title: Gastrointestinal stromal tumors with internal tandem duplications in 3' end of KIT juxtamembrane domain occur predominantly in stomach and generally seem to have a favorable course.
abstract: Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the gastrointestinal tract. GISTs express KIT and have KIT mutations. Majority of these mutations cluster in the 5' end of the KIT juxtamembrane domain. Little is known about the clinicopathological profile of GIST carrying internal tandem duplications in the 3' end of KIT juxtamembrane domain (ITDs in the 3' KIT-JM). In this study, 500 immunohistochemically KIT-positive GISTs were screened for this type of mutation, and 18 cases were identified (3.6%). The majority of the ITDs consisted of 1 to 18 codon duplications, with Tyr(578), Asp(579), and Leu(576) being the most commonly duplicated codons. There were 14 gastric (78%), 2 small intestinal (11%), and 2 anal (11%) primary tumors diagnosed in 12 females and 6 males with median age of 71 years. The frequency of IDTs in gastric GISTs was 6.5% and was only 0.5% in intestinal GISTs. There was a strong female predominance (79%) among the patients with gastric tumors. Histologically, 16 GISTs were spindle cell, and 2 had epithelioid morphology. The sizes of primary tumors varied from 1 to >20 cm. Based on the combination of tumor size and mitotic activity, six tumors were classified as benign or probably benign, eight as having uncertain malignant potential, and only four as malignant. Follow-up data available in 17 patients confirmed the malignant course of disease in 3 cases. Only one of the tumors classified as potentially malignant metastasized, although the follow-up was limited in some cases. In summary, the great majority of GISTs with ITDs in the 3' KIT-JM were mitotically inactive tumors occurring predominantly in the stomach and that seemed to have a favorable course. This suggests that presence of these IDTs may define a clinicopathologically favorable subset of GISTs. The consequence of these mutations to KIT signaling should be investigated.
authors.affiliation: Department of Soft Tissue Pathology, Armed Forces Institute of Pathology, Washington, DC 20306-6000, USA. lasota@afip.osd.mil
authors.forename: Jerzy
authors.initials: J
authors.lastname: Lasota
authors.forename: Agnieszka
authors.initials: A
authors.lastname: Dansonka-Mieszkowska
authors.forename: Tomasz
authors.initials: T
authors.lastname: Stachura
authors.forename: Regine
authors.initials: R
authors.lastname: Schneider-Stock
authors.forename: Markku
authors.initials: M
authors.lastname: Kallajoki
authors.forename: Sonja E
authors.initials: SE
authors.lastname: Steigen
authors.forename: Maarit
authors.initials: M
authors.lastname: Sarlomo-Rikala
authors.forename: Carsten
authors.initials: C
authors.lastname: Boltze
authors.forename: Radzislaw
authors.initials: R
authors.lastname: Kordek
authors.forename: Albert
authors.initials: A
authors.lastname: Roessner
authors.forename: Jerzy
authors.initials: J
authors.lastname: Stachura
authors.forename: Markku
authors.initials: M
authors.lastname: Miettinen
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000595:Amino Acid Sequence; D018952:Antigens, CD34 / Q000032:analysis; D001483:Base Sequence; D004252:DNA Mutational Analysis; D004273:DNA, Neoplasm / Q000737:chemistry / Q000235:genetics; D005260:Female; D005753:Gastric Mucosa / Q000378:metabolism; D005770:Gastrointestinal Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D009154:Mutation; D019009:Proto-Oncogene Proteins c-kit / Q000032:analysis / Q000235:genetics*; D013270:Stomach / Q000473:pathology; D017154:Stromal Cells / Q000473:pathology; D020080:Tandem Repeat Sequences / Q000235:genetics
chemical_list: D018952:Antigens, CD34; D004273:DNA, Neoplasm; D019009:Proto-Oncogene Proteins c-kit