Mutations in Exon 11 of c-Kit Occur Preferentially in Malignant versus Benign Gastrointestinal Stromal Tumors and Do Not Occur in Leiomyomas or Leiomyosarcomas

Lasota, Jerzy; Jasiński, Marek; Sarlomo-Rikala, Maarit; Miettinen, Markku

doi:10.1016/s0002-9440(10)65250-9

Cited by 503 publications

(354 citation statements)

References 18 publications

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“…A unique feature for these tumors is the presence of activating mutations in the exon 11 of some c-kit genes, especially in the malignant tumors. Such mutations in the c-kit gene are a possible pathogenesis or explanation for the autonomous, unrestricted growth of malignant GISTs (2)(3)(4)(5)(6)(7)(8)(9)(10)(11).…”

Section: Discussionmentioning

confidence: 99%

Immunohistochemical Spectrum of GISTs at Different Sites and Their Differential Diagnosis with a Reference to CD117 (KIT)

2000

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Gastrointestinal (GI) stromal tumor (GIST) is the designation for the major subset of GI mesenchymal tumors and encompasses most tumors previously classified as GI smooth muscle tumors. Although GISTs typically express CD117 (KIT), often express CD34, and sometimes express ␣-smooth muscle actin (SMA), the relative frequency of these markers has not been characterized in large series of GISTs of different sites, and the CD117 expression has not been fully characterized in intra-abdominal tumors. In this study, we immunohistochemically analyzed 292 GISTs throughout the GI tract, including omentum and mesentery, and compared the immunoreactivities with 211 other tumors that may enter in the differential diagnosis. GISTs were defined in this study as CD117-positive primary spindled or epithelioid mesenchymal tumors of the GI tract, omentum, or mesentery. The CD34 positivity of GISTs varied from 47% in small bowel to 96 to 100% in rectum and esophagus, whereas SMA expression showed the opposite patterns and was most frequent in the GISTs of small bowel (47%) and rarest in the GISTs of rectum and esophagus (10 -13%). Desmin was seen only occasionally. S100 positivity was rare but was seen most frequently in small intestinal GISTs (15%). True leiomyomas from esophagus, muscularis mucosae of colorectum, and pericolic leiomyomas similar to uterine leiomyomas were negative for CD117 and CD34 and positive for SMA and desmin (46 of 46). Inflammatory fibroid polyps of stomach and small intestine were negative for CD117 but were often positive for CD34 (6 of 8) and variable for SMA (3 of 8). Inflammatory myofibroblastic tumors involving gastric or colonic wall were negative for CD117 but some showed CD117-positive endothelia. GI schwannomas were all negative for CD117 and positive for S100 protein (11 of 11). Extremely focal CD117 positivity was seen in the neoplastic cells of some retroperitoneal leiomyosarcomas and liposarcomas. Among other CD117-positive tumors were intestinal metastatic melanomas (8 of 11) and extraskeletal Ewing's sarcomas (5 of 11), two of which were abdominal. In conclusion, strong CD117 expression defines most primary GI mesenchymal tumors as GISTs, which show different patterns for CD34 and SMA in various parts of the GI tract. Some unrelated CD117-positive tumors (melanomas, Ewing's sarcomas) should not be confused with GISTs.

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Section: Discussionmentioning

confidence: 99%

Immunohistochemical Spectrum of GISTs at Different Sites and Their Differential Diagnosis with a Reference to CD117 (KIT)

2000

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“…The inhibitory effect of imatinib has already been used in the treatment of GISTs, in which c-kit mutations in the juxtamembrane domain of exon 11 lead to constitutive activation of the tyrosine kinase domain (TKD) of the receptor. 18 Inhibition of the TKD of c-kit in GISTs using imatinib was the first effective treatment for patients with metastatic disease, resulting in an overall response rate of 82%. 19 Based on these results, the growth-inhibitory effects of imatinib on c-kit ϩ cell lines have been examined by different groups.…”

Section: Clinical Parameters Survival and C-kit Expression In Multivmentioning

confidence: 99%

Expression of the tyrosine kinase c‐kit is an independent prognostic factor in patients with small cell lung cancer

Rohr

Rehfeld

Pflugfelder

et al. 2004

Intl Journal of Cancer

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“…8 The expression of c-kit in mammary phyllodes tumor has not been widely investigated, 9,10 with the reported case number being less than 50. Another stromal tumor of the breast, termed 'periductal stromal tumor', has also been demonstrated to express c-kit.…”

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Increased c-kit (CD117) expression in malignant mammary phyllodes tumors

et al. 2004

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Mammary phyllodes tumors are uncommon stromal neoplasms, and are divided into benign, borderline and malignant groups basing on histologic criteria. While benign phyllodes tumors may recur, borderline phyllodes tumors show higher propensity to recur locally and rarely metastasize, and malignant phyllodes tumors show even higher chances of local recurrences or distant metastases. c-kit is a proto-oncogene that encodes a tyrosine kinase receptor (CD117) and is a marker for gastrointestinal stromal tumors (GIST). With the advent of therapeutic agent targeted at this receptor for GIST, we investigated 179 phyllodes tumors (101 benign, 50 borderline, 28 malignant) for c-kit expression using immunohistochemistry. The staining was compared to the degree of malignancy, and to the degree of stromal cellularity, mitotic activity, nuclear pleomorphism and stromal overgrowth. The overall positive rate for c-kit was 29% (52/179) and 17% (17/101), 24% (12/50) and 46% (13/28), respectively, for benign, borderline malignant and frank malignant phyllodes and the differences between all categories were significant (v 2 ¼ 13.844, P ¼ 0.001). In mammary phyllodes tumors, there was increasing c-kit expression with increasing degree of malignancy, up to 46% in malignant cases. This provides strong evidence that c-kit receptor mediated tyrosine kinase involvement in the pathogenesis of phyllodes tumors, and the therapeutic agent, STI571, Glivec, may be a potentially useful drug for its management.

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Mutations in Exon 11 of c-Kit Occur Preferentially in Malignant versus Benign Gastrointestinal Stromal Tumors and Do Not Occur in Leiomyomas or Leiomyosarcomas

Cited by 503 publications

References 18 publications

Immunohistochemical Spectrum of GISTs at Different Sites and Their Differential Diagnosis with a Reference to CD117 (KIT)

Immunohistochemical Spectrum of GISTs at Different Sites and Their Differential Diagnosis with a Reference to CD117 (KIT)

Expression of the tyrosine kinase c‐kit is an independent prognostic factor in patients with small cell lung cancer

Increased c-kit (CD117) expression in malignant mammary phyllodes tumors

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