Cutaneous Melanoma Workup

Updated: Mar 22, 2022
  • 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 recommended for pathologic staging of the regional nodal basin(s) in 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 asymptomatic stage I/II (cutaneous) melanoma patients, and obtaining these studies is discouraged. [61, 62, 63, 64, 38]

A metastatic workup should be initiated if physical findings or symptoms suggest the presence of metastasis at the time of diagnosis or for concern of metastatic disease recurrence following initial treatment of cutaneous melanoma. Distant metastasis work-up with CT (chest/abdomen/pelvis) 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). [65]

Practice guidelines developed by the National Comprehensive Cancer Network (NCCN) [38] and American Academy of Dermatology [66] 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 2019 also do not recommend baseline imaging or laboratory tests in asymptomatic patients with any stage of cutaneous melanoma (IA-IIC). [66]

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 and AAD 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 may be considered to screen for recurrent/metastatic disease in patients with stage IIB-IV disease, although there is little evidence to suggest that asymptomatic, surveillance-detected recurrence improves patient outcomes. [67]  Routine radiologic imaging in asymptomatic melanoma patients of any stage is not recommended after 3-5 years of follow-up. [38, 66]

While abnormal laboratory test results are rarely the sole indicator of metastatic disease, serum LDH levels were first incorporated into AJCC melanoma staging in 2002 for subclassification of stage IV (distant) disease. Elevated LDH levels are associated with worse survival in patients with distant disease and have remained a powerful predictor of survival in subsequent AJCC melanoma staging. Serum S-100 protein levels may also be useful as a tumor marker in patients with metastatic disease, but this test is not widely used in the United States. [68]

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Imaging Studies

As discussed previously, studies have confirmed that extensive radiologic studies such as CT, MRI, 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 or ulcerated tumors >2.0-4 mm thickness (i.e. AJCC-8 stage IIB/IIC), although this practice remains optional in the absence of signs or symptoms of metastatic disease. [69]  Melanomas at higher risk for metastasis (stage IIC, III) are generally followed with surveillance imaging, to expedite initiation of therapeutic intervention if disease recurs.

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. [70] As such, NCCN guidelines 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 apositive SLNB who did not undergo complete lymph node dissection, a practice which is now typical for most SLNB-positive melanomas. [69]

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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 (1-3 mm) 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 to capture potential invasive melanoma) may be the best technique to provide optimal tissue for histopathologic assessment. The biopsy report should generally include the following [66, 71, 72] :

Mandatory histologic features for pathology reporting include:

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

  • Ulceration (present or absent)

  • Microsatellitosis (which updates a melanoma to stage III)

  • Margin status for biopsies and excisions (to include whether tumor extends to the peripheral and/or deep margin)

Optional (but encouraged) histologic features for reporting include:

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

  • Lymphovascular/angiolymphatic invasion
  • Histologic subtype (if desmoplastic, pure vs mixed features should be noted)

  • Neurotropism/perineural invasion (particularly in desmoplastic melanoma)

  • Regression (if extensive [>75%] or extending below measured Breslow thickness, through regression is generally associated with lower rates of sentinel node positivity and improved disease-free survival) [73]

Immunohistochemical staining for lineage (S-100, homatropine methylbromide 45 [HMB-45], melan-A/Mart-1), nuclear transcription factor (SOX10) , melanoma associated antigen (Preferentially expressed Antigen in Melanoma [PRAME]), and/or proliferation markers (proliferating cell nuclear antigen, Ki67) may be helpful for histologic differentiation from melanoma simulators.

When an excisional biopsy is performed, 1-3 mm of normal skin surrounding the pigmented lesion should be removed to completely remove the lesion and 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. As noted above, an important exception to this rule is the lentigo maligna subtype of melanoma in situ, in which the risk of misdiagnosis is higher if small (partial) biopsy is performed. The best diagnostic biopsy technique 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. [74, 75] 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. [76, 77] 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. [78] 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 5 mm) 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). [79]

The Clark level was used for more than 40 years to provide a measurement of tumor invasion anatomically, though its relevance diminished with greater understanding of histologic prognostic factors. In the 2002 AJCC melanoma staging system, Clark level was included only in thin primary tumors (≤1 mm depth) because its prognostic value was minimal in thicker primary melanomas. However, analysis of the worldwide AJCC 2008 melanoma staging database 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 7th edition of the AJCC Cancer Staging Manual (effective January 2010) excluded Clark level in T1 melanomas (≤1 mm depth), replacing it with dermal mitotic rate (greater than or equal to 1/mm2) to upstage a T1a melanoma to a T1b melanoma. [80]

While dermal mitotic rate is no longer incorporated into AJCC 8th edition melanoma staging for T1 melanoma, it remains a key prognostic factor and should be measured for all invasive melanomas. Higher mitotic rate (as a continuous variable) across all tumor thicknesses confers a greater risk for metastasis, including SLNB 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 invasionlevel of invasion (Clark level) 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.

Following publication of the AJCC melanoma guidelines in 2002, an international multidisciplinary Melanoma Staging Committee established a new clinicopathologic database of more than 17,000 patients worldwide to test the validity of the proposed staging changes. [81, 82, 83]  Several important modifications to prior AJCC staging 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. [39] Furthermore, microscopic regional lymph node metastasis detected largely by SLNB was differentiated from macroscopic (palpable) nodal metastasis. Further changes in AJCC melanoma  staging for the 7th edition were made based on an improved understanding of prognostic factors that relate to melanoma-specific survival.

The 8th edition of the AJCC Cancer Staging manual (effective January 2018) used a newly created international AJCC Collaborative database that included over 49,0000 patients with staged I-III melanoma from 1998 on (meaning that most were pathologically staged with SLNB) from the US, Australia, and Europe (Italy, Greece, Spain) to provide the best available prognostic information. [84] The estimated 5-year overall survival (OS) in the Table below is based on analysis of these worldwide data. Patients with T2 to T4 melanoma were included only if they had negative sentinel lymph nodes, whereas those with T1N0 melanoma were included regardless of whether they underwent SLNB. Survival estimates for stage IV melanoma (distant disease) were not included due to the rapidly changing treatment landscape. [37]

The 8th edition of the AJCC Cancer Staging manual [84]  had several important changes, 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. [84] Thin melanoma less than or equal to 1 mm (T1), was subdivided into T1a (for tumors < 0.8 mm without ulceration) and T1b (for tumors < 0.8 mm with ulceration or 0.8-1.0 mm with or without ulceration). 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. The 8th edition excluded Clark level from staging, again noting its lack of predictive value for survival compared with other prognostic variables.

For stage III melanoma, tumor thickness and presence or absence of lymphatic metastasis (microsatellite, satellite or in-transit) were incorporated, and stage IIID was added to reflect worse prognosis for T4b primaries with nodal and/or lymphatic metastasis. For stage IV disease, the subcategory of M1d was added to include distant metastasis to the central nervous system (CNS).

Table. AJCC Eighth Edition Melanoma Staging (2018) (Open Table in a new window)

Clinical Stage

TNM Classification

Histologic/Clinical Features

5-Year Survival Rate, %

0

Tis N0 M0

Intraepithelial/in situ melanoma

100

IA

T1a N0 M0

< 0.8 mm without ulceration

99

IB

T1b N0 M0

T2a N0 M0

< 0.8 mm with ulceration or 0.8 mm with or without ulceration

>1.0-2.0 mm without ulceration

99

96

IIA

T2b N0 M0

T3a N0 M0

>1.0-2.0 mm with ulceration

>2.0-4.0 mm without ulceration

93

94

IIB

T3b N0 M0

T4a N0 M0

>2.0-4.0 mm with ulceration

>4.0 mm without ulceration

86

90

IIC

T4b N0 M0

>4.0 mm with ulceration

82

IIIA

T1a/b, T2a N1a M0

T1a/b, T2a N2a M0

1 regional nodal micrometastasis (clinically occult), without lymphatic metastasis*, ulcerated primary ≤1.0 mm or nonulcerated primary ≤2.0 mm

2-3 microscopic positive regional nodes (clinically occult) without lymphatic metastasis*, ulcerated primary ≤1.0 mm or nonulcerated primary ≤2.0 mm

93

IIIB

T1a/b, T2a N1b/c, N2a/b M0

 

T2b, T3a  N1a/b/c, N2a/b M0

1 regional nodal macrometastasis (clinically detected) without lymphatic metastasis*, or no lymph node disease with lymphatic metastasis*, ulcerated primary ≤1.0 mm or nonulcerated primary ≤2.0 mm

 

2-3 regional nodal macrometastasis (clinically detected) or 2-3 involved nodes, at least one of which was clinically detected without lymphatic metastasis*, ulcerated primary ≤1.0 mm or nonulcerated primary ≤2.0 mm

 

1 regional nodal micrometastasis (clinically occult), or 1 regional nodal nodal macrometastasis (clinically detected) without lymphatic metastasis*, or no regional lymph node disease with lymphatic metastasis*, ulcerated primary >1.0-2.0 mm or nonulcerated primary >2.0-4.0 mm

83

IIIC

T1a/b, T2a/b, T3a N2c, N3a/b/c M0

 

T3b, T4a, Any N ≥ N1 M0

 

T4b N1a/b/c, N2a/b/c

1 clinically occult or clinically detected metastasis with lymphatic metastasis*, or 4+ regional nodal micrometatasis (clinically occult) or 4+ tumor involved nodes, at least 1 of which was clinically detected, or any matted nodes without lymphatic metastasis*, or 2+ clinically occult or clinically detected and/or matted nodes with lymphatic metastasis*, ulcerated or nonulcerated primary ≤2.0 mm or nonulcerated primary >2.0-4.0 mm

 

N2 or N3 disease with ulcerated primary >2.0-4.0 mm or nonulcerated primary >4.0 mm

One regional nodal micrometastasis (clinically occult), or one regional nodal macrometastasis (clinically detected) without lymphatic metastasis* or no regional lymph node disease with lymphatic metastasis*, ulcerated primary >4.0 mm

 

2-3 regional nodal macrometastasis (clinically detected) or 2-3 involved nodes, at least one of which was clinically detected without lymphatic metastasis*, or one clinically occult or clinically detected involved node with lymphatic metastasis*, ulcerated primary >4.0 mm

69

IIID

T4b N3a/b/c M0

4+ regional nodal micrometastasis (clinically occult) or 4+ tumor involved nodes, at least 1 of which was clinically detected, or any matted nodes without lymphatic metastasis*, or 2+ clinically occult or clinically detected and/or matted nodes with lymphatic metastasis*, ulcerated primary >4.0 mm

32

IV

Any T, Tis Any N M1a

 

Any T, Tis Any N M1b

 

Any T, Tis Any N M1c

 

Any T, Tis Any N M1d

Distant skin, soft tissue/muscle and/or nonregional lymph node metastasis with normal [M1a(0)] or elevated [M1a(1)] LDH** levels

 

Distant metastasis to non-CNS*** visceral sites with or without M1a or M1b sites of disease lung with normal [M1b(0)] or elevated [M1b(1)] LDH levels 

 

All other visceral metastasis with normal LDH or any distant metastasis with elevated LDH with normal [M1c(0)] or elevated [M1c(1)] LDH levels

 

Distant metastasis to CNS with or without M1a, M1b, or M1c sites of disease with normal [M1d(0)] or elevated [M1d(1)] LDH levels

 

*Lymphatic metastasis is presence of in-transit, satellite, and/or microsatellite metastasis.

**LDH is lactate dehydrogenase.

***CNS is central nervous system.

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