ETIOLOGY OF DISEASE DEVELOPMENT

Cutaneous melanoma evolves from aberrant melanocytes located within the basal layer of the epidermis. These melanocytes are responsible for the production of melanin, a substance which absorbs potentially harmful ultraviolet (UV) radiation. Left unchecked, UV radiation affects integumentary cells by causing direct damage to individual DNA strands. Although UV-induced DNA damage is normally repaired by specific DNA repair mechanisms, genetic or environmentally derived errors within this repair complex can lead to the formation of an invasive melanoma (3, 4).

GENERAL RISK FACTORS

Like most other neoplastic conditions, known risk factors of melanoma include genetic defects, environmental exposure, and a combination of both (5). Although multiple genetic syndromes incur a significantly increased risk for the development of cutaneous malignancy (discussed later), inherited phenotypic traits associated with melanoma include fair skin, light hair, red hair, freckles, and light eye color. Unsurprisingly, a positive family history is a strong risk factor for the evolution of this disease. As the number of first-degree relatives with melanoma increases, so does the risk of developing the disease (6). Patients with one first-degree relative with melanoma are 1.7 times more likely to be diagnosed with melanoma, whereas two first-degree relatives incur a nine-fold increase in risk. In addition, as patients with a positive family history grow older, the cumulative risk of melanoma also increases (7).

Regarding environmental risks, UV exposure is the most important and the most potentially modifiable risk factor contributing to the development of melanoma. Compared with those with chronic and continuous exposure, patients with intermittent, more intense exposure to the sun are at much higher risk (4). A history of sunburns, specifically blistering sunburns in childhood and adulthood, can be associated with approximately twice the baseline risk of melanoma development (5). Significant UV radiation exposure before the age of 35 significantly increases the risk of melanoma (7). Although UV-A sunlight has certainly been implicated as a cause of melanoma (e.g., tanning salon-related UV radiation), most skin damage is actually caused by UV-B rays (4).

Chronic immunosuppression represents another exposure-related risk factor for melanoma development. Such immunosuppression may be the result of an existing neoplastic condition. For example, approximately 5% of patients with a personal history of melanoma will be diagnosed with a second melanoma (6). In addition, patients with a personal history of nonmelanoma skin cancer have more than a fourfold relative risk of developing melanoma. Other causes of chronic immunosuppression may result from pharmaceutical agents used in the treatment of AIDS, chronic lymphocytic leukemia, non-Hodgkin’s lymphoma, or patients with organ transplantation (7).

POPULATIONS AT INCREASED RISK

As discussed previously, several genetic syndromes involve a significantly increased risk of melanoma development. These conditions include xeroderma pigmentosum (XP), familial atypical multiple moles and melanoma (FAMMM) syndrome, BRCA2 mutation, and congenital melanocytic nevi (7, 8). XP, an autosomal recessive condition in which UV-related DNA repair mechanisms are deficient, carries an approximately 1000-fold increase in the risk of melanoma. Sun avoidance and regular self-skin examinations are mandatory, as is frequent surveillance by a dermatologist with extensive XP experience (6, 7).

FAMMM syndrome, also known as the B-K mole syndrome, is caused by germ-line mutations in CDKN2A (6). An autosomal dominant condition, FAMMM syndrome has incomplete penetrance. Diagnosis is determined through family history and is confirmed when at least two first-degree relatives have both melanoma and multiple dysplastic nevi. Interestingly, overall survival is similar to that of sporadic melanoma (7). Families with a suspected diagnosis of FAMMM should undergo frequent skin examinations and should complete a genetics consultation to evaluate for CDKN2A mutation. As CDKN2A mutations are also associated with pancreatic cancer, extensive documentation of the family history is mandatory in these patients, and screening for other associated malignancies should occur (6).

More widely associated with inherited breast and ovarian carcinomas, a BRCA2 mutation nearly triples the risk of cutaneous melanoma development. A tumor suppressor gene, mutations in BRCA2 also degrade cellular DNA repair mechanisms. As BRCA2 mutations can also lead to prostate and pancreatic cancers, potential patients should similarly undergo genetics or risk assessment evaluations following the documentation of a thorough family history (8).

The presence of congenital melanocytic nevi also increases the risk of melanoma development, with larger lesions having the highest risk. These lesions can be either followed closely or removed prophylactically. Since melanomas that occur within congenital melanocytic nevi usually develop before the age of 10, prophylactic removal of these lesions should be considered early in life (7).

SCREENING RECOMMENDATIONS

The most effective melanoma screening technique is the whole-body skin examination (WBE). WBE involves a review of the entire cutaneous surface of a disrobed patient by the treating provider. Despite the proven efficacy of this approach, completion of this screening technique is less common than preventative screening modalities used in the early detection of other malignancies. The implementation of the WBE as an annual melanoma screening tool in the United States has been controversial (1, 9). Although many within the dermatology and oncology communities have called for the institution of routine melanoma screening recommendations, the United States Preventative Service Task Force (USPSTF) stopped short of endorsing annual screening WBEs as an effective prevention measure in 2016 due to insufficient evidence. Because of the paucity of data examining potential screening-related harms or program feasibility concerns in the United States, the USPSTF limited its support for WBE as a recommended intervention for patients at particularly high risk of cutaneous malignancy (10).

Despite the recommendations issued by the USPSTF, evidence does exist which supports the concept of widespread screening to facilitate early melanoma detection and decreased mortality (11). One of the most cited study examining the feasibility and efficacy of a population-based melanoma screening program is the SCREEN project in Northern Germany. Begun in 2003, this program involved the screening of over 360,000 patients by physicians of various specialties who had completed an 8 h WBE training course. The SCREEN project resulted in a 30% increase of melanoma detection within the study population and an approximately 50% decrease in melanoma-related mortality compared with the rest of Germany (12). Another study with similar findings was performed in Australia in 2008. This case-control study demonstrated a 38% increase in the probability of a thin melanoma (<0.75 mm) being identified and that pre-diagnosis WBE screening leads to a 14% risk reduction of thick melanoma (>0.75 mm) diagnosis (5).

Although broad consensus is lacking regarding routine melanoma screening in the United States, many dermatologists, oncologists, and primary care providers have incorporated annual WBEs into their practices and institutional preventative care programs. In addition, there is uniform agreement that patients at increased risk of melanoma should absolutely undergo yearly WBE, ideally at the hands of a dermatologist. Such patients include those with albinism, XP, a family history of melanoma, a personal history of skin cancer and individuals on chronic immunosuppressive medications (7).

PATIENT HISTORY

Typically, melanoma lesions are incidentally discovered during routine skin examination (5). Occasionally, patients may be alerted to the presence of a concerning nodule by persistent itching, bleeding, or crusting of a pigmented lesion. Unfortunately, most melanomas are asymptomatic and may only cause the aforementioned symptoms of local inflammation after growth progression has occurred (7). Once the diagnosis is suspected, questions pertaining to sites of potential metastasis should be included in the history. Potential indicators of metastatic spread may include seizures, headaches, vision changes, coughing, hemoptysis, shortness of breath, dyspnea, changes in bowel habits, new-onset back pain, or any systemic symptoms (fevers, chills, night sweats, weight loss, etc.). Other concerning items within a patient’s history that should alert the examining physician include a past medical history of cutaneous malignancy, chronic sun exposure, history of blistering sun burns, use of tanning salons, family history of melanoma, pancreatic cancer, other familial syndromes, or a procedural history of prior skin biopsies. Finally, it should be noted that patients with fair skin (Fitzpatrick type I) are at increased risk of melanoma compared with those with darker skin (Fitzpatrick type VI) (Table 1) (13–15).

TABLE 1

Fitzpatrick Classification of Skin Types I through VI.

PHYSICAL EXAMINATION FINDINGS

During a clinical examination, any pigmented lesion with features contained within the “ABCDE” mnemonic should be considered suspicious for melanoma (Figure 1). Developed for both physicians and patients to recognize characteristics often associated with melanoma, the ABCDE system includes Asymmetry, Border irregularity, Color variegation, Diameter larger than 6 mm, and Evolution or timing of the lesion’s growth. Should such a lesion be identified, the surrounding area should be assessed for possible satellite lesions or in-transit metastatic foci (7). Once a concerning lesion is thoroughly assessed, the remaining cutaneous surfaces (i.e., scalp, perineum, interdigital space, genitalia, and subungual regions) should be closely inspected for the presence of any additional lesions of suspicion. All lesions with a benign appearance should be documented and all lymph node basins should be palpated for lymphadenopathy (14).

Figure 1

ABCDE System for Diagnosis of Melanoma.

HISTOLOGIC CONFIRMATION

Diagnostic confirmation involves routine histologic analysis by the receiving pathology department (14). Microscopic findings including cytologic atypia, amplified cellularity, and the number of dermal mitotic figures should be noted in an effort to distinguish benign disease from malignant melanoma. Established guidelines recommend the formal reporting of Breslow thickness (mm), histologic subtype; dermal mitotic rate; peripheral margin status; deep margin status; and the presence or absence of histologic ulceration, microsatellitosis, tumor infiltrating lymphocytes, cellular regression, angiolymphatic invasion, vertical growth phase, neurotropism, and pure desmoplasia. In addition, Clark’s levels of anatomic staging should be reported for lesions <1 mm in thickness. By combining the reported histologic features with a patient’s gross clinical findings, the proper diagnosis can be achieved and ambiguity avoided (13).

DISEASE TYPES AND PROGNOSTIC FACTORS

The primary histologic subtypes of melanoma include superficial spreading, lentigo maligna, nodular, acral lentiginous, desmoplastic, and amelanotic (Table 2) (17). In situ melanoma is considered Stage 0 and occurs when tumor cells are microscopically identified but have not penetrated the epidermis (18). Comprising approximately 70% of confirmed melanomas, the superficial spreading subtype is the most common type and arises from an existing nevus. The lentigo maligna subtype is less common, typically demonstrates slow progression, and frequently appears in sun-exposed areas (face, head, etc.). Nodular melanomas are characterized by the absence of a radial growth phase, variable presentation, and robust vertical invasion. Acral lentiginous melanomas have a higher incidence in patients with darker skin pigmentation and frequently occur on the palms, soles, and subungual spaces. Desmoplastic melanomas are uncommon lesions that are typically seen in elderly patients and feature limited spindle or atypical cells. Possibly the most challenging subtype in terms of diagnosis, amelanotic melanomas have a characteristic absence of pigmentation and are considered rare (14).

TABLE 2

Melanoma Subtypes.