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Pigmented lesions are among the most common findings on skin examination. The challenge is to distinguish cutaneous melanomas, which account for the overwhelming majority of deaths resulting from skin cancer, from the remainder, which with rare exceptions are benign. Cutaneous melanoma can occur in adults of all ages, even young individuals, and people of all colors; it is located on the skin, where it is visible; and it has distinct clinical features that make it detectable at a time when complete surgical excision is possible. Examples of malignant and benign pigmented lesions are shown in Fig. 33-1.
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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. In the United States, nearly 69,000 individuals were expected to develop melanoma and approximately 9000 were expected to die in 2010. Although the overall incidence and mortality have increased over the past decades, the mortality rates for younger patients have flattened, but those rates for individuals older than age 65 years have continued to increase. It 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. 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 diagnosed more often at a higher stage, and patients tend to have worse outcomes. Furthermore, in nonwhite populations, there is a much higher frequency of acral (subungual, plantar, palmar) and mucosal melanomas.
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The strongest risk factors for melanoma are the presence of multiple benign or atypical nevi and a family or personal history of melanoma (Table 33-1). The presence of melanocytic nevi, common or dysplastic, is a marker for an increased risk of melanoma. Nevi have been referred to as precursor lesions because they can transform into melanomas; however, the actual risk for any specific nevus is exceedingly low. About one-quarter of melanomas are histologically associated with nevi, but the majority arise de novo. Table 33-2 lists the characteristic features of clinically atypical moles and the features that differentiate them from benign acquired nevi. The number of clinically atypical moles may vary from one to several hundred, and they usually differ from one another in appearance. 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 melanoma patients whose disease is regarded as 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, which is a rare malformation that affects 1 in 30,000–100,000 individuals, with a lifetime risk of melanoma development estimated to be as high as 6%. At present, there are no uniform management guidelines for giant congenital nevi, but because of the potential for malignancy, 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 approximately 1% of persons; the risk of melanoma developing in these lesions is not known but appears to be relatively low. The management of small- to medium-size congenital melanocytic nevi remains controversial.
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Personal and family history
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Perhaps the single greatest risk factor for melanoma is a personal history of melanoma. Once diagnosed, patients with melanoma require a lifetime of surveillance because their risk is 10 times that of the general population. First-degree relatives have a 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, survival is improved, 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 germ-line mutations in the cell cycle regulatory gene cyclin-dependent kinase inhibitor 2A (CDKN2A). In fact, 70% of all cutaneous melanomas have somatic 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.
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The melanocortin-1 receptor (MC1R) gene is also an 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 pheomelanin, which is not sun-protective and produces red hair. This red hair color (RHC) phenotype is associated with fair skin, red hair, freckles, increased sun sensitivity, and increased risk of melanoma.
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CLINICAL CLASSIFICATION
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Traditionally, four major types of cutaneous melanoma have been recognized (Table 33-3). In three of these types—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. The 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. When tumors begin to penetrate deeply into the skin, they 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. An increase in size or change in color is noted by the patient in 70% of early lesions. Bleeding, ulceration, and pain are late signs and are of little help in early recognition. Superficial spreading melanoma is the most common variant observed in the white population. The back is the most common site for melanoma in men. In women, the back and the lower leg (from knee to ankle) are common sites. Nodular melanomas are dark brown-black to blue-black nodules. Lentigo maligna melanoma usually is confined to chronically sun-damaged, sun-exposed sites (face, neck, back of hands) in older individuals. Acral lentiginous melanoma occurs on the palms, soles, nail beds, and mucous membranes. Although this type occurs in whites, it occurs most frequently (along with nodular melanoma) in blacks and East Asians. 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 histologically after biopsy of a new or a changing skin nodule or because of suspicion of a basal cell carcinoma.
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Although melanoma subtypes are clinically and histopathologically distinct, this classification does not have independent prognostic value and has fallen out of favor. Histologic subtype is not part of American Joint Committee on Cancer (AJCC) staging and often is not identified in current pathology reports. Future classification schemes will be based on molecular features of each melanoma (see later discussion). The molecular analysis of individual melanomas will provide a basis for distinguishing benign nevi from melanomas, identify distinct subclasses of melanoma on the basis of the anatomic site, indicate the extent of ultraviolet (UV) exposure, and determine the mutational status of the tumor, which will help elucidate the molecular mechanisms of tumorigenesis and identify targets that will serve as a basis for selection of therapy.
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PATHOGENESIS AND MOLECULAR CLASSIFICATION
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Considerable evidence from epidemiologic and molecular studies suggests that cutaneous melanomas arise via multiple pathways. There are both environmental and genetic components. Uv solar radiation causes genetic changes in the skin, 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. A comprehensive catalog of somatic mutations from a human melanoma revealed more than 33,000 base mutations with damage to almost 300 protein-coding segments compared with normal cells from the same patient. The dominant mutational signature reflected DNA damage due to UV light exposure. The melanoma also contained previously described driver mutations (i.e., mutations that confer selective clonal growth advantage and are implicated in oncogenesis). These driver mutations affect pathways that promote cell proliferation and inhibit normal pathways of apoptosis in response to DNA repair (see later discussion). 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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An understanding of the molecular changes that occur during the transformation of normal melanocytes into malignant melanoma not only would help classify patients in similar prognostic groups but also would contribute to the understanding of etiology and help identify new therapeutic options. A genomewide assessment of melanomas classified into four groups based on their location and degree of exposure to the sun has confirmed that there are distinct genetic pathways in the development of melanoma. The four groups were melanomas on skin without chronic sun-induced damage, melanomas on skin with chronic sun-induced damage, mucosal melanomas, and acral melanomas. Remarkably, distinct patterns of DNA alterations were noted that varied with the site of origin and were independent of the histologic subtype of the tumor. What that work and research done by others have shown is that the overall pattern of mutation, amplification, and loss of cancer genes indicate that although the genetic changes are diverse, they have convergent effects on key biochemical pathways involved in proliferation, senescence, and apoptosis. The p16 mutation that leads to 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. 33-2).
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The RAS family 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. N-RAS is mutated in approximately 20% of melanomas, and somatic activating BRAF mutations are found in most benign nevi and 40–60% of melanomas. Neither mutation by itself appears to be sufficient to cause melanoma; they often are accompanied by other mutations, (e.g., CDKN2A) or phosphatidylinositol 3′ kinase pathway (e.g., loss of PTEN). The BRAF mutation is almost always a point mutation (T→A nucleotide change) that results in a valine-to-glutamate amino acid substitution (V600E). V600E BRAF mutations do not have the standard UV signature mutation (pyrimidine dimer) but are present in most melanomas that arise on sites with intermittent sun exposure and are absent in melanomas from chronically sun-damaged skin.
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Melanomas also contain 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 prolong survival through inactivation of BAD, Bc12-antagonist of cell death, and activation of the forkhead transcription factor FOXO1, which leads to synthesis of prosurvival genes. In melanoma, these two signaling pathways enhance tumorigenesis, chemoresistance, migration, and cell cycle dysregulation. Targeted agents are being employed that inhibit each pathway, but it is likely that effective antimelanoma therapy will require simultaneous inhibition of both MAPK and PI3K.
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The main goal is to diagnose melanoma early in its natural history, before tumor invasion and life-threatening metastases have occurred. Early detection of melanoma 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); evolving (any change in size, shape, color, or elevation or new symptoms such as bleeding, itching, and crusting). The aim of differential diagnosis is to distinguish benign pigmented lesions from melanoma and its precursor. If melanoma is a consideration, biopsy is appropriate. Some benign look-alikes may be removed in the process of trying to detect melanoma. Several factors may help distinguish benign nevi from atypical moles:
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Size: Benign nevi usually are <6 mm in diameter; atypical moles usually are >6 mm in diameter.
Shape: Benign nevi usually are round with distinct borders and may be flat or elevated; atypical moles usually have irregular borders with pigment fading off at the edge.
Color: Benign nevi usually are uniformly brown or tan; atypical moles usually have variable mixtures of brown, tan, black, and reddish pigment and differ from one another.
Location: Benign nevi usually appear on sun-exposed skin above the waist, rarely involving the scalp, breasts, or buttocks; atypical moles usually appear on sun-exposed skin, most often on the back, but can involve the scalp, breasts, or buttocks.
Number: Benign nevi are present in 85% of adults, with 10–40 moles scattered over the body; atypical nevi can be present in the hundreds.
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The entire cutaneous 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 and may allow a more precise visualization of patterns of pigmentation than is possible with the naked eye. Complete physical examination with attention to the regional lymph nodes is part of the initial evaluation in a patient with suspected melanoma. The patient should be advised to have other family members screened if either melanoma or clinically atypical moles (dysplastic nevi) are present. Patients who fit into high-risk groups should be instructed to perform monthly self-examinations.
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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. The recommended technique is an excisional biopsy, which facilitates pathologic assessment of the lesion, permits accurate measurement of thickness if the lesion is melanoma, and constitutes treatment if the lesion is benign. For large lesions or lesions 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; this should include the vertical growth phase of the primary tumor, if present. 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 biopsies and cauterization should be avoided. The biopsy should be read by a pathologist experienced in pigmented lesions, and the minimal elements of the report should include Breslow thickness, mitoses per square millimeter for lesions ≤1 mm, presence or absence of ulceration, 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 cases with challenging histology, fluorescence in situ hybridization (FISH) with multiple probes can be helpful.
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The prognostic factors of greatest importance to a newly diagnosed patient are included in the staging classification (Table 33-4). The best predictor of metastatic risk is the lesion's Breslow thickness. The Clark level, which defines melanomas on the basis of the layer of skin to which a melanoma has invaded, does not add significant prognostic information and no longer is used. Other important factors recognized via the staging classification include the presence of ulceration, evidence of nodal involvement, serum lactate dehydrogenase (LDH) level, and presence and site of distant metastases. The effects of these important prognostic factors on survival can be seen in Fig. 33-3, where survival is depicted according to stage (Table 33-4). Another determinant is anatomic site; 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 impact of age is not straightforward. Older individuals, especially men older than age 60 years, 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.
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Once the diagnosis of melanoma has been made, the tumor must be staged to determine the prognosis and treatment. The 2009 AJCC revised melanoma staging and classification are depicted in Table 33-4. The clinical stage of the patient is determined after the pathologic evaluation of the melanoma skin lesion and any clinical or radiologic assessment for metastatic disease. Pathologic staging also includes the pathologic evaluation of the regional lymph nodes obtained at sentinel lymph node biopsy or complete lymphadenectomy. All patients with melanoma should have a complete history and physical examination with attention to symptoms that may represent metastatic disease such as malaise, weight loss, headaches, visual difficulty, and pain. The physical examination should be 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. Physical examination also should include the regional draining lymph nodes, CNS, liver, and lungs. A complete blood count (CBC), complete metabolic panel, and LDH level should be performed. Although these are low-yield tests for uncovering metastatic disease, a microcytic anemia would raise the possibility of bowel metastases, particularly in the small bowel, and an unexplained elevated LDH should prompt a more extensive evaluation, including CT scan or possibly a positron emission tomography (PET) (or CT and PET combined) scan. If signs or symptoms of metastatic disease are uncovered, appropriate diagnostic imaging should be performed. At initial presentation, more than 80% of patients will have disease confined to the skin and a negative history and physical examination, in which case imaging generally 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 primary melanoma: in situ, 0.5 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 nodal 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 processing with serial section with hematoxylin and eosin stains as well as immunohistochemical stains to identify melanocytes (e.g., S100, HMB45, and MelanA).
Not every patient is a candidate for an SLNB. Patients whose melanomas are ≤1 mm thick and have <1 mitotic figure/mm2 have an excellent prognosis and generally do not need an SLNB unless they have high-risk features such as young age, an ulcerated primary, and positive deep margins. They usually can be referred for wide excision as definitive therapy. Most other patients with clinically negative lymph nodes should undergo an SLNB. Patients whose SLNB findings are negative are spared a complete node dissection and its attendant morbidities. They can simply be followed or considered for adjuvant therapy or a clinical trial as appropriate for the primary lesion. The current standard of care for all patients with a positive SLN result is to perform a complete lymphadenectomy; however, ongoing clinical studies are attempting to determine whether patients with small-volume metastases in the sentinel node can be managed safely without additional surgery. Patients with microscopically positive lymph nodes should be considered for adjuvant therapy with interferon (IFN) or enrolled in a clinical trial.
MANAGEMENT OF REGIONALLY METASTATIC MELANOMA (STAGE III) Regional metastases may occur as a local recurrence at the edge of the scar or graft; as satellite metastases, which are separate from the scar but within 2–5 cm of the scar; as in-transit metastases, which are recurrences >5 cm from the scar; or, as in the most common case, as metastasis to a draining lymph node basin. Each of these recurrences is managed surgically, if possible, with the possibility of achieving long-term disease-free survival. An option for patients with extensive cutaneous regional recurrences in an extremity is isolated limb perfusion or infusion with melphalan and hyperthermia. High complete response rates have been reported, and responses are associated with significant palliation of symptoms.
After surgery, patients with regional metastases who are rendered free of disease may be at high risk for a local or distant recurrence. Therefore, some patients should be considered for adjuvant therapy. Adjuvant radiotherapy can reduce the risk of local recurrence after lymphadenectomy but does not affect overall survival. Patients with large (>3–4 cm) or multiple 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. IFN-α2b, which is given for 1 year at 20 million units/m2 intravenously 5 days a week for 4 weeks followed by 10 million units/m2 subcutaneously three times a week for 11 months, is the only U.S. Food and Drug Administration (FDA)–approved agent for adjuvant therapy. High-dose IFN is associated with significant toxicity, including a flulike illness, decline in performance status, and the development of depression in a large fraction of patients. The toxicity can be managed in most patients by appropriate therapy for symptoms, dose reduction; treatment interruption; and, for one-third of patients, early discontinuation of IFN. Adjuvant treatment with high-dose IFN has been associated with improved disease-free survival, but its impact on overall survival is unclear. Enrollment in a clinical trial is appropriate for these patients, many of whom will otherwise be observed without treatment either because they are poor candidates for IFN or because a patient (or his or her oncologist) does not believe the beneficial effects of IFN outweigh the toxicity.
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TREATMENT: Metastatic Disease
When a patient with a history of melanoma develops signs or symptoms of recurrent disease, he or she should undergo restaging. This typically includes an MRI of the brain and total-body PET/CT or CT scans of the chest, abdomen, and pelvis. Distant metastases (stage IV), which may involve any organ, commonly include skin and lymph node metastases as well as visceral, bone, or brain metastases. Metastatic melanoma is generally incurable, and the median survival time ranges from 6 to 15 months, depending on the organ involved (Fig. 33-3C, D). The prognosis is better for skin and subcutaneous metastases (Mla) than for lung (M1b) or other visceral metastases (Mlc). An elevated serum LDH in a patient with metastatic disease is a poor prognostic factor and puts the patient in stage Mlc regardless of the site of the metastases.
The only FDA-approved chemotherapy for melanoma is dacarbazine (DTIC). Other agents with modest activity include temozolomide (TMZ), cisplatin and carboplatin, the taxanes, paclitaxel and docetaxel alone or albumin-bound, and carmustine (BCNU), which have reported response rates of 12–20%. Although limited in efficacy, single-agent DTIC is still considered the standard treatment because drug combinations have never been shown to improve survival. Although not FDA-approved for melanoma, TMZ, which shares an active metabolite with DTIC, has been used widely because of its ease of oral administration, excellent tolerance, and penetration across the blood–brain barrier. Attempts to define superior combinations and identify new active agents are ongoing.
Interleukin 2 (IL-2)–based therapy has been associated with long-term disease-free survival (probable cures) in 5% of treated patients. Treatment usually consists of high-dose IL-2 alone, but some centers combine IL-2 with IFN-α and chemotherapy (biochemotherapy). IL-2 therapy generally is reserved for patients with a good performance status and administered at centers with experience managing IL-2–related toxicity. The mechanism by which IL-2 effects tumor regression has not been identified, but it is presumed that it induces melanoma-specific T cells that cause tumor regression. Based on this assumption, Rosenberg and his colleagues in the National Cancer Institute (NCI) Surgery Branch have used adoptive immunotherapy with in vitro-expanded tumor-infiltrating lymphocytes with high-dose IL-2. A series of studies of adoptive T cell therapy in patients who have been treated with nonmyeloablative chemotherapy (sometimes combined with total-body irradiation) have reported tumor regression in more than 50% of patients with IL-2–refractory melanoma. Multiple investigators have attempted to develop vaccination strategies against melanoma using purified tumor proteins, peptides, DNA vectors, dendritic cells, and unmodified or genetically altered tumor cells as immunogens to elicit melanoma-specific T cell responses, but none of these approaches has met with much clinical success.
A promising new approach is CTLA-4 blockade with a monoclonal antibody. CTLA-4 antibodies block the inhibitory signal produced when CTLA-4 is engaged on activated T cells, enhance T cell function, and cause tumor regression in animal models. Administration of anti–CTLA-4 (ipilimumab) to patients with previously treated metastatic melanoma in a randomized study was shown to improve overall survival compared with patients receiving a peptide vaccine. A novel spectrum of side effects that implies development of autoimmunity, so-called immune-related adverse events, has been noted. Patients who develop skin rashes, diarrhea and colitis, and hypophysitis, all of which can be managed, appear to have higher rates of tumor regression.
Targeted therapies are an exciting approach for patients with metastatic melanoma. The most promising available agents are those that target activating mutations in BRAF and c-kit, which result in constitutive activation of the MAP kinase pathway. V600E BRAF is the most common kinase mutation in melanoma. A highly selective oral BRAF inhibitor, PLX4032, has been developed, and tumor regression rates up to 70% have been reported in early clinical trials; to date, most remissions appear to be partial and of limited duration. Activating mutations in the c-kit receptor tyrosine kinase are also found in melanoma but primarily in mucosal, acral lentiginous, and lentigo maligna melanoma. Since these tumors are found in only 5% of the patients with metastatic melanoma, the number of patients with c-kit mutations is exceedingly small. Nevertheless, if present, they are largely identical to mutations found in gastrointestinal stromal tumors (GISTs), and melanomas with activating c-kit mutations can have rather dramatic responses to imatinib. The availability of targeted therapies will require that selected patients have their tumors sent for molecular typing to determine their suitability for treatment with available agents or their eligibility for clinical trials of newly developed agents. Some patients with stage IV disease will experience long-term disease-free survival after surgical resection of their metastases (metastatectomy). Surgery often is performed in patients with metastatic disease involving a small number of sites, either before or after systemic therapy. These patients may have a solitary lung or brain metastasis, but surgery increasingly is being employed in patients with metastases at more than one site. After surgery, patients with no evidence of disease can be considered for INF therapy or a clinical trial because their risk of developing additional metastases is very high.
Current therapy for the overwhelming majority of patients is palliative, so enrollment in a clinical trial is always an appropriate option, even for previously untreated patients. However, because most stage IV disease is incurable, a major focus of care, particularly for patients with poor performance status, should be the timely integration of palliative care and hospice.
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Skin examination and surveillance at least once a year is recommended for all patients with melanoma. The National Cancer Comprehensive Network (NCCN) guidelines for patients with stage IB–IV melanoma recommend a comprehensive history and physical examination every 3–6 months for 2 years, then every 3–12 months for 3 years, and annually thereafter, as clinically indicated. Particular attention should be paid to the draining lymph nodes in stage I–III patients as resection of lymph node recurrences may still be curative. A CBC, LDH, and chest radiography are recommended at the physician's discretion. Routine imaging for metastatic disease is not recommended at this time because there is no discernible survival benefit to the early detection of metastatic disease.
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Primary melanoma prevention is based on protection from the sun, which includes wearing protective clothing, avoiding intense midday UV exposure and tanning booths, and routine application of a broad-spectrum ultraviolet-A/ultraviolet-B (UV-A/UV-B) sunblock with sun protection factor ≥15. This includes use of protective clothing and avoidance of intense midday UV exposure. Secondary prevention consists of education and screening. Patients should be educated in the clinical features of melanoma (ABCDEs) and advised to report any growth or other 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 6- to 8-week 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 cancer screening seems to be a simple, practical way to approach reducing the mortality rate for skin cancer. This is particularly true for patients with clinically atypical moles (dysplastic nevi) and those with a personal history of melanoma. 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.