Differential expression of KIT/PDGFRA mutant isoforms in epithelioid and mixed variants of gastrointestinal stromal tumors depends predominantly on the tumor site

Wasąg, Bartosz; Dębiec‐Rychter, Maria; Pauwels, Patrick; Stul, Michel; Vranckx, Hilde; Oosterom, Allan Van; Hagemeijer, Anne; Sciot, Raf

doi:10.1038/modpathol.3800136

Cited by 92 publications

(82 citation statements)

References 16 publications

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“…3 Tumors with these mutations were found to be associated with gastric location and epithelioid morphology. [3][4][5]18,25 Considering the previous and current study, it appears that the presence of any type of PDGFRA mutation is associated with gastric location and predominantly epithelioid cytologic features. However, a few exceptions have been reported including occasional finding of PDGFRA-mutant GISTs in intestines, mesentery and omentum.…”

Section: Discussionmentioning

confidence: 99%

GISTs with PDGFRA exon 14 mutations represent subset of clinically favorable gastric tumors with epithelioid morphology

Lasota

Stachura

Miettinen

2006

Laboratory Investigation

124

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Gastrointestinal stromal tumors (GISTs) are common mesenchymal tumors of the gastrointestinal tract. Activating KIT or PDGFRA (platelet-derived growth factor receptor a) mutations have been shown to be a major force in GIST pathogenesis. Recently, a previously undescribed N659K PDGFRA exon 14 mutation has been reported in GISTs. The purpose of this study was to evaluate the frequency of GISTs with PDGFRA exon 14 mutations and define the clinicopathologic profile of such tumors. In all, 200 GISTs negative for mutations in KIT exons 9, 11, 13 and 17 and PDGFRA exons 12 and 18 were evaluated for PDGFRA exon 14 mutations by PCR amplification and direct sequencing. Mutations were found in 11 of 119 (9%) gastric GISTs. None of the 81 GISTs from other than gastric location had such a PDGFRA mutation. A majority of these mutations (eight cases) represented simple 2125C4A or C4G missense mutations, leading to substitution of the lysine for asparagine (N659K). However, in two cases, 2123A4T missense mutations leading to substitution of the tyrosine for asparagine (N659Y) was found instead. Of 11 PDGFRA N659-mutant GISTs, 10 had pure epithelioid morphology. One tumor had mixed, predominantly spindle and focally epithelioid cell morphology. Frequency of PDGFRA N659-mutant GISTs among pure epithelioid GISTs was almost 19%. Immunohistochemically, the majority (64%) of these tumors lacked KIT expression or showed only focal scattered KIT positivity. Tumor size ranged from 2.5 to 16 cm (average 7.1 cm). Low mitotic activity, r5 mitoses/50 high power field was detected in six GISTs including larger, 45 cm tumors. Based on mitotic activity and tumor size, six tumors were classified as probably benign with very low malignant potential. Low to moderate malignant potential and high malignant potential was suggested in three and two tumors, respectively. In four cases with moderate or high malignant potential GISTs, a long-term follow-up (average 235.5 months) showed favorable course of disease.

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Section: Discussionmentioning

confidence: 99%

GISTs with PDGFRA exon 14 mutations represent subset of clinically favorable gastric tumors with epithelioid morphology

Lasota

Stachura

Miettinen

2006

Laboratory Investigation

124

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“…Further, as discussed below, both genotypes are associated with cytogenetic changes that are distinctive for GIST. 37,43 Despite these molecular similarities, PDGFRAmutant GISTs do show features distinctive from KIT-mutant GISTs, including differences in gene expression profile, 39,44 a striking predilection for the stomach, variable (sometimes negative) expression of KIT, 20,41,[45][46][47][48] and a generally lower potential for malignancy. 49 Morphologically, however, PDGFRAmutant GISTs are not reliably distinguishable from KIT-mutant GISTs ( Figure 1).…”

Section: Platelet-derived Growth Factor Receptor-amentioning

confidence: 99%

Gastrointestinal stromal tumors: what do we know now?

2014

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Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the GI tract, arising from the interstitial cells of Cajal, primarily in the stomach and small intestine. They manifest a wide range of morphologies, from spindle cell to epithelioid, but are immunopositive for KIT (CD117) and/or DOG1 in essentially all cases. Although most tumors are localized at presentation, up to half will recur in the abdomen or spread to the liver. The growth of most GISTs is driven by oncogenic mutations in either of two receptor tyrosine kinases: KIT (75% of cases) or PDGFRA (10%). Treatment with tyrosine kinase inhibitors (TKIs) such as imatinib, sunitinib, and regorafenib is effective in controlling unresectable disease; however, drug resistance caused by secondary KIT or PDGFRA mutations eventually develops in 90% of cases. Adjuvant therapy with imatinib is commonly used to reduce the likelihood of disease recurrence after primary surgery, and for this reason assessing the prognosis of newly resected tumors is one of the most important roles for pathologists. Approximately 15% of GISTs are negative for mutations in KIT and PDGFRA. Recent studies of these so-called wild-type GISTs have uncovered a number of other oncogenic drivers, including mutations in neurofibromatosis type I, RAS genes, BRAF, and subunits of the succinate dehydrogenase complex. Routine genotyping is strongly recommended for optimal management of GISTs, as the type and dose of TKI used for treatment is dependent on the mutation identified.

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“…On the other hand, the predominance of the epithelioid/mixed phenotypes in PDGFRA-mutant GISTs demonstrated in several previous studies 7,8,[13][14][15] suggests a primary commitment of this subset of GISTs toward an epithelioid phenotype. This view is supported by the generally favorable clinical course of PDGFRAmutated GISTs, which contrasts with our findings in epithelioid/mixed KIT-mutant GISTs.…”

Section: Discussionmentioning

confidence: 83%

“…6,[9][10][11][12] On the other hand, PDGFRA-mutated epithelioid GISTs frequently exhibit a less aggressive behavior. 7,8,[13][14][15] Recently, we identified a morphological shift from spindled to epithelioid phenotype in GISTs that were composed of well-circumscribed spindled and epithelioid components. 16 The epithelioid component displayed unfavorable histological features (higher cellularity, higher mitotic activity and higher Ki67 index), and was associated with more aggressive clinical course.…”

mentioning

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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Differential expression of KIT/PDGFRA mutant isoforms in epithelioid and mixed variants of gastrointestinal stromal tumors depends predominantly on the tumor site

Cited by 92 publications

References 16 publications

GISTs with PDGFRA exon 14 mutations represent subset of clinically favorable gastric tumors with epithelioid morphology

GISTs with PDGFRA exon 14 mutations represent subset of clinically favorable gastric tumors with epithelioid morphology

Gastrointestinal stromal tumors: what do we know now?

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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