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Pigmented lesions are among the most common findings on skin examination. The challenge for the physician is to distinguish cutaneous melanomas, which account for the overwhelming majority of deaths resulting from skin cancer, from the remainder, which are usually benign. Cutaneous melanoma can occur in adults of all ages, even young individuals, and people of all colors; its location on the skin and its distinct clinical features often permit detection at a time when complete surgical excision leads to cure. Examples of malignant and benign pigmented lesions are shown in Fig. 72-1.
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Melanoma is an aggressive malignancy of melanocytes, pigment-producing cells that originate from the neural crest and migrate to the skin, meninges, mucous membranes, upper esophagus, and eyes. Melanocytes in each of these locations have the potential for malignant transformation, but the vast majority arise in the skin. Melanomas can also arise in the mucosa of the head and neck (nasal cavity, paranasal sinuses, and oral cavity), the gastrointestinal tract, the CNS, the female genital tract (vulva, vagina), and the uveal tract of the eye. Cutaneous melanoma is predominantly a malignancy of white-skinned people (98% of cases), and the incidence correlates with latitude of residence, providing strong evidence for the role of sun exposure. Men are affected slightly more than women (1.3:1), and the median age at diagnosis is the late fifties. In 2016, >76,000 individuals in the United States were expected to develop melanoma, and ∼10,130 were expected to die. Mortality rates begin to rise at age 55, with the greatest increase in men age >65 years. Of particular concern is the increase in incidence among women <40 years of age, an increase believed to be associated with a greater emphasis on tanned skin as a marker of beauty, the increased availability and use of indoor tanning beds, and exposure to intense ultraviolet (UV) light in childhood. The latest Surveillance, Epidemiology and End Results (SEER) Registry data reveal that from 2004 to 2013, the rate of new melanoma cases has risen 1.4% each year, while death rates have remained stable. This is in the context of a 5-year relative survival improvement from 93.1% to 93.3% overall, despite a 17.9% survival rate for those diagnosed with distant metastases. These statistics highlight the need to promote prevention and early detection.
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GLOBAL CONSIDERATIONS
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The incidence of both non-melanoma and melanoma skin cancers around the world has been increasing. Every year between 2 and 3 million people will get non-melanoma skin cancer and in 2012 there were 232,000 cases of melanoma. The highest incidence of melanoma is found in New Zealand and Australia consistent with Caucasians living in latitudes with increased UV exposure. The likelihood of developing melanoma is 25 per 100,000 in non-Hispanic whites, 4 per 100,000 in Hispanics, and 1 per 100,000 in African Americans.
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Dark-skinned populations (such as those of India and Puerto Rico), blacks, and east Asians also develop melanoma, albeit at rates 10–20 times lower than those in whites. Cutaneous melanomas in these populations are more often diagnosed at a higher stage, and patients tend to have worse outcomes. Furthermore, in nonwhite populations, the frequency of acral (subungual, plantar, palmar) and mucosal melanomas is much higher. In China, about 20,000 new cases are reported each year and, in contrast to the United States where rates are stable, mortality is increasing. This may be due in part to the gap that remains in the diagnosis and treatment of melanoma between China and Western countries or to the fact that in Asians and dark-skinned populations, the melanomas that arise from the skin (comprising 50–70% of patients versus 90% in the West) arise from acral areas and the others from mucosal areas, all of which carry a poorer prognosis than cutaneous melanomas diagnosed in the West.
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The risk of developing melanoma is related to genetic, environmental, and host factors. The strongest risk factors for melanoma are the presence of multiple benign or atypical nevi and a family or personal history of melanoma. The presence of >40 melanocytic nevi, common or dysplastic, is a marker for increased risk of melanoma. Nevi have been referred to as precursor lesions because they can transform into melanomas; however, the actual risk of transformation for any individual nevus is exceedingly low. About one-quarter of melanomas are histologically associated with nevi, but the majority arise de novo. The number of clinically atypical moles may vary from one to several hundred, and they usually differ from one another in appearance, although individuals can develop multiple similar atypical nevi (signature nevi). The borders are often hazy and indistinct, and the pigment pattern is more highly varied than that in benign acquired nevi. Individuals with clinically atypical moles and a strong family history of melanoma have been reported to have a >50% lifetime risk for developing melanoma and warrant close follow-up with a dermatologist. Of the 90% of patients whose disease is sporadic (i.e., who lack a family history of melanoma), ∼40% have clinically atypical moles, compared with an estimated 5–10% of the population at large.
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Congenital melanocytic nevi, which are classified as small (≤1.5 cm), medium (1.5–20 cm), and giant (>20 cm), can be precursors for melanoma. The risk is highest for the giant melanocytic nevus, also called the bathing trunk nevus, a rare malformation that affects 1 in 30,000–100,000 individuals. Since the lifetime risk of melanoma development is estimated to be as high as 6%, prophylactic excision early in life is prudent. This usually requires staged removal with coverage by split-thickness skin grafts. Surgery cannot remove all at-risk nevus cells, as some may penetrate into the muscles or central nervous system (CNS) below the nevus. Small- to medium-size congenital melanocytic nevi affect ∼1% of persons; the lifetime risk of melanoma development in a typical nevus is low, estimated to be about 0.03% (1 in 3164) for men and 0.009% (1 in 10,800) for women. The management of small- to medium-size congenital melanocytic nevi remains controversial and is primarily based on histologic findings from biopsies of clinically atypical nevi.
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Personal and Family History
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Once diagnosed, patients with melanoma require a lifetime of surveillance because their risk of developing another melanoma is 10 times that of the general population. First-degree relatives have a twofold higher risk of developing melanoma than do individuals without a family history, but only 5–10% of all melanomas are truly familial. In familial melanoma, patients tend to be younger at first diagnosis, lesions are thinner, and multiple primary melanomas are common.
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Genetic Susceptibility
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Approximately 20–40% of cases of hereditary melanoma (0.2–2% of all melanomas) are due to germline mutations in the cell cycle regulatory gene cyclin-dependent kinase inhibitor 2A (CDKN2A). In fact, 70% of all cutaneous melanomas have mutations or deletions affecting the CDKN2A locus on chromosome 9p21. This locus encodes two distinct tumor-suppressor proteins from alternate reading frames: p16 and ARF (p14ARF). The p16 protein inhibits CDK4/6-mediated phosphorylation and inactivation of the retinoblastoma (RB) protein, whereas ARF inhibits MDM2 ubiquitin-mediated degradation of p53. The end result of the loss of CDKN2A is inactivation of two critical tumor-suppressor pathways, RB and p53, which control entry of cells into the cell cycle. Several studies have shown an increased risk of pancreatic cancer among melanoma-prone families with CDKN2A mutations. A second high-risk locus for melanoma susceptibility, CDK4, is located on chromosome 12q13 and encodes the kinase inhibited by p16. CDK4 mutations, which also inactivate the RB pathway, are much rarer than CDKN2A mutations. Germline mutations in the melanoma lineage-specific oncogene microphthalmia-associated transcription factor (MITF) and telomerase reverse transcriptase (TERT) mutations predispose to both familial and sporadic melanomas.
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The melanocortin-1 receptor (MC1R) gene is a moderate-risk inherited melanoma susceptibility factor. Solar radiation stimulates the production of melanocortin (α-melanocyte-stimulating hormone [α-MSH]), the ligand for MC1R, which is a G-protein-coupled receptor that signals via cyclic AMP and regulates the amount and type of pigment produced. MC1R is highly polymorphic, and among its 80 variants are those that result in partial loss of signaling and lead to the production of red/yellow pheomelanins, which are not sun-protective and produce red hair, rather than brown/black eumelanins that are photoprotective. This red hair color (RHC) phenotype is associated with fair skin, red hair, freckles, increased sun sensitivity, and increased risk of melanoma. In addition to its weak UV shielding capacity relative to eumelanin, increased pheomelanin production in patients with inactivating polymorphisms of MC1R also provides a UV-independent carcinogenic contribution to melanomagenesis via oxidative damage and reduced DNA damage repair.
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A number of other more common, low-penetrance polymorphisms that have small effects on melanoma susceptibility include other genes related to pigmentation, nevus count, immune responses, DNA repair, metabolism, and the vitamin D receptor. Approximately 50% of the genetic risk for hereditary melanoma can be ascribed to previously identified melanoma predisposition genes, with ∼40% of the risk being due to CDKN2A. The missing inherited risk is most likely due to the inheritance of additional modifier genes and/or shared environmental exposures.
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PREVENTION AND EARLY DETECTION
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Primary prevention of melanoma and nonmelanoma skin cancer (NMSC) is based on protection from the sun. Public health initiatives, such as the SunSmart program that started in Australia and now is operative in Europe and the United States, have demonstrated that behavioral change can decrease the incidence of NMSC and melanoma. Preventive measures should start early in life because damage from UV light begins early despite the fact that cancers develop years later. Some individuals tan compulsively. There is greater understanding of tanning addiction and the biology of cutaneous-neural connections that may give rise to this behavior. Compulsive tanners exhibit differences in dopamine binding and reactivity in reward pathways in the brain, such as the basal striatum, resulting in cutaneous secretion of β-endorphins after UV exposure. Identifying individuals with tanning addiction may be another method for preventive intervention. Regular use of broad-spectrum sunscreens that block UVA and UVB with a sun protection factor (SPF) of at least 30 and protective clothing should be encouraged. Avoidance of sunburns, tanning beds, and midday sun exposure is recommended.
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Secondary prevention comprises education, screening, and early detection. Patients should be taught to recognize the clinical features of melanoma (ABCDEs; see below) and advised to report any change in a pigmented lesion. Brochures are available from the American Cancer Society, the American Academy of Dermatology, the National Cancer Institute, and the Skin Cancer Foundation. Self-examination at monthly intervals may enhance the likelihood of detecting change. Although the U.S. Preventive Services Task Force states that evidence is insufficient to recommend for or against skin cancer screening, a full-body skin exam seems to be a simple, practical way to approach reducing the mortality rate for skin cancer. Depending on the presence or absence of risk factors, strategies for early detection can be individualized. This is particularly true for patients with clinically atypical moles (dysplastic nevi) and those with a personal history of melanoma. For these individuals, surveillance should be performed by the dermatologist and include total-body photography and dermoscopy where appropriate. Individuals with three or more primary melanomas and families with at least one invasive melanoma and two or more cases of melanoma and/or pancreatic cancer among first- or second-degree relatives on the same side of the family may benefit from genetic testing. Precancerous and in situ lesions should be treated early. Early detection of small tumors allows the use of simpler treatment modalities with higher cure rates and lower morbidity.
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The goal is to identify a melanoma before it invades and life-threatening metastases have occurred. Early detection may be facilitated by applying the ABCDEs: asymmetry (benign lesions are usually symmetric); border irregularity (most nevi have clear-cut borders); color variegation (benign lesions usually have uniform light or dark pigment); diameter >6 mm (the size of a pencil eraser); and evolving (any change in size, shape, color, or elevation or new symptoms such as bleeding, itching, and crusting). In addition, any nevus that appears atypical and different from the rest of the nevi on that individual (an “ugly duckling”) should be considered suspicious.
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The entire skin surface, including the scalp and mucous membranes, as well as the nails should be examined in each patient. Bright room illumination is important, and a hand lens is helpful for evaluating variation in pigment pattern. Any suspicious lesions should be biopsied, evaluated by a specialist, or recorded by chart and/or photography for follow-up. A focused method for examining individual lesions, dermoscopy, employs low-level magnification of the epidermis with polarized light and may allow a more precise visualization of patterns of pigmentation than is possible with the naked eye. Additional technologies, including in vivo confocal microscopy, multi- and hyper-spectral imaging, optical coherence tomography, gene expression panels, tape stripping, and electrical conductance methods have been developed and are being refined for improved early detection of melanoma.
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Any pigmented cutaneous lesion that has changed in size or shape or has other features suggestive of malignant melanoma is a candidate for biopsy. An excisional biopsy with 1- to 3-mm margins is suggested though excision can be accomplished tangentially or in a fusiform fashion. This facilitates pathologic assessment of the lesion, permits accurate measurement of thickness if the lesion is melanoma, and constitutes definitive treatment if the lesion is benign. For lesions that are large or on anatomic sites where excisional biopsy may not be feasible (such as the face, hands, and feet), an incisional biopsy through the most nodular or darkest area of the lesion is acceptable. Incisional biopsy does not appear to facilitate the spread of melanoma. For suspicious lesions, every attempt should be made to preserve the ability to assess the deep and peripheral margins and to perform immunohistochemistry. Shave, saucerization or tangential biopsies are an acceptable alternative, particularly if the suspicion of malignancy is low. They should be deep enough to include the deepest component of the entire lesion and any pigment at the base of the lesion should be removed and included with the biopsy specimen. The biopsy should be read by a pathologist experienced in pigmented lesions, and the report should include Breslow thickness, mitotic rate, presence or absence of ulceration and lymphatic invasion, microsatellitosis and peripheral and deep margin status. Breslow thickness is the greatest thickness of a primary cutaneous melanoma measured on the slide from the top of the epidermal granular layer, or from the ulcer base, to the bottom of the tumor. To distinguish melanomas from benign nevi in challenging cases, fluorescence in situ hybridization (FISH) with multiple probes and comparative genome hybridization (CGH) can be helpful. Gene expression profiling assays have been developed to enhance diagnosis but are not yet widely applied.
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CLASSIFICATION AND PATHOGENESIS
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The features of five major types of cutaneous melanoma are described in Table 72-1. In superficial spreading melanoma, lentigo maligna melanoma, and acral lentiginous melanoma, the lesion has a period of superficial (so-called radial) growth during which it increases in size but does not penetrate deeply. It is during this period that the melanoma is most capable of being cured by surgical excision. A fourth type—nodular melanoma—does not have a recognizable radial growth phase and usually presents as a deeply invasive lesion that is capable of early metastasis. Tumors that begin to penetrate deeply into the skin are in the so-called vertical growth phase. Melanomas with a radial growth phase are characterized by irregular and sometimes notched borders, variation in pigment pattern, and variation in color. A fifth type of melanoma, desmoplastic melanoma, is associated with a fibrotic response, neural invasion, and a greater tendency for local recurrence. Occasionally, melanomas appear clinically to be amelanotic, in which case the diagnosis is established microscopically after biopsy.
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Although these subtypes are clinically and histopathologically distinct, this classification has minimal prognostic value and histologic subtype is not part of American Joint Committee on Cancer (AJCC) staging. Characterizing the genomic and mutational profiles of melanoma has become increasingly common and can reflect the mechanisms of tumorigenesis. These molecular classifications inform treatment and surveillance strategies.
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Considerable evidence from epidemiologic and molecular studies indicate that cutaneous melanomas arise via multiple causal pathways. There are both environmental and genetic components (susceptibility genes discussed earlier), and the major environmental factor in cutaneous melanomagenesis is sun exposure. The major effect of UV solar radiation is to cause genetic changes in the skin. However, it also impairs cutaneous immune function, increases the production of growth factors, and induces the formation of DNA-damaging reactive oxygen species that affect keratinocytes and melanocytes.
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The advent of next-generation sequencing (NGS) has led to whole exome sequencing of hundreds of cutaneous melanomas derived from non-glabrous skin. This has revealed a very complex genetic landscape with genetic changes resulting from both germline (described earlier) and somatic mutations. Cutaneous melanomas have one of the highest somatic mutation rates (>10 mutations/Mb) compared to other cancers; the majority (76% primary tumors and 84% of metastatic melanomas) exhibit a mutation signature indicating UVR exposure. The mutation rate varies based on body site; melanomas arising in chronic sun-damaged skin harbor substantially more mutations than melanomas from non-sun-damaged skin.
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Melanoma tumors can harbor thousands of mutations, but only a few are driver mutations; a mutation that is causally implicated in oncogenesis by virtue of a conferred growth advantage on the cancer cell. The driver mutations that have been identified for cutaneous melanoma are depicted in Fig. 72-2. As more melanomas are sequenced, more driver mutations have been identified. These mutations tend to be found in a smaller fraction of patients. Driver mutations often affect pathways that promote cell proliferation or inhibit normal pathways of apoptosis in response to DNA repair. They are often found in combination with mutations to the genetic susceptibility genes described earlier. The altered melanocytes accumulate DNA damage, and selection occurs for all the attributes that constitute the malignant phenotype: invasion, metastasis, and angiogenesis.
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A recent report from the Cancer Genome Atlas (TCGA) has proposed a genomic classification of cutaneous melanoma based on the pattern of the most prevalent significantly mutated genes: BRAF, RAS, NF-1, and triple-WT (wild type). Distinct patterns of DNA mutations can vary with the site of origin and can be independent of the histologic subtype of the tumor. Thus, although the genetic landscape of melanoma is complex, and continues to evolve, the overall pattern of mutation, amplification, and loss of cancer genes indicates they have convergent effects on key biochemical pathways involved in proliferation, senescence, and apoptosis. An advantage of this classification is that these mutations can be used to select therapy.
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The p16 mutation that affects cell cycle arrest and the ARF mutation that results in defective apoptotic responses to genotoxic damage were described earlier. The proliferative pathways affected were the mitogen-activated protein (MAP) kinase and phosphatidylinositol 3’ kinase/AKT pathways (Fig. 72-2). RAS and BRAF, members of the MAP kinase pathway, which classically mediates the transcription of genes involved in cell proliferation and survival, undergo somatic mutation in melanoma and thereby generate potential therapeutic targets. N-RAS is mutated in ∼20% of melanomas, and somatic activating BRAF mutations are found in most benign nevi and 40–50% of cutaneous melanomas. Neither mutation by itself appears to be sufficient to cause melanoma; thus, they often are accompanied by other mutations, such as TERT. The BRAF mutation is most commonly a point mutation (T→A nucleotide change) that results in a valine-to-glutamate amino acid substitution (V600E). V600E BRAF mutations are more common in younger patients and are present in most melanomas that arise on sites with intermittent sun exposure and are less common in melanomas from chronically sun-damaged skin. At present, BRAF mutations are the most important in therapeutic decision making in patients with advanced melanoma.
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Melanomas also harbor mutations in AKT (primarily in AKT3) and PTEN (phosphatase and tensin homolog). AKT can be amplified, and PTEN may be deleted or undergo epigenetic silencing that leads to constitutive activation of the PI3K/AKT pathway and enhanced cell survival by antagonizing the intrinsic pathway of apoptosis. Loss of PTEN, which dysregulates AKT activity, and mutation of AKT3 both prolong cell survival through inactivation of BAD, BCL-2-antagonist of cell death, and activation of the forkhead transcription factor FOXO1, which leads to synthesis of prosurvival genes. A loss-of-function mutation in NF1, which can affect both MAP kinase and PI3K/AKT pathways, has been described in 10–15% of melanomas. In melanoma, these two signaling pathways (MAP kinase and PI3K/AKT) enhance tumorigenesis, chemoresistance, migration, and cell cycle dysregulation. Drugs that inhibit some of these pathways have been developed, and have proven to be effective therapeutic agents (see below).
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The most important prognostic factors for a newly diagnosed patient are incorporated in the staging classification (Table 72-2). The best predictor of metastatic risk is Breslow thickness. The anatomic site of the primary is also prognostic; favorable sites are the forearm and leg (excluding the feet), and unfavorable sites include the scalp, hands, feet, and mucous membranes. In general, women with stage I or II disease have better survival than men, perhaps in part because of earlier diagnosis; women frequently have melanomas on the lower leg, where self-recognition is more likely and the prognosis is better. The effect of age is not straightforward. Older individuals, especially men >60, have worse prognoses, a finding that has been explained in part by a tendency toward later diagnosis (and thus thicker tumors) and in part by a higher proportion of acral melanomas in men. However, there is a greater risk of lymph node metastasis in young patients. Other important adverse factors recognized via the staging classification include high mitotic rate, presence of ulceration, microsatellite lesions and/or in-transit metastases, evidence of nodal involvement, elevated serum lactate dehydrogenase (LDH), and presence and site of distant metastases.
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Once the diagnosis of melanoma has been made, the tumor is staged to determine the prognosis and aid in treatment selection. The current melanoma staging criteria and estimated 15-year survival by stage are depicted in Table 72-2. The clinical stage is determined after the microscopic evaluation of the melanoma skin lesion and clinical and radiologic assessment. Pathologic staging also includes the microscopic evaluation of the regional lymph nodes obtained at sentinel lymph node biopsy or completion lymphadenectomy as indicated. All patients should have a complete history, with attention to symptoms that may suggest metastatic disease, such as malaise, weight loss, headaches, visual changes, and pain, and physical examination directed to the site of the primary melanoma, looking for persistent disease or for dermal or subcutaneous nodules that could represent satellite or in-transit metastases, and to the regional draining lymph nodes, CNS, liver, and lungs. A complete blood count (CBC), complete metabolic panel, and LDH should be performed. Although these rarely help uncover occult metastatic disease, a microcytic anemia would raise the possibility of bowel metastases, and the LDH, if elevated, should prompt a more extensive evaluation, including computed tomography (CT) scan or possibly a positron emission tomography (PET) (or CT/PET combined) scan. If signs or symptoms of metastatic disease are present, appropriate diagnostic imaging should be performed. At initial presentation, >80% of patients will have disease confined to the skin and a negative history and physical examination, in which case imaging is not indicated.
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TREATMENT Melanoma MANAGEMENT OF CLINICALLY LOCALIZED MELANOMA (STAGE I, II)
For a newly diagnosed cutaneous melanoma, wide surgical excision of the lesion with a margin of normal skin is necessary to remove all malignant cells and minimize possible local recurrence. The following margins are recommended for a primary melanoma: in situ, 0.5–1.0 cm; invasive up to 1 mm thick, 1 cm; >1.01–2 mm, 1–2 cm; and >2 mm, 2 cm. For lesions on the face, hands, and feet, strict adherence to these margins must give way to individual considerations about the constraints of surgery and minimization of morbidity. In all instances, however, inclusion of subcutaneous fat in the surgical specimen facilitates adequate thickness measurement and assessment of surgical margins by the pathologist. Topical imiquimod also has been used, particularly for lentigo maligna, in cosmetically sensitive locations.
Sentinel lymph node biopsy (SLNB) is a valuable staging tool that has replaced elective regional node dissection for the evaluation of regional nodal status. SLNB provides prognostic information and helps identify patients at high risk for relapse who may be candidates for adjuvant therapy. The initial (sentinel) draining node(s) from the primary site is (are) identified by injecting a blue dye and a radioisotope around the primary site. The sentinel node(s) then is (are) identified by inspection of the nodal basin for the blue-stained node and/or the node with high uptake of the radioisotope. The identified nodes are removed and subjected to careful histopathologic analysis with serial section using hematoxylin and eosin stains as well as immunohistochemical stains (e.g., S100, HMB45, and MelanA) to identify melanocytes.
Not every patient requires a SLNB. Patients whose melanomas are ≤0.75 mm thick have <5% risk of sentinel lymph node (SLN) disease and do not require a SLNB. Patients with tumors >1 mm thick generally undergo SLNB. For melanomas 0.76–1.0 mm thick, SLNB may be considered for lesions with high-risk features such as ulceration, high mitotic index, or lymphovascular invasion, but wide excision alone is the usual definitive therapy. Most other patients with clinically negative lymph nodes should undergo a SLNB. Patients whose SLNB is negative are spared a complete node dissection and its attendant morbidities, and can simply be followed, or based on the features of the primary melanoma, be considered for adjuvant therapy or a clinical trial. The current standard of care for all patients with a positive SLN is to perform a complete lymphadenectomy; however, complete lymph node dissection is not necessary for patients with lymph node micrometastases <1 mm. Patients with positive lymph nodes should be considered for adjuvant therapy with ipilimumab, interferon alpha or enrollment in a clinical trial.
MANAGEMENT OF REGIONALLY METASTATIC MELANOMA (STAGE III) Melanomas may recur at the edge of the scar or graft, as satellite metastases, which are separate from but within 2 cm of the scar; as in-transit metastases, which are recurrences >2 cm from the primary lesion but not beyond the regional nodal basin; or, most commonly, as metastasis to a draining lymph node basin. Each of these presentations is managed surgically, following which there is the possibility of long-term disease-free survival. Isolated limb perfusion or infusion with melphalan and hyperthermia are options for patients with extensive cutaneous regional recurrences in an extremity. High complete response rates have been reported and significant palliation of symptoms can be achieved, but there is no change in overall survival. Other options for in-transit disease and distant skin and soft tissue metastases include topical immunotherapy and direct injection of melanoma lesions. Topical therapy with imiquimod has been useful for patients with low-volume dermal lesions. Historically, intralesional bacille Calmette-Guerin (BCG) has been used with high rates of regression of injected lesions and occasional regression of a distant, uninjected lesion. Talimogene laherparepvec is an engineered, oncolytic herpes simplex virus type 1 that is U.S. Food and Drug Administration (FDA) approved for injection of melanoma lesions that cannot be completely removed by surgery.
Patients rendered free of disease after surgery may be at high risk for a local or distant recurrence and should be considered for adjuvant therapy. Radiotherapy can reduce the risk of local recurrence after lymphadenectomy, but does not affect overall survival. Patients with large nodes (>3–4 cm), four or more involved lymph nodes, or extranodal spread on microscopic examination should be considered for radiation. Systemic adjuvant therapy is indicated primarily for patients with stage III disease, but high-risk, node-negative patients (>4 mm thick or ulcerated lesions), and patients with completely resected stage IV disease also may benefit.
Current treatment options include ipilimumab, interferon α2b (IFN-α2b) or investigational therapy. Ipilimumab is a fully human monoclonal antibody that blocks the immune checkpoint cytotoxic T-lymphocyte antigen-4 (CTLA-4) and augments antitumor immune responses. Treatment with ipilimumab 10 mg/kg IV every three weeks for four doses, then every three months for up to three years, improved survival of patients with high-risk stage III disease compared to placebo. IFN-α2b may be administered at high doses for one year or pegylated IFN can be administered at a lower dose for five years. The single study of ipilimumab documented a survival benefit whereas multiple trials of IFN have reported clear improvement in disease-free survival, but questionable improvement in overall survival. The two agents have not been compared directly. Ongoing clinical trials will address this issue as well as evaluate the potential value of other immunotherapies (e.g., PD-1/PD-L1 blocking agents) and targeted therapies in patients with BRAF mutated tumors in the adjuvant setting.
Both IFN and ipilimumab are accompanied by significant toxicity. For IFN, this may include a flulike illness, decline in performance status, and the development of depression. Side effects can be managed in most patients by appropriate treatment of symptoms, dose reduction, and treatment interruption. IFN may need to be discontinued prematurely because of unacceptable toxicity. The major side effects of ipilimumab are discussed below.
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TREATMENT Metastatic Disease
At diagnosis, 84% patients with melanoma will have early-stage disease and 4% will present with metastases. Many others will develop metastases after initial therapy for loco-regional disease. The probability of recurrence is related to initial stage, ranging from <5% with stage IA to >90% for subsets of patients with stage IIIC disease at presentation. Patients with a history of melanoma who develop signs or symptoms suggesting recurrent disease should undergo restaging as described earlier. Distant metastases (stage IV) may involve any organ and commonly involve the skin and lymph nodes as well as viscera, bone, or the brain. The prognosis is better for patients with skin and subcutaneous metastases (M1a) than for lung (M1b) and worst for those with metastases to liver, bone, and brain (M1c). An elevated serum LDH is a poor prognostic factor and places the patient in stage M1c regardless of the site of the metastases (Table 72-2). Although historical data suggest that the 15-year survival of patients with melanoma is <10%; advances in targeted and immunotherapy have improved disease-free and overall survival, especially for patients with M1a and M1b disease.
The treatment for patients with stage IV melanoma has changed dramatically since 2011. FDA-approved agents include three immune T-cell checkpoint inhibitors, ipilimumab, nivolumab, and pembrolizumab, four oral agents that target the MAP kinase pathway: the BRAF inhibitors, vemurafenib and dabrafenib, the MEK inhibitors, trametinib and cobimetinib, and the oncolytic virus talimogene laherparepvec (Table 72-3).
Surgery should be considered for patients with oligometastatic disease because they may experience long-term disease-free survival after metastasectomy. Patients with solitary metastases are the best candidates, but surgery can also be used for patients with metastases at more than one site if a complete resection of all sites can be achieved. Patients rendered free of disease can be considered for adjuvant therapy or a clinical trial because their risk of developing additional metastases is very high. Surgery can also be used as an adjunct to systemic therapy when for example, a few of many metastatic lesions prove resistant to immunotherapy.
IMMUNOTHERAPY Interleukin 2 (IL-2 or aldesleukin) is used effectively to treat stage IV patients who have a good performance status. High-dose IL-2, which requires hospitalization in an intensive care unit–like setting, is administered by intravenous bolus doses over a 1-week cycle mainly at centers with experience managing IL-2-related toxicity. Treatment is continued until maximal benefit is achieved, usually 4–6 cycles distributed over 4–6 months to allow for recovery from toxicities between cycles. Long-term disease-free survival (probable cure) is observed in 5% of treated patients.
Checkpoint Blockade Newer immunotherapies are based on an understanding of the control mechanisms of the normal immune response. Inhibitory receptors or checkpoints, including CTLA-4 and PD-1, are upregulated on T cells after engagement of the T-cell receptor by cognate tumor antigen in the context of the appropriate class I or II HLA molecules during the interaction between a T cell and antigen-presenting cell. An absolute requirement to ensure proper regulation of a normal immune response, the continued expression of inhibitory receptors during chronic infection (hepatitis, HIV) and in cancer patients leads to exhausted T cells with limited potential for proliferation, cytokine production, or cytotoxicity (Fig. 72-3). Checkpoint blockade with an antagonistic monoclonal antibody results in improved T-cell function and eradication of tumor cells in preclinical animal models. Ipilimumab, a fully human IgG1 antibody that binds CTLA-4 and blocks inhibitory signals, was the first drug shown in a randomized trial to improve survival in patients with metastatic melanoma. A full course of therapy is four outpatient infusions of ipilimumab 3 mg/kg every 3 weeks. Although response rates are low (∼10%), overall survival is improved.
Chronic T-cell activation also leads to induction of PD-1 on the surface of T cells. Expression of one of its ligands, PD-L1, on tumor cells can protect them from immune destruction (Fig. 72-3). Blockade of the PD-1:PD-L1 axis by IV administration of anti-PD-1 or anti-PD-L1 has substantial clinical activity in patients with advanced melanoma (and lung, renal, bladder and oral head and neck cancers as well as Hodgkin lymphoma) with significantly less toxicity than ipilimumab. The PD-1 blockers, nivolumab and pembrolizumab, have been approved to treat patients with advanced melanoma. Combination T-cell checkpoint therapy, blocking both inhibitory pathways with ipilimumab and nivolumab, leads to superior antitumor activity compared to treatment with either agent alone. Combined therapy with intravenous ipilimumab and nivolumab is administered in the outpatient setting every 3 weeks for 4 doses (induction), followed by nivolumab given every 2 weeks (maintenance) for up to one year. This regimen produces an objective response rate of 56% and enhanced survival compared to ipilimumab monotherapy. There may be subsets of patients, specifically those who have >5% expression of PD-1 on T cells in a melanoma biopsy sample, who derive a similar level of clinical benefit from nivolumab monotherapy.
The main benefit to patients from immune-based therapy is the durability of the responses achieved. The percentage of patients whose tumors regress following combination anti-CTLA-4 and anti-PD-1 immunotherapy is comparable to the response rate after targeted therapy (see below); however, the durability of immunotherapy-induced responses (>10 years in some cases with checkpoints and greater than 20 years in some patients after IL-2) appears to be superior to responses after targeted therapy and suggests that many of these patients have been cured.
T-cell checkpoint antibodies can also interfere with normal immune regulatory mechanisms, which may produce a novel spectrum of side effects. The most common immune-related adverse events were skin rash and diarrhea (sometimes severe, life-threatening colitis), but toxicity can involve most any organ (e.g., hypophysitis, hepatitis, nephritis, pneumonitis, myocarditis, neuritis). The severity and frequency of toxicity is greatest with combination T-cell checkpoint antibody therapy, followed by anti-CTLA-4 and then anti-PD-1 monotherapies. Vigilance, interruption of therapy and early intervention with steroids or other immunosuppressive agents, such as anti-tumor necrosis factor antibodies or mycophenolate mofetil, can mitigate toxicity and prevent permanent organ damage. The management of drug-induced toxicity with immunosuppressive agents does not appear to interfere with antitumor activity. The use of T-cell checkpoint antibodies for metastatic melanoma has become commonplace, but there is controversy about whether all patients need combined anti-CTLA-4 and anti-PD-1, whether biomarkers can be used to select patients who may benefit from anti-PD-1 alone and the best sequence of targeted and immunotherapy in patients who have a BRAF mutation. There is also a significant economic impact with the cost of combination anti-CTLA-4 and anti-PD-1, which must be placed in the context of the survival benefit.
TARGETED THERAPY The high frequency of oncogenic mutations in the RAS-RAF-MEK-ERK pathway, which delivers proliferation and survival signals from the cell surface to the cytoplasm and nucleus, has led to the development of inhibitors to BRAF and MEK. RAF and MEK inhibitors of the MAP kinase pathway can induce regression of melanomas that harbor a BRAF mutation. Two BRAF inhibitors, vemurafenib and dabrafenib, have been approved for the treatment of patients whose stage IV melanomas harbor a mutation at position 600 in BRAF. Monotherapy with BRAF inhibitors has been supplanted with combined BRAF and MEK inhibition to address the rapid adaptation of the majority of melanomas that use MAP kinase pathway reactivation to facilitate growth when BRAF is inhibited. Combined therapy with BRAF and MEK inhibitors (dabrafenib and trametinib or vemurafenib with cobimetinib) improved progression-free survival compared to monotherapy with a BRAF inhibitor. The durability of responses following combined therapy is superior to monotherapy and survival is also enhanced. Long-term results of inhibition of the MAP kinase pathway are not yet available, but the major limitation of both monotherapy and combined therapy appears to be the acquisition of resistance; the vast majority of patients relapse and eventually die. The mechanisms of resistance are diverse and reflect the genomic heterogeneity of melanoma; however, most instances involve reactivation of the MAPK pathway, often through RAS mutations or mutant BRAF amplification. Patients who develop resistance to BRAF and MEK inhibition are candidates for immunotherapy or clinical trials.
Targeted therapy is accompanied by manageable side effects that differ from those experienced during immunotherapy or chemotherapy. A class-specific side effect of BRAF inhibition is the development of numerous skin lesions, some of which are well-differentiated squamous cell skin cancers (SCC) (seen in up to 25% of patients). These hyperproliferative lesions are believed to be due to paradoxical activation of the MAPK pathway resulting from BRAF inhibitor-mediated changes in BRAF-wild type cells. The paradoxical activation is blocked by the MEK inhibitor, which explains why these lesions occur much less frequently during combined therapy. Patients should be co-managed with a dermatologist as these skin cancers will need excision. Metastases of the treatment-induced SCCs have not been reported, and BRAF and MEK inhibitors can be continued safely following simple excision. Cardiac and ocular toxicities, although infrequent, can occur with BRAF and MEK inhibitors and require medical evaluation and management.
Activating mutations in the c-kit receptor tyrosine kinase are found in a minority of cutaneous melanomas with chronic sun damage, but are more common in mucosal and acral lentiginous subtypes. Overall, the number of patients with c-kit mutations is exceedingly small, but when present, they are similar to those found in gastrointestinal stromal tumors; melanomas with activating c-kit mutations can have clinically meaningful responses to imatinib. The probability of objective response in patients whose melanomas harbor a c-kit mutation is 29%. N-RAS mutations occur in 15–20% of melanomas. At present, there are no effective targeted agents for these patients, but MEK inhibitors are being investigated in clinical trials.
CHEMOTHERAPY No chemotherapy regimen has ever been shown to improve survival of patients with metastatic melanoma. The advances in immunotherapy and targeted therapy have relegated chemotherapy to the palliation of symptoms. Drugs with antitumor activity include dacarbazine (DTIC) or its orally administered analog temozolomide (TMZ), cisplatin and carboplatin, the taxanes (paclitaxel alone or albumin-bound), and carmustine (BCNU), which have reported response rates of 12–20%.
INITIAL APPROACH TO PATIENT WITH METASTATIC DISEASE Upon diagnosis of stage IV disease, a sample of the patient’s tumor should be submitted for molecular testing to determine whether a druggable mutation (e.g., BRAF and c-kit) is present. Analysis of a metastatic lesion biopsy (if possible) is preferred, but any sample will suffice because there is little discordance between primary and metastatic lesions. Treatment algorithms start with the tumor’s BRAF status. For BRAF wild-type tumors, immunotherapy is recommended. For patients whose tumors harbor a BRAF mutation, initial therapy with either combination BRAF and MEK inhibitors or immunotherapy is acceptable. Combined therapy with BRAF and MEK inhibitors is favored for patients with rapidly growing and symptomatic disease when a BRAF mutation is present. The sequence of immunotherapy and targeted therapy that confers the greatest survival benefit in patients with minimally symptomatic melanoma is not yet known, but ongoing randomized phase III trials should answer this important question. Despite improvements in therapy, the majority of patients with metastatic melanoma are not cured so enrollment in a clinical trial is always an important consideration, even for previously untreated patients.
Since most patients with stage IV disease will eventually experience tumor progression despite therapy and many, because of extensive disease burden, poor performance status, or concomitant illness, will be poor candidates for therapy, the timely integration of palliative care and hospice should be a major focus of care. Future advances in the management of melanoma will likely include biomarkers to select the optimal combination and sequence of agents or to identify patients who are unlikely to respond to extant therapies and for whom clinical trials should be considered. New therapeutic agents could include T-cell co-stimulatory antibodies, engineered T cells, oncolytic viruses and possibly vaccines to prevent melanoma development or recurrence.
FOLLOW-UP Skin examination and surveillance at least once a year are recommended for all patients with melanoma. Routine blood work and imaging for patients with stage IA–IIA disease is not recommended unless symptoms are present. In general, because there is no survival benefit to patients, routine surveillance diagnostic imaging is not recommended for patients with higher stage disease and imaging should be reserved for patients with signs or symptoms of recurrent disease. For stage-specific recommendations, please consult the National Comprehensive Cancer Network (NCCN) guidelines (see Further Reading).
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