Answer: Gastrointestinal stromal tumor (GIST)

Histology: The lesion is a well-circumscribed, non-infiltrative spindle cell tumor centered in the gastric sub-serosa. Focal lymphoid aggregates are seen at the periphery of the lesion. The individual spindle cells have elongated nuclei with blunt to pointed ends and occasional perinuclear vacuoles. The nuclei are focally palisaded. There is no necrosis and no mitotic figures. Immunohistochemical stains show the lesional cells to be positive for c-kit (CD117), CD34, and DOG-1, but negative for the S100-protein.

Discussion: Gastrointestinal stromal tumors (GISTs) are mesenchymal tumors that arise from the interstitial cells of Cajal, or their derivatives, which are driven primarily by KIT and to a lesser degree PDGFRA mutations. The presence of mutations in KIT is pertinent, because it enables GISTs to be treated with targeted tyrosine kinase inhibitors, such as imatinib mesylate (Gleevec). Most KIT mutations occur in exon 11, while a subset occur in exon 9; this is also pertinent, because the tumors with exon 9 mutations do not respond as well to the tyrosine kinase inhibitors.

GISTs can arise anywhere along the GI tract, either sporadically or syndromically. Syndromic GISTs are associated with neurofibromatosis type 1, which is characterized predominantly by multiple neurofibromas (solitary or plexiform) café-au-lait skin pigmentation, pigmented iris hamartomas (Lisch nodules), and an increased incidence of MPNST and other soft tissue tumors. Familial GISTs also arise in the setting of hereditary KIT/PDGFRA mutations, loss of succinate dehydrogenase subunit B (SDHB), Carney triad, and Carney-Stratakis syndrome. The prognostication of GISTs depends upon the tumor site, size and mitotic rate. In general, gastric GISTs do well even with large size or moderate mitotic rate, while small intestinal (particularly jejunal/ileal) and rectal GISTs do worse.

The morphology of GISTs is classically spindled but the tumors can also display epithelioid, hypercellular, or sarcomatoid morphologies. Extracellular collagen globules called skeinoid fibers may be seen, particularly in the small intestinal tumors. Hyalinized vessels, nuclear palisading, and lymphocytic cuffing may also be seen, mimicking gastrointestinal schwannomas. GISTs can also cytologically malignant, recur, or metastasize. The differential diagnosis of low grade, spindled GISTs includes schwannoma, leiomyoma, inflammatory myofibroblastic tumor, inflammatory fibroid polyp, and desmoid fibromatosis. Most GISTs are diffusely positive for c-KIT, CD34, and DOG-1, and some can display focal smooth muscle markers; schwannomas are diffusely positive for the S-100 protein; and leiomyomas are diffusely positive for smooth muscle actin.

Reference(s):
– Miettinen M, Lasota J. Gastrointestinal stromal tumors. Arch Pathol Lab Med 2006; 130:1466–1478.
– Miettinen M, Lasota J.Histopathology of gastrointestinal stromal tumor. J Surg Oncol. 2011;104:865-73.