Malignant melanoma is an aggressive form of skin cancer and has demonstrated an increasing mortality among men in the last quarter century.1 The 5-year survival rate is approximately 15–20 % for stage IV melanoma.2 Surgical management of primary melanoma remains wide excision with or without the addition of sentinel lymph node biopsy. While 5-year survival for stage I and II melanomas is good, outcome for stage IV melanoma remains bleak. Recently, a number of directed therapies have been developed for treatment of metastatic malignant melanoma. Many of these are predicated on the presence of specific mutations sensitizing the malignant cells to specific chemotherapeutic agents. Molecular techniques are required to document the specific mutations, thus tissue from metastatic sites is needed to guide selection of specific therapies. Given that specific therapies with efficacy against metastatic disease now exist, the early recognition of distant metastases by imaging modalities and their biopsy have become important in the management of stage III and IV melanoma patients. Herein, we review blood marker testing, imaging methods and indications, biopsy techniques, and ancillary testing for directed therapies in patients with metastatic malignant melanoma. The current review is limited to cutaneous melanoma and its metastases.
Clinical History and Initial Physical Examination
Following the identification of a clinically suspicious pigmented lesion, the patient should have a focused medical history taken documenting the presence of any family history of melanoma or other skin cancer as well as whether or not there is a family history of multiple, irregular, or prominent moles. The history should also include documentation of the presence or absence of pancreatic ductal carcinoma or astrocytoma within the family. The patient should be specifically questioned about a history of prior personal melanomas. A history of significant prior sun exposure should be documented. The patient should be asked about changes they have noted in other moles specifically regarding alterations in size, color, shape, or the presence of bleeding or ulceration. A personal history or family history of multiple nevus syndrome should be queried.
Physical examination should include a total body skin examination with photography of nevi and other suspicious cutaneous lesions. This total body skin examination is performed to assess the number of nevi present and to distinguish between typical and atypical lesions.
Biopsy of Primary Lesion and Histologic Examination
The index atypical pigmented lesion should be excised in total if possible. Shave biopsies are suboptimal specimens as they may preclude accurate evaluation of depth of invasion and assessment of architectural features that are important for diagnosis. Excisional biopsies are recommended because they allow the evaluation of junctional activity at the edges of the lesion and the deep margin. Such assessment also aids in the diagnosis of melanoma because it allows evaluation of lesional symmetry.
Histopathologic evaluation is performed and expert consultation is desirable for difficult lesions. The College of American Pathologists synoptic report should be addended to the diagnostic report. This synoptic checklist should include a statement as to the type of melanoma (superficial spreading, lentigo maligna melanoma, acral lentiginous, nodular, or other types) present. Clark’s level of invasion and Breslow thickness should be given. The thickness should be measured with the aid of a micrometer. The checklist should also include a statement on the lymphoid host response at the base of the lesion being designated as none/minimal, mild (nonbrisk), marked (brisk), or other. Associated lesions should be documented. The presence or absence of ulceration should be documented as well as the mitotic index (rate). Angiolymphatic invasion should be documented as present or absent. The presence of regression should be described as well as satellitosis, if present. Operative margins need to be evaluated. The presence or absence of involvement of peripheral margins should be documented and the distance between the melanoma and margin stated for uninvolved peripheral margins. Similarly, the status of the deep margin should be documented and when negative, the distance between the melanoma and the deep margin stated.
Both Clark’s level and Breslow thickness have prognostic value.3–5 Many experts in dermatopathology believe that both should be reported. Determination of Breslow thickness requires a micrometer while Clark’s level does not and may be the easier measurement to determine. Tables 1 and 2 describe Clark’s level and Breslow thickness cutpoints.
Following a histopathologic diagnosis of melanoma, re-excision should generally be performed. Elective lymph node dissection for patients with clinically enlarged lymph nodes should be undertaken. When lymph nodes are clinically within normal limits, sentinel lymph node biopsy is often performed for staging purposes.6–8 Dynamic lymphoscintigraphy is used for localization of sentinel lymph nodes.9,10 Sentinel lymph nodes histopathologic examination may include either microscopic examination of multiple hematoxylin and eosin stain (H&E) stained levels or the use of immunohistochemistry for s100 protein, melanin-A, and, perhaps, HMB- 45.11,12 Subsequent therapy is based upon status of the sentinel lymph nodes and the thickness of the primary melanoma.
Histopathologic staging involves assessment of Clark’s level and Breslow thickness as defined in Tables 1 and 2. The American Joint Committee on Cancer (AJCC) has proposed a TNM system for staging melanoma.13 T classification is based on thickness and the presence of ulceration as shown in Table 3.
Imaging Techniques and Indications
Traditionally, imaging studies are performed in patients with recently diagnosed melanoma. While low-cost studies such as chest radiographs are useful in establishing a baseline, more-expensive imaging techniques may not be cost-effective.14 Few guidelines exist that define appropriate testing protocols for initial evaluation and follow-up of patients with melanoma.15 Malignant melanoma has a propensity to metastasize widely with common sites for deposits of melanoma being skin, lymph nodes, liver, bone, lung, gastrointestinal tract, and brain. Multi-institutional studies have shown that ultrasound (US) is the superior technique for documentation of metastases to sentinel lymph nodes while positron emission tomography (PET) and computed tomography (CT) appear to be the best methods for identifying metastases at other sites.16 Current American Academy of Dermatology guidelines do not recommend baseline testing in asymptomatic patients with stage 1a–2c cutaneous melanoma.17 Similarly, guidelines proposed by the National Comprehensive Cancer Network (NCCN) indicate that no laboratory testing or baseline imaging studies should be obtained in asymptomatic patients with stage IA, IB, or IIA melanomas. Chest radiographs are optional for stage IIB and IIC patients.18 The NCCN guidelines support the concept that most melanoma recurrences are initially recognized clinically. Imaging studies are indicated for confirmation of clinically suspected metastatic disease and potentially in patients with stage IIB to IV disease.18 Scheduling of followup imaging studies for patients with thick melanomas or after treatment for metastatic disease is controversial and definitive guidelines do not exist. Patients with positive sentinel lymph nodes often undergo extensive imaging studies either before or after completion lymphadenectomy or when being considered for further therapy.15 Despite the widespread use of such testing in patients with only a positive sentinel lymph node, the yield of such studies is small bringing into question their utility.19–21 Patients with stage III disease with locoregional melanoma should have further imaging studies including CT, magnetic resonance imaging (MRI), or PET due to their relatively high (50 %) risk for systemic disease. CT examination should include the chest and abdomen/pelvis.22–24 PET-CT is the dominate imaging technique for evaluation of patients with highstage disease.25 PET-CT has considerable advantages including: 1) higher sensitivity in comparison to CT and 2) gives whole-body coverage in one examination possibly eliminating the need for other tests. Patients with known stage IV disease should undergo comprehensive imaging evaluation to detect additional sites of involvement.15