Cutaneous Melanoma Workup

Updated: Apr 29, 2019
  • Author: Susan M Swetter, MD; Chief Editor: Dirk M Elston, MD  more...
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Workup

Laboratory Studies

The most important aspects of the initial workup for patients with cutaneous melanoma are a careful history, review of systems, and physical examination.

Sentinel lymph node biopsy (SLNB) is generally indicated for pathologic staging of the regional nodal basin(s) for primary tumors greater than 1 mm depth and when certain adverse histologic features (eg, ulceration, high mitotic rate, lymphovascular invasion) are present in thinner melanomas.

Published data have shown that baseline laboratory studies (eg, lactate dehydrogenase [LDH] level, liver function tests, chemistry panel, CBC count), chest radiography (CXR), and other imaging studies (eg, CT scanning, positron emission tomography [PET] scanning, bone scanning, MRI) are not useful for stage I/II (cutaneous) melanoma patients without signs or symptoms of metastasis, and obtaining these studies is discouraged. [48, 49, 50, 51]

A metastatic workup should be initiated if physical findings or symptoms suggest the presence of metastasis at the time of diagnosis or of metastatic disease recurrence following initial treatment of cutaneous melanoma. Screening CT or PET-CT may be considered if the patient has documented regional nodal micrometastasis based on results from the SLNB, although the yield is low (0.5-3.7%) and correlates with increasing tumor thickness, ulceration of the primary tumor, and/or large tumor burden in the sentinel lymph node(s). [52]

Practice guidelines developed by the National Comprehensive Cancer Network (NCCN) support the concept that most melanoma recurrences are diagnosed clinically. The current guidelines recommend against further workup (ie, baseline laboratory tests and imaging studies) in patients with stage 0 (melanoma in situ) and in asymptomatic patients with any thickness of invasive cutaneous melanoma (stages I and II). Further imaging (CT, PET-CT, MRI) should be obtained only as clinically indicated to evaluate specific signs or symptoms.

Guidelines established by the American Academy of Dermatology in 2011 also do not recommend baseline imaging or laboratory tests in asymptomatic patients with any stage of cutaneous melanoma (IA-IIC). [53]

The key components to melanoma follow-up are careful physical examination (with attention to lymph nodes and skin) and review of systems. Patients should be educated in the performance of monthly skin self-examination for early detection of new primary melanoma as well as self-lymph node examinations (in those with invasive melanoma).

Current NCCN guidelines do not recommend surveillance (follow-up) laboratory or imaging studies for asymptomatic patients with stage IA, IB, and IIA melanoma (ie, tumors ≤4 mm depth). Imaging studies (chest radiograph, CT and/or PET-CT) should be obtained as clinically indicated for confirmation of suspected metastasis or to delineate the extent of disease and may be considered to screen for recurrent/metastatic disease in patients with stage IIB-IV disease, although this latter recommendation remains controversial. Routine laboratory or radiologic imaging in asymptomatic melanoma patients of any stage is not recommended after 3-5 years of follow-up. [54]

While abnormal laboratory test results are rarely the sole indicator of metastatic disease, serum LDH levels were incorporated into the American Joint Committee on Cancer (AJCC) 2002 melanoma staging guidelines for the classification of stage IV (distant) disease. Elevated LDH levels are associated with worse survival in this subgroup and remain a powerful predictor of survival in the 2009 AJCC Cancer Staging Manual (7th ed) for melanoma of the skin. Serum S-100 protein levels may also be useful as a tumor marker in patients with metastatic disease, but this practice is not widely used in the United States. [55]

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Imaging Studies

As discussed previously, studies have confirmed that extensive radiologic studies such as CT, MRI, PET, PET-CT, and bone scans have an extremely low yield in asymptomatic patients with primary cutaneous melanoma (AJCC stages I and II) and are generally not indicated. However, maintaining a low threshold for obtaining symptom-directed tests is important in melanoma surveillance.

Surveillance CXR, CT, or PET-CT may be obtained for asymptomatic melanoma patients with primary tumors greater than 4 mm in depth, although this practice remains optional in the absence of signs or symptoms of metastatic disease. [54]

Current NCCN guidelines recommend the use of regional nodal ultrasound in certain clinical settings, including physical examination with equivocal lymph node findings. Regional nodal ultrasound has shown to be superior to palpation alone for assessment of regional lymph node metastasis and surveillance of the regional nodes. A meta-analysis of 74 studies conducted between 1990 and 2009 encompassing 10,528 patients demonstrated the superiority of ultrasonography over CT, PET, and PET-CT for detecting lymph node metastasis. [56] As such, NCCN guidelines now recommend consideration of regional nodal ultrasound in patients (1) with an equivocal lymph node examination, (2) who were offered but did not undergo SLNB staging, (3) in whom SLNB was not possible or technically successful, and (4) with a positive SLNB who did not undergo complete lymph node dissection. [54]

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Procedures

The criterion standard for melanoma diagnosis is histopathologic examination of clinically suggestive skin or mucosal lesions. An excisional biopsy with narrow margins is preferred and may consist of a fusiform/elliptical excision, an excisional punch biopsy, or a saucerization/deep shave biopsy (into the deeper reticular dermis), the latter of which is the most common technique used. In the case of melanoma in situ, lentigo maligna type, a broad shave biopsy (into the deeper papillary or superficial reticular dermis) may be the best technique to provide optimal tissue for histopathologic assessment. The biopsy report should generally include the following [53] :

  • Tumor thickness in millimeters (mm), ie, Breslow depth

  • Ulceration (present or absent)

  • Dermal mitotic rate (measured as number of mitoses/mm2)

  • Microsatellitosis

  • Anatomic level of invasion (Clark level) – Only for tumors 1 mm or smaller when mitotic rate cannot be determined)

Optional histologic features for primary melanoma include the following:

  • Angiolymphatic/lymphovascular invasion

  • Histologic subtype

  • Neurotropism/perineural invasion (particularly in desmoplastic melanoma)

  • Regression (which is associated with lower rates of sentinel node positivity and improved disease-free survival) [57]

  • Host response (tumor-infiltrating lymphocytes)

  • Vertical growth phase

Immunohistochemical staining for lineage (S-100, homatropine methylbromide 45 [HMB-45], melan-A/Mart-1) or proliferation markers (proliferating cell nuclear antigen, Ki67) may be helpful in some cases for histologic differentiation from melanoma simulators. Additionally, evidence of lack of maturation with HMB-45 staining and patchy, rather than diffuse, staining with S-100A6 may be helpful for distinguishing spitzoid melanoma from Spitz nevus.

Generally, when an excisional biopsy is performed, 1-3 mm of normal skin surrounding the pigmented lesion should be removed to provide accurate diagnosis and histologic microstaging. Wider margins (>1 cm) could theoretically disrupt afferent cutaneous lymphatic flow and affect the ability to identify the sentinel node(s) accurately in patients eligible for this staging procedure. Most data, however, suggest that accurate mapping is possible after wider excision, although an increased number of regional lymph nodes may be removed as a result.

Superficial shave biopsies of suggestive pigmented lesions are discouraged because partial removal of the primary melanoma may not provide an accurate measurement of tumor thickness, which is the most important histologic prognostic factor for cutaneous melanoma. As noted above, an important exception to this rule is the lentigo maligna subtype of melanoma in situ. In the case of lentigo maligna, the risk of misdiagnosis is high if small (partial) biopsy specimens are taken. The best diagnostic biopsy technique in this case is often a broad shave biopsy that extends into at least the papillary dermis, which provides the opportunity to exclude microinvasive melanoma and allows for optimal histopathologic interpretation of the tumor.

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Histologic Findings

Superficial spreading melanoma has an in situ (radial growth) phase characterized by increased numbers of intraepithelial melanocytes, which (1) are large and atypical, (2) are arranged haphazardly at the dermoepidermal junction, (3) show upward (pagetoid) migration, and (4) lack the biologic potential to metastasize. Lentigo maligna melanoma and acral lentiginous melanoma demonstrate predominant in situ growth at the dermoepidermal junction and with little tendency for the pagetoid scatter of cells.

Dermal invasion confers metastatic potential, although the greatest risk occurs in the setting of a vertical growth (tumorigenic) phase. [58, 59] Tumorigenicity is characterized by a distinct population of melanoma cells with evidence of proliferation (mitoses, MIB-1 staining) and nuclear pleomorphism within the dermis and, possibly, the subcutaneous fat. Lateral intraepidermal extension of melanoma cells occurs in all subtypes except nodular melanoma. Failure of melanocyte maturation and dispersion as the tumor extends downward into the dermis is characteristic of melanoma. Some investigators have defined a vertical growth phase as (1) any dermal nest larger than the largest junctional nest or (2) invasion into either the reticular dermis or band of solar elastosis.

Tumor thickness, as defined by the Breslow depth, is the most important histologic determinant of prognosis and is measured vertically in millimeters from the top of the granular layer (or base of superficial ulceration) to the deepest point of tumor involvement. Increased tumor thickness confers a higher metastatic potential and a poorer prognosis. [60, 61] Analysis of worldwide data has shown that the presence of ulceration microscopically, defined as a full-thickness epidermal defect overlying the melanoma, is the next most important histologic determinant of patient prognosis and, when present, should be used to up-stage patients with both primary and nodal melanoma. [62] Data have suggested that both the presence and extent of histologic ulceration predict survival, with extent of ulceration (measured either as diameter or percentage of tumor width) providing more accurate prognostic information than the presence of ulceration alone. Specifically, in an analysis of 4661 patients,those with minimally/moderately ulcerated tumors (defined as less than or equal to 70% or less than or equal to 5mm) had a significantly higher risk of death (HR=1.53 and HR=1.39, respectively), compared with nonulcerated melanoma, and the risk of death was even higher for patients with extensively ulcerated tumors (>70%: HR=2.20 and >5 mm: HR=2.03). [63]

The Clark level has been used for more than 40 years and provides a measurement of tumor invasion anatomically. However, analysis of the worldwide AJCC 2008 melanoma staging database has demonstrated lower statistical correlation with melanoma survival when level of invasion was compared with thickness, mitotic rate, ulceration, age, sex, and site. As such, the seventh edition of the AJCC Cancer Staging Manual (effective January 2010) no longer includes the Clark level in T1a melanomas (≤1 mm depth). Dermal mitotic rate of greater than or equal to 1/mm2 has been incorporated in thin melanomas in place of Clark level and upstages a T1a melanoma to a T1b melanoma. [64]

Data from the AJCC Melanoma Staging Database and other studies have demonstrated a highly significant correlation between increasing mitotic rate and declining survival rates, particularly in thin melanomas. Higher mitotic rate (as a continuous variable) across all tumor thicknesses confers a greater risk for metastasis and is an independent predictor of worse survival.

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Staging

The melanoma staging system initially developed in 1983 by the AJCC and the International Union Against Cancer (UICC) divided melanoma into 4 stages and incorporated tumor thickness and anatomic level of invasion for stages I and II (localized cutaneous disease), with the later recommendation to follow Breslow depth over Clark level when any discordance arose. Stage III disease involved the regional lymph nodes; stage IV disease included distant skin, subcutaneous, nodal, visceral, skeletal, or CNS metastasis.

Major revisions in the 2002 AJCC/UICC melanoma staging system were made based on a critical analysis of prior versions of the staging protocol. [62] The AJCC formed an international multidisciplinary Melanoma Staging Committee and established a new clinicopathologic database of more than 17,000 patients worldwide to test the validity of the proposed staging changes. [65, 66, 67]

Several important modifications in the 2002 AJCC staging system included the incorporation of histologic ulceration of the primary tumor and number of lymph nodes involved (instead of size) to better stratify metastatic risk and patient prognosis. [27] In the 2002 staging system, Clark level was included only in thin primary tumors (≤1 mm depth, stages IA and IB) because its prognostic value was minimal in thicker primary melanomas. Furthermore, microscopic regional lymph node metastasis detected largely by SLNB was differentiated from macroscopic (palpable) nodal metastasis.

The seventh edition of the AJCC Cancer Staging manual (effective January 2010) recommended no major changes for TNM categories and stage groupings, with the exception of removing Clark level and instead incorporating mitotic rate of greater than or equal to 1/mm2 to upstage T1a to T1b melanomas, given the adverse effect of higher mitotic rate on melanoma survival. [64] Updated analysis of the worldwide AJCC collaborative melanoma database is underway, in preparation for revised AJCC melanoma staging based on the best available prognostic information.

The estimated 5-year overall survival (OS) in the Table below is based on analysis of worldwide data encompassing nearly 60,000 patients in the 2008 AJCC Melanoma Staging Database. [64] Publication of current survival data used for the AJCC eighth edition is pending.

The eighth edition of the AJCC Cancer Staging manual (published in 2016 and effective January 2018) recommended several important changes for cutaneous melanoma, including reporting of Breslow thickness to the nearest 0.1 mm, rather than the nearest 0.01 mm, owing to the lack of precision in measurement beyond the 1/10th decimal point. [68] Tumor mitotic rate was removed as a staging criterion in T1 melanoma, although histopathologic measurement of mitotic rate (in #/mm2) is recommended across all tumor thicknesses given its impact on prognosis. Finally, the eighth edition excludes Clark level from staging, noting its lack of predictive value for survival, compared with other prognostic variables.

Table. AJCC 2002 Revised Melanoma Staging (Open Table in a new window)

Stage

TNM Classification

Histologic/Clinical Features

5-Year Survival Rate, %

0

Tis N0 M0

Intraepithelial/in situ melanoma

100

IA

T1a N0 M0

≤1 mm without ulceration and mitotic rate < 1/mm2

97

IB

T1b N0 M0

T2a N0 M0

≤1 mm with ulceration or mitotic rate ≥1/mm2

1.01-2 mm without ulceration

91-94

IIA

T2b N0 M0

T3a N0 M0

1.01-2 mm with ulceration

2.01-4 mm without ulceration

79-82

IIB

T3b N0 M0

T4a N0 M0

2.01-4 mm with ulceration

4 mm without ulceration

68-71

IIC

T4b N0 M0

>4 mm with ulceration

53

IIIA

T1-4a N1a M0

T1-4a N2a M0

Single regional nodal micrometastasis, nonulcerated primary

2-3 microscopic positive regional nodes, nonulcerated primary

78

IIIB

T1-4b N1a M0

T1-4b N2a M0

T1-4a N1b M0

T1-4a N2b M0

T1-4a/b N2c M0

Single regional nodal micrometastasis, ulcerated primary

2-3 microscopic regional nodes, nonulcerated primary

Single regional nodal macrometastasis, nonulcerated primary

2-3 macroscopic regional nodes, no ulceration of primary

In-transit met(s)* and/or satellite lesion(s) without metastatic lymph nodes

54-59

IIIC

T1-4b N2a M0

T1-4b N2b M0

Any T N3 M0

Single macroscopic regional node, ulcerated primary

2-3 macroscopic metastatic regional nodes, ulcerated primary

4 or more metastatic nodes, matted nodes/gross extracapsular extension, or in-transit met(s)/satellite lesion(s) and metastatic nodes

40

IV

Any T any N M1a

Any T any N M1b

Any T any N M1c

Distant skin, subcutaneous, or nodal mets with normal LDH levels

Lung mets with normal LDH

All other visceral mets with normal LDH or any distant mets with elevated LDH

< 20

*Met is metastasis.

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