melanoma
MELANOMA
Melanoma is a skin neoplasm that originates from malignant transformation of melanocytes.
It commonly occurs in the extremities of women and on trunk or head and neck in men.
Metastases are via lymphatic and hematogenous routes.

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) with 1-3 mm peripheral margins should be the basis of diagnosis
    • Wide surgical margins may affect accuracy of succeeding lymphatic mapping
    • 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 (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

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
    • 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
  • Generally not considered with tumor thickness ≤0.75 mm, though it may be done in high-risk patients or if microstaging result is uncertain
  • Should be discussed with patient if tumor thickness is 0.76-1 mm
  • Recommended in intermediate-thickness (1-4 mm) and thick (>4 mm) melanomas

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 2017 AJCC TNM definitions for melanoma
  •  

    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 microsatellitemetastases
      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: No 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 2017 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, Tis ≥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 T1a/b-T2a N1b/c or N2b M0
    T2b/T3a N1a-N2b M0
    Stage IIIC 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

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
  • Routine genetic testing is not encouraged on primary localized melanomas
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