Melanoma 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

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

• 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

 

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

• Based on the eighth edition of AJCC Anatomic Stage and Prognostic Groups

 

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

• 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

• 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