eMedicine Specialties > Dermatology > Malignant Neoplasms
Malignant Melanoma: Differential Diagnoses & Workup
Updated: Feb 12, 2009
- Overview
- Differential Diagnoses & Workup
- Treatment & Medication
- Follow-up
- Multimedia
Differential Diagnoses
Other Problems to Be Considered
Chronic paronychia (for subungual melanoma)
Subungual hematoma (for subungual melanoma)
Melanonychia striata (for subungual melanoma)
Traumatized nevus (for superficial spreading or nodular subtypes)
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 or equal to 1 mm depth and when certain high-risk histologic features (eg, ulceration, extensive regression, high mitotic rate, angiolymphatic invasion) are present in thinner melanomas.
- Published data have shown that baseline and surveillance laboratory studies (eg, lactate dehydrogenase [LDH] level, liver function tests), chest radiography (CXR), and other imaging studies (eg, CT scanning, positron emission tomography [PET] scanning, bone scanning, MRI) are not typically beneficial for stage I/II (cutaneous) melanoma patients without signs or symptoms of metastasis.31,32,33,34
- A metastatic workup should be initiated if physical findings or symptoms suggest disease recurrence or if the patient has documented nodal metastasis based on results from the SLNB.
Practice guidelines developed by the National Comprehensive Cancer Network support the concept that most melanoma recurrences are diagnosed clinically. The current guidelines state that no further workup (ie, baseline laboratory tests and imaging studies) is required in stage 0 (melanoma in situ) and for asymptomatic patients with stage IA, IB, or IIA melanoma. Chest radiography is considered optional for stage IB-II melanoma, although routine baseline imaging is not recommended for asymptomatic patients with stage IA-IIA melanoma. Further imaging (CT scanning, PET, MRI) should be obtained as clinically indicated (to evaluate specific signs or symptoms) in stage IIB and IIC patients with higher-risk melanoma.
The key components to melanoma follow-up are careful physical examination (with attention to 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). No surveillance studies are recommended for asymptomatic patients with stage IA melanoma, and routine imaging is also not recommended for stages IB and IIA melanoma. Surveillance CXR, LDH, and CBC studies for asymptomatic patients with stage Ib-IV melanoma may be performed on an "optional" basis every 6-12 months at the discretion of the clinician. Advanced imaging studies should be obtained as clinically indicated for confirmation of suspected metastasis or to delineate the extent of disease. Current recommendations do not indicate that baseline or surveillance studies are necessary in patients with melanoma in situ (stage 0) or stage IA disease (£ 1 mm thickness).35
While abnormal laboratory test results are rarely the sole indicator of metastatic disease, serum LDH levels have been 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. 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.36
Imaging Studies
Studies have confirmed that extensive radiologic studies such as CT scanning, MRI, PET scanning, ultrasonography, and bone scanning 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.
Baseline metastatic staging for melanoma patients with primary tumors greater than 1 mm in depth may include CXR, which typically is repeated every 6-12 months for routine surveillance (optional in the absence of signs or symptoms of metastatic disease).35
Procedures
The criterion standard for melanoma diagnosis is histopathologic examination of clinically suggestive skin or mucosal lesions. An excisional biopsy (or deep saucerization technique) with narrow margins is preferred when possible. In the case of lentigo maligna, a broad, paper-thin shave biopsy or multiple smaller biopsies may be the best techniques. The biopsy report should generally include the following:
- Tumor thickness (Breslow depth)
- Presence of ulceration
- Anatomic level of invasion (Clark level)
- Presence of mitoses
- Presence of regression (associated with lower rates of sentinel node positivity and improved disease-free survival)37
- Lymphatic/vessel (lymphovascular) invasion or vascular involvement
- Host response (tumor-infiltrating lymphocytes)
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. Some data, however, suggest that accurate mapping is possible after wider excision.
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), deep 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.
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.38,39 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.40,41 Analysis of worldwide data has shown that the presence of ulceration microscopically, defined as the loss of epidermis overlying the melanoma, is the next most important histologic determinant of patient prognosis and, when present, should be used to up-stage patients with melanoma.42 The Clark level is a measurement of tumor invasion anatomically and appears to affect prognosis only in thinner (<1 mm depth) melanomas.
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.42 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.43,44,45 Several important modifications in the 2002 AJCC staging system include the incorporation of histologic ulceration and number of lymph nodes involved (instead of size) to better stratify metastatic risk and patient prognosis.46 In the revised staging system, the Clark level is included only in thin primary tumors (<1 mm depth, stages IA and IB) because its prognostic value is minimal in thicker primary melanoma. Microscopic regional lymph node metastasis as detected by SLNB is differentiated from macroscopic nodal metastasis.
Overall survival (OS) in the staging Table below is based on worldwide AJCC data.44 The next iteration of the AJCC melanoma staging system is anticipated in 2009.
AJCC 2002 Revised Melanoma StagingOpen table in new window
Table
| 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 level II/III | >95 |
| IB | T1b N0 M0 T2a N0 M0 | £ 1 mm with ulceration or level IV/V 1.01-2 mm without ulceration | 89-91 |
| IIA | T2b N0 M0 T3a N0 M0 | 1.01-2 mm with ulceration 2.01-4 mm without ulceration | 77-79 |
| IIB | T3b N0 M0 T4a N0 M0 | 2.01-4 mm with ulceration ³ 4 mm without ulceration | 63-67 |
| IIC | T4b N0 M0 | >4 mm with ulceration | 45 |
| IIIA | T1-4a N1a M0 T1-4a N2a M0 | Single regional nodal micrometastasis, nonulcerated primary 2-3 microscopic positive regional nodes, nonulcerated primary | 63-69 |
| 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 | 46-53 30-50 |
| 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 | 24-29 |
| 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 | 7-19 |
| 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 level II/III | >95 |
| IB | T1b N0 M0 T2a N0 M0 | £ 1 mm with ulceration or level IV/V 1.01-2 mm without ulceration | 89-91 |
| IIA | T2b N0 M0 T3a N0 M0 | 1.01-2 mm with ulceration 2.01-4 mm without ulceration | 77-79 |
| IIB | T3b N0 M0 T4a N0 M0 | 2.01-4 mm with ulceration ³ 4 mm without ulceration | 63-67 |
| IIC | T4b N0 M0 | >4 mm with ulceration | 45 |
| IIIA | T1-4a N1a M0 T1-4a N2a M0 | Single regional nodal micrometastasis, nonulcerated primary 2-3 microscopic positive regional nodes, nonulcerated primary | 63-69 |
| 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 | 46-53 30-50 |
| 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 | 24-29 |
| 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 | 7-19 |
*Met is metastasis.
More on Malignant Melanoma |
| Overview: Malignant Melanoma |
 Differential Diagnoses & Workup: Malignant Melanoma |
| Treatment & Medication: Malignant Melanoma |
| Follow-up: Malignant Melanoma |
| Multimedia: Malignant Melanoma |
| References |
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Further Reading
Keywords
melanoma, skin cancer, cutaneous melanoma, malignancy of pigment-producing cells, malignant melanoma, malignancy of melanocytes, invasive cutaneous melanoma, melanoma in situ, metastatic melanoma, acral melanoma, changing mole, superficial spreading melanoma, nodular melanoma, lentigo maligna melanoma
