Microscopic gastrointestinal stromal tumors (GISTs) (synonyms: sporadic interstitial cell of Cajal hyperplasia, seedling GISTs, minimal GISTs) are common incidental findings in gastroesophageal resections (9% to 35%). To our knowledge, their frequency, clinicopathologic features, and molecular pathogenesis from nongastroesophageal sites have so far not been sufficiently analyzed. We studied 19 lesions from distal esophagus (n=8), gastroesophageal junction (n=2), sigmoid colon (n=5), and vermiform appendix, cecum, rectum, and small intestine (1 each). Microscopic GISTs were detected in 0.2%, 0.1%, and 0.01% of routinely processed resection specimens from sigmoid colon, vermiform appendix, and rectum, respectively. Patients were 11 men and 8 women with a mean age of 66 years (range, 57 to 86 y). Thirteen patients had GI cancers and 5 had diverticular disease. None has a family history of GIST or features of neurofibromatosis 1. Lesions were 0.5 to 4 mm in size (mean, 1.12 mm), were all spindled and had noncircumscribed infiltrating borders. All arose in the muscularis propria and 2 were predominantly subserosal. Immunohistochemistry revealed a CD117/CD34/smooth muscle actin-negative phenotype in 18/19 lesions. Three KIT exon 11 mutations (2 point mutations and 1 deletion, all involving W557) were detected in 3/12 lesions with successful molecular analysis. In conclusion, incidental microscopic GISTs are uncommon in intestinal resections (< or =0.1%), contrasting with their gastroesophageal counterparts (> or =9%). Somatic KIT mutations are early initiating molecular events in a subset of them. The remarkable variation in the incidence of microscopic GISTs at different GI sites suggests an origin from heterogeneous subsets of interstitial cells of Cajal with varying potentials for neoplastic transformation.
"Frequent KIT mutations (about 46%) and occasional PDGFRA mutations (about 4%) are present in these " GIST tumorlets "  . However, these " GIST tumorlets " do not always develop into clinical GIST. "
[Show abstract][Hide abstract] ABSTRACT: Small cell carcinoma (SCC) of the oral cavity is extremely rare; only one case has been reported in the English Literature. The author herein reports the second case of SCC of the oral cavity. A 59-year-old man presented with oral tumor (5 cm) in the right cheek mucosa. A biopsy was taken. The HE histology was typical SCC consisting of small epithelial cells with hyperchromatic nuclei, molded nuclei, scant nucleocytoplasmic ratio, and negative nucleoli. Immunohistochemically, the tumor cells are positive for pancytokeratin (PCK) WSS, PCK MNF-116, cytokeratin (CK) 34BE12, CK5/6, CK14, vimentin, KIT (CD117), CD56, synaptophysin, p53 protein, and Ki67 antigen (Ki-67 labeling = 70%). The tumor cells are negative for PCK AE1/3, PSK CAM5.2, CK7, CK8, CK18, CK19, CK20, EMA, NSE, chromogranin, platelet-derived growth factor-α (PDGFRA), CD45, CD45RO, CD3, CD20, CD30, CD79a, and bcl-2. A retrospective genetic analysis using PCR-direct sequencing method in paraffin sections identified no mutations of KIT (exons 9, 11, 13 and 17) and PDGFRA (exons 12 and 18) genes. Various imaging modalities including CT and MRI and upper and lower gastrointestinal endoscopy did not identified no tumors other than the oral tumor. Thus, the oral tumor was thought primary. The oral tumor rapidly enlarged, and distant metastases to cervical lymph nodes, ribs and iliac bones emerged. The patient is now treated by cisplatin-based chemotherapy 16 months after the first manifestation.
International journal of clinical and experimental pathology 04/2013; 6(4):780-7. · 1.89 Impact Factor
"The liver and the peritoneum are the main sites of metastases, but rarely lymph nodes, bones, or the lung may be affected . Appendiceal GISTs are exceptionally rare with only 11 cases reported in the English literature to date       . Because of their rarity, the risk profile and appropriate management of appendiceal GISTs have not been yet fully defined. "
[Show abstract][Hide abstract] ABSTRACT: Gastrointestinal stromal tumors of the vermiform appendix are rare. To date, only 11 cases have been reported in the English literature. Here, we present a new case of appendiceal gastrointestinal stromal tumor associated with complete situs inversus. A 48-year-old man was operated on due to appendicitis-like symptoms. Laparotomy revealed a ruptured conglomerate tumor in the lower abdomen associated with extensive peritoneal adhesions. Histology showed a spindle cell gastrointestinal stromal tumor with prominent sclerosis and calcification without low mitotic activity. The tumor cells expressed strongly CD117 and CD34. The mutation analysis revealed a heterozygous deletion/insertion involving exon 11 of KIT (pK558_V559delNNins). Because the tumor was ruptured intraoperatively, a high risk was assigned according to the revised National Institute of Health criteria and adjuvant therapy with imatinib mesylate was recommended. The patient is currently alive without evidence of progression 27 months after surgery.
Human pathology 10/2012; 44(4). DOI:10.1016/j.humpath.2012.09.003 · 2.77 Impact Factor
"GISTs can metastasize to the liver and peritoneal cavity, warranting a very poor prognosis. In humans, approximately 70% of GISTs occur in the stomach and 20% occur in the small intestine [6,7], whereas in dogs the reverse is true with 76% of GISTs occurring in the small intestine and colon, while 19% occur in the stomach . "
[Show abstract][Hide abstract] ABSTRACT: Gastrointestinal stromal tumors (GISTs) are common mesenchymal neoplasms in the gastrointestinal tract of humans and dogs. Little is known about the pathogenesis of these tumors. This study evaluated the role of c-KIT in canine GISTs; specifically, we investigated activating mutations in exons 8, 9, 11, 13, and 17 of c-KIT and exons 12, 14, and 18 of platelet-derived growth factor receptor, alpha polypeptide (PDGFRA), all of which have been implicated in human GISTs.
Seventeen canine GISTs all confirmed to be positive for KIT immunostaining were studied. Exons 8, 9, 11, 13 and 17 of c-KIT and exons 12, 14, and 18 of PDGFRA, were amplified from DNA isolated from formalin-fixed paraffin-embedded samples.
Of these seventeen cases, six amplicons of exon 11 of c-KIT showed aberrant bands on gel electrophoresis. Sequencing of these amplicons revealed heterozygous in-frame deletions in six cases. The mutations include two different but overlapping six base pair deletions. Exons 8, 9, 13, and 17 of c-KIT and exons 12, 14, and 18 of PDGFRA had no abnormalities detected by electrophoresis and sequencing did not reveal any mutations, other than synonymous single nucleotide polymorphisms (SNPs) found in exon 11 of c-KIT and exons 12 and 14 of PDGFRA.
The deletion mutations detected in canine GISTs are similar to those previously found in the juxtamembrane domain of c-KIT in canine cutaneous mast cell tumors in our laboratory as well as to those reported in human GISTs. Interestingly, none of the other c-KIT or PDGFRA exons showed any abnormalities in our cases. This finding underlines the critical importance of c-KIT in the pathophysiology of canine GISTs. The expression of KIT and the identification of these activating mutations in c-KIT implicate KIT in the pathogenesis of these tumors. Our results indicate that mutations in c-KIT may be of prognostic significance and that targeting KIT may be a rational approach to treatment of these malignant tumors. This study further demonstrates that spontaneously occurring canine GISTs share molecular features with human GISTs and are an appropriate model for human GISTs.
BMC Cancer 10/2010; 10(1):559. DOI:10.1186/1471-2407-10-559 · 3.36 Impact Factor
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