Mucosal melanoma is a rare disease that is distinct from melanomas arising at other sites in the body. While melanocytes are most abundant in the skin, they can be found in smaller numbers in the mucous membranes, as well as in the eye. There are epidemiologic, genetic, and other physiologic differences between melanomas arising from melanocytes at these various sites, and these differences have important implications for both disease prognosis and treatment. Here, we review the features of mucosal melanoma that distinguish it from melanomas arising at other sites, and we highlight recent biological discoveries and emerging treatment options for this aggressive disease.
Mucosal melanoma is a rare disease, accounting for only 0.03% of new cancer diagnoses, and it is distinct from melanomas that develop at other sites in the body. While melanocytes are most abundant in the skin, they are also present in smaller numbers in the mucous membranes of the respiratory, gastrointestinal, and urogenital tracts, as well as in the eye. Melanocytes in any of these locations have the potential to transform into melanoma. However, it is now clear that melanomas arising from different sites are epidemiologically and genetically distinct. In addition, they differ in how they interact with the immune system and respond to various forms of therapy.
Of the estimated 87,110 cases of melanoma to be diagnosed in the United States in 2017, less than 2% will arise in the mucosal surfaces of the body.[1-3] While melanomas can develop within any mucosal surface, the vast majority arise in the mucosae of the head and neck (31% to 55%), anorectal (17% to 24%), and vulvovaginal (18% to 40%) regions.[1,2] Less frequent sites of origin include the mucosae of the pharynx, larynx, urinary tract, cervix, esophagus, and gallbladder.
The epidemiology of mucosal melanoma is distinct from that of its cutaneous counterpart, reflecting biological differences between these diseases (Table 1). Mucosal melanoma tends to develop later in life compared with cutaneous melanoma, with a median age at diagnosis of 70 vs 55 years. Whereas the incidence of cutaneous melanoma has increased at a faster rate than that of any other cancer in the United States, the incidence of mucosal melanoma has remained stable. Mucosal melanoma is more often diagnosed at an advanced stage of disease and is associated with worse outcomes. While the 5-year overall survival rate for cutaneous melanoma is 80%, the rate for mucosal melanoma is only 25%. The inferior outcomes may be related to the generally more advanced disease at time of diagnosis, anatomic factors complicating complete resection, the rich lymphovascular supply of the mucosal surfaces, and other biological factors. Interestingly, in addition to having an inferior survival from the time of diagnosis, patients with mucosal melanoma may have a poorer stage-matched survival than other melanoma subtypes from the time of development of clinical metastatic disease.
Whereas cutaneous melanoma is slightly more common in men than women, the incidence rate of mucosal melanoma is 87% higher in women than men. This increased incidence is due to higher rates of genital tract melanomas in women.[2,6,7] There are also significant racial disparities in incidence rates. Mucosal melanomas account for 5% to 13% of melanomas in black patients, 23% of melanomas in Chinese patients, and only 1% to 2% of melanomas in white patients.[2,8] These differences are reflective of the lower incidence rates of cutaneous melanoma in non-white groups. In fact, the absolute incidence rate of mucosal melanoma is twice as high in white compared with black individuals. Unlike cutaneous melanoma, which is more common in southern and coastal states, mucosal melanoma has no consistent predilection for any particular geographic area. One study suggested that the incidence of anorectal melanoma is associated with more northern latitudes; however, a more recent study found the opposite to be the case.[9,10] While cutaneous melanoma is associated with exposure to ultraviolet (UV) radiation, no clear environmental risk factors have been identified for mucosal melanoma; however, having a family history of cutaneous melanoma may increase one’s risk of developing vulvovaginal and anorectal mucosal melanoma.
Anatomy of the Mucosal Immune System
The mucosal immune system is unique, complex, and distinct from that of the skin, and one could hypothesize that features of this distinctive immune system may affect the biology of melanoma arising in mucosal surfaces. When considering the anatomy of the mucosal immune system, sites can be defined as either inductive or effector sites. Inductive sites include regions such as mucosa-associated lymphoid tissue (MALT) and local/regional mucosa-draining lymph nodes, where antigens from mucosal surfaces stimulate naive T and B lymphocytes. Effector sites include areas such as the lamina propria, exocrine gland stroma, and surface epithelia, where mature lymphocytes perform their functions, such as releasing cytokines and secreting antibodies.[13,14]
Throughout the mucosa of the gastrointestinal tract, a very particular balance must be continuously maintained in order to regulate immune reactions to a wide array of both harmless and potentially harmful antigens. This regulation of immune reactions is known as immune tolerance. Despite high bacterial colonization with both commensal and pathologic microbes, as well as frequent contact with antigens from food protein, acute inflammatory and allergic reactions are rarely seen in the mucosa of the gastrointestinal tract. In the gut, the release of cytokines and chemokines is important in initiating an adaptive immune response. When antigens are presented to T lymphocytes by antigen-presenting cells, the presence or absence of inflammation determines whether or not the immune system is activated. During exposure to food antigens or nonpathogenic microbes, inflammation is absent, which results in immune tolerance—the default response. There are three possible mechanisms by which tolerance is effected in both the gut and oral mucosa. These include T-cell depletion by apoptosis; anergy (ie, the process by which T cells that are presented with a peptide in the absence of costimulatory signals become refractory to further stimulation with the antigen and are therefore inactivated); and the development of regulatory T cells, which can actively suppress antigen-specific responses following re-challenge with the antigen.[14,15]
Mucosal Melanoma of the Head and Neck
The head and neck region is the most common site for mucosal melanoma in men and the second most common site in women, although mucosal melanomas represent only 0.5% of all head and neck cancers.[2,16] The incidence of mucosal melanomas of the head and neck is 0.7 to 0.9 cases per million people per year and is not significantly different between men and women. The median age at diagnosis of mucosal melanoma of the head and neck ranges from 60 to 69 years. Interestingly, melanoma of the oral cavity typically presents at a younger age, with as many as 18% of cases occurring in persons aged 40 years or younger.[17,18]
Sinonasal melanomas constitute 70% of mucosal melanomas of the head and neck, with 80% arising in the nasal cavity.[2,16,19] Within the nasal cavity, the turbinates and nasal wall are most commonly involved, followed by the nasal septum. Of the sinuses, the maxillary sinus is most often involved, followed by the ethmoid, frontal, and sphenoid sinuses. Oral cavity melanomas make up almost 30% of mucosal melanomas of the head and neck, and usually involve the palate and maxillary gingiva.[2,17,19] Preexisting melanosis is seen in about one-third of patients with oral melanoma. While use of alcohol and tobacco have been shown to increase one’s risk of developing squamous cell carcinoma of the head and neck, no similar evidence exists for mucosal melanoma.[17,20] The 5-year overall survival rate for mucosal melanoma of the head and neck ranges from 17% to 35%. The prognosis, however, appears to vary by site, with nasal cavity disease having a relatively better prognosis and sinus disease having an inferior prognosis.[19,21,22]
Anatomically, the mucosa of the head and neck can be divided into a layer of stratified squamous epithelium and an underlying connective tissue layer known as the lamina propria (Table 2). The oral mucosa does not contain MALT. Instead, immune responses are induced in the local and regional lymph nodes (ie, the tonsils, adenoids, and cervical lymph nodes). The majority of Langerhans cells can be found in the mucosal surfaces lining the oral cavity.[13,23] Studies show higher Toll-like receptor (TLR)2 and TLR4 expression on oral Langerhans cells compared with Langerhans cells of the epidermis in steady state. When TLRs are triggered by lipopolysaccharides, oral Langerhans cells upregulate expression of coinhibitory molecules B7-H1 and B7-H3, whereas expression of the costimulatory molecule CD86 (B7-2) is decreased. This leads to regulatory T-cell development, subsequent interleukin (IL)-10 and transforming growth factor beta secretion, and ultimate suppression of the immune response.
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