Diagnosis of gastrointestinal stromal tumors: A consensus approach

Fletcher, Christopher D.�M.; Berman, Jules J.; Corless, Christopher L.; Gorstein, Fred; Lasota, Jerzy; Longley, B. Jack; Miettinen, Markku; O’Leary, Timothy J.; Remotti, Helen; Rubin, Brian P.; Shmookler, Barry M.; Sobin, Leslie H.; Weiss, Sharon W.

doi:10.1053/hupa.2002.123545

Cited by 3,009 publications

(3,107 citation statements)

References 31 publications

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“…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).…”

Section: Survival Analysesmentioning

confidence: 98%

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

Wei

et al. 2009

Modern Pathology

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Ezrin, a member of the ezrin-radixin-moesin family, acts as a link between the cell membrane and actin cytoskeleton to integrate cell adhesion-mediated signaling. It implicates tumor progression, metastatic dissemination, and adverse outcomes in several cancer types, including pediatric and adult sarcomas. Although ezrin upregulation was shown by cDNA expression profiling, no study has systematically evaluated the significance of ezrin expression in a large cohort of gastrointestinal stromal tumors (GISTs). Ezrin immunostaining was carried out on tissue microarrays of primary GISTs and assessable in 347 cases, 188 of which were successfully evaluated for mutation variants of KIT and PDGFRA receptor tyrosine kinase (RTK) genes by sequencing with or without screening by denatured high-performance liquid chromatography. These GISTs with known RTK genotypes were dichotomized into two prognostically different groups. The endogenous expression and phosphorylation of ezrin in GIST cell lines were analyzed by western blotting. By immunohistochemistry, ezrin overexpression was present in 66% of GISTs and significantly associated with the nongastric location (P ¼ 0.002) and decreased disease-free survival (P ¼ 0.032, univariately). However, it was not related to the National Institute of Health (NIH) risk category, Ki-67 labeling index, RTK genotypes, and other variables. In multivariate analyses, ezrin overexpression remained independently predictive of adverse outcome (P ¼ 0.008, risk ratio ¼ 2.363), together with Ki-67 labeling index 45% (Po0.001, risk ratio ¼ 3.581), high-risk category (Po0.001, risk ratio ¼ 2.156), and the non-gastric location (P ¼ 0.029, risk ratio ¼ 1.899). Despite the variation in the ezrin expression level, phosphorylated ezrin at threonine 567 was only detectable in GIST882 and GIST48 cells, but not in colonic smooth muscle cells. In conclusion, ezrin is frequently overexpressed in GISTs, especially those arising from the non-gastric sites. Given that its impact is independent of the NIH risk category, cell proliferation, and tumor location, ezrin immunoreactivity represents a valuable prognostic adjunct of GISTs, suggesting a causative role in conferring an aggressive phenotype.

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Section: Survival Analysesmentioning

confidence: 98%

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

Wei

et al. 2009

Modern Pathology

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“…Tumors were classified into very low-, low-, intermediate-and high-grade groups depending on tumor size (2, 5 or 10 cm) and mitotic count (5 or 10 per 50 high-power fields (HPFs)), in accordance with the consensus meeting report at the National Institutes of Health. 23 The tumor grading was assigned by two pathologists (NN and HY).…”

Section: Case Materials and Pathological Evaluationmentioning

confidence: 99%

Prognostic significance of angiogenesis in gastrointestinal stromal tumor

et al. 2007

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Angiogenesis is important in the growth and metastasis of various kinds of solid tumors. To investigate the potential role of angiogenesis in gastrointestinal stromal tumor (GIST), an immunohistochemical analysis was performed in 95 cases of GISTs for microvessel density (MVD) and vascular endothelial growth factor (VEGF) expression. MVD was evaluated with immunohistochemical staining for CD31. A high level of MVD was significantly correlated with overexpression of VEGF, tumor location (intestine4stomach), tumor size (Z5 cm), tumor grade (high4intermediate4low grade) (P ¼ o0.0001, 0.0422, 0.0006, 0.0359, respectively). Of the 70 GISTs analyzed, KIT exon 11 mutations were detected in 45 cases (64.3%) and KIT exon 9 mutations in two cases (2.9%). No mutations were found in KIT exons 13 and 17, and platelet-derived growth factor receptor-alpha exons 12 and 18. Interestingly, VEGF expression level was significantly higher in the non-KIT exon 11 mutant group than in the KIT exon 11 mutant group (P ¼ 0.0266). In univariate analysis, tumor grade (high grade), tumor size (Z5 cm), mitotic count (Z5/50 high-power fields), Ki-67 labeling index (Z4.6%), MVD (Z7.0/0.95 mm 2 ) and VEGF expression (high) were significantly associated with a shorter period of disease-free survival (P ¼ o0.0001, 0.0199, 0.0055 0.0027, 0.0028 and 0.0302, respectively). In multivariate analysis, tumor grade and MVD were identified as independent worse prognostic factors (P ¼ 0.0007, 0.0152, respectively). In conclusion, our results suggest that the evaluation of MVD and VEGF expression is useful for predicting the aggressive biologic behavior of GIST, and that angiogenesis associated with VEGF may play an important role, at least in part, in the progression of GIST. Modern Pathology (2007) 20, 529-537.

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“…Epithelioid/ mixed GISTs were significantly more often of the high-risk categories according to Fletcher et al (P ¼ 0.001) and Miettinen and Lasota (P ¼ 0.001). 1,6 While there was no significant difference in the expression of G1-phase cyclin D1 or the G1/S-phase transcription factor E2F1, the epithelioid/mixed GISTs had a significantly higher expression of the G2-phase cyclin B1 (P ¼ 0.04), and also of the G1-to M-phase proliferation marker Ki67 (P ¼ 0.005). To evaluate whether there was a site-dependent difference, we analyzed KIT-mutated GISTs from the stomach and from the small and large bowel separately.…”

Section: Comparison Of Histomorphology With Clinicopathological Variamentioning

confidence: 96%

“…In general, GISTs display pure spindled (70%), pure epithelioid (20%) and mixed phenotypes. 1 However, this distribution varies greatly with the anatomical site. In the largest series published by the Armed Forces Institute of Pathology (AFIP), the spindled, epithelioid and mixed phenotypes comprised 43, 27 and 30% of gastric, and 86, 5 and 9% of small bowel GISTs, respectively.…”

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confidence: 99%

Epithelioid/mixed phenotype in gastrointestinal stromal tumors with KIT mutation from the stomach is associated with accelerated passage of late phases of the cell cycle and shorter disease-free survival

et al. 2011

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In gastrointestinal stromal tumors (GISTs), the occurrence of an epithelioid/mixed phenotype has been correlated to PDGFRA mutations, gastric localization and favorable outcome. On the other hand, the prognostic significance of an epithelioid/mixed growth pattern occasionally observed in GISTs with KIT mutation is unclear. The aim of this study was to evaluate the prognostic significance of an epithelioid/mixed phenotype in correlation to anatomical localization, genotype, and expression of cell-cycle markers in a series of 116 primary GISTs with KIT mutation on a tissue microarray. Independent of their anatomical localization, the majority of KIT-mutated GISTs displayed a pure spindled phenotype (72%), with the remaining tumors showing an epithelioid/mixed growth pattern. In KIT-mutated GISTs from the stomach, the occurrence of an epithelioid/ mixed growth pattern was significantly correlated with larger tumor diameters (P ¼ 0.005), higher mitotic counts (P ¼ 0.0001), high-risk category (P ¼ 0.001), higher expression of the G2-phase cell-cycle marker cyclin B1 (P ¼ 0.04), higher expression of the G1 to M-phase proliferation marker Ki67 (P ¼ 0.02) and a significantly shorter disease-free survival (P ¼ 0.003) compared with tumors with pure spindled morphology. In contrast, there were no significant differences between pure spindled and epithelioid/mixed GISTs from the small/large bowel. Our findings indicate that the epithelioid/mixed phenotype in KIT-mutant gastric GISTs represents a secondary tumor growth pattern associated with tumor progression and adverse outcome, probably through accelerated G1/S-phase restriction point passage.

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Diagnosis of gastrointestinal stromal tumors: A consensus approach

Cited by 3,009 publications

References 31 publications

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

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

Prognostic significance of angiogenesis in gastrointestinal stromal tumor

Epithelioid/mixed phenotype in gastrointestinal stromal tumors with KIT mutation from the stomach is associated with accelerated passage of late phases of the cell cycle and shorter disease-free survival

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