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Cutaneous melanoma is responsible for the vast majority of skin cancer-related deaths in the United States. Known risk factors include genetic defects, environmental exposures, and a combination of both. Among environmental risks, exposure to ultraviolet rays is the most important and the most modifiable risk factor. Several genetic syndromes involve increased risk of melanoma, including xeroderma pigmentosum, familial atypical multiple moles and melanoma syndrome, BRCA2 mutation, and congenital melanocytic nevi. Although the necessity of implementation remains controversial, the most effective melanoma screening technique is the whole-body skin examination. Typically, melanoma lesions are incidentally discovered during routine skin examination using the “ABCDE” mnemonic. Once suspected, questions pertaining to the sites of potential metastasis should be asked and excisional or partial biopsy should be considered. The primary histologic subtypes of melanoma include superficial spreading, lentigo maligna, nodular, acral lentiginous, desmoplastic, and amelanotic. Melanoma staging is completed via clinical and histologic assessment using the American Joint Committee on Cancer TNM system. Delayed or deficient elements of initial melanoma evaluation can limit patient outcomes and increase disease-related mortality. Clinicians involved in the diagnosis or treatment of cutaneous melanoma must be familiar with the available screening options, key steps of diagnosis, and the staging ramifications of disease discovery.
Despite the important progress seen in the treatment of oncologic diseases over the past few decades, the incidence and mortality associated with malignant melanoma continues to increase (1). Among the most common malignancies in the United States, the incidence of melanoma currently ranks fifth overall when compared to other common cancers (2). As a result of its aggressive behavior and diagnostic challenges, it is responsible for the vast majority of skin cancer-related deaths. This chapter will focus on appropriate screening considerations for melanoma, clinical approaches to diagnosis and confirmation, and updated staging guidelines to facilitate subsequent therapy (1).
The New Melanoma Staging System
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).
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).
Treatment Of Melanoma (05.12.2008)
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).
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).
Stages — Know Melanoma
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).
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).
Skin Cancer Surgery
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).
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
Cutaneous Melanoma, Version 2.2019, Nccn Clinical Practice Guidelines In Oncology In: Journal Of The National Comprehensive Cancer Network Volume 17 Issue 4 (2019)
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).
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).
Skin Cancer Surgery
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).
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
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