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 [1] [2] [3]. Constitutional symptoms suggestive of cancer, such as fever and night sweats, are rarely observed [4].

• Pain

  The lungs If melanoma spreads to the lungs, it may cause: breathlessness a cough that does not go away pain in the chest a build-up of fluid around the lungs (pleural effusion). [macmillan.org.uk]

  Clinical presentation includes rectal bleeding, tenesmus, pain, and change in bowel habit. [ebi.ac.uk]

  This discrepancy seems to be attributed to the nonspecific symptoms and signs of GIT involvement, which include weakness, fatigue, bleeding, anemia, and abdominal pain. Sometimes a diagnosis is only made when bowel obstruction occurs. [ncbi.nlm.nih.gov]

  The most frequently reported site is in the esophagus and anorectum.[1] Symptoms of a digestive system melanoma may be nonspecific, including blood in the stool, stomach pain, vomiting, diarrhea, weight loss and anemia (low red blood cell count).[2] The [rarediseases.info.nih.gov]

• Anemia

  They are usually being diagnosed with a complication on the small bowel, such as occlusion, bleeding, anemia and perforation of the intestine. [ncbi.nlm.nih.gov]

  It has been shown to alleviate gastrointestinal hemorrhages and subsequent anemia. DSM are associated with a poor prognosis. [symptoma.com]

  The most frequently reported site is in the esophagus and anorectum.[1] Symptoms of a digestive system melanoma may be nonspecific, including blood in the stool, stomach pain, vomiting, diarrhea, weight loss and anemia (low red blood cell count).[2] The [rarediseases.info.nih.gov]

• Weight Loss

  The most frequently reported site is in the esophagus and anorectum.[1] Symptoms of a digestive system melanoma may be nonspecific, including blood in the stool, stomach pain, vomiting, diarrhea, weight loss and anemia (low red blood cell count).[2] The [rarediseases.info.nih.gov]

• Fatigue

  This discrepancy seems to be attributed to the nonspecific symptoms and signs of GIT involvement, which include weakness, fatigue, bleeding, anemia, and abdominal pain. Sometimes a diagnosis is only made when bowel obstruction occurs. [ncbi.nlm.nih.gov]

  Six months later, she represented with severe symptomatic anemia (shortness of breath, fatigue) and melena. She requested a palliative red blood cell transfusion and possible intervention to stop any bleeding. [hindawi.com]

• Vomiting

  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. [symptoma.com]

  The most frequently reported site is in the esophagus and anorectum.[1] Symptoms of a digestive system melanoma may be nonspecific, including blood in the stool, stomach pain, vomiting, diarrhea, weight loss and anemia (low red blood cell count).[2] The [rarediseases.info.nih.gov]

• Diarrhea

  The most frequently reported site is in the esophagus and anorectum.[1] Symptoms of a digestive system melanoma may be nonspecific, including blood in the stool, stomach pain, vomiting, diarrhea, weight loss and anemia (low red blood cell count).[2] The [rarediseases.info.nih.gov]

• Hematochezia

  Case Report An 82-year-old female with chronic obstructive pulmonary disease and diastolic cardiomyopathy presented with three weeks of fatigue, abdominal distention, and hematochezia. She was found to be anemic with bright red blood in her stool. [hindawi.com]

• Blood in Stool

  Symptoms tend to be non-specific including: nausea, vomiting, stomachache, fatigue, hemorrhage (broken blood vessels), blood in stool, and anemia (low red blood cell count).[1][3][4][2] Last updated: 6/23/2016 How is digestive system melanoma diagnosed [rarediseases.info.nih.gov]

  The signs and symptoms of Digestive System Melanoma may vary from person to person and include: Nausea Vomiting Stomachache Fatigue Hemorrhage (broken blood vessels) Blood in stool Anemia (low red blood cell count) (Source: Digestive System Melanoma; [dovemed.com]

  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. [symptoma.com]

• Epigastric Pain

  He suffered from epigastric pain with suspicious melanoma when was referred to endoscopy. A 1 × 1.5 cm white and black colored ulcer and 1 × 2 cm mass was found at D1 and lesser curvature. [cancerjournal.net]

• Hypertension

  Vitamin b 17 - benefits for health: Along with being an acknowledged alternative medicine for cancer, this b 17 vitamin is believed to render other health benefits too: The anti-hypertensive properties of this vitamin help in keeping the blood pressure [lybrate.com]

  Michl, Patrik; Beer, Sebastian; Rosendahl, Jonas Tezės Clarivate Analytics Web of Science ar/ir Scopus / Theses in Clarivate Analytics Web of Science and/or Scopus DB (T1a) 18 2019 Endogenous motion of the liver correlates with the severity of portal hypertension [lsmuni.lt]

• Jaundice

  […] liver Cancer cells that spread to the liver can cause: swelling and discomfort in the liver area (right side of the tummy, under the ribs) sickness (nausea) loss of appetite a build-up of fluid in the tummy area (ascites) yellowing of the skin and eyes (jaundice [macmillan.org.uk]

  If it shows up in your liver, you may have indigestion, a swollen belly, or yellow skin and eyes, a condition called jaundice. [webmd.com]

  Spread to the liver may be first identified by abnormal blood tests of liver function long before the patient has jaundice, a swollen liver, or any other signs of liver failure. Spread to the kidneys may cause pain and blood in the urine. [medicinenet.com]

• Lacrimation

  […] of peritoneum Stomach Body Cardia Fundus Greater curvature, unspecified Lesser curvature, unspecified Overlapping lesion Pyloric antrum Pylorus Stomach, unspecified Eye and Orbit Eye and Adnexa Choroid Ciliary body Conjunctiva Cornea Eye, unspecified Lacrimal [cdc.gov]

• Freckles

  Other factors that increase the risk of melanoma include: Certain types of moles called dysplastic nevi, or atypical moles Large nevi present at birth Fair skin, freckling Red or blonde hair Light-colored eyes Caucasian race Family members with melanoma [uvahealth.com]

  If you have blond or red hair, light-colored eyes, and freckle or sunburn easily, you're more likely to develop melanoma than is someone with a darker complexion. [mayoclinic.org]

  Risk factors for melanoma include: Positive family history of melanoma Prior melanoma Multiple atypical moles or dysplastic nevi (often these are large and raised, with poorly defined borders and uneven colors) Light complexion or fair skin that freckles [montefiore.org]

  Other factors that may increase your chances of melanoma include: Certain types of moles called dysplastic nevi, or atypical moles Large nevi present at birth Fair skin and a tendency to have freckles Red or blonde hair Light-colored eyes Family members [winchesterhospital.org]

• Skin Lesion

  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. [symptoma.com]

  Use sunscreen daily, limit your exposure to UV rays, wear protective clothing, avoid tanning beds and lamps, and examine your skin regularly for any new skin growths or changes in existing skin lesions. [montefiore.org]

  These guidelines are can be helpful, but the problem is that many pigmented lesions of the skin are not perfectly symmetrical in their shape or color. [medicinenet.com]

  Biopsy of these lesions confirmed diagnosis of melanoma with many sites of involution (Figure 1). Figure 1 Histological examination of primary skin lesion (hemalun-erythrosin-safran, HES). [jgo.amegroups.com]

  Test Yourself With These Suspicious Lesions, a Critical Images slideshow, to help identify various skin lesions. [emedicine.medscape.com]

• Blonde Hair

  Other risk factors include UV exposure (sunlight or tanning booths), history of blistering sunburns, dysplastic nevi, large numbers of ordinary moles, red or blonde hair, blue or green eyes, very fair skin, personal or family history of melanoma and weakened [dermspecpa.com]

  Other factors that increase the risk of melanoma include: Certain types of moles called dysplastic nevi, or atypical moles Large nevi present at birth Fair skin, freckling Red or blonde hair Light-colored eyes Caucasian race Family members with melanoma [uvahealth.com]

  Other factors that may increase your chances of melanoma include: Certain types of moles called dysplastic nevi, or atypical moles Large nevi present at birth Fair skin and a tendency to have freckles Red or blonde hair Light-colored eyes Family members [winchesterhospital.org]

  Fair skin: Melanoma occurs more frequently in people who have fair skin that burns or freckles easily (these people also usually have red or blond hair and blue eyes) than in people with dark skin. [medicinenet.com]

• Headache

  The brain Secondary cancer in the brain may cause headaches and sickness. These may be worse first thing in the morning. The cancer may affect an area of the brain that controls a certain part of the body. [macmillan.org.uk]

  Metastases to the brain may first appear as headaches, unusual numbness in the arms and legs, or seizures. [medicinenet.com]

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 [1] [3] [5]. Positron emission tomography is widely and effectively used for tumor staging [4].

Most DSM are of dark brown, nearly black color, but amelanotic DSM have been reported [1] [3]. During early stages, melanomas are flat or slightly elevated tumors. By contrast, polypoid growth is characteristic of advanced-stage disease [4]. The surface of these tumors may be ulcerated [3]. Tissue samples are densely populated by epitheliod or spindle-shaped tumor cells that are organized in a sheet-like manner [4]. While pigmented granules are readily observed in melanotic DSM, they are lacking in amelanotic tumor cells. Nuclei may have irregular borders [2]. 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 [1] [3].

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:

• Histological and immunohistochemical confirmation of DSM
• Exclusion of other primary malignant melanoma
• No history of skin lesions that have been removed without being subjected to a histological examination

The complete surgical resection of DSM is the treatment of choice [4]. 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 [6]. 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 [6] [7] [8]. In patients suffering from advanced-stage mucosal melanoma, best response rates have been obtained with anti-PD-1 agents nivolumab and pembrolizumab [9]. 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 [6]. 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 [8].

Adjuvant radiotherapy has also been used to lessen the likelihood of recurrence but more studies on its efficacy are needed [4] [10]. Furthermore, radiotherapy has been applied in a palliative manner. It has been shown to alleviate gastrointestinal hemorrhages and subsequent anemia [11].

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 [1] [11].

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 [4]. 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 [4] [10]. 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 [4].

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 [4].

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 [4] [8]. By contrast, mutations of the KIT genes are commonly found in DSM [4]. 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 [12].

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.

1. Ravi A. Primary gastric melanoma: a rare cause of upper gastrointestinal bleeding. Gastroenterol Hepatol (N Y). 2008; 4(11):795-797.
2. Simons M, Ferreira J, Meunier R, Moss S. Primary versus Metastatic Gastrointestinal Melanoma: A Rare Case and Review of Current Literature. Case Rep Gastrointest Med. 2016; 2016:2306180.
3. Suganuma T, Fujisaki J, Hirasawa T, et al. Primary amelanotic malignant melanoma of the small intestine diagnosed by esophagogastroduodenoscopy before surgical resection. Clin J Gastroenterol. 2013; 6(3):211-216.
4. Mikkelsen LH, Larsen AC, von Buchwald C, Drzewiecki KT, Prause JU, Heegaard S. Mucosal malignant melanoma - a clinical, oncological, pathological and genetic survey. Apmis. 2016; 124(6):475-486.
5. Zhang Y, Hu Z, Wu W, Liu J, Hong D, Zhang C. Partial hepatectomy for primary hepatic melanoma: a report of two cases and review of the literature. World J Surg Oncol. 2014; 12:362.
6. Jakub JW, Racz JM, Hieken TJ, et al. Neoadjuvant systemic therapy for regionally advanced melanoma. J Surg Oncol. 2017.
7. Carvajal RD, Antonescu CR, Wolchok JD, et al. KIT as a therapeutic target in metastatic melanoma. Jama. 2011; 305(22):2327-2334.
8. Rozeman EA, Dekker TJA, Haanen J, Blank CU. Advanced Melanoma: Current Treatment Options, Biomarkers, and Future Perspectives. Am J Clin Dermatol. 2017.
9. Shoushtari AN, Munhoz RR, Kuk D, et al. The efficacy of anti-PD-1 agents in acral and mucosal melanoma. Cancer. 2016; 122(21):3354-3362.
10. Chang AE, Karnell LH, Menck HR. The National Cancer Data Base report on cutaneous and noncutaneous melanoma: a summary of 84,836 cases from the past decade. The American College of Surgeons Commission on Cancer and the American Cancer Society. Cancer. 1998; 83(8):1664-1678.
11. Slater JM, Ling TC, Slater JD, Yang GY. Palliative radiation therapy for primary gastric melanoma. J Gastrointest Oncol. 2014; 5(1):E22-26.
12. Postow MA, Carvajal RD. Therapeutic implications of KIT in melanoma. Cancer J. 2012; 18(2):137-141.