiginous melanoma has equal distribution across all ethnic groups

Inheritance

• Familial atypical multiple mole melanoma – associated with mutations in the CDKN2A (also known as p16) gene
  • Mutations in CDKN2A and CDK4 associated with high risk of developing melanoma

Classification

• Superficial spreading melanoma (~70%)
• Nodular melanoma (10-15%)
• Lentigo maligna melanoma (10%)
• Acral lentiginous melanoma (~5%)
• Mucosal lentiginous melanoma (3%)

Risk Factors

• Sunlight – sunburns in childhood, intermittent UV exposure associated with higher risk
• Blue or green eyes; red or blond hair
• Melanocytic nevus – increased risk by number and size of nevi
• Family history – twofold risk if first-degree relative had melanoma
  • Clustering of melanoma in familial retinoblastoma and Li-Fraumeni syndrome
  • Increased risk of familial melanoma in the presence of family history of pancreatic cancer or astrocytoma
• Immunosuppression

Genetics

• BRAF mutations
  • 40-60% of melanomas
  • Most common in cutaneous melanomas derived from intermittent sun-exposed skin
• KIT mutations
  • As many as 15% of melanomas
  • Most common in mucosal and acral lentiginous, sun-damaged skin; small presence in sun-damaged melanomas
  • Most common mutations located at exons 9,11,13, and 17
  • Predicted to respond favorably to the tyrosine kinase inhibitor imatinib
• RAS mutations
  • 15-20% of melanomas
  • Associated with thicker tumors, high mitotic rate, and worse prognosis than BRAF mutation or BRAF/NRAS wild type
  • Most common mutations located at codons 12,13, and 61
  • Generally mutually exclusive of BRAF mutation
• PTEN mutations
  • Generally mutually exclusive of NRAS mutations but usually inclusive for BRAF mutations

Clinical Presentation

• 82-85% of melanoma patients present with localized disease; 10-30% present with regional disease; 2-5% with distant metastatic disease
• Nevus with Asymmetry, Border irregularity, Color variation, Diameter >6 mm and Evolving changes (ABCDE criteria)
• Head and neck most common sites
• Ulceration, pigment loss
• Rare sites – eye (iris, ciliochoroidal), mucosa, unknown primary
• Mortality rates have plateaued in recent years (attributed to early diagnosis)

Prevention

• Decrease UV exposure
  • Use sunscreen
  • Avoid midday sun
  • Cover skin with hat and clothing
• Skin self-examination
• Regular skin evaluation by primary care physician or dermatologist

Pediatrics

Clinical Background

Epidemiology

• Prevalence – 300-425 cases annually in the U.S. (NCI, 2006)
• Age – 15-19 years most common
• Sex – M>F (minimal)

Risk Factors

• Family history – twofold risk if first-degree relative had melanoma
  • Clustering of melanoma in familial retinoblastoma and Li-Fraumeni syndrome
  • Increased risk of familial melanoma in the presence of family history of pancreatic cancer or astrocytoma
• History of severe sunburns (>3 before 20 years)
• Xeroderma pigmentosa
• Immunosuppression
• Dysplastic nevi (three- to sixfold increased risk)

Clinical Presentation

• Lesions frequently amelanotic or nodular
• ABCDE ABCDE criteria (Asymmetry, Border irregularity, Color variation, Diameter >6 mm, and Evolving changes) less reliable than in adults

Diagnosis

Indications for Testing

• Refer to Diagnosis tab

Laboratory Testing

• Refer to Diagnosis tab

Histology

• Congenital nevus has slightly different histologic appearance
• Refer to Histology section in Diagnosis tab

Imaging Studies

• Refer to Diagnosis tab

Differential Diagnosis

• Spitz nevus
• Blue nevus
• Congenital nevus

Indications for Laboratory Testing

• Tests generally appear in the order most useful for common clinical situations
• Click on number for test-specific information in the ARUP Laboratory Test Directory

Click the plus sign to expand the table of additional tests.

Test Name and Number	Comments
BRAF V600E Mutation Detection by Allele-Specific PCR, Fine Needle Aspirate 2006516 Method: Polymerase Chain Reaction	Molecular test for the detection of the BRAF V600E mutation in direct smear specimens from FNA For tissue block or formalin-fixed, paraffin-embedded (FFPE) cell blocks prepared from FNA, BRAF codon 600 Mutation Detection by Pyrosequencing may be used
Solid Tumor Mutation Panel by Next Generation Sequencing 2007991 Method: Massively Parallel Sequencing	Prognosis/treatment of individuals with solid tumor cancers at initial diagnosis or with refractory disease