GENERAL PRINCIPLES
Definition
Malignant melanoma is an aggressive neoplasm that arises from melanocytes, which are long-lived pigment–producing cells.1 Melanocytes are located in the basal layer of the epidermis, hair bulb, eyes, ears, and meninges. Melanoma most commonly arises in the skin; however, melanoma can also arise in non-cutaneous sites as well. Intraocular melanoma of the choroid and ciliary body is the most common ocular malignant tumor in adults, and the most common non-cutaneous melanoma.2
Classification
Malignant melanoma is traditionally classified into superficial spreading melanoma (estimated 50% to 75% of melanomas), nodular melanoma (15% to 35%), lentigo maligna melanoma (5% to 15%), acral lentiginous melanoma (5% to 10%), desmoplastic melanoma (uncommon) and a miscellaneous group (rare).1Superficial spreading melanoma (SSM) is the most common form of melanoma. In SSM, the melanoma cells demonstrate pagetoid spread in the epidermis, and the lesions classically show variation in pigmentation. Nodular melanoma (NM) can appear nodular, polypoid, or pedunculated. Lentigo maligna melanoma (LMM) is a variant of melanoma that affects the sun-exposed skin, face, and upper extremities of elderly patients. Lentigo maligna (LM) is a subtype of melanoma in situ and should be distinguished from LMM. LM typically presents on sun-exposed areas of middle-aged and elderly individuals, and appears as centrifugally expanding large patch with variable shades ranging from tan to black.3 The lifetime risk of progression to LMM is approximately 5%. Acral lentiginous melanoma (ALM) arises in the palmar, plantar, or ungual skin. Most mucosal melanomas, including those affecting the oral cavity, vulva, vagina, and cervix, share histological features of ALM.
Epidemiolgy
In the United States, an estimated 68,130 new cases of melanoma will be diagnosed in 2010, and an estimated 8700 deaths will result from the disease.4 Overall, the incidence of melanoma increased 3.1% annually over the last two decades.5 The incidence of melanoma rises with increasing age, and is significantly lower in non-Caucasian populations. About 10% of malignant melanomas present in familial clusters.
Etiology
The transformation of benign melanocytes to melanoma results from a collection of genetic changes. Hereditary melanoma typically demonstrates an autosomal-dominant pattern within multiplex families [reviewed in6]. Germline mutations in the cyclin-dependent kinase inhibitor 2A (CDKN2A) gene located on chromosome 9p21 conferred susceptibility to melanoma with high penetrance. Subsequently, a second high penetrance gene, the cyclin-dependent kinase 4 (CDK4) gene located on chromosome 12q14, was identified in certain kindreds that lacked hereditable CDKN2A mutations. Together, these foci account for about 20% to 57% of disease susceptibility. Two proteins, p14Arf and p16Ink4a, are encoded by splice variants of the CDKN2A locus. The p14Arf protein regulates the p53 tumor suppressor network, and loss of p14Arf results in the indirect loss of p53 function, thereby leading to dysregulation of cell cycling and DNA damage response. The p16Ink4a mutant proteins are unable to inhibit Cdk4 and Cdk6, thereby leading to the inability to suppress phosphorylation of the retinoblastoma (Rb) protein. Hyperphosphorylation of Rb allows the cell to transition from G1 to S-phase of the cell cycle, and to proliferate. A key pigmentation gene, the melanocortin-1-receptor (MC1R), has also been implicated as a low to moderate penetrance melanoma susceptibility gene.
Activating mutations in the BRAF gene have been found in 60% to 80% of melanoma cases.7 The BRAF gene encodes a serine/threonine protein kinase that plays an important role in regulating signaling pathways, such as the mitogen activated protein kinase (MAPK) pathway. Dysregulated BRAF signaling is thought to promote dysregulated cell division and differentiation. Curtin et al. postulated that the clinical heterogeneity seen in melanoma could be explained by genetically distinct types of melanoma, and used array-based comparative genomic hybridization to interrogate four groups of melanomas, namely, melanoma on skin without chronic sun-induced damage, melanoma on skin with chronic sun-induced damage, mucosal melanoma and acral melanoma.8 Acral or mucosal melanoma had significantly higher degree of chromosomal aberrations. While amplifications were found in the majority of acral and mucosal melanomas, they involved different genomic regions. On the other hand, amplifications were infrequent in the other two groups. Melanomas on mucosal membranes, acral skin, and skin with chronic sun-induced damage were found to have infrequent mutations in BRAF and NRAS, two genes involved with the MAPK pathway, in contrast to melanomas on skin without chronic sun-induced damage. On the other hand, somatic activation of KIT was found in a fraction of melanomas on mucosal membranes (39%), acral skin (36%), and skin with chronic sun-induced damage (28%), but not in melanomas on skin without chronic sun-induced damage.9These findings have implications for the development of targeted therapies.
Risk Factors
Risk factors for melanoma include environmental factors such as sun exposure and exposure to artificial ultraviolet (UV) rays via indoor tanning [reviewed in5 and10]. Persons with fair skin, freckles, and inability to tan are more likely to develop melanoma. Family history of malignant melanoma in a first or second-degree relative confers increased risk. Persons with large numbers of nevi (>100) or atypical nevi of any number have a higher risk of developing melanoma. Large congenital nevi pose a risk of melanoma of approximately 5% to 10%. Organ-transplant patients on chronic immunosuppression have a higher risk of developing skin cancers, including melanoma.
Prevention
Given the association between UV radiation and the development of melanoma, the use of sunscreen and avoidance of UV rays have been advocated as means of reducing the risk of developing melanoma. For secondary prevention, patients at risk for developing melanoma might benefit from education on self skin examinations. Patients should be encouraged to report any unusual or changing nevus.
DIAGNOSIS
Clinical Presentation
The “ABCDE” mnemonic in melanoma diagnosis refers to asymmetry, border irregularity, color variations, dimension, and evolution. The clinical history should include queries about risk factors for melanoma (as outlined earlier in this chapter) and changing nevi 10. Changes in the color or an increase in size in a new mole are usually the early signs noted by patients. Later changes include bleeding, itching and tenderness. A global evaluation of the skin is necessary to assess the degree of sun damage, number of nevi, distribution of nevi, and the presence of atypical or dysplastic nevi.
When a lesion suspicious for melanoma is identified, the next key step is an appropriate biopsy. If melanoma is suspected, a complete excisional removal into adipose tissue, with a 2-mm margin of adjacent normal-appearing skin, is preferred. Shave biopsies should be avoided as they may not provide an accurate Breslow depth, which is an important part of melanoma staging. For large lesions that are not easily amenable to complete excision, an incisional full-thickness biopsy or multiple representative punch biopsies might be acceptable.
Once a diagnosis of melanoma is made, a thorough history and physical examination will help guide further testing. Lymph nodes should be carefully examined, and patients with clinically palpable suspicious lymph nodes should be referred for a lymph node aspirate or open biopsy. Patients with symptoms suspicious for metastatic disease should be worked up as appropriate. In patients with distant metastases, a serum lactate dehydrogenase (LDH) is of prognostic value.
Staging
Staging of melanoma is based on the thickness of the tumor and the presence of nodal or distant metastases. The absolute depth of invasion (millimeters) is referred to as the Breslow thickness. The Clark level refers to the depth of invasion into the layers of the skin. Tables 22-1 and 22-2 summarize the 2009 American Joint Committee on Cancer (AJCC) melanoma staging and classifi-cation.11 The AJCC Melanoma Staging Committee recommends that a sentinel lymph node (SLN) biopsy be discussed with otherwise healthy patients who have T2, T3, and T4 melanomas and clinically uninvolved lymph nodes. Select patients with T1b melanomas (mitotic rate ≥1/mm2 and a thickness of ≥0.76 mm) may also benefit from a SLN biopsy as such melanomas are associated with an approximately 10% risk of occult metastases in their sentinel lymph nodes.11
In the Multicenter Selective Lymphadenectomy Trial (MSLT), patients with intermediate thickness melanomas (1.2 to 3.5 mm in thickness) were randomized to SLN biopsy or observation.12 All patients underwent wide excision of the primary melanoma. For those randomized to the biopsy group, an immediate complete lymphadenectomy was performed only on those with a positive SLN biopsy. In the observation group, a delayed complete lymphadenectomy was performed when nodal recurrence was observed. Among patients with nodal metastases, the 5-year survival rate was higher among those who underwent immediate lymphadenectomy compared to those in whom lymphadenectomy was delayed, with a hazard ratio (HR) of death of 0.51 (95% confidence interval (CI) of 0.32 to 0.18, p = 0.004), supporting the use of SLN biopsy as a tool for identifying patients with nodal metastases in whom early intervention may be beneficial.12
TREATMENT
Local and Locoregional Disease (Stage I to III)
Surgical excision, when feasible, is the primary treatment for cutaneous melanoma10. Recommended excision margins depend on the Breslow depth. For melanoma in situ (excluding LM), the recommended margin is 0.5 to 1.0 cm. For stage Ia (<1 mm) melanomas, a margin of 1 cm is considered adequate. For melanomas that are 1 to 2 mm deep, the recommended margin is at least 1 cm, but up to 2 cm is recommended if feasible. For melanomas >2 mm deep, the recommended margin is 2 cm.10 Dissection should be sufficiently deep, typically to the level of the deep subcutaneous tissue at the level of the fascia. As discussed above, SLN biopsy, followed by an immediate lymphadenectomy if positive, may be appropriate in select patients. For patients with in-transit melanoma, local excision of isolated metastases is sometimes feasible. For in-transit melanoma patients with more widespread cutaneous disease not amenable to resection, nonsurgical modalities including localized immune therapy, heated limb perfusion, and external beam radiation may offer reasonable control.13
Adjuvant systemic therapy with interferon alpha-2b (IFN α2b) has been extensively evaluated in high-risk stage II and stage III melanoma after definitive surgical resection. The Eastern Cooperative Group (ECOG) E1684 trial randomized patients to either high-dose interferon (20 MIU/m2/d intravenously for 1 month then 10 MIU/m2 3 times per week subcutaneously for 48 weeks) or observation. All patients in this trial underwent a complete regional lymphadenectomy. Earlier reports of this trial indicated a significant prolongation of relapse free survival (RFS) and overall survival (OS) in favor of adjuvant high-dose interferon.14 However, with longer term follow-up, whilst the benefit in RFS is maintained, the improvement in OS reported earlier was diminished.15 A pooled analysis of ECOG and Intergroup trials of high-dose inter-feron (HDI) in melanoma (which included E1684) failed to demonstrate an OS survival benefit in the pooled population. Different dosing16,17 and duration of interferon treatment18 have been evaluated, with largely similar results. Toxicities of HDI include constitutional symptoms, neurologic toxicities, myelosuppression, and hepatotoxicity. The nontrivial toxicities of HDI and the absence of unequivocal benefit led to controversy regarding its appropriateness in this setting. Other investigations into systemic adjuvant therapies were reviewed by Algazi et al.13
Distant Metastatic Disease (Stage IV)
Survival in patients with distant metastases is poor. Resection of solitary skin, lung, or brain metastases can be considered. As treatment options for metastatic melanoma are limited, enrollment in a clinical trial, whenever feasible, is recommended for patients with stage IV disease. Dacarbazine, an alkylating agent, is the only chemotherapy approved by the Federal Food and Drug Administration (FDA) for treatment of metastatic melanoma. Temozolomide, a close analog of dacarbazine, is more commonly used because it can be administered orally. In a randomized Phase III trial comparing temozolomide to dacarbazine, the response rates were similar at 13.1% and 12.1%, respectively.19 The median OS was similar in both arms, although temozolomide has a marginally longer median progression free survival of 1.9 months versus 1.5 months. High dose interleukin-2 (IL-2) is also FDA-approved for treatment of metastatic melanoma. Atkins et al. reported on 270 assessable patients with metastatic melanoma who were entered onto eight clinical trials involving IL-2 conducted between 1985 and 1993.20 The overall objective response rate was 16% (95% CI of 12% to 21%), with 17 complete responses (CRs) (6%) and 26 partial responses (PRs) (10%). In this series, high dose IL-2 appeared to produce durable CRs or PRs in a small subset of patients. Unfortunately, high dose IL-2 is a highly toxic regimen that is challenging to administer. Some patients receiving high dose IL-2 will even require vasopressor support in an intensive care unit.
Two recently published trials provided encouraging results for systemic treatment of metastatic melanoma. Hodi et al.21 reported on a Phase III trial evaluating ipilimumab, an antibody that blocks cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4), and the gp100 vaccine, a synthetic peptide cancer vaccine consisting of amino acid residues 209 through 217 of the glycoprotein 100 (gp100) melanoma antigen. In this study, 676 patients with unresectable stage III or IV malignant melanoma were randomly assigned, in a 3:1:1 ratio, to receive ipilimumab plus gp100 (n = 403 patients), ipilimumab alone (n = 137), or gp100 alone (n = 136).16 The median OS was 10.0 months among patients receiving ipilimumab plus gp100, compared to 6.4 months among patients receiving gp100 alone (HR for death, 0.68; P < 0.001). Median OS with ipilimumab alone was 10.1 months (HR for death in the comparison with gp100 alone, 0.66; P = 0.003). These data demonstrated the efficacy of ipilimumab in metastatic melanoma. In another study, Flaherty et al.22 reported on a phase I dose-escalation trial of PLX4032, an oral inhibitor of mutated BRAF. In the dose-escalation cohort, of the 16 patients with melanoma whose tumors carried the V600E BRAF mutation, there were 10 PRs and 1 CR. Among the 32 patients in the extension cohort of melanoma patients whose tumors carried the V600E BRAF mutation, 24 had a PR and 2 had a CR. The estimated median progression-free survival among all patients was more than 7 months, suggesting that BRAF inhibition may be a viable therapeutic strategy in BRAF mutated melanoma. Another potential therapeutic target is c-kit. Hodi et al. reported a major response to imatinib mesylate, an oral tyrosine kinase inhibitor which inhibits c-kit, in a patient with a c-kit-mutated melanoma, suggesting that targeting of this pathway may also represent a therapeutic avenue worth evaluating in select patients.23
PROGNOSIS
Prognosis is dependent on stage of disease.11 In patients with localized melanomas (stage I and II), 10-year survival ranges from 93% for stage IA to 39% for stage IIC. In these patients, increasing tumor thickness and mitotic rate are associated with declining survival rates. Patients with ulcerated melanomas have proportionately lower survival rates than those with equivalent T staged non-ulcerated tumors. In patients with regional metastatic melanoma (stage III), the 5-year survival rates were 78%, 59%, and 40% for patients with stage IIIA, IIIB, and IIIC melanoma, respectively. In patients with distant metastatic melanoma (stage IV), the site(s) of metastases and serum LDH levels delineate the M1 stage into M1a, M1b, and M1c (as shown in Table 22-1). The 1-year survival rates were 62%, 53%, and 33% for M1a, M1b, and M1c melanomas, respectively.
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