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.

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 & 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 & leads to performance of a biopsy

 Biopsy

  • A full-thickness, narrow, excisional biopsy 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) & the Clark classification (anatomic level of invasion)]
  • Various biopsy methods exist, eg incisional, punch, elliptical 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 & in uncertain diagnosis or low clinical suspicion
    • Broad shave biopsy for lentigo maligna melanoma in situ
    • Fine-needle aspiration may be done for confirmation of lymph node involvement in stage III & IV disease & of initial clinical recurrence 
  • Pathology report should include the maximum histologic depth of lesion (Breslow thickness), ulceration, Clark level (optional for tumors >1 mm), mitotic rate, & peripheral & deep margins
    • Other histologic features reported include satellitosis, vertical growth phase, tumor-infiltrating lymphocytes, dermal regression, angiolymphatic invasion, histologic subtypes, neurotropism, & 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 of Melanoma

  • Clinicopathologic cellular subtypes of malignant melanoma are descriptive terms & are w/o significance prognostically or therapeutically
  • Superficial spreading: Most common subtype, starts as an initially slow-growing, asymptomatic, brown macule or plaque w/ irregular borders & changes in size, shape, & color
  • Nodular: Second most common subtype, a rapidly enlarging, vertically growing, blue or gray to black nodule that may ulcerate
  • Lentigo maligna & lentigo maligna melanoma: Begin as irregular tan macules that grow slowly to become larger lesions
    • When normal & 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 w/ heavy sun exposure, in the head & neck area, & in non-melanoma skin cancer
  • Acral-lentiginous: Has a similar appearance as superficial spreading melanoma & histologic picture as lentigo maligna melanoma
    • Develops on the palms, soles, & subungual skin
    • Equally common in dark-skinned individuals & may not be related to UV exposure
  • Unusual variants of melanoma: Subungual, mucosal lentiginous, amelanotic, desmoplastic, verrucous

Molecular Classification of Melanoma

  • Molecular subtypes of melanoma resulted from identification of activating mutations in the mitogen-activated protein kinase pathway & are the targets of drug therapy
  • BRAF (V-raf murine sarcoma viral oncogene homolog B1) gene is the most common mutation & occurs in superficial spreading & nodular melanoma
    • Majority have a substitution at position 600 BRAF (V600E)
  • NRAS [neuroblastoma RAS viral (v-ras) oncogene homolog] also occurs in superficial spreading & nodular melanoma
  • C-KIT mutation or increased copy number & CDK4 (cyclin-dependent kinase 4) mutation are seen in mucosal & acral melanomas
    • C-KIT mutation occurs in lentigo maligna melanoma & is the most common subtype in Asians and African Americans

Staging

  • Preliminary workup includes a thorough medical history & physical examination
    • A detailed history should include an evaluation of melanoma-related risk factors & review of systems paying attention to skin, lymphatic, neurologic, pulmonary, gastrointestinal, & musculoskeletal systems
    • Physical examination (PE) should be focused on a complete examination of the skin & lymph nodes
  • Staging studies may include lab tests (CBC, LDH, liver function tests) & imaging procedures (chest x-ray, CT & PET scans, MRI, & nodal ultrasound)
    • In asymptomatic patients w/ newly diagnosed melanoma of any thickness, baseline lab tests & imaging studies are generally not advised; may be performed if clinically indicated based on patient’s signs & 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 biopsy 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 w/ 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 & 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 & 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 w/ tumor thickness ≤0.75 mm, though it may be done in high-risk patients or if microstaging result is uncertain
  • Should be discussed w/ patient if tumor thickness is 0.76-1 mm
  • Recommended in intermediate-thickness (1-4 mm) & thick (>4 mm) melanomas

TNM Classification

  • Developed by the American Joint Committee on Cancer (AJCC)
  • It details tumor thickness, degree of lymph node involvement, & metastatic spread
    • Information provided helps determine treatment, follow-up, & prognosis of patient

  • Based on the 2010 American Joint Committee on Cancer TNM definitions for melanoma
  • Primary Tumor (T)
    TX: Primary tumor unassessable
    T0: No evidence of primary tumor
    Tis : : Melanoma in situ
    T1a: <1.0 mm thickness w/o ulceration & <1 mitosis/mm2
    T1b: <1.0 mm thickness w/ ulceration or ≥1 mitosis/mm2
    T2a: 1.01-2.0 mm thickness w/o ulceration
    T2b: 1.01-2.0 mm thickness w/ ulceration
    T3a: 2.01-4.0 mm thickness w/o ulceration
    T3b: 2.01-4.0 mm thickness w/ ulceration
    T4a: >4.0 mm thickness w/o ulceration
    T4b: >4.0 mm thickness w/ ulceration
    Regional Lymph Nodes (N)
    NX: Regional lymph nodes unassessable
    N0: No detectable regional metastases
    N1a: 1 metastatic node w/ micrometastasis1
    N1b: 1 metastatic node w/ macrometastasis2
    N2a: 2-3 metastatic nodes w/ micrometastasis1
    N2b: 2-3 metastatic nodes w/ macrometastasis2
    N2c: 2-3 metastatic nodes w/ in-transit metastases/satellites w/o metastatic nodes
    N3: ≥4 metastatic nodes, or matted nodes, or in-transit metastases/satellites w/ metastatic nodes
    Distant Metastasis (M)
    M0: No distant metastasis
    M1a: Distant skin, subcutaneous, or nodal metastases w/ normal serum LDH
    M1b: Lung metastases w/ normal serum LDH
    M1c - All other visceral metastases w/ normal serum LDH
    - Any distant metastases w/ elevated serum LDH

  • Based on the 2010 American Joint Committee on Cancer 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
    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 IIIA T1-4a N1a M0
    T1-4a N2a M0
    Stage IIIB T1-4b N1a M0
    T1-4b N2a M0
    T1-4a N1b M0
    T1-4a N2b M0
    T1-4a N2c M0
    Stage IIIC T1-4b N1b M0
    T1-4b N2b M0
    T1-4b N2c M0
    Any T N3 M0
    Stage IV Any T Any N M1

1Micrometastasis is diagnosed after biopsy of sentinel lymph node (SLN)

2Macrometastasis is defined as nodal metastasis detected clinically & confirmed pathologically

3Clinical staging includes primary melanoma microstaging & clinical &/or radiologic metastatic evaluation

4Pathologic staging includes primary melanoma microstaging & regional LN pathologic information after partial or total lymphadenectomy

Prognosis

  • Important prognostic factors include the Breslow depth, ulceration, mitotic rate, SLN status, & systemic metastasis
    • Breslow depth & 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 w/ ulceration & deeper levels of tumor, vascular, or lymphatic invasion
  • Other significant factors include age & gender of patient
    • Younger female patients w/ extremity melanomas have better prognosis
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