Elsevier

Human Pathology

Volume 34, Issue 12, December 2003, Pages 1306-1312
Human Pathology

Original contribution
KIT 1530ins6 mutation defines a subset of predominantly malignant gastrointestinal stromal tumors of intestinal origin1 ,

https://doi.org/10.1016/S0046-8177(03)00407-6Get rights and content

Abstract

Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the gastrointestinal tract. GISTs express KIT and show gain-of-function KIT mutations. Most of these mutations affect the KIT juxtamembrane domain, but other KIT domains are mutated at a lower frequency. In this study, frequency of GCC TAT insertion mutation (1530ins6) in KIT exon 9 (extracellular domain) and its possible clinicopathologic significance was investigated. Screening of 520 GISTs identified 26 cases with 1530ins6 KIT mutation and confirmed the previously reported low frequency of this type of KIT mutation among GISTs of different locations. Of the 26 tumors with 1530ins6 KIT mutation studied, 21 originated from the small intestine, 1 from the colon, and 3 from the rectum. In 1 case, primary small intestinal versus colonic localization could not be clearly established because of intra-abdominal dissemination. No distinctive morphological features were identified for the cohort of tumors defined by 1530ins6 KIT mutations. Most of the tumors showed predominant spindle cell morphology, and a few cases had epithelioid or pleomorphic histological features. Following previously published criteria based on tumor size and mitotic rate, 22 of 26 (85%) tumors were classified as malignant or potentially malignant, and 4 (15%) were classified as probably benign. A malignant clinical course was documented in 18 of 19 tumors from the malignant category. The survival times of 11 patients who died of disseminated GISTs ranged from 1 month to 105 months (median survival time, 26 months). In contrast, 2 of 4 GISTs assigned as probably benign tumors with follow-up information had long disease-free survival. GISTs carrying 1530ins6 occur exclusively in the intestinal location, and a great majority of these tumors follow a malignant course.

Section snippets

Tissue material

A total of 520 GISTs were obtained from the files of the Armed Forces Institute of Pathology, Haartman Institute of the University of Helsinki, Department of Pathomorphology of the Jagiellonian University in Krakow, Department of Pathology of Otto-von-Guericke University in Magdeburg, Chair of Oncology of the Medical University of Lodz, and Department of Pathology of the Faculty Hospital in Pilsen. In 8 cases, some of the data have been previously published in our study and collaborative

Results

The clinicopathological and molecular genetic data are summarized in Table 1.

Discussion

KIT-activating mutations have been documented in most GISTs. First, Hirota at al18 reported in-frame deletions and missense mutations in KIT juxtamembrane domain (exon 11) in 5 of 6 GISTs analyzed. In subsequent studies, this type of mutation has been found in most GISTs.29, 31, 32, 33 However, other mutational “hot spots” in KIT exons 9, 13, and 17 have been identified in the GISTs negative for the exon 11 mutation.19, 34

In exon 9, insertion of 6 nucleotides GCC TAT (1530ins6) resulting in

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      Single KIT exon 11 substitutions are associated with longer relapse-free survival (RFS) and overall survival [8]. Conversely, the KIT exon 9 duplications, occurring almost exclusively in intestinal tumours, have been associated with malignant behaviour [11, 12]. Homo-/hemizygous KIT mutations were reported to associate with tumour liver metastasis and poor clinical outcome of the disease [13].

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    This study was partially supported by the American Registry of Pathology and by a grant from the Polish Committee for Scientific Research (3 P05C 059 25).

    1

    The opinions and assertions contained herein are the expressed views of the authors and are not to be construed as official or reflecting the views of the Departments of the Army or Defense.

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