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 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 make it detectable at a time when complete surgical excision is possible. Examples of malignant and benign pigmented lesions are shown in Fig. 105-1.
Atypical and malignant pigmented lesions. The most common melanoma is superficial spreading melanoma (not pictured). A. Acral lentiginous melanoma is the most common melanoma in blacks, Asians, and Hispanics and occurs as an enlarging hyperpigmented macule or plaque on the palms and soles. Lateral pigment diffusion is present. B. Nodular melanoma most commonly manifests as a rapidly growing, often ulcerated or crusted black nodule. C. Lentigo maligna melanoma occurs on sun-exposed skin as a large, hyperpigmented macule or plaque with irregular borders and variable pigmentation. D. Dysplastic nevi are irregularly pigmented and shaped nevomelanocytic lesions that may be associated with familial melanoma.
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. 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. 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. In 2014, more than 76,000 individuals in the United States were expected to develop melanoma, and approximately 9700 were expected to die. There will be nearly 50,000 annual deaths worldwide as a result of melanoma. Data from the Connecticut Tumor Registry support an unremitting increase in the incidence and mortality of melanoma. In the past 60 years, there have been 17-fold and 9-fold increases in incidence for men and women, respectively. In the same six decades, there has been a tripling of mortality rates for men and doubling for women. Mortality rates begin to rise at age 55, with the greatest increase in men age >65 years. Of particular concern is the increase in rates among women <40 years of age. Much of this increase is 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. These statistics highlight the need to promote prevention and early detection.
The risk of developing melanoma is related to genetic, environmental, and host factors (Table 105-1). 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 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 for any specific 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. 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.
TABLE 105-1Factors Associated with Increased Risk of Melanoma ||Download (.pdf) TABLE 105-1Factors Associated with Increased Risk of Melanoma
|Total body nevi (higher number = higher risk) |
|Dysplastic nevi (10-fold increased risk) |
|Family or personal history |
|Ultraviolet exposure/sunburns/tanning booths |
|Light skin/hair/eye color |
|Poor tanning ability |
|CDKN2A, CDK4, MITF mutations |
|MC1R variants |
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 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.
Personal and Family History
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 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.
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) predispose to both familial and sporadic melanomas.
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.
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.
PREVENTION AND EARLY DETECTION
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. Biological factors are increasingly being understood, such as tanning addiction, which is postulated to involve stimulation of reward centers in the brain involving dopamine pathways, and cutaneous secretion of β-endorphins after UV exposure, and may represent another area 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 tanning beds and midday (10:00 a.m. to 2:00 p.m.) sun exposure is recommended.
Secondary prevention comprises education, screening, and early detection. Patients should be educated in the clinical features of melanoma (ABCDEs; see following “Diagnosis” section) 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 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.
The main goal is to identify a melanoma before tumor invasion 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); andevolving (any change in size, shape, color, or elevation or new symptoms such as bleeding, itching, and crusting). 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. Benign nevi are present in 85% of adults, with 10–40 moles scattered over the body; atypical nevi can be present in the hundreds.
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 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.
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. 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; 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 are an acceptable alternative, particularly if the suspicion of malignancy is low, but they should be deep and include underlying fat; cauterization should be avoided. The biopsy should be read by a pathologist experienced in pigmented lesions, and 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 and comparative genome hybridization (CGH) can be helpful.
Four major types of cutaneous melanoma have been recognized (Table 105-2). 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 sites 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 microscopically after biopsy of a new or a changing skin nodule. 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.
TABLE 105-2Histologic Subtypes of Malignant Melanoma ||Download (.pdf) TABLE 105-2Histologic Subtypes of Malignant Melanoma
|Type ||Site ||Average Age at Diagnosis, Years ||Duration of Known Existence, Years ||Color |
|Lentigo maligna melanoma ||Sun-exposed surfaces, particularly malar region of cheek and temple ||70 ||5–20 or longera ||In flat portions, shades of brown and tan predominate, but whitish gray occasionally present; in nodules, shades of reddish brown, bluish gray, bluish black |
|Superficial spreading melanoma ||Any site (more common on upper back and, in women, lower legs) ||40–50 ||1–7 ||Shades of brown mixed with bluish red (violaceous), bluish black, reddish brown, and often whitish pink, and the border of lesion is at least in part visibly and/or palpably elevated |
|Nodular melanoma ||Any ||40–50 ||Months–<5 years ||Reddish blue (purple) or bluish black; either uniform in color or mixed with brown or black |
|Acral lentiginous melanoma ||Palm, sole, nail bed, mucous membrane ||60 ||1–10 ||In flat portions, dark brown predominantly; in raised lesions (plaques), brown-black or blue-black predominantly |
Although cutaneous melanoma subtypes are clinically and histopathologically distinct, this classification does not have independent prognostic value. Histologic subtype is not part of American Joint Committee on Cancer (AJCC) staging, although the College of American Pathologists (CAP) recommends inclusion in the pathology report. Newer classifications will increasingly emphasize molecular features of each melanoma (see below). The molecular analysis of individual melanomas will provide a basis for distinguishing benign nevi from melanomas, and determination of the mutational status of the tumor will help elucidate the molecular mechanisms of tumorigenesis and be used to identify targets that will guide therapy.
PATHOGENESIS AND MOLECULAR CLASSIFICATION
Considerable evidence from epidemiologic and molecular studies suggests that cutaneous melanomas arise via multiple causal 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 below). The altered melanocytes accumulate DNA damage, and selection occurs for all the attributes that constitute the malignant phenotype: invasion, metastasis, and angiogenesis.
An understanding of the molecular changes that occur during the transformation of normal melanocytes into malignant melanoma would not only help classify patients but also would contribute to the understanding of etiology and aid the development of new therapeutic options. A genome-wide 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 cutaneous melanomas on skin without chronic sun-induced damage, cutaneous melanomas with chronic sun-induced damage, mucosal melanomas, and acral melanomas. Distinct patterns of DNA alterations were noted that varied with the site of origin and were independent of the histologic subtype of the tumor. Thus, although the genetic changes are diverse, 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. 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. 105-2).
Major pathways involved in melanoma. The MAP kinase and PI3K/AKT pathways, which promote proliferation and inhibit apoptosis, respectively, are subject to mutations in melanoma. ERK, extracellular signal-regulated kinase; MEK, mitogen-activated protein kinase kinase; NF-1; neurofibromatosis type 1 gene; PTEN, phosphatase and tensin homolog.
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 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; thus, they often are accompanied by other mutations. 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 do not have the standard UV signature mutation (pyrimidine dimer); they 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.
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, Bc12-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. Targeted agents that inhibit these pathways have been developed, and some are available for clinical use (see below). Optimal treatment of patients with melanoma may require simultaneous inhibition of both MAPK and PI3K pathways as well as promotion of immune eradication of malignancy.
The prognostic factors of greatest importance to a newly diagnosed patient are included in the staging classification (Table 105-3). 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 has minimal influence on treatment decisions. 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 over 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.
Once the diagnosis of melanoma has been made, the tumor must be staged to determine the prognosis and treatment. Staging helps determine prognosis and aids in treatment selection. The current melanoma staging criteria and estimated 15-year survival by stage are depicted in Table 105-3. The clinical stage of the patient is determined after the pathologic evaluation of the melanoma skin lesion and clinical/radiologic assessment for metastatic disease. 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 represent 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 are low-yield tests for uncovering occult 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 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, more than 80% of patients will have disease confined to the skin and a negative history and physical exam, in which case imaging is not indicated.
TABLE 105-3Staging Criteria for Melanoma ||Download (.pdf) TABLE 105-3Staging Criteria for Melanoma
|Pathologic and TNM Stage ||Thickness, mm ||Ulceration ||No. of Involved Lymph Nodes ||Nodal Involvement ||15-Year Survival Estimate (%) |
|0 || || || || ||98 |
| Tis ||In situ ||No ||0 ||None || |
|IA || || || || ||92 |
| T1a ||<1 ||No, mitosis <1/mm ||0 ||None || |
|IB || || || || ||80 |
| T1b ||<1 ||Yes or mitosis >1/mm ||0 ||None || |
| T2a ||1.01–2 ||No ||0 ||None || |
|IIA || || || || ||62 |
| T2b ||1.01–2 ||Yes ||0 ||None || |
| T3a ||2.01–4 ||No ||0 ||None || |
|IIB || || || || ||51 |
| T3b ||2.01–4 ||Yes ||0 ||None || |
| T4a ||>4 ||No ||0 ||None || |
|IIC || || || || ||37 |
| T4b ||>4 ||Yes ||0 ||None || |
|IIIA || || || || ||68 |
| N1a ||T1-4a ||No ||1 ||Microscopic || |
| N2a ||T1-4a ||No ||2 or 3 ||Microscopic || |
|IIIB || || || || ||38 |
| N1a ||Any ||Yes ||1 ||Microscopic || |
| N2a ||Any ||Yes ||2 or 3 ||Microscopic || |
| N1b ||Any ||Yes or no ||1 ||Macroscopic || |
| N2b ||Any ||Yes or no ||2 or 3 ||Macroscopic || |
| N2c ||Any ||Yes or no ||In-transit metastases/satellites, no nodal involvement || || |
|IIIC || || || || ||22 |
| N1b ||Any ||Yes or no ||1 ||Macroscopic || |
| N2b ||Any ||Yes or no ||2 or 3 ||Macroscopic || |
| N2c ||Any ||Yes or no ||In-transit metastases/satellites, no nodal involvement || || |
| N3 ||Any ||Yes or no ||4+ metastatic nodes, matted nodes or in-transit metastases/satellites, with metastatic nodes || || |
|IV || ||Distant metastasis || || ||<10 |
| M1a || ||Skin, subcutaneous || || || |
| M1b || ||Lung || || || |
| M1c || ||Other visceral site || || || |
| || ||Elevated lactate dehydrogenase || || || |
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 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 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, ongoing clinical studies will determine whether patients with small-volume SLN metastases can be managed safely without additional surgery. Patients with microscopically positive lymph nodes should be considered for adjuvant therapy with interferon 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.
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. Either interferon α2b (IFN-α2b), which is given at 20 million units/m2 IV 5 days a week for 4 weeks followed by 10 million units/m2 SC three times a week for 11 months (1 year total), or subcutaneous peginterferon α2b (6 μg/kg per week for 8 weeks followed by 3 μg/kg per week for a total of 5 years) is acceptable adjuvant therapy. Treatment is accompanied by significant toxicity, including 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. Sometimes IFN must be permanently discontinued before all of the planned doses are administered because of unacceptable toxicity. The high-dose regimen is significantly more toxic than peginterferon, but the latter requires 4 additional years of therapy. Adjuvant treatment with IFN improves disease-free survival, but its impact on overall survival remains controversial. 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 the patient (or their oncologist) does not believe the beneficial effects of IFN outweigh the toxicity. The recently approved immunotherapy and targeted agents are being evaluated in the adjuvant setting.
TREATMENT Metastatic Disease
At diagnosis, most patients with melanoma will have early-stage disease; however, some will present with metastases, and others will develop metastases after initial therapy. Patients with a history of melanoma who develop signs or symptoms suggesting recurrent disease should undergo restaging that includes physical examination, CBC, complete metabolic panel, LDH, and appropriate diagnostic imaging that may include a magnetic resonance image (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 involve the skin and lymph nodes as well as viscera, bone, or the brain. Historically, metastatic melanoma was considered incurable; median survival ranges from 6 to 15 months, depending on the organs involved. 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 105-3). Although historical data suggest that the 15-year survival of patients with M1a, M1b, and M1c disease is less than 10%, there is optimism that newer therapies will increase the number of melanoma patients with long-term survival, especially patients with M1a and M1b disease.
The treatment for patients with stage IV melanoma has changed dramatically in the past 2 years. Two new classes of therapeutic agents for melanoma have been approved by the U.S. Food and Drug Administration (FDA). The immune T cell checkpoint inhibitor, ipilimumab, and three new oral agents that target the MAP kinase pathway: the BRAF inhibitors, vemurafenib and dabrafenib, and the MEK inhibitor, trametinib, are now available, so patients with stage IV disease now have multiple therapeutic options (Table 105-4).
Patients with oligometastatic disease should be referred to a surgical oncologist for consideration of metastasectomy, because they may experience long-term disease-free survival after surgery. Patients with solitary metastases are the best candidates, but surgery increasingly is being used even for patients with metastases at more than one site. Patients rendered free of disease can be considered for IFN therapy or a clinical trial because their risk of developing additional metastases is very high. Surgery can also be used as an adjunct to immunotherapy when only a few of many metastatic lesions prove resistant to systemic therapy. IMMUNOTHERAPY
The cytokine interleukin 2 (IL-2 or aldesleukin) has been approved to treat patients with melanoma since 1995. IL-2 is used to treat stage IV patients who have a good performance status and is administered at centers with experience managing IL-2-related toxicity. Patients require hospitalization in an intensive care unit–like setting to receive high-dose IL-2 600,000 or 720,000 IU every 8 h for up to 14 doses (one cycle). Patients continue treatment until they achieve maximal benefit, usually 4–6 cycles. Treatment is associated with long-term disease-free survival (probable cures) in 5% of treated patients. The mechanism by which IL-2 causes tumor regression has not been identified, but it is presumed that IL-2 induces melanoma-specific T cells that eliminate tumor cells by recognizing specific antigens. Rosenberg and his colleagues at the National Cancer Institute (NCI) have combined adoptive transfer of in vitro–expanded tumor-infiltrating lymphocytes with high-dose IL-2 in patients who were preconditioned with nonmyeloablative chemotherapy (sometimes combined with total-body irradiation). Tumor regression was observed in more than 50% of patients with IL-2-refractory metastatic melanoma.
Immune checkpoint blockade with monoclonal antibodies to the inhibitory immune receptors CTLA-4 and PD-1 has shown promising clinical efficacy. An array of inhibitory receptors are upregulated during an immune response. 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 denotes exhausted T cells with limited potential for proliferation, cytokine production, or cytotoxicity (Fig. 105-3). Checkpoint blockade with a monoclonal antibody results in improved T cell function with eradication of tumor cells in preclinical animal models. Ipilimumab, a fully human IgG antibody that binds CTLA-4 and blocks inhibitory signals, was the first treatment of any kind to improve survival in patients with metastatic melanoma. A full course of therapy is four IV outpatient infusions of ipilimumab 3 mg/kg every 3 weeks. Although response rates were low (∼10%) in randomized clinical trials, survival of both previously treated and untreated patients was improved, and ipilimumab was approved by the FDA in March 2011.
In addition to its antitumor effects, ipilimumab’s interference with normal regulatory mechanisms produced a novel spectrum of side effects that resembled autoimmunity. The most common immune-related adverse events were skin rash and diarrhea (sometimes severe, life-threatening colitis), but toxicity could involve most any organ (e.g., hypophysitis, hepatitis, nephritis, pneumonitis, myocarditis, neuritis). Vigilance and early treatment with steroids that do not appear to interfere with the antitumor effects are required to manage these patients safely. Widespread use of ipilimumab has not been completely embraced by the oncology community because of the low objective response rate, significant toxicity (including death), and high cost (drug cost alone for a course of therapy is approximately $120,000 in 2013). Despite these reservations, ipilimumab’s overall survival benefit (17% of patients alive at 7 years) indicates that treatment should be strongly considered for all eligible patients.
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. 105-3). Early trials attempting to block the PD-1:PD-L1 axis by IV administration of anti-PD-1 or anti-PD-L1 have shown substantial clinical activity in patients with advanced melanoma (and lung cancer) with significantly less toxicity than ipilimumab. Anti-PD-1 therapy looks promising, but is not currently available except by participation in clinical trials. Intriguingly, preliminary results from a clinical trial indicate that blocking both inhibitory pathways with ipilimumab and anti-PD-1 leads to superior antitumor activity than treatment with either agent alone. The main benefit to patients from immune-based therapy (IL-2, ipilimumab, and anti-PD-1) is the durability of the responses achieved. Although the percentage of patients whose tumors regress following immunotherapy is lower than the response rate after targeted therapy (see below), the durability of immunotherapy-induced responses (>10 years in some cases) appears to be superior to responses after targeted therapy and suggests that many of these patients have been cured. TARGETED THERAPY
RAF and MEK inhibitors of the MAP kinase pathway are a new and exciting approach for patients whose melanomas harbor a BRAF mutation. 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. Two BRAF inhibitors, vemurafenib and dabrafenib, have been approved for the treatment of stage IV patients whose melanomas harbor a mutation at position 600 in the gene for BRAF. The oral BRAF inhibitors cause tumor regression in approximately 50% of patients, and overall survival is improved compared to treatment with chemotherapy. Treatment is accompanied by manageable side effects that differ from those following immunotherapy or chemotherapy. A class-specific complication of BRAF inhibition is the development of numerous skin lesions, some of which are well-differentiated squamous cell skin cancers (seen in up to a quarter of patients). Patients should be co-managed with a dermatologist as these skin cancers will need excision. Metastases have not been reported, and treatment can be continued safely following simple excision. Long-term results following treatment with BRAF inhibitors are not yet available, but the current concern is that over time the vast majority of patients will relapse and eventually die from drug-resistant disease. There are a number of mechanisms by which resistance develops, usually via maintenance of MAP kinase signaling; however, mutations in the BRAF gene that affect binding of the inhibitor are not among them. The MEK inhibitor trametinib has activity as a single agent, but appears to be less effective than either of the BRAF inhibitors. Combined therapy with the BRAF inhibitor and MEK inhibitor showed improved progression-free survival compared to BRAF inhibitor therapy alone; and, interestingly, the neoplastic skin lesions that were so troubling with BRAF inhibition alone did not occur. Although the durability of responses following combined therapy remains to be determined, its use in metastatic melanoma is FDA approved. Activating mutations in the c-kit receptor tyrosine kinase are found in a minority of cutaneous melanomas with chronic sun damage, but more commonly in mucosal and acral lentiginous subtypes. Overall, the number of patients with c-kit mutations is exceedingly small, but when present, they are largely identical to mutations found in gastrointestinal stromal tumors (GISTs); melanomas with activating c-kit mutations can have clinically meaningful responses to imatinib. CHEMOTHERAPY
No chemotherapy regimen has ever been shown to improve survival in metastatic melanoma, and 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 docetaxel), and carmustine (BCNU), which have reported response rates of 12–20%. INITIAL APPROACH TO PATIENT WITH METASTATIC DISEASE
Upon diagnosis of stage IV disease, whether by biopsy or diagnostic imaging, a sample of the patient’s tumor needs to undergo molecular testing to determine whether a druggable mutation (e.g., BRAF) is present. Analysis of a metastatic lesion is preferred, but any biopsy 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 a BRAF inhibitor or immunotherapy is acceptable. Molecular testing may also include N-RAS and c-kit in appropriate tumors.
The majority of patients still die from their melanoma, despite improvements in therapy. Therefore, enrollment in a clinical trial is always an important consideration, even for previously untreated patients. Most patients with stage IV disease will eventually progress despite advances in therapy, and many, because of disease burden, poor performance status, or concomitant illness, will be unsuitable for therapy. Therefore, a major focus of care should be the timely integration of palliative care and hospice.
TABLE 105-4Treatment Options for Metastatic Melanoma
Inhibitory regulatory pathways that influence T cell function, memory, and lifespan after engagement of the T cell receptor by antigen presented by antigen-presenting cells in the context of MHC I/II. CTLA-4 and PD-1 are part of the CD28 family and have inhibitory effects that can be mitigated by antagonistic antibodies to the receptors or ligand, resulting in enhanced T cell function and antitumor effects. CTLA-4, cytotoxic T lymphocyte antigen-4; MHC, major histocompatibility complex; PD-1, programmed death-1; PD-L1, programmed death ligand-1; PD-L2, programmed death ligand-2; TCR, T cell receptor.
Skin examination and surveillance at least once a year are recommended for all patients with melanoma. The National Comprehensive Cancer Network (NCCN) guidelines for patients with stage IA–IIA melanoma recommend a comprehensive history and physical examination every 6–12 months for 5 years, and then annually 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 x-ray are recommended at the physician’s discretion, but are ineffective tools for the detection of occult metastases. Routine imaging for metastatic disease is not recommended at this time. For patients with higher stage disease (IIB–IV), imaging (chest x-ray, CT, and/or PET/CT scans) every 4–12 months can be considered. Because no discernible survival benefit has been demonstrated for routine surveillance, it is reasonable to perform scans only if clinically indicated.