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A 51-year-old woman noticed a rapidly growing black lesion on the upper arm (Figure 179-1) and presented to her doctor. A narrow-margin biopsy confirmed an 8-mm-thick nodular melanoma. She was referred to surgical oncology for sentinel lymph-node biopsy, and one node was positive. She underwent a course of chemotherapy, and though she remains disease-free 2 years later, she is carefully monitored for metastasis and new primary lesions by a multidisciplinary team including family medicine, dermatology, and medical and surgical oncology.
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A 60-year-old man underwent a skin exam as part of his regular physical exam. His family doctor noticed an irregular brown black patch on the back (Figure 179-2) and performed a narrow-margin scoop shave, which was diagnostic for melanoma in situ. The patient underwent wide local excision in the office with 5-mm margins and follows up regularly for skin exams with a cure rate very near 100%.
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Melanoma is the third most common skin cancer and the most deadly. The incidence of melanoma and the mortality from it are rising. Most lesions are found by clinicians on routine examination. When discovered early, surgical treatment is almost always curative. However, as depth increases, so does the risk of metastasis and mortality. New chemotherapy regimens are more promising than ever, but the best prognosis comes with prevention and early detection.
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In 2018, the American Cancer Society estimates that 91,270 people in the United States will be diagnosed with melanoma, and 9320 will die from it.1
Melanoma incidence has increased in every age group and in every thickness over the course of 1992 to 2006 among non-Hispanic whites, with death rates increasing in those older than age 65 years.2
Incidence continues to increase worldwide at approximately 4% to 8% per year.3
In the United States, the death rate for melanoma is decreasing among persons younger than age 65 years.2
Deaths from thin melanomas account for more than 30% of total deaths.
The lifetime risk of developing melanoma is 2.6%.1
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Risk factors can be broadly thought of as genetic risks, environmental risks, and phenotypic risks arising from a combination of genetic and environmental risks. For example, a fair-skinned child (genetic) who gets a sunburn (environmental) is much more likely to develop freckles (phenotypic) and melanoma.
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Exposure to sunlight.
Living closer to the equator.
Indoor tanning.
History of immunosuppression.
Higher socioeconomic status (likely associated with more frequent opportunity for sunburns).
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Fair skin, blue or green eyes, red or blonde hair.
Male sex.
Melanoma in a first-degree relative.
History of xeroderma pigmentosum or familial atypical mole melanoma syndrome.
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Remember the ABCDE guidelines for diagnosing melanoma (Figure 179-3).4
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A = Asymmetry. Most early melanomas are asymmetric: a line through the middle will not create matching halves. Benign nevi are usually round and symmetric.
B = Border. The borders of early melanomas are often uneven and may have scalloped or notched edges. Benign nevi have smoother, more even borders.
C = Color variation. Benign nevi are usually a single shade of brown. Melanomas are often in varied shades of brown, tan, or black, but may also exhibit red, white, or blue.
D = Diameter greater than or equal to 6 mm. Early melanomas tend to grow larger than most nevi. (Note: Congenital nevi are often large.)
E = Evolving. Any evolving or enlarging nevus should make you suspect melanoma. Evolving could be in size, shape, symptoms (itching, tenderness), surface (especially bleeding), and shades of color.
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A prospective controlled study compared 460 cases of melanoma with 680 cases of benign pigmented tumors and found significant differences for all individual ABCDE criteria (p <0.001) between melanomas and benign nevi.4
Sensitivity of each criterion: A 57%, B 57%, C 65%, D 90%, E 84%; specificity of each criterion: A 72%, B 71%, C 59%, D 63%, E 90%.4
Sensitivity of ABCDE criteria varies depending on the number of criteria needed: using 2 criteria it was 89.3%; with 3 criteria, it was 65.5%. Specificity was 65.3% using 2 criteria and 81% using 3.4
The number of criteria present was different between benign nevi (1.24 ± 1.26) and melanomas (3.53 ± 1.53; p <0.001). Unfortunately, no significant difference was found between melanomas and atypical nevi.4
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There are 4 major categories of melanomas. With the exception of nodular melanoma, the growth patterns of the 3 other subtypes are characterized by a radial growth phase prior to dermal invasion. At the present time, the thickness of the lesion, ulceration, and lymphovascular invasion histologically are used for tumor staging and prognosis regardless of the morphologic subtype. Here are the major categories of melanomas:
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Superficial spreading melanoma is the most common type, representing about 69% of all melanoma (Figures 179-3, 179-4, 179-5, 179-6). This melanoma has the radial growth pattern before dermal invasion occurs. The first sign is the appearance of a flat macule or slightly raised discolored plaque that has irregular borders and is somewhat geometric in form. The color varies, with areas of tan, brown, black, red, blue, or white. These lesions can arise in an older nevus. The melanoma can be seen almost anywhere on the body, but is most likely to occur on the trunk in men, the legs in women, and the upper back in both. Superficial spreading melanoma is the most common type identified in young non-Hispanic white adults.6
Nodular melanoma occurs in 14% of cases (Figures 179-1, 179-7, 179-8, 179-9).6 It is usually invasive at the time it is first diagnosed, and the malignancy is recognized when it becomes raised. The color is often black, but occasionally blue, gray, white, brown, tan, red, or nonpigmented. The nodule in Figure 179-9 is multicolored.
Lentigo maligna melanoma occurs in about 15% of cutaneous melanoma.6 It is similar to the superficial spreading type and appears as a flat or mildly elevated mottled tan, brown, or dark brown discoloration on sun-damaged skin (Figures 179-10 and 179-11). This type of melanoma is found most often in 50- to 80-year-olds and occurs on the head 90% of the time. Although it is most often found on the face and scalp, it can occur in other areas of sun-damaged skin. These grow slowly over 3–15 years, arising from the precursor lesion, lentigo maligna, which is melanoma in situ (Figure 179-10). The in situ precursor lesion may be quite large and has often existed for years or over a decade (see Chapter 175, Lentigo Maligna).
Acral lentiginous melanoma is the least common major subtype of melanoma and accounts for about 2% of all melanomas; however, it is one of the most frequent subtypes seen in African Americans (37%) though it actually occurs even more often in Hispanic and non-Hispanic whites.6 It may occur under the nail plate or on the soles or palms (Figures 179-12, 179-13, 179-14, 179-15, 179-16). This subtype often carries a worse prognosis because of delays in diagnosis and the accompanying thickness at the time of diagnosis. Subungual melanoma may manifest as diffuse nail discoloration or a longitudinal pigmented band within the nail plate. When subungual pigment spreads to the proximal or lateral nail fold, it is referred to as the Hutchinson sign and is highly suggestive of acral lentiginous melanoma (Figure 179-14) (see Chapter 199, Pigmented Nail Disorders).
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Less common types of melanomas include:
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Amelanotic melanoma (<5% of melanomas) is nonpigmented and appears pink or flesh-colored, often mimicking basal cell or squamous cell carcinoma or a ruptured hair follicle. Any of the 4 principal subtypes may present as an amelanotic variant, but nodular melanomas are highly represented. These may be intrinsically more aggressive and often present with a thicker Breslow depth than similarly pigmented melanomas (Figures 179-17, 179-18, 179-19).7
Other rare melanoma variants include (a) nevoid melanomas, (b) malignant blue nevus, (c) desmoplastic/spindled/neurotropic melanoma, (d) clear cell sarcoma (in fact a melanoma), (e) animal-type melanoma, (f) ocular melanoma, and (g) mucosal (lentiginous) melanoma.8
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Melanoma occurs most commonly on the trunk in white males and the lower legs and back in white females, but may occur in any location where melanocytes exist. The most common site in African Americans, Hispanics, and Asians is the plantar foot, followed by the subungual, palmar, and mucosal sites.
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Dermoscopy can be used to determine if a pigmented lesion has features suspicious for a melanoma, and it can also help determine when a biopsy is needed.9 In a prospective study of 401 lesions evaluated for melanoma by experts in dermoscopy, the sensitivity of 66.6% with ABCDE criteria improved to 80%, and specificity rose from 79.3% to 89.1% (Figure 179-20).9
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In a study of dermoscopy done by 60 physicians (35 general practitioners, 10 dermatologists, and 16 dermatology trainees) on unaided photos of 40 lesions using the ABCD rule, the Menzies method, a 7-point checklist, and pattern analysis, the sensitivity rose over the unaided eye.10 Physicians were instructed in each of the dermoscopy methods using a CD-ROM. The unaided eye using a standard photo of the lesion was 61% sensitive and 85% specific with a 73% diagnostic accuracy. The dermoscopic photo increased sensitivity (68% for pattern analysis, 77% for the ABCD rule, 81% for the 7-point checklist, and 85% for the Menzies method). The specificity did not improve. Sensitivity is more important than specificity to avoid missing melanoma. Although the number of biopsies could increase with some drop in specificity, the biopsy itself is the most specific test to differentiate melanoma from benign pigmented lesions.10
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Accepted dermoscopic features of melanoma include:
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Atypical network (includes branched streaks).
Streaks: pseudopods and radial streaming.
Atypical dots and globules.
Negative pigment network.
Blotch (off center).
Blue-white veil/peppering over macular areas (regression).
Blue-white veil over raised areas.
Atypical vascular structures.
Peripheral tan/brown structureless areas.
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Figure 179-20 demonstrates a number of these features. (See Chapters 111, Dermoscopy, and 181, Advanced Dermoscopy of Skin Cancer.)
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A full-thickness skin biopsy remains the gold standard for diagnosing melanoma. Narrow-margin (1–3 mm) biopsy by shave saucerization, punch, or elliptical excision is ideal for histologic diagnosis and tumor staging (Box 179-1). Wider margins are avoided to preserve accurate subsequent lymphatic mapping. Although there is evidence that a partial biopsy of a portion of a melanoma does not worsen the prognosis, this should only be performed when a lesion is too large to excise in the office. If the clinical impression differs markedly from the pathology report, discuss with the pathologist and share clinical photos if you haven't done so already. You may need to have the pathologist prepare "deeper sections" or "step sections"—meaning more slices from the same loaf of bread. Additionally, if the diagnosis of melanoma was expected and the result of an incisional biopsy does not meet the expectation, go forward with a complete excision or refer to a colleague who can.
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BOX 179-1 The National Comprehensive Cancer Network (NCCN) Melanoma Guidelines on the Principles of Biopsy of a Suspicious Pigmented Lesion5
Excisional biopsy (elliptical, punch, or saucerization/deep shave) with 1- to 3-mm margins is preferred. Avoid wider margins to permit accurate subsequent lymphatic mapping.
The orientation of an elliptial/fusiform excisional biopsy should be planned with definitive wide excision in mind (eg, vertically/parallel to underlying lymphatics on the extremities).
Full-thickness incisional or punch biopsy of clinically thickest portion of the lesion is acceptable in certain anatomic areas (e.g., palm/sole, digit, face, and ear) or for very large lesions.
Superficial shave biopsy may compromise pathologic diagnosis and complete assessment of Breslow thickness, but is acceptable when the index of suspicion is low.
For lentigo maligna melanoma in situ, lentigo maligna type broad shave biopsy may help to optimize diagnostic sampling.
If clinical evaluation of incisional biopsy suggests that microstaging is inadequate, consider narrow margin excisional biopsy.
Repeat narrow-margin excisional biopsy is recommended if an initial partial biopsy is inadequate for diagnosis or microstaging but should not generally be performed if the initial specimen meets criteria for Sentinel lymph node staging.
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Saucerization (scoop or deep shave biopsy) leads to an accurate diagnosis and staging 97% of the time (Figure 179-21).11 This is because it provides breadth of sampling in addition to depth when performed correctly. The goal of the saucerization is to get under the lesion, especially in the region with the greatest depth. In most cases this is about the depth of a dime, and the visible pigment depth can be the guide (see Chapter 113, Biopsy Principles and Techniques). If pigment is seen at the base of the biopsy, a second saucerization can be added to the first pass to provide the pathologist with more tissue. Too shallow of a biopsy may miss important staging information. For very large lesions, such as a suspected lentigo maligna, a saucerization should provide better tissue to the pathologist than a single or several punch biopsies (see Figure 179-10).12
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The impact of partial biopsy on histopathologic diagnosis of cutaneous melanoma has been studied extensively by Ng and colleagues in Australia. They found that increased odds of histopathologic misdiagnosis were associated with punch biopsy of part of the melanoma (odds ratio [OR] 16.6) and shallow shave biopsy (OR 2.6) compared with excisional biopsy (including saucerization). Punch biopsy of part of the melanoma was also associated with increased odds of misdiagnosis with an adverse outcome (OR 20).13
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DIFFERENTIAL DIAGNOSIS
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Nevi of all types can mimic melanoma. Congenital nevi can be especially large and asymmetric. Therefore, it is important to ask the patient if the pigmented area has been there from birth. Because some melanomas arise in congenital nevi, a changing congenital nevus needs to be biopsied to rule out melanoma.
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Dysplastic nevi, also called atypical nevi, can mimic melanoma. When an atypical nevus is suspicious for melanoma, perform a narrow-margin biopsy. Only the less-suspicious and flat dysplastic nevi should be monitored with photography or serial exams (see Chapter 171, Dysplastic Nevus and Spitz Nevus).
Spitz nevi can mimic melanoma or actually be a spitzoid melanoma. If a lesion appears to be a Spitz nevus, it should be biopsied. The only exceptions are typical Spitz nevi in children under age 12. However, if the lesion is atypical, a biopsy is always needed (see Chapter 171, Dysplastic Nevus and Spitz Nevus).
Seborrheic keratoses (SKs) usually look like they are stuck on, with surface cracks and a verrucous (wartlike) appearance. These are benign and not precancerous. SKs can be darkly pigmented or asymmetric with irregular borders and can have varied colors. Perform a biopsy if the diagnosis is uncertain. Be careful to not mistake a melanoma for an SK (Figure 179-4) (see Chapter 164, Seborrheic Keratosis). Do not perform cryosurgery on an SK with any atypical features. These should be biopsied. A number of malpractice lawsuits have been filed against physicians who froze a melanoma thought to be an SK.
Solar lentigines appear as light brown macules on the face and the dorsum of the hands. Many patients call them liver spots, but they are unrelated to the liver. A large isolated solar lentigo on the face can mimic lentigo maligna melanoma. In this case, perform a broad scoop shave of the most suspicious area or the whole lesion. Dermoscopy is helpful to guide selecting the area to biopsy (see Chapters 111 and 181 on dermoscopy).
Dermatofibromas are fibrotic nodules that occur most frequently on the legs and arms. They can be any color from skin color to black and often have a brown halo surrounding them. A pinch test will produce a dimpling of the skin in most cases (see Chapter 166, Dermatofibroma).
Pyogenic granulomas can resemble an amelanotic melanoma, and sending for pathologic exam will ensure that the clinical diagnosis is correct (Figure 179-22) (see Chapter 167, Pyogenic Granuloma).
Pigmented basal cell carcinomas (BCCs) may resemble a melanoma. However, the pigment in the BCC is often scattered throughout the lesion, and it has other features of a BCC, such as a pearly appearance with a rolled border (Figure 179-23) (see Chapter 177, Basal Cell Carcinoma). Dermoscopy can be very helpful, as a pigmented BCC has a number of specific dermoscopic structures to look for (see Chapters 111 and 181 on dermoscopy).
Merkel cell carcinoma (see Figure 178-20) is a rare cutaneous neuroendocrine malignancy that is most common on the head and neck of elderly individuals as an enlarging pink to dark purple nodule that may mimic amelanotic or nodular melanoma.
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Cutaneous melanoma is surgically treated with complete full-skin-depth excision using margins determined by the Breslow depth. This depth is a measure of tumor thickness from the granular layer of the epidermis to the point of deepest invasion using an ocular micrometer.
Current recommendations for excision margins range from 5 mm for in situ lesions to 1 to 2 cm for invasive lesions. Table 179-1 shows a comparison of world recommendations.14 SORⒶ
Mohs micrographic surgery, performed by specially trained physicians, may prove useful in completely removing subclinical tumor extension in certain subtypes of melanoma in situ, such as lentigo maligna, desmoplastic melanoma, and acral lentiginous melanoma in situ.15
Sentinel lymph node biopsy (SLNB) is not recommended when the risk of a positive node is less than 5%. This includes tumors less than 0.8 mm without ulceration. SLNB should be discussed and considered when there is a 5%–10% chance of a positive node. This includes tumors >0.8 mm thick with ulceration, mitotic index of ≥2 mitoses per square millimeter, or the presence of lymphovascular invasion. Rare cases with microsatellitosis within the original specimen upstage the tumor to stage III in transit, and SLNB is recommended regardless of the tumor thickness.
Patients with advanced melanoma (Figure 179-24) should be referred to medical oncology and may receive combination therapy with multiple chemotherapeutic agents and immunotherapy. Many trials are ongoing, and new chemotherapy regimens are emerging rapidly. Consideration should be given to consulting palliative care early to improve quality of life (see Chapter 5, End of Life).
Systemic therapy options for metastatic or unresectable disease are complex and evolving rapidly based on trial data and include immunotherapy with pembrolizumab, nivolumab, combination nivolumab/ipilimumab, and targeted BRAF therapy with dabrafenib/trametinib or vemurafenib/cobimetinib as well as conventional chemotherapy options.
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PREVENTION AND SCREENING
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Melanoma prevention starts with sun protection.
Sunscreen use has been shown in a randomized controlled trial to reduce the number of melanomas by roughly half.16
Sun protection should include sun avoidance, protective clothing, and sunscreen.
Indoor tanning is not safe and should be avoided.
The U.S. Preventive Services Task Force has not found sufficient evidence to recommend regular screening for melanoma or skin cancer in the general population.17
Most experts believe that persons at high risk for melanoma (including previous personal history of melanoma, high-risk family history, and high-risk skin types with significant sun exposure) should be screened regularly for melanoma by a physician trained in such screening.
Evidence for the value of self-screening is lacking, but persons at high risk for melanoma should also be encouraged to observe their own skin and to come in for evaluation if they see any suspicious changes or growths.
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Prognosis depends on tumor depth, mitotic rate, the presence of ulceration, positive lymph nodes, and metastases. In stage 0 disease, surgical excision is almost always curative. Five-year survival in patients by tumor thickness is almost 100% for in situ lesions, 92% for lesions less than 0.8 mm thick, 81% for lesions between 1 and 2 mm thick, 70% for lesions 2 to 4 mm thick, and 53% for lesions thicker than 4 mm. When accounting for nodal and distant metastasis, stage III disease carries a 40% to 78% 5-year survival, depending on the number of nodal metastases, and stage IV disease carries a 15% to 20% 5-year survival.18
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The need for follow-up is largely determined by the stage of the disease (Figure 179-25). The prognosis is worsened by increasing depth, mitotic rate, presence of ulceration, positive lymph nodes, and metastases.
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Follow-up for stages 0 and I cutaneous melanoma includes regular skin examinations by a physician trained in skin cancer screening. Total body photography may be of benefit in monitoring patients with multiple nevi (Figure 179-26). The rate of subsequent cutaneous melanomas among persons with a history of melanoma was found to be more than 10 times the rate of a first cutaneous melanoma, and the highest incidence of recurrence was in the first 3 to 5 years after initial diagnosis.19,20
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Advise patients who have had melanoma to avoid future sun exposure and monitor their skin for new and changing moles. Recommend a complete skin examination yearly by a physician trained to detect early melanoma.
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