During embryogenesis, melanocytes migrate from the neural crest and eventually are widely distributed throughout skin, mucosa, and other sites. Melanomas arising in noncutaneous sites are a heterogenous group that account for less than 1.5% of all melanomas. Sinonasal and vulval melanomas account for the majority of these cases; however, other sites include the uveal tract and the mucosa of the respiratory, genitourinary, and gastrointestinal tracts and glaborous (nonhair bearing) skin. Apart from some orbital melanomas, these sites are not exposed to ultraviolet (UV) radiation and recent genomic analyses indicate that they lack the typical signature of UV exposure seen in many cutaneous melanomas. Recent genomic studies have also identified unique mutations in a proportion of noncutaneous melanomas that distinguish them from cutaneous melanomas. In very rare cases, melanomas may arise in unusual mucosal sites such as the bowel, bronchus, and gall bladder. In these situations, it may not be possible to determine whether these are truly primary lesions or isolated metastases from an unknown primary.
Noncutaneous melanomas have a slight female preponderance due to the excess of female genitourinary melanomas, but otherwise there are no gender differences. Noncutaneous melanoma is a disease of older patients and unlike cutaneous melanoma rarely occurs in younger patients. Comorbidities associated with older age may complicate the management of these patients.
The rarity of noncutaneous melanomas has a number of consequences for their management, not the least of which is a reliance on data derived from patients with cutaneous melanomas, which may not be entirely appropriate. The quality of the evidence available is poor as it is invariably based on small series, frequently from a single institution and often collected over many decades. Furthermore, patients with noncutaneous melanomas are usually excluded from large randomized controlled trials in melanoma. Management of these patients is therefore based on consensus recommendations in the absence of high-level evidence. Although many noncutaneous melanomas present at an advanced stage, the lack of validated staging systems makes prediction of outcomes and comparison of results difficult. In the case of lesions arising in mucosa, the lack of a dermal/epidermal junction means tumor thickness is a less reliable prognostic factor than for cutaneous melanoma. There are no site-specific staging systems for most regions where noncutaneous melanomas arise. The use of staging systems for more common cancers located in the same region, for example, the International Federation of Obstetrics and Gynecology (FIGO) staging system for vulval squamous cell cancer, has generally been unsatisfactory. Most recent reports employ the current AJCC/UICC Staging System for Cutaneous Melanoma, which although it has limitations where tumor thickness cannot be appropriately assessed, provides acceptable results.
At the time of writing this chapter, the management of disseminated cutaneous melanoma, as well as the prospects for effective adjuvant therapy, was undergoing an extraordinary revolution. At the present time, there is little information on the role of targeted therapies or immune checkpoint inhibitors in patients with ...