Melanoma

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

Epidemiology

Incidence – 18/100,000
- Estimated 68,720 new melanomas and 8,650 deaths in U.S. in 2009
- 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 – most common in cutaneous melanomas derived from intermittent sun-exposed skin
KIT mutations – most common in mucosal and acral melanomas; small presence in sun-damaged melanomas
- 69% of KIT-activating mutations occur in exon 11 (juxtamembrane region)
- Predicted to respond favorably to the tyrosine kinase inhibitor Gleevec^®
NRAS mutations
Presence of oncogenic mutation in codons 12, 13, or 61 may indicate tumor that will respond to drugs targeted at genes downstream of NRAS in mitogen activating protein kinase (MAPK) signaling cascade

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 guideline)
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

Clinical Background

Epidemiology

Prevalence – 300-420 cases annually in the U.S.
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 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 Testing

Atypical melanocytic lesion (mole) requires histologic evaluation
- Early diagnosis
  - Skin self-examination
  - Regular skin evaluations by primary care physician or dermatologist

Laboratory Testing

Molecular testing
- KIT mutation – aid in prediction of response to imatinib (Gleevec^®) or CD117 therapy
- BRAF mutation – determine presence of BRAF mutation; may be helpful in determining response to therapy
- NRAS mutation
  - If NRAS mutation positive in codons 12, 13 or 61, patients may have an inhibited response to anti-EGFR therapy

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 (non-melanocytic 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 is used to determine prognosis
- Breslow thickness is 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
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)

American Academy of Dermatology (AAD) and American Cancer Society (ACS) recommend regular skin exams in all patients
- U.S. Preventive Services Task Force finds insufficient evidence to recommend regular skin exams

NCCN recommends skin examination at least once per year for melanoma patients (including those with stage 0 in situ melanoma)
- Patients with stage IA-IIA melanoma, no evidence of disease
  - Comprehensive exam every 3-12 months for five years and annually thereafter as clinically indicated
- Patients with stage IIB-IV melanoma, no evidence of disease
  - Comprehensive exam every 3-6 months for two years, then every 3-12 months for three years and annually thereafter
S-100B, Serum
- Not useful in diagnosis
- Rising concentrations after treatment indicate disease recurrence

Tests generally appear in the order most useful for common clinical situations

Test name: Cytokeratin 8,18 Low Molecular Weight (CAM 5.2) by Immunohistochemistry

ARUP #: 2003493