Answer: High grade gastrointestinal stromal tumor (GIST)

Histology: The current example of small intestinal GIST demonstrate a typical spindle cell morphology and high mitotic rate of more than 8/50 HPFs and areas of necrosis.

Discussion: This high grade GIST is expected to have a malignant biologic behavior according to the RISK ASSESSMENT scheme described by Rubin et al, Archives, Path & Lab Med, Vol 134, 2010 (High risk: 90%).

Mutually exclusive activating c-KIT and PDGFRA mutations are important oncogenic events in GIST. Response to Tyrosine Kinase inhibitors can be predicted by type of mutation in a given GIST. C-KIT mutations in GIST are clustered in four exons. Most common are exon 11 (juxtamembrane domain) mutations that include deletions, point mutations and duplications (mostly in the 3′ region).

Molecular differences among gastric and small intestinal GISTs are worth noting. In gastric tumors, tumors with c-Kit deletions are more aggressive than those with point mutations. The latter difference in biologic behavior does not hold in small intestinal tumors. Exon 9 mutations (5-10%) occur predominantly in intestinal GISTs where lesser imatinib sensitivity has been noted. PDGFRA mutations usually occur in gastric GISTs, especially in the epithelioid variants (30% to 40% of KIT mutation negative tumors) and are also associated with imatinib resistance. GIST develop secondary mutations in KIT kinase domains post imatinib treatment leading to loss of Rx response. Finally, familial GIST syndrome have germ line KIT/PDGFRA mutations similar to those in sporadic GISTs.

Reference(s):
– Semin Diagn Pathol. 2006 May;23(2):91-102. KIT and PDGFRA mutations in gastrointestinal stromal tumors (GISTs). Lasota J, Miettinen M.