Gastrointestinal stromal tumors (GISTs) are mesenchymal neoplasms driven by oncogenic, mutational activation of KIT or platelet-derived growth factor receptor a (PDGFRA). GIST-specific KIT or PDGFRA mutations have been linked to tumor location, tumor cell morphology and clinical behavior. The purpose of this study was to evaluate the clinicopathologic profile of GISTs that have KIT exon 13 or exon 17 mutations. Through the collaboration of several GIST research groups, we gathered 54 cases from the pre-imatinib era that had such primary mutations. From our observations and those in the literature, we estimate that the frequency of these mutations is no higher than 1-2%. Almost all (32 of 33, 97%) of the KIT exon 13 mutations were the 1945A4G substitution leading to Lys642Glu. A majority (15 of 21, 71.4%) of the KIT exon 17 mutations were the 2487T4A substitution leading to Asn822Lys. Demographic and clinicopathologic data were available for 26 and 14 KIT exon 13 and exon 17 mutant GISTs, respectively. Median age and male to female ratio were similar to ones reported in other GIST studies. Small intestinal tumors were two times more frequent than gastric ones among KIT exon 17 mutants. Also, intestinal tumors were slightly overrepresented among KIT exon 13 mutants when compared with population-based studies. The majority of KIT exon 13 or exon 17 mutants had a spindlecell morphology and only a few had epithelioid features. Tumor size varied from 1.2 to 25 cm and average mitotic rates were 9.5 and 4.2 for KIT exon 13 and exon 17 mutants, respectively. Gastric KIT exon 13 mutant GISTs tend to be slightly larger and more aggressive than gastric GISTs in average, whereas the behavior of small intestinal GISTs with KIT exon 13 mutations does not differ from other small intestinal GISTs. The latter is also true for all KIT exon 17 mutant GISTs. Modern Pathology (2008) 21, 476-484; doi:10.1038/modpathol.2008 published online 1 February 2008 Keywords: GIST; KIT; tyrosine kinase domain; mutation Gastrointestinal stromal tumor (GIST) is the most common gastrointestinal, mesenchymal neoplasm driven by oncogenic activation of KIT or plateletderived growth factor receptor a (PDGFRA), a tyrosine kinase receptor. GISTs occur in different parts of GI tract and show a histological spectrum. Although spindle-cell morphology predominates, tumors with epithelioid or pleomorphic cell features

Undifferentiated gastrointestinal tract carcinomas are rare highly aggressive neoplasms with frequent but not obligatory rhabdoid features. Recent studies showed loss of SMARCB1 (INI1), a core subunit of the SWI/SNF chromatin remodeling complex, in 50% of tested cases. However, the molecular pathways underlying histologically similar but SMARCB1-intact cases are unknown. We herein analyzed 13 cases for expression of 4 SWI/SNF complex subunits SMARCB1, SMARCA2, SMARCA4, and ARID1A and the mismatch-repair proteins MLH1, MSH2, MSH6, and PMS2 by immunohistochemistry. Patients included 12 men and 1 woman aged 32 to 81 years (median, 57 y). Site of origin was colon (5), small bowel (2), stomach (3), small+large intestine (1), small intestine+ampulla of Vater (1), and esophagogastric junction (1). All tumors showed anaplastic large to medium-sized cells with variable rhabdoid features, pleomorphic giant cells, and, rarely, spindle cell foci. Abortive gland formation was seen in 3 cases and bona fide glandular component in 1 case. Most cases strongly expressed vimentin and variably pancytokeratin. In total, 12/13 cases (92%) showed loss of at least 1 SWI/SNF component. Loss of SMARCB1 (5/13), SMARCA2 (10/13), SMARCA4 (2/13), and ARID1A (2/13) was observed either in combination or isolated. SMARCA2 loss was isolated in 5 cases and coexisted with lost SMARCB1 in 5 cases (all 5 SMARCB1-deficient tumors showed loss of SMARCA2 as well). Co-inactivation of SMARCB1 and SMARCA4 or of SMARCA2 and SMARCA4 was not observed. Two mismatch-repair-deficient cases (MLH1/PMS2) showed concurrent loss of SMARCB1, SMARCA2, and (one of them) ARID1A. This study illustrates for the first time loss of different components of the SWI/SNF complex other than SMARCB1 in undifferentiated gastrointestinal carcinomas including novel SMARCA4-deficient and SMARCA2-deficient cases. Our results underline the close link between SWI/SNF deficiency and the aggressive rhabdoid phenotype. Frequent loss of SMARCA2 possibly points to fragility/vulnerability of the SWI/SNF complex as a consequence of lost core subunit SMARCB1. The exact molecular mechanisms underlying co-inactivation of different SWI/SNF subunits merit further investigations.

No abstract

Vanek's tumor (inflammatory fibroid polyp) is a rare benign lesion occurring throughout the digestive tract. Histologically, two patterns can be recognized. Classical Vanek's tumor contains concentric formations of proliferating spindle cells which are CD34 positive. Atypical, inflammatory pseudotumor-like Vanek's tumor lacks concentric formations and is CD34 negative. Recently, mutations in platelet-derived growth factor receptor alpha (PDGFRA) were reported in gastric and small intestinal Vanek's tumors. In this study, KIT exons 9, 11, 13, and 17, PDGFRA exons 12, 14, and 18, and a part of exon 15 BRAF for point mutation V600E were screened in 23 cases of Vanek's tumor, both classical (n = 16) and inflammatory pseudotumor-like (n = 7). No mutations in all analyzed exons of KIT and BRAF and in exon 14 of PDGFRA were detected. Six Vanek's tumors harbored activating mutations in PDGFRA exons 12 (n = 5) and 18 (n = 1) respectively: S566_E571delinsK (n = 1), S566_E571delinsR (n = 4), and D842 del (n = 1). The mutations were detected in the classical (n = 5), as well as inflammatory pseudotumor-like (n = 1) Vanek's tumors. The results of this study suggest that the two morphological patterns of Vanek's tumor more probably represent only variants of one type of tumor than two different lesions. Furthermore, BRAF mutations were not shown to drive growth of PDGFRA wild-type Vanek's tumors.

No abstract

No abstract

No abstract

Eight cases of reactive nodular fibrous pseudotumor of the gastrointestinal tract are presented. The patients included 6 males and 2 females between the ages of 1 and 68 years (mean age 41.5 years). Three tumors involved the small intestine, and 5 of the investigated lesions were located in the large bowel. Of these, 2 originated in the sigmoid colon, 1 in the cecum, 1 in the appendix, and 1 in the large bowel not otherwise specified. The tumors' size varied from 3 to 10 cm in the greatest diameter (mean 6.2 cm). Histologically they were composed of stellate or spindle shaped cells resembling fibroblasts arranged haphazardly or in intersecting fascicles, embedded in a collagen-rich stroma, with sparse intralesional mononuclear cells frequently arranged in lymphoid aggregates. Immunohistochemically, the lesions were positive for vimentin (7/7), smooth muscle actin (8/8), muscle-specific actin (5/7), cytokeratins AE1/AE3 (6/7), and CAM 5.2 (1/7), and antigen CD68 (1/7). No case (0/8) reacted positively with antibody to CD117 (c-kit). Genetically no substitutions, deletions, or insertions occurred in exon 11 in all analyzed samples. Likewise, no deletions or insertions in part of exon 9 were observed. Ultrastructurally the tumor cells revealed features typical of myofibroblasts. According to the morphologic, immunohistochemical, and ultrastructural features mentioned above, especially to the positivity of low-molecular-weight cytokeratins, we propose this lesion to be related to a proliferation of multipotential subserosal cells rather than ordinary myofibroblasts or fibroblasts.