Digestive system melanoma (DSM) is a general term that refers to a melanoma developing anywhere in the digestive system, i.e., in the mucosa of the oral cavity, esophagus, stomach, small or large intestines, anorectal region, or in the liver, gallbladder, or pancreas. Clinical presentation, treatment options, and prognosis depend on the site of tumor growth. Primary DSM are very rare, and the exclusion of a primary melanoma of the skin or uvea is a prerequisite for their diagnosis.
There are no symptoms that would be characteristic of DSM. They are mass lesions that may interfere with the function of the affected part of the digestive system, of adjacent tissues and organs. Accordingly, DSM patients may present with a wide variety of non-specific symptoms resulting from maldigestion, malabsorption, and intestinal obstruction, or they may present with pain resulting from space-occupying processes or mucosal ulceration: Dysphagy, nausea, vomiting, and difficulties passing stools are frequently reported. In the long term, patients tend to lose weight. DSM may induce gastrointestinal hemorrhages leading to hematemesis, melena, or hematochezia, and clinical anemia   . Constitutional symptoms suggestive of cancer, such as fever and night sweats, are rarely observed .
After a detailed clinical history has been obtained, imaging techniques should be employed to depict the digestive system and to localize the origin of the disease. Besides the visual inspection of the oral cavity and anorectal region, endoscopy is the method of choice to visualize the inner surfaces of the digestive tract. It also provides the opportunity to collect biopsy specimens. Sonography, computed tomography, or magnetic resonance imaging may have to be carried out to assess the depth of tissue invasion, and they are also required to display non-superficial tumors like hepatic melanoma   . Positron emission tomography is widely and effectively used for tumor staging .
Most DSM are of dark brown, nearly black color, but amelanotic DSM have been reported  . During early stages, melanomas are flat or slightly elevated tumors. By contrast, polypoid growth is characteristic of advanced-stage disease . The surface of these tumors may be ulcerated . Tissue samples are densely populated by epitheliod or spindle-shaped tumor cells that are organized in a sheet-like manner . While pigmented granules are readily observed in melanotic DSM, they are lacking in amelanotic tumor cells. Nuclei may have irregular borders . Moderate to severe nuclear atypia should be considered an indicator of malignancy but is not specific for DSM, whose diagnosis requires an immunohistochemical characterization. Such an analysis usually reveals the expression of HMB-45, melanoma antigen/MART-1, and S100 protein  .
Of note, primary melanoma developing elsewhere in the body are much more common than primary DSM and may metastasize to the digestive system. Therefore, all patients should be thoroughly examined for the presence of skin lesions suspicious of cutaneous melanoma. Similarly, uveal melanoma must be excluded by means of an ophthalmological examination. The diagnosis of primary DSM cannot be confirmed before cutaneous and uveal melanoma have been ruled out, which leads to the following criteria for the diagnosis of primary DSM:
The complete surgical resection of DSM is the treatment of choice . Neoadjuvant or adjuvant chemotherapy may be administered, but conclusive evidence regarding the efficacy of determined treatment regimens is scarce. Most studies focus on the management of skin cancer, and it should be noted that their results cannot necessarily be extrapolated to DSM.
In a recent study on the efficacy of neoadjuvant systemic therapy in advanced-stage melanoma, both alkylator-based and taxane-based chemotherapies induced complete or partial responses in a considerable proportion of patients . Similar results have been achieved with molecular.- targeted therapies based on the application of imatinib, ipilimumab, nivolumab, pembrolizumab, BRAF and MEK kinase inhibitors, and high-dose interleukin-2   . In patients suffering from advanced-stage mucosal melanoma, best response rates have been obtained with anti-PD-1 agents nivolumab and pembrolizumab . The administration of molecular-targeted therapies should be based on a detailed genetic characterization of the tumor.
Even partial responses may incline the balance towards a more favorable prognosis, because they may allow for a down-staging of non-resectable to resectable tumors . Still, progression-free survival times of patients with advanced melanoma treated with any of the aforementioned drugs don't usually exceed 12 months - and they may be much shorter in case of DSM .
Adjuvant radiotherapy has also been used to lessen the likelihood of recurrence but more studies on its efficacy are needed  . Furthermore, radiotherapy has been applied in a palliative manner. It has been shown to alleviate gastrointestinal hemorrhages and subsequent anemia .
DSM are associated with a poor prognosis. The unfavorable outcome is partly due to delays in diagnosis - DSM is often diagnosed in advanced stages -, but it is also related to knowledge gaps regarding the pathogenesis of DSM and the resulting lack of effective treatment options. Since surgery is deemed the only option of cure, the feasibility of a complete resection of the primary tumor and its metastases is considered the main prognostic factor for long-term survival. Recurrence despite presumed curative surgery may suggest the presence of an as-of-yet undetected primary tumor outside the digestive system. In this context, disease-free survival for more than a year has been proposed as a criterion for the distinction of primary DSM from metastatic melanoma  .
Most primary DSM originate from melanocytes in the mucous membranes that line the digestive tract. The origin of primary DSM growing in tissues and organs void of melanocytes remains unclear. It has been speculated that they may originate from ectopic melanocytes that undergo malignant transformation. In general, melanocytes arise from neural crest cells that migrate along the peripheral nerves to invade the dermis and epidermis, so ectopic melanocytes may be the result of the misguided migration or disturbed differentiation of multipotent neural crest progenitors.
While exposure to ultraviolet radiation has been known for a long time as a major risk factor for the development of cutaneous melanoma, no predisposing factors could yet be identified for DSM. What's more, the function of extracutaneous melanocytes remains elusive . It has yet to be studied whether the ingestion of carcinogenic substances augments the individual risk of developing DSM.
Mucosal malignant melanoma accounts for 1.3% of all melanomas, and the vast majority of mucosal melanomas develops outside the digestive system, primarily as malignant melanoma of the conjunctiva  . The most common type of primary DSM is anorectal melanoma, followed by melanoma of the oral cavity. Their overall incidence has been estimated to be 4 and 2 per 10,000,000 inhabitants and year, respectively. While several hundred cases of primary esophageal melanoma have been described, less than two dozen cases of melanomas originating from other parts of the digestive system have been reported .
DSM is usually diagnosed in the elderly. The incidence of DSM peaks during the sixth and seventh decade of life. Females have a slight predisposition to anorectal melanoma while melanomas of the oral cavity, esophagus, and biliary tract are more frequently diagnosed in males. Asians, particularly Japanese, seem to be predisposed to oral melanoma. Otherwise, no predisposition of race or gender has been demonstrated .
Little is known about the pathophysiological events leading to the development of primary DSM. DSM have a relatively low mutational rate and differ from cutaneous and uveal melanoma with regard to their genomic signature. While activating mutations of the BRAF and NRAS genes are detected in about 50% of all melanoma, they are rarely identified in DSM  . By contrast, mutations of the KIT genes are commonly found in DSM . They affect the MAP kinase pathway, which is involved in the regulation of cell growth, differentiation, and apoptosis.
After KIT mutations have been identified in non-cutaneous melanoma, c-kit kinase inhibitors like imatinib have been tested for their efficacy in the treatment of the respective kinds of cancer. Initial results have been disappointing but taught researchers that mutations of a single gene don't necessarily result in homogenous responsiveness to determined drugs: While certain mutations of the KIT gene render the tumor sensitive to imatinib and related agents, others don't imply sensitivity to c-kit kinase inhibitors .
No recommendations can be given to prevent the development of primary DSM. Prophylactic measures that reduce the likelihood of developing other forms of melanoma, such as cutaneous melanoma, may help to prevent metastatic melanoma of the digestive tract. In this context, the avoidance of exposure to ultraviolet radiation seems to be the most effective measure. Patients should be recommended to use sunscreen with high protection factors and long-sleeved clothes. Elderly patients are to undergo regular dermatological examinations to allow for an early diagnosis of skin cancer.
Malignant melanoma is best known as a type of skin cancer. However, melanocytes can be found in other tissues, and melanoma may develop in an extracutaneous manner. Besides uveal melanoma, the most common primary malignant intraocular neoplasm, melanocyte-derived malignancies have been described in the digestive system. Along the digestive tract, melanocytes are mainly present in the mucous membranes of the oral cavity and anorectal region, and the respective types of DSM are most frequently reported. While they still are rare diseases, DSM originating from other parts of the digestive system are exceedingly rare.
Malignant melanoma is a well-known type of skin cancer. It originates from degenerated melanocytes, from cells that carry dark pigments and are responsible for the color of skin. Melanocytes can also be found elsewhere in the human body, e.g., in the mucous membranes of the oral cavity and anorectal region. Accordingly, melanoma may also develop in these regions. Melanoma of the oral cavity or anorectal region are variants of digestive system melanoma (DSM), whereby this term may also refer to malignant tumors developing in the esophagus, stomach, intestines, liver, gallbladder, or pancreas. All these diseases are very rare.
Tumors developing in the gastrointestinal tract may interfere with the digestion of food, the absorption of nutrients, and food transit in general. Accordingly, patients suffering from DSM may present with loss of appetite, early satiety, nausea, and vomiting. They may claim difficulties in swallowing and passing stools. DSM may induce gastrointestinal hemorrhages leading to vomiting of blood, bloody stools, and anemia. In the long term, many DSM patients lose weight and strength. Because these symptoms are non-specific, the diagnosis of DSM is often delayed. It requires the visualization of the tumor, which is most commonly achieved using endoscopy, and the collection of tissue samples for subsequent histological examinations.
Most DSM patients are diagnosed in advanced stages of the disease and have a poor prognosis. The complete surgical resection of DSM is considered the only option of cure and may be difficult to achieve in case of large tumors, metastatic disease, or comorbidities that preclude surgery. Patients who cannot be recommended for surgery may be offered palliative treatment. The latter may or may not include chemotherapy, radiotherapy, or molecular-targeted therapy. Due to the rarity of DSM, evidence regarding the efficacy of determined treatment regimens is scarce.