For 2010, 68,130 new cases of cutaneous malignant melanoma were estimated, or 5% of all newly diagnosed cancers.⁴ 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.⁴ The reason for the rise in incidence has not been explained. The number of deaths due to melanoma in 2010 was estimated to be 8700.

Several lines of evidence link sun or ultraviolet (UV) radiation exposure to the development of cutaneous melanoma.^5,⁶ There is a higher incidence of melanoma in populations living in areas of high ambient sunlight, among sun-sensitive people, on sun-exposed body sites, in populations with high sun exposure, and among people with other sun-related skin conditions.^7,8 The development of melanoma may also be reduced by protection of the skin against sun exposure.⁷

Analysis of patients with familial clustering of melanoma has identified two genes, CDKN2A and CDK4, that confer increased susceptibility to melanoma development.⁹ 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.^10,¹¹

The presence of an increasing number of nevi also represents a well-accepted risk factor for the development of melanoma.¹² 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 the 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. 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.

A panel of the American College of Preventive Medicine (ACPM)¹³ performed a thorough review of the medical literature and issued a practice policy statement regarding skin cancer prevention. 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. If sun exposure cannot be limited because of occupational, cultural, or other factors, the use of sunscreens that are opaque or that block ultraviolet A and B radiation is recommended.

The ACPM recommends periodic separate or mass screening for high-risk individuals, consisting 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 other skin cancers.

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.¹⁴ The most prevalent variant is superficial spreading melanoma, which constitutes approximately 70% of cases.^15,¹⁶ This growth pattern can occur at any age after puberty and affects women more frequently than men. 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. There are often patches of amelanotic areas within the lesion thought to result from focal regression. As the lesion grows, the surface and perimeter may become irregular. On histologic examination, it is characterized by a prominent intraepidermal proliferation of malignant melanocytes. The malignant cells resemble the cells of Paget’s disease; hence, this pattern is called pagetoid melanoma.¹⁷ 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% to 25% of melanoma lesions).^15,¹⁶ 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, and, therefore, this type of lesion is called amelanotic melanoma. Histologic 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.^16,¹⁸ This variant occurs most frequently on the face or neck of white women older than 50 years, and it arises from a precursor lesion of melanoma in situ called lentigo maligna (i.e., Hutchinson’s melanotic freckle).¹⁹ 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 histologic 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.^19,²⁰

Acral lentiginous melanoma occurs characteristically on the palms or soles or beneath nail beds.²¹^–²³ The relative frequency of acral lentiginous melanoma varies substantially with race. It represents about 5% of melanomas in white individuals and 35% to 60% in dark-skinned individuals.^24,²⁵ 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.^22,²³ Histologic 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.²⁰ Sometimes, infiltration to deeper structures occurs, predominantly through the eccrine ducts.¹⁷

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 and, 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.²⁶ The Clark method categorizes lesions into five groups by the level of dermal or subcutis invasion: level I, confined to the epidermis; level II, invasion to the papillary dermis; level III, invasion to the papillary-reticular dermal interface; level IV, invasion to the reticular dermis; and level V, invasion to the subcutaneous tissue.¹⁵ 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.²⁷

In an analysis of 17,600 patients with melanoma, several clinical and histologic variables were found to be of prognostic value, and they formed the basis for an updated American Joint Committee on Cancer (AJCC) staging system 27,28 (Table 40-1). For patients without clinical evidence of nodal spread, primary thickness and ulceration were the most important prognostic features. The 10-year melanoma-specific mortality increased proportionally as the thickness of the primary tumor increased (Fig. 40-1), and the survival of patients with ulcerated primary lesions diminished to a level equivalent to that of patients with thicker primary lesions that were not ulcerated²⁷ (Fig. 40-2). There was significantly inferior 10-year disease-specific survival (DSS) according to site of the primary lesion (i.e., worse for trunk, head, and neck lesions than extremity lesions), gender (i.e., worse for male than female patients), and age (i.e., worse for older than younger patients).²⁷

TABLE 40-1 American Joint Committee on Cancer Staging System for Melanoma of the Skin

Figure 40-1 Observed and predicted 10-year mortality rate of 15,320 patients with clinically localized melanoma based on the mathematical model f(t) = 1 − 0.998e(−211t = 0.009 t₂), which is derived from the melanoma database of the American Joint Committee on Cancer (AJCC). t is the measured thickness (mm), and f(t) is the 10-year melanoma-specific mortality rate (p <.0001).

From Balch CM, Soong S, 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 19:3622-3634, 2001.

Figure 40-2 Survival curves for 14,914 patients with localized melanoma stratified by melanoma thickness and presence or absence of ulceration. The correlation of the subgroups used for defining melanoma TNM staging with melanoma-specific survival is significant (p <.0001).

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 (microscopic vs. macroscopic) remained of prognostic significance on multivariate analysis ²⁷ (Table 40-2). Patients with skin, subcutaneous, and distant lymph node metastases fared better than those with visceral metastases.²⁷

TABLE 40-2 Five-Year Survival Rates for Patients with Stage III (Nodal Metastases) Disease Stratified by Number of Metastatic Nodes, Ulceration, and Tumor Burden

Patient Evaluation and Staging

Suggested staging guidelines for patients with melanoma are shown in Table 40-3. 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 IV or V. Imaging studies (i.e., CT scans of the chest, abdomen, and pelvis or MRI studies of the brain) should be obtained as indicated by the result of immunohistochemical examination of the sentinel node. If the sentinel node is involved, CT scanning of the lungs, abdomen, and pelvis is warranted as a baseline evaluation.²⁹

TABLE 40-3 Staging Guidelines and Diagnostic Algorithm

Disease Presentation	Workup
Primary lesion <1 mm, and Clark level II-III, and not ulcerated	History and physical examination*
Primary lesion ≥1 mm, or Clark level IV-V, or ulcerated	History and physical examination*
Primary lesion ≥1 mm, or Clark level IV-V, or ulcerated	Sentinel lymph node biopsy
Microscopic nodal metastases	History and physical examination*
	Chest radiograph and serum LDH level
	Further imaging if warranted
Macroscopic nodal metastases	History and physical examination*
	Serum LDH level
	CT imaging of chest, abdomen, pelvis
	CT imaging of head and neck if primary tumor above clavicles
	Consider brain MRI
	Further imaging if warranted
Distant metastases	History and physical examination*
	Chest radiograph and serum LDH level
	CT imaging of chest, abdomen, pelvis
	CT imaging of head and neck if primary tumor above clavicles
	Brain MRI
	Further imaging if warranted

CT, computed tomography; LDH, lactate dehydrogenase; MRI, magnetic resonance imaging.

* Attention to comprehensive skin and nodal basin examination.

Chest radiography plays little or no role in the initial management of patients with localized disease. MRI of the brain is indicated for patients with multiple or clinically palpable nodal metastases and for all patients with documented distant disease.

Primary Therapy and Results

Primary Tumor

Standard treatment for localized melanoma (stages I and II) is wide local excision. Wide local excision is a therapeutic intervention, but it also establishes tissue diagnosis and provides accurate microstaging. Five randomized trials have examined the appropriate width of excision for primary melanoma.30–33,34 The recommended skin margins are 1 cm for lesions less than 1 mm thick and 2 cm for melanomas 1 mm or thicker.^34,35

Sentinel lymph node biopsy is recommended according to the aforementioned criteria (see Patient Evaluation and Staging). This procedure provides accurate nodal staging, but it should be followed by nodal irradiation (see Regional Nodes) or formal lymph node dissection if the sentinel node is involved. The rate of nodal spread according to primary thickness is shown in Table 40-4; it is less than 5% for lesions 0.75 mm or smaller, 10% for lesions 0.76 to 1.5 mm, 20% for lesions 1.51 to 4 mm, and 30% to 50% for lesions larger than 4 mm.^{36–44,45,46,47}

TABLE 40-4 Percentage of Patients with Positive Sentinel Lymph Nodes by Primary Melanoma Thickness