Small Intestine

This case first appeared as Performance Improvement Program in Surgical Pathology (PIP) 2021, Case 24, and is metastatic melanoma of the small intestine.

The information provided in this case was accurate and correct at the time of publication in 2021.

Any changes in terminology since the time of publication may not be reflected in this case.

Sections of the distal jejunal mass demonstrate a cellular neoplasm comprised of sheets of small cells with vesiculated to hyperchromatic nuclei, occasional nuclear pseudo-inclusions, prominent mitotic activity and variable amounts of intracytoplasmic melanin pigment. Lymphovascular invasion is present. Immunostains are positive for SOX10, S100, and HMB45. Immunostains for CD45, cytokeratin AE1/3, synaptophysin, and DOG1 are negative. These findings support the diagnosis of melanoma. The patient’s known history of melanoma and the predominant mural involvement of tumor cells favor metastatic origin.

Primary melanoma of the gastrointestinal tract is exceedingly rare; the vast majority represent metastatic disease. Melanoma can metastasize to any location and can show a wide variety of morphologic appearances. Classically, melanoma consists of large, pleomorphic cells with prominent nucleoli. Melanin pigment, though helpful when present, may not always be seen.

When the cells appear epithelioid, they can look very similar to various carcinomas. When the cells appear spindled, they can look similar to gastrointestinal stromal tumors. Additionally, the poorly differentiated histology can mimic neuroendocrine carcinomas. Therefore, in the setting of a bowel mass, melanocytic immunohistochemical markers such as S100, SOX10, Melan-A, HMB-45, and tyrosinase can be integral to diagnosing melanoma. Molecular analyses have revealed that about two thirds of melanomas show activation of the MAPK pathway, carrying a mutated BRAF (approximately 50%) or NRAS (approximately 20%) gene, which are mutually exclusive in nearly all cases. The prognosis of patients with melanoma, especially advanced stage, has improved due to discovery of targeted therapy such as anti-BRAF medications, as well as immunotherapy.

Diffuse large B-cell lymphoma (DLBCL) of the bowel often presents as a thickened bowel wall or ulcerated mass. The bowel is the most common extranodal site. It may arise de novo, in the setting of immune suppression, or secondary to transformation of a low-grade lymphoma. Microscopically, it consists of sheets of large cells that may have centroblastic, immunoblastic, or anaplastic features and are immunoreactive for CD45 and B-cell markers such as CD20, PAX5, and CD79a. They are negative for SOX10 and cytokeratins.

Gastrointestinal stromal tumor (GIST): GIST typically lacks overt cytologic pleomorphism and is often less cellular than the current case. Immunostains for DOG1, CD117, and CD34 are positive, though CD117 can also be positive in anorectal melanomas. Typically, GIST contains either a KIT or a PDGFRA mutation. Succinate dehydrogenase-deficient GIST is a subtype of GIST that more often occurs in younger patients (less than 40 years old) with Carney’s triad (GIST, pulmonary chondroma, paraganglioma). An SDHB immunostain should show aberrant loss of staining in tumor nuclei in such cases.

Medullary adenocarcinoma of bowel is a poorly differentiated form of primary colonic adenocarcinoma associated with microsatellite instability and good prognosis. As a primary lesion, it always involves the mucosal surface, which is often ulcerated. Histology shows sheets of vesicular cells with prominent nucleoli and amphophilic cytoplasm, somewhat resembling the current case. It also usually harbors a prominent intratumoral inflammatory infiltrate. Medullary adenocarcinoma, which is more common in the colon than the small intestine, will be positive for keratins and is usually positive for CDX2.

Poorly differentiated neuroendocrine carcinoma may be primary or metastatic to the bowel and may have large-cell or small-cell morphology. The former resembles the current case, with enlarged cells showing prominent nucleoli and amphophilic cytoplasm. The latter resembles small-cell lung carcinoma, with small, tightly packed cells lacking much cytoplasm that mold to one another. Both types show prominent necrosis and mitoses. Both are positive for neuroendocrine markers such as synaptophysin and chromogranin but negative for melanoma markers.

1. Which mutation is most often associated with melanoma?
   1. BRAF
   2. EGFR
   3. KIT
   4. NRAS
   5. PDGFRA
2. Which of the following is true about medullary adenocarcinoma of the bowel?
   
   
   1. Intratumoral inflammatory cells are often rare to absent.
   2. It has a very poor prognosis.
   3. It has a characteristic t(14;18) translocation.
   4. It often harbors MAPK pathway mutations.
   5. It usually demonstrates microsatellite instability.
3. Which of the following tumors is most associated with Carney’s triad?
   
   
   1. Diffuse large B-cell lymphoma
   2. Gastrointestinal stromal tumor
   3. Melanoma
   4. Medullary adenocarcinoma of bowel
   5. Neuroendocrine carcinoma

1. Palmieri G, Ombra M, Colombino M, et al. Multiple Molecular Pathways in Melanomagenesis: Characterization of Therapeutic Targets. Front Oncol. 2015;5:183.
2. Park JS, Ng KS, Saw RPM, et al. Metastatic melanoma to the colon, rectum, and anus: A 50-year experience. Ann Surg Oncol. 2018;25:2178-83.
3. Bosman FT, Carneiro F, Hruban RH, et al, eds. WHO classification of tumours of the digestive system, 4th ed. IARC Press 2010.
4. Swerdlow SH, Campo E, Harris NL, et al, eds. WHO classification of Tumours of Haematopoietic and Lymphoid Tissues, revised 4th ed. IARC Press; 2017.

1. BRAF (a)
2. It usually demonstrates microsatellite instability (e)
3. Gastrointestinal stromal tumor (b)