Tumor mitotic rate, size, and location independently predict recurrence after resection of primary gastrointestinal stromal tumor (GIST)

Abstract

BACKGROUND. Gastrointestinal stromal tumor (GIST) is the most frequent sarcoma of the intestinal tract and often shows constitutive activation of either the KIT or PDGFRA receptor tyrosine kinases because of gain‐of‐function mutation. Although the efficacy of tyrosine kinase inhibitors in metastatic GIST depends on tumor mutation status, there have been conflicting reports on the prognostic importance of KIT mutation in primary GIST. METHODS. A total of 127 patients were studied who presented to our institution from 1983 to 2002 with localized primary GIST and underwent complete gross surgical resection of disease. The majority of tumors originated in the stomach (58%) or small intestine (28%). By using polymerase chain reaction (PCR) and direct sequencing, a KIT mutation was found in 71% of patients and a PDGFRA mutation in 6%. RESULTS. After a median follow‐up of 4.7 years, recurrence‐free survival was 83%, 75%, and 63% at 1, 2, and 5 years, respectively. On multivariate analysis recurrence was predicted by ≥5 mitoses/50 high‐power fields, tumor size ≥10 cm, and tumor location (with patients having small bowel GIST doing the worst). In particular, a high mitotic rate conferred a hazard rate of 14.6 (95% confidence interval, 6.5–32.4). Specific KIT mutations had prognostic importance by univariate but not multivariate analysis. Patients with KIT exon 11 point mutations and insertions had a favorable prognosis. Those with KIT exon 9 mutations or KIT exon 11 deletions involving amino acid W557 and/or K558 had a higher rate of recurrence, whereas patients without a tyrosine kinase mutation had intermediate outcome. CONCLUSIONS. In the absence of therapy with tyrosine kinase inhibitors, recurrence in completely resected primary GIST is independently predicted by mitotic rate, tumor size, and tumor location. Cancer 2008. © 2007 American Cancer Society.

Prognosis and predictive value of KIT exon 11 deletion in GISTs

“…Recently, some studies reported that GISTs with delWK557 -558 have an increased risk of relapse after curative surgery (Wardelmann et al, 2003;Martin et al, 2005;DeMatteo et al, 2008). In our study, GISTs with delWK557 -558 and GISTs with delTyr did not differ for the risk of relapse after curative surgery and both convey a poor prognosis.…”

“…KIT exon 11 deletions and deletions affecting codons 557 -558 of KIT exon 11 were described to be independent adverse prognostic factors in patients with GIST (Wardelmann et al, 2003;Martin et al, 2005;DeMatteo et al, 2008). Conversely, in another study, GISTs in which the last part of exon 11 (codons 562 -579) was deleted were most frequently associated with malignancy than GISTs with deletion of the first part of exon 11 (codons 550 -561; Emile et al, 2004Emile et al, , 2006.…”

“…Others deletions, in the distal part of the exon, include in particular deletions of Tyr568 and/or Tyr570, and may thus have more specific effects on KIT signalling pathways and degradation. Such deletions account for 3 -8% of exon 11 mutations in published series (Ernst et al, 1998;Taniguchi et al, 1999;Debiec-Rychter et al, 2004Wardelmann et al, 2004;Martin et al, 2005;Penzel et al, 2005;Andersson et al, 2006;Emile et al, 2006;DeMatteo et al, 2008).…”

Ezrin overexpression in gastrointestinal stromal tumors: an independent adverse prognosticator associated with the non-gastric location

“…In this series, similar to our and others' previous reports, inferior disease-free survival was significantly associated with several clinicopathological factors, including older age (P ¼ 0.048), non-gastric location (P ¼ 0.035), presence of epithelioid histology (Po0.001), larger tumor size (Po0.001), higher mitotic count (Po0.001), and increasing NIH risk levels (Po0.001, Figure 4a). 5,6,9,13,[30][31][32][33] In addition, high proliferative index (Po0.001, Figure 4b) and unfavorable RTK genotypes (Po0.001, Figure 4c) were both highly predictive of adverse outcomes. It is noted that ezrin overexpression was also significantly associated with inferior disease-free survival (P ¼ 0.032, Figure 4d).…”

Gastric GISTs: Analysis of c-Kit, PDGFRA and BRAF mutations in relation to prognosis and clinical pathological characteristics of patients – A GIRCG study

“…15,21,23,25,26 Moreover, KIT exon 9 duplications, which occur mainly in intestinal tumors, have been associated with aggressive behavior. 21,25 A number of studies have also analyzed BRAF gene alterations in GISTs, reporting a mutation frequency of about 4e13%. 8e10 A predominant small intestinal location of GISTs with BRAF V600E has been observed, followed by a location in the stomach.…”