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Malignant Melanoma
Key Points
Incidence
It was estimated that in 2018 there would be 91,270 new cases of melanoma diagnosed and 9320 deaths in the United States.
Biological Characteristics
Sun exposure is clearly associated with the development of cutaneous melanoma. Inherited mutations may also play a role in some cases. The natural history of melanoma is usually characterized by early, stepwise dissemination from a primary tumor to regional lymph node lesions and then to lesions at distant sites. The main determinants of survival are the thickness of the primary tumor (measured in millimeters), the presence or absence of primary ulceration, the status of regional lymph nodes, and the sites of distant disease.
Staging Evaluation
For evaluating localized disease, a thorough history and physical examination, including dermoscopy, can suffice. For patients with nodal spread, the staging evaluation should include serum level measurement of lactate dehydrogenase and imaging with contrast-enhanced computed tomography (CT) and positron emission tomography (PET). Magnetic resonance imaging (MRI) of the brain should be considered, and it should be routine for patients with distant metastases.
Primary Therapy
Treatment of a primary melanoma lesion that is less than 0.8 mm thick is wide local excision alone. Sentinel lymph node biopsy is generally recommended for any lesion that is 1 mm or thicker or if ulceration exists in a lesion that is greater than or equal to 0.8 mm and less than 1 mm. If the sentinel node is not involved, the patient may be observed, but if it is involved, complete lymph node dissection should be considered because it offers a survival benefit in patients who are node positive. If complete lymph node dissection is not possible because of medical comorbidities, elective radiotherapy to the involved nodal basin is preferred to observation.
Adjuvant Therapy
For patients at risk of nodal spread in whom sentinel lymph node biopsy will not alter subsequent management because of medical comorbidities, regional irradiation (i.e., elective irradiation) is preferred compared to observation. Indications for postdissection nodal radiotherapy are high-risk pathological features, including nodal extracapsular extension, lymph nodes measuring 3 cm or more in the widest diameter, at least two involved lymph nodes, and recurrent nodal disease after previous dissection for pathologically involved lymph nodes. Adjuvant CTLA-4 blockers and BRAF inhibitors improve relapse-free survival and overall survival for patients with nodal metastases. However, like interferon alpha, which it replaced, immunotherapy is associated with significant toxicity.
Locally Advanced Disease and Metastases
Palliative radiotherapy reduces symptoms in more than 80% of patients with inoperable disease or metastatic masses. Significant improvements in overall survival (OS) are seen in patients receiving systemic CTLA-4 blockers and BRAF inhibitors.
Malignant melanoma remains a predominantly surgically treated disease; most patients with early-stage disease are cured by simple excision of the primary lesion. By the time growth of the primary tumor reaches a few millimeters, however, the risk of nodal and distant spread increases rapidly, and the role of adjuvant radiotherapy and systemic therapy takes on increasing importance. As for many diseases, radiotherapy is often recommended as an adjuvant to surgical dissection of locally advanced disease or as a palliative treatment of distant metastases. Until recently, the acceptance of radiotherapy as part of a standard treatment algorithm for patients with melanoma has been marred by controversy.
In the early 1930s, melanoma was considered to be categorically radioresistant. This belief was perpetuated by popular textbooks of the time until laboratory data showed that the reputed radioresistance of melanoma might reflect a broad shoulder in the low-dose portion of the cell survival curve. The data suggested that melanoma cells might be more sensitive to radiation delivered as a large dose per fraction (i.e., hypofractionation regimen). Although a randomized trial performed by the Radiation Therapy Oncology Group (RTOG) did not confirm clinical superiority for hypofractionation in a heterogeneous group of patients receiving palliative radiotherapy, these types of regimens are favored by clinicians specializing in melanoma radiotherapy. Retrospective reviews of clinical experiences have suggested that the hypofractionated regimens are effective and can be safely delivered in a short period of time to a group of patients for whom survival is ultimately dictated by the risk of distant metastasis.
Although hypofractionated radiotherapy has been shown to be effective in several clinical settings, the perceived risk of distant metastatic disease and concern over the rate of long-term radiation-related toxicity often precludes its use regardless of effectiveness. In this chapter, we present the rates of local failure, regional failure, distant failure, and long-term treatment-related toxicity for patients with melanoma and provide data supporting the use of radiotherapy in a defined group of patients. Only by balancing the competing risks of failure and treatment-related toxicity can physicians appropriately integrate radiotherapy into the management of patients with malignant melanoma.
Etiology and Epidemiology
For 2018, 91,270 new cases of cutaneous malignant melanoma were estimated to occur in the United States, or 5% of all newly diagnosed cancers. Although the incidence of malignant melanoma more than doubled between 1975 and 2000, new cases of melanoma are being diagnosed earlier in the course of the disease because of increased public awareness, and the mortality rate has steadily decreased. The reason for the rise in incidence has not been explained. The number of deaths resulting from melanoma in 2018 is estimated to be 9320.
Several lines of evidence link sun or ultraviolet (UV) radiation exposure to the development of cutaneous melanoma. There is a higher incidence of melanoma in populations with high levels of sun exposure, among sun-sensitive people, on sun-exposed body sites, in populations with high sun exposure, among people with other sun-related skin conditions, and in those using artificial sources of UV radiation, such as sunbeds. The development of melanoma may also be reduced by protection of the skin against sun exposure.
Analysis of patients with familial clustering of melanoma has identified two genes, CDKN2A and CDK4 , that confer increased susceptibility to melanoma development. Although only a small percentage of patients with melanoma has a mutation in CDKN2A , carriers of this mutation have an almost 70% chance of developing melanoma by the age of 80 years.
The presence of an increasing number of nevi also represents a well-accepted risk factor for the development of melanoma. Whether the type of nevi (i.e., common, atypical, or dysplastic) is also important or merely reflects the degree of previous sun-related damage remains controversial.
Prevention and Early Detection
Advocates of early detection and screening programs generally assume that early detection and treatment will significantly affect the mortality rate and quality of life, particularly in melanoma, for which the association between tumor thickness and survival is well documented. Unfortunately, there are no randomized clinical trials to support routine screening of the general population. In the United States, routine screening of high-risk populations is still generally recommended, and educational efforts have been directed to clinicians and the public to promote early recognition of suspicious skin lesions. Periodic separate or mass screening for high-risk individuals consists of a total cutaneous examination and a 2- to 3-minute visual inspection of the entire integument by adequately trained physicians. Risk factors include a family history of skin cancer, fair skin, multiple nevi, and a history of melanoma or other skin cancers. Recognized signs of melanoma include the ABCDs of early diagnosis: A, asymmetry; B, border irregularity; C, color variation; and D, a diameter greater than 6 mm.
The US Preventive Services Task Force (USPSTF) performed a thorough review of the medical literature and issued a practice policy statement regarding skin cancer prevention counseling. Recommended preventive measures include avoidance of sunlight exposure—particularly limiting time spent outdoors between 10 am and 3 pm —and wearing protective physical barriers, such as hats and clothing and sunscreens that are opaque or that block UVA and UVB radiation.
Clinical Manifestations, Pathobiology, and Pathways of Spread
Clinical Presentation and Pathology
Primary cutaneous melanoma may develop in or adjacent to one of the precursor lesions (e.g., lentigo maligna, dysplastic nevus) or in normal skin, and it can manifest clinically in four major growth patterns. The most prevalent variant is superficial spreading melanoma , which constitutes approximately 70% of cases. Superficial spreading melanoma often arises in a junctional nevus, where it first appears as a deeply pigmented area, progressing gradually to a flat induration, generally over several years. As the lesion grows, the surface and perimeter may become irregular, with amelanotic patches. On histological examination, it is characterized by a prominent intraepidermal proliferation of malignant melanocytes similar to Paget disease; hence, this pattern is called pagetoid melanoma . The malignant cell may be confined to the lower portion of the epidermis or may spread up into the granular cell layer of the epidermis, which is frequently hyperplastic. As the lesion enlarges, clusters of malignant cells invade the dermis and subcutaneous tissues.
Nodular melanoma is the second most common variant (15%-25% of melanoma lesions). Nodular melanoma develops more frequently de novo on the trunk, head, or neck of middle-aged individuals. In contrast to superficial spreading melanoma, the nodular variant affects men more than women. It manifests as a raised or dome-shaped, blue-black lesion, which is usually darker than superficial spreading melanoma. Approximately 5% of nodular variants manifest as nonpigmented, fleshy nodules—this type of lesion is called amelanotic melanoma . Histological testing shows that nodular melanoma is characterized by an expansile nodule centered at the papillary dermis, with little or no epidermal component, composed of epithelioid cells. Spindle cells, small epithelioid cells, and mixtures of cells may be present. Deeper invasion of the dermis and subcutis occurs as the lesion grows.
Lentigo maligna melanoma is seen in less than 10% of malignant melanoma lesions. This variant occurs most frequently on the face or neck of whites older than 50 years, and it arises from a precursor lesion of melanoma in situ called lentigo maligna (i.e., Hutchinson's melanotic freckle). It manifests as a relatively large (> 3 cm), flat, tan-colored (with different shades of brown) lesion that often has been present for more than 5 years. The border becomes irregular as the lesion enlarges. On histological examination, an invasive tumor is usually composed of spindle-like cells. These cells may be embedded in a fibrous stroma (i.e., desmoplastic pattern) or may form fascicles displaying neural features and infiltrating endoneural and perineural structures of the cutaneous nerves.
Acral lentiginous melanoma occurs characteristically on the palms or soles or beneath nail beds. The relative frequency of acral lentiginous melanoma varies substantially with race. It represents about 5% of melanomas in whites and 35% to 60% in dark-skinned individuals. Most acral lentiginous melanomas occur on the foot sole in individuals older than 60 years. They generally start as tan or brown stains and evolve over a period of years to reach an average diameter of 3 cm before a diagnosis is established. Histological testing reveals that early-stage acral lentiginous melanoma is composed of large, highly atypical, pigmented cells along the dermoepidermal junction in an area of hyperplastic epidermis. At the invasive stage, infiltrating cells may be epithelioid or spindle shaped. Sometimes, infiltration to deeper structures occurs, predominantly through the eccrine ducts.
Biology and Patterns of Spread
Superficial spreading and lentigo maligna melanomas generally grow slowly over many years (i.e., radial growth phase). Left untreated, however, these lesions gradually invade the dermis and subcutis (i.e., vertical growth phase) and acquire metastatic potential. Acral lentiginous melanomas—particularly, nodular melanomas—have a shorter natural history, with rapid progression to the vertical growth pattern.
Previously, two microstaging systems were used. The Breslow system classifies lesions by the vertical thickness between the granular layer of the epidermis and the deepest part of invasion, measured with an ocular micrometer. In ulcerated lesions, measurements are made from the surface to the deepest part. The Clark method categorizes lesions into five groups by the level of dermal or subcutis invasion: level 1, confined to the epidermis; level 2, invasion to the papillary dermis; level 3, invasion to the papillary-reticular dermal interface; level 4, invasion to the reticular dermis; and level 5, invasion to the subcutaneous tissue. Of the two systems, tumor thickness is more accurate in predicting outcome, although level of invasion remains prognostic for patients with lesions less than 1 mm thick.
In an analysis of more than 46,000 patients with melanoma, several clinical and histological variables were found to be of prognostic value and now form the basis for the eighth edition of the American Joint Committee on Cancer (AJCC) staging system ( Table 48.1 ). For patients without clinical evidence of nodal spread, primary thickness and ulceration remain the most important prognostic features. The 10-year melanoma-specific mortality increases proportionally as the thickness of the primary tumor increases ( Fig. 48.1 ) and as the burden of nodal disease increases ( Fig. 48.2 ).
TABLE 48.1
American Joint Committee on Cancer Staging System for Melanoma of the Skin
From Edge SB, Byrd DR, Compton CC, et al. AJCC Cancer Staging Manual . 7th ed. New York: Springer; 2010.
| Primary Tumor (T) | Clinical Stage Grouping | ||
| TX | Primary tumor thickness cannot be assessed (e.g., diagnosis by curettage) | Stage 0 | TisN0M0 |
| Stage IA | T1aN0M0 | ||
| T0 | No evidence of primary tumor (e.g., unknown primary or completely regressed melanoma) | Stage IB | T1bN0M0 |
| Tis | Melanoma in situ | T2aN0M0 | |
| T1 | Melanoma ≤ 1.0 mm thick, unknown or unspecified ulceration status | Stage IIA | T2bN0M0 |
| T1a | Melanoma < 0.8 mm thick, without ulceration | T3aN0M0 | |
| Stage IIB | T3bN0M0 | ||
| T1b | Melanoma < 0.8 mm thick with ulceration, 0.8-1.0 mm with or without ulceration | T4aN0M0 | |
| Stage IIC | T4bN0M0 | ||
| T2 | Melanoma > 1.0-2.0 mm thick, unknown or unspecified ulceration | Stage III | Any T, Tis ≥N1M0 |
| T2a | Melanoma > 1.0-2.0 mm thick, without ulceration | ||
| T2b | Melanoma > 1.0-2.0 mm thick, with ulceration | Stage IV | Any T, Any N,M1 |
| T3 | Melanoma > 2.0-4.0 mm thick, unknown or unspecified ulceration | ||
| T3a | Melanoma > 2.0-4.0 mm thick, without ulceration | ||
| T3b | Melanoma > 2.0-4.0 mm thick, with ulceration | ||
| T4 | Melanoma > 4.0 mm thick, unknown or unspecified ulceration | ||
| T4a | Melanoma > 4.0 mm thick, without ulceration | ||
| T4b | Melanoma > 4.0 mm thick, with ulceration | ||
| Regional Lymph Nodes (N) | Pathologic Stage Grouping | ||
| NX | Regional lymph nodes cannot be assessed (e.g., SLN biopsy not performed, regional nodes previously removed for another reason) Exception: pathological N category is not required for T1 melanomas, use cN. No in-transit, satellite, and/or microsatellite metastases. |
Stage 0 | TisN0M0 |
| Stage IA | T1aN0M0 T1bN0M0 |
||
| N0 | No regional lymph node metastasis; no in-transit, satellite, and/or microsatellite metastases | Stage IB | T2aN0M0 |
| N1 | One tumor-involved node or in-transit, satellite, and/or microsatellite metastases with no tumor-involved nodes | ||
| N1a | One clinically occult (i.e., detected by SLN biopsy) node No in-transit, satellite, and/or microsatellite metastases |
Stage IIA | T2bN0M0 |
| N1b | One clinically detected node; no in-transit, satellite, and/or microsatellite metastases | T3aN0M0 | |
| N1c | No regional lymph node disease, in-transit, satellite, and/or microsatellite metastases | ||
| N2 | Two or three tumor-involved nodes or in-transit, satellite, and/or microsatellite metastases with one tumor-involved node | Stage IIB | T3bN0M0 |
| T4aN0M0 | |||
| Stage IIC | T4bN0M0 | ||
| N2a | Two or three clinically occult nodes (i.e., detected by SLN biopsy); no in-transit, satellite, and/or microsatellite metastases | Stage IIIA | T1a/b-T2aN1a or N2aM0 |
| N2b | Two or three—at least one of which is clinically detected—nodes; no in-transit, satellite, and/or microsatellite metastases | ||
| N2c | One clinically occult or clinically detected node; in-transit, satellite, and/or microsatellite metastases | Stage IIIB | T0N1b, N1cM0 T1a/b-T2aN1b/c or N2bM0 T2b/T3aN1a-N2bM0 |
| Stage IIIC | T0N2b, N2c, N3b, or N3c, M0 T1a-T3aN2c or N3a/b/cM0 T3b/T4a, Any N >=N1, M0 T4b, N1a-N2c, M0 |
||
| N3 | Four or more tumor-involved nodes, or in-transit, satellite, and/or microsatellite metastases with two or more tumor-involved nodes, or any number of matted nodes without or with in-transit, satellite, and/or microsatellite metastases | IIID | T4bN3a/b/cM0 |
| IV | Any T, Tis, Any N, M1 | ||
| N3a | Four or more clinically occult (i.e., detected by SLN biopsy); no in-transit, satellite, and/or microsatellite metastases | ||
| N3b | Four or more—at least one of which was clinically detected—or presence of any number of matted nodes; no in-transit, satellite, and/or microsatellite metastases | ||
| N3c | Two or more clinically occult or clinically detected and/or presence or any number of matted nodes, in-transit, satellite, and/or microsatellite metastases | ||
| Distant Metastasis (M) | Stage IIIC | T1-4bN1bM0 | |
| T1-4bN2bM0 | |||
| M0 | No evidence of distant metastasis | T1-4bN2cM0 | |
| M1 | Evidence of distant metastasis | TanyN3M0 | |
| M1a | Distant metastasis to skin, soft tissue, including muscle, and/or nonregional lymph node; LDH not recorded or unspecified M1a(0) LDH not elevated M1a(1) LDH elevated |
Stage IV | TanyNanyM1 |
| M1b | Distant metastasis to lung with or without M1a sites of disease; LDH not recorded or unspecified M1b(0) LDH not elevated M1b(1) LDH elevated |
||
| M1c | Distant metastasis to non-CNS visceral sites with or without M1a or M1b sites of disease; LDH not recorded or unspecified M1c(0) LDH not elevated M1c(1) LDH elevated |
||
| M1d | Distant metastasis to CNS with or without M1a, M1b, or M1c sites of disease; LDH not recorded or unspecified M1d(0) LDH normal M1d(1) LDH elevated |
||
CNS, Central nervous system; LDH, lactate dehydrogenase; SLN, sentinel lymph node.
For patients with documented nodal metastases, the most important prognostic feature was the number of involved lymph nodes, but primary tumor ulceration and burden of nodal disease (clinically occult compared with clinically apparent) remained of prognostic significance on multivariate analysis ( Table 48.2 ). Patients with metastases are further subdivided into three distinct subgroups: those with skin, soft tissue or nonregional lymph nodes; those with non–central nervous system (CNS) visceral metastases; and those with CNS metastases.
TABLE 48.2
Five-Year Survival Rates for Patients With Stage III (Nodal Metastases) Disease Stratified by Number of Metastatic Nodes, Ulceration, and Tumor Burden
From Balch CM, Soong SJ, Gershenwald JE, et al. Prognostic factors analysis of 17,600 melanoma patients. Validation of the American Joint Committee on Cancer melanoma staging system. J Clin Oncol . 2001;19:3622-3634.
| Melanoma Ulceration | MICROSCOPIC NODAL DISEASE (NO. INVOLVED) | MACROSCOPIC NODAL DISEASE (NO. INVOLVED) | ||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 1 Node, % ± SE | No. | 2-3 Nodes, % ± SE | No. | > 3 Nodes, % ± SE | No. | 1 Node, % ± SE | No. | 2-3 Nodes, % ± SE | No. | >3 Nodes, % ± SE | No. | |
| Absent | 69 ± 3.7 | 252 | 63 ± 5.6 | 130 | 27 ± 9.3 | 57 | 59 ± 4.7 | 122 | 46 ± 5.5 | 93 | 27 ± 4.6 | 109 |
| Present | 52 ± 4.1 | 217 | 50 ± 5.7 | 111 | 37 ± 8.8 | 46 | 29 ± 5.0 | 98 | 25 ± 4.4 | 109 | 13 ± 3.5 | 104 |
SE, Standard error.
Patient Evaluation and Staging
Suggested staging guidelines for patients with melanoma are shown in Table 48.3 . Clinical evaluation of patients with melanoma consists of inspection and palpation of the involved area of skin and the regional lymph nodes. Patients with primary lesions 1 mm thick or larger are generally staged at the time of wide local excision with sentinel lymph node biopsy. Patients with thinner lesions may still be at risk of nodal disease and may benefit from sentinel lymph node biopsy if the primary lesion is ulcerated, is associated with satellitosis, or is Clark level 4 or 5. If the sentinel node is involved, CT scanning of the lungs, abdomen, and pelvis is warranted as a baseline evaluation.
TABLE 48.3
Staging Guidelines and Diagnostic Algorithm
| Disease Presentation | Workup |
|---|---|
| Primary lesion < 1 mm, and Clark levels 2-3, and not ulcerated | History and physical examination a |
| Primary lesion ≥ 1 mm, or Clark levels 4-5, or ulcerated | History and physical examination a |
| Sentinel lymph node biopsy | |
| Microscopic nodal metastases | History and physical examination a |
| Chest radiograph and serum LDH level | |
| Further imaging if warranted | |
| Macroscopic nodal metastases | History and physical examination a |
| Serum LDH level | |
| CT imaging of chest, abdomen, pelvis | |
| CT imaging of head and neck if primary tumor is above clavicles | |
| Consider brain MRI | |
| Further imaging if warranted | |
| Distant metastases | History and physical examination a |
| Chest radiograph and serum LDH level | |
| CT imaging of chest, abdomen, pelvis | |
| CT imaging of head and neck if primary tumor is above clavicles | |
| Brain MRI | |
| Further imaging if warranted |
CT, Computed tomography; LDH, lactate dehydrogenase; MRI, magnetic resonance imaging.
a Attention must be paid to comprehensive skin and nodal basin examination.
Chest radiography plays little or no role in the initial management of patients with localized disease. Positron emission tomography (PET) scans and magnetic resonance imaging (MRI) of the brain are indicated for patients with multiple or clinically palpable nodal metastases and for all patients with documented distant disease.
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