Melanoma originates in melanocytes, the cells responsible for producing the pigment melanin. While this uncontrolled growth is most commonly associated with the skin, melanocytes are also found in other parts of the body. This gives rise to a distinct and much rarer group of malignancies known as non-cutaneous melanoma (NCM). These internal forms are characterized by unique biology and diagnostic challenges, setting them apart from common skin cancer.
Categorizing Non-Cutaneous Melanoma
Non-cutaneous melanoma (NCM) includes any primary melanoma that does not originate in the skin, arising instead from melanocytes located in mucosal tissues, the eye, or internal organs. This category is divided into three main anatomical subtypes. The most common form of NCM is ocular or uveal melanoma, which develops in the uvea, the middle layer of the eye (including the iris, ciliary body, and choroid).
Mucosal melanoma is the second major category, involving the moist linings of the body’s various tracts. These melanomas can occur in the head and neck (such as the nasal cavity and sinuses), or in the gastrointestinal and genitourinary tracts. Specific sites include the lining of the mouth, the rectum and anus, and the vulva or vagina.
The third, significantly less common group is primary visceral or leptomeningeal melanoma, which rarely originates directly in internal organs or the central nervous system. These rare tumors have been reported in sites such as the esophagus, lungs, and the membranes covering the brain and spinal cord.
The Numbers: Incidence and Rarity
The incidence of internal melanoma confirms its status as an ultra-rare cancer compared to its cutaneous counterpart. Non-cutaneous melanoma accounts for a small fraction of all melanoma diagnoses, typically representing between 1% and 4% of total cases. While skin melanoma is the fifth most common cancer overall, NCM is considered an orphan disease due to its low occurrence.
Ocular melanoma is the most frequently diagnosed non-cutaneous subtype, making up approximately 80% of all NCM cases. The annual incidence of uveal melanoma is reported at around 5.2 cases per million people. Mucosal melanoma is even less common, accounting for roughly 1% to 1.3% of all melanoma cases in North America.
Unique Causes and Risk Factors
A primary biological distinction of NCM is the lack of a direct link to ultraviolet (UV) radiation exposure, which drives most skin melanomas. Instead, NCM development is tied to distinct genetic alterations and the presence of melanocytes in specific tissue environments. In ocular melanoma, for example, a majority of tumors harbor activating mutations in the \(GNAQ\) or \(GNA11\) genes.
These gene mutations are mutually exclusive and result in the constant activation of cell signaling pathways, promoting tumor growth. Mucosal melanomas present a different molecular landscape, often lacking the \(BRAF\) mutations common in skin melanoma. Instead, they sometimes exhibit \(c-KIT\) mutations, which can influence therapeutic approaches.
For many mucosal and primary visceral melanomas, the specific cause remains unknown, suggesting that localized factors in the non-cutaneous tissues play an initiating role. The presence of melanocytes, which are neural crest-derived cells, provides the cellular origin for these malignancies. Genetic syndromes, such as those involving the \(BAP1\) gene, can also predispose individuals to an increased risk of uveal melanoma and other cancers.
Challenges in Early Detection
The anatomical locations of non-cutaneous melanomas present substantial hurdles to early detection, often resulting in diagnosis at a later, more advanced stage. Unlike skin melanoma, which is visible and monitored using the \(\text{ABCDE}\) criteria, internal lesions are largely hidden from view. Symptoms are often vague and non-specific, mimicking those of common, benign conditions.
Ocular melanoma may cause subtle visual changes, such as blurring or a dark spot in the field of vision, or it may be entirely asymptomatic until an eye examination is performed. Mucosal melanomas can present with symptoms like persistent nosebleeds, a non-healing sore in the mouth, or unexplained rectal bleeding. These symptoms are easily mistaken for less serious ailments.
By the time a non-cutaneous melanoma causes noticeable symptoms, it has frequently grown larger or spread to distant sites in the body. This advanced stage at presentation contributes to the less favorable outcomes associated with NCM compared to early-stage skin melanoma. The difficulty in finding these rare tumors early underscores the need for high clinical suspicion when evaluating persistent, unexplained symptoms.