Melanoma Diagnosis
Diagnosis
- Suspicious lesions are assessed by examining the entire skin surface including nevi
- ABCDE mnemonic is utilized in characterizing lesions, eg Asymmetry, Border irregularities, Color changes, Diameter and Evolution
- “Ugly duckling” concept: Melanotic lesions have a different appearance from the surrounding nevi
Dermoscopy
- A noninvasive technique using a magnifying device to visualize diagnostic features of pigmented lesion
- Enhances diagnostic accuracy and leads to performance of a biopsy
Biopsy
- A full-thickness, narrow, excisional biopsy (punch, elliptical or saucerization/deep shave removal)) with 1-3 mm peripheral margins should be the basis of diagnosis
- Wide surgical margins may affect accuracy of succeeding lymphatic mapping
- Full-thickness incisional or punch biopsy may be preferred in certain anatomic areas (eg palm/sole, digit, face, ear) or for very large lesions
- An experienced pathologist should examine the specimen for microstaging [a staging technique determined histologically by the Breslow classification (vertical thickness of lesion) and the Clark classification (anatomic level of invasion)]
- Various biopsy methods exist, eg incisional, punch, elliptical, superficial or broad shave; however, chosen method should be able to obtain an adequate specimen for a definitive diagnosis or exclusion of melanoma
- Partial sampling or incisional biopsy can be performed on facial, acral, or large lesions and in uncertain diagnosis or low clinical suspicion
- Broad shave biopsy for lentigo maligna melanoma in situ; used for the assessment of the presence of focal microinvasion
- Deep shave or saucerization is the most commonly used technique by dermatologists to obtain a depth below a lesion’s plane
- Superficial shave biopsy may be considered only when with low clinical suspicion for melanoma
- Fine-needle aspiration may be done for confirmation of lymph node involvement in stage III and IV disease and of initial clinical recurrence
- Pathology report should include the specimen size, maximum histologic depth of lesion (Breslow thickness), ulceration, Clark level (optional for tumors >1 mm), mitotic rate, peripheral and deep margins, and microsatellitosis
- Other histologic features reported include vertical growth phase, tumor-infiltrating lymphocytes, dermal regression, angiolymphatic invasion, histologic subtypes, neurotropism, and desmoplasia
- Genetic testing of obtained samples should be offered if targeted systemic therapy is being considered
- Repeat biopsy may be performed if specimen was inadequate for diagnosis or microstaging
Classification
Cellular Classification
- Clinicopathologic cellular subtypes of malignant melanoma are descriptive terms and are without significance prognostically or therapeutically
- Superficial spreading: Most common subtype, starts as an initially slow-growing, asymptomatic, brown macule or plaque with irregular borders and changes in size, shape, and color
- Nodular: Second most common subtype, a rapidly enlarging, vertically growing, blue or gray to black nodule that may ulcerate
- Lentigo maligna and lentigo maligna melanoma: Begin as irregular tan macules that grow slowly to become larger lesions
- When normal and malignant melanocytes are limited to the epidermis, it is called lentigo maligna; when it extends into the dermis, it is then called lentigo maligna melanoma
- Most often occur in older people with heavy sun exposure, in the head and neck area, and in non-melanoma skin cancer
- Acral-lentiginous: Has a similar appearance as superficial spreading melanoma and histologic picture as lentigo maligna melanoma
- Develops on the palms, soles, and subungual skin
- Equally common in dark-skinned individuals and may not be related to UV exposure
- Unusual variants of melanoma: Subungual, mucosal lentiginous, amelanotic, desmoplastic, verrucous
Molecular Classification
- Molecular subtypes of melanoma resulted from identification of activating mutations in the mitogen-activated protein kinase pathway and are the targets of drug therapy
- BRAF, CDKN2A, NRAS and TP53 are associated with cutaneous melanoma
- BRAF (V-RAF murine sarcoma viral oncogene homolog B1) gene is the most common mutation and occurs in superficial spreading and nodular melanoma
- Majority have a substitution at position 600 BRAF (V600E)
- NRAS [neuroblastoma RAS viral (V-RAS) oncogene homolog] also occurs in superficial spreading and nodular melanoma
- C-KIT mutation or increased copy number and CDK4 (cyclin-dependent kinase 4) mutation are seen in mucosal and acral melanomas
- C-KIT mutation occurs in lentigo maligna melanoma and is the most common subtype in Asians and African Americans
- SF3B1 is associated with mucosal melanoma
Staging
- Preliminary workup includes a thorough medical history and physical examination (PE)
- A detailed history should include an evaluation of melanoma-related risk factors and review of systems paying attention to skin, lymphatic, neurologic, pulmonary, gastrointestinal, and musculoskeletal systems
- PE should be focused on a complete examination of the skin and lymph nodes
- Staging studies may include lab tests (CBC, LDH, liver function tests) and imaging procedures (chest x-ray, CT with contrast and whole body FDG PET scans, MRI with contrast, and nodal ultrasound)
- In asymptomatic patients with newly diagnosed melanoma of any thickness, baseline lab tests and imaging studies are generally not advised; may be performed if clinically indicated based on patient’s signs and symptoms
- Workup is unnecessary in low-risk melanoma; however, imaging is recommended in higher stages of melanoma for proper staging
- Baseline imaging may be considered if sentinel lymph node (LN) biopsy (SLNB) is positive, recommended in clinically positive nodes and in-transit metastases or recurrence
- Brain MRI and PET-CT/CT scan may be considered for very high-risk patients
- Ultrasound of the nodal basin may be considered if PE of regional LN is uncertain; histologic confirmation should be done if with abnormal results
- Genetic mutation testing may be performed if targeted therapy is being considered for the patient or if it is pertinent for candidacy in clinical trials
- Routine genetic testing is not encouraged on primary localized melanomas
Sentinel Lymph Node Biopsy (SLNB)
- A minimally invasive microstaging technique that has become a staging standard for cutaneous melanoma
- Considered the most specific and sensitive staging technique for detection of micrometastases in LN
- Performance of SLNB may depend on presence of comorbidities or patient preference
- Biopsies the node that immediately drains the primary tumor
- Identifies nodal metastasis
- Identifies patients who may need lymph node dissection and patients who may gain from adjuvant therapy
- Should be done before wide excision of the lesion for accurate lymphatic mapping
- Not recommended for melanoma in situ or T1a melanoma (<0.8 mm)
- May be considered in T1b melanoma (0.8-1 mm) after discussion with patient of potential risks and benefits of the procedure
- Recommended in intermediate-thickness (1-4 mm) T2 or T3 melanomas
- May be recommended in thick (>4 mm) T4 melanomas after discussion with patient
TNM Classification
- Developed by the American Joint Committee on Cancer (AJCC)
- It details tumor thickness, degree of lymph node involvement, and metastatic spread
- Information provided helps determine treatment, follow-up, and prognosis of patient
- Based on the eighth edition of AJCC staging system
- Based on the eighth edition of AJCC Anatomic Stage and Prognostic Groups
Primary Tumor (T) | |
---|---|
TX: | Primary tumor unassessable |
T0: | No evidence of primary tumor |
Tis : | Melanoma in situ |
T1: | ≤1.0 mm thickness with unknown or unspecified duration |
T1a: | <0.8 mm thickness without ulceration |
T1b: | <0.8 mm thickness with ulceration; 0.8-1.0 mm thickness with or without ulceration |
T2: | >1-2 mm thickness with unknown or unspecified ulceration |
T2a: | >1-2 mm thickness without ulceration |
T2b: | >1-2 mm thickness with ulceration |
T3: | >2-4 mm thickness with unknown or unspecified ulceration |
T3a: | >2-4 mm thickness wihtout ulceration |
T3b: | >2-4 mm thickness with ulceration |
T4 | >4 mm thickness with unknown or unspecified ulceration |
T4a: | >4 mm thickness without ulceration |
T4b: | >4 mm thickness with ulceration |
Regional Lymph Nodes (N) | |
NX: | Regional lymph nodes unassessable; without in-transit, satellite, and/or microsatellite metastases |
N0: | No detectable regional metastases; without in-transit, satellite, and/or microsatellite metastases |
N1: | 1 tumor-involved node or with any number of in-transit, satellite, and/or microsatellite metastases without tumor-involved node |
N1a: | 1 clinically occult regional LN (detected by SLNB) without in-transit, satellite, and/or microsatellite metastases |
N1b: | 1 clinically detected regional LN without in-transit, satellite, and/or microsatellite metastases |
N1c: | Regional LN absent; with in-transit, satellite, and/or microsatellite metastases |
N2: | 2-3 tumor-involved nodes or with any number of in-transit, satellite, and/or microsatellite metastases with 1 tumor-involved node |
N2a: | 2-3 clinically occult regional LN (detected by SLNB) without in-transit, satellite, and/or microsatellite metastases |
N2b: | 2-3 regional LN, with >1 clinically detected regional LN, without in-transit, satellite, and/or microsatellite metastases |
N2c: | 1 clinically occult or clinically detected regional LN; with in-transit, satellite, and/or microsatellite metastases |
N3: | ≥4 tumor-involved nodes or with any number of in-transit, satellite, and/or microsatellite metastases with ≥2 tumor-involved nodes, or any number of matted nodes with or without in-transit, satellite, and/or microsatellite metastases |
N3a: | ≥4 clinically occult regional LN (detected by SLNB) without in-transit, satellite, and/or microsatellite metastases |
N3b: | ≥4 regional LN, with >1 clinically detected regional LN or with any number of matted nodes, without in-transit, satellite,and/or microsatellite metastases |
N3c: | ≥2 clinically occult or clinically detected regional LN and/or any number of matted nodes, with in-transit, satellite, and/or microsatellite metastases |
Distant Metastasis (M) | |
M0: | No distant metastasis |
M1: | Evidence of distant metastasis |
M1a: | Distant skin, soft tissue including muscle, and/or nonregional LN metastases; serum LDH not recorded or unspecified |
M1a(0): | Normal serum LDH |
M1a(1): | Serum LDH elevated |
M1b: | Distant lung metastasis with or without M1a; serum LDH not recorded or unspecified |
M1b(0): | Normal serum LDH |
M1b(1): | Serum LDH elevated |
M1c | Distant non-CNS visceral metastasis with or without M1a or M1b; serum LDH not recorded or unspecified |
M1c(0): | Normal serum LDH |
M1c(1): | Serum LDH elevated |
M1d | Distant CNS metastasis with or without M1a, M1b or M1c; serum LDH not recorded or unspecified |
M1d(0) | Normal serum LDH |
M1d(1) | Serum LDH elevated |
Clinical Staging3 | |||
---|---|---|---|
Stage 0: | Tis | N0 | M0 |
Stage IA: | T1a | N0 | M0 |
Stage IB: | T1b | N0 | M0 |
T2a | N0 | M0 | |
Stage IIA: | T2b | N0 | M0 |
T3a | N0 | M0 | |
Stage IIB: | T3b | N0 | M0 |
T4a | N0 | M0 | |
Stage IIC: | T4b | N0 | M0 |
Stage III: | Any T | ≥N1 | M0 |
Stage IV: | Any T | Any N | M1 |
Pathologic Staging4 | |||
Stage 0 | Tis | N0 | M0 |
Stage IA | T1a | N0 | M0 |
T1b | N0 | M0 | |
Stage IB | T2a | N0 | M0 |
Stage IIA | T2b | N0 | M0 |
T3a | N0 | M0 | |
Stage IIB | T3b | N0 | M0 |
T4a | N0 | M0 | |
Stage IIC | T4b | N0 | M0 |
Stage IIIA | T1a/b-T2a | N1a or N2a | M0 |
Stage IIIB | T0 | N1b, N1c |
M0 |
T1a/b-T2a | N1b/c or N2b | M0 | |
T2b/T3a | N1a-N2b | M0 | |
Stage IIIC | T0 | N2b, N2c, N3b or N3c | M0 |
T1a-T3a | N2c or N3a/b/c | M0 | |
T3b/T4a | Any N ≥N1 | M0 | |
T4b | N1a-N2c | M0 | |
Stage IIID | T4b | N3a/b/c | M0 |
Stage IV | Any T, Tis | Any N | M1 |
Prognosis
- Important prognostic factors include the Breslow depth, ulceration, mitotic rate, SLN status, and systemic metastasis
- Breslow depth and mitotic rate are strong survival predictors
- SLN status is the most significant prognostic factor for disease-specific survival in tumors >1 mm thick, though its impact on overall survival (OS) is still unclear
- Cure rates are high in early superficial lesions but are low with ulceration and deeper levels of tumor, vascular, or lymphatic invasion
- Other significant factors include age and gender of patient
- Younger female patients with extremity melanomas have better prognosis
- Prognostic factors in patients with positive SLN include number of positive nodes, tumor burden in the sentinel node, primary tumor thickness, mitotic rate and ulceration, and patient's age
- Prognostic factors in patients with clinically positive nodes include number of positive nodes, extranodal extension, primary tumor ulceration and patient's age
Genetic and Molecular Testing
- May be considered in patients highly suspected of cancer, or if targeted therapy or enrollment into a clinical trial is being considered for the patient
- Molecular techniques that may help with the diagnosis of melanoma include comparative genomic hybridization (CGH), fluorescent in situ hybridization (FISH) and gene expression profiling (GEP)
- Immunohistochemistry is used to confirm the melanocytic origin of carcinomas without conclusive morphologic evidence
- Includes Sox10, S100, Melan-A/MART1, HMB45, tyrosinase
- Genetic tests that may be considered include BRAF, NRAS, p16 staining, Ki-67 proliferation marker
- Genetic mutation testing may be performed if targeted therapy is being considered for the patient or if it is pertinent for candidacy in clinical trials
- Mutation testing is mandatory in patients with resectable or unresectable stage III or stage IV and highly recommended in high-risk resectable disease stage IIC
- Routine genetic testing is not encouraged on primary localized melanomas