Association of Platelet-Derived Growth Factor Receptor α Mutations with Gastric Primary Site and Epithelioid or Mixed Cell Morphology in Gastrointestinal Stromal Tumors

Wardelmann, Eva; Hrychyk, Aksana; Merkelbach‐Bruse, Sabine; Pauls, K. Amande M.; Goldstein, Jennifer; Hohenberger, Peter; Losen, Inge; Manegold, Christoph; Büttner, Reinhard; Pietsch, Torsten

doi:10.1016/s1525-1578(10)60510-7

Cited by 151 publications

(124 citation statements)

References 15 publications

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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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Section: Platelet-derived Growth Factor Receptor-amentioning

confidence: 99%

Gastrointestinal stromal tumors: what do we know now?

2014

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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: 80%

“…6 On the other hand, the majority of PDGFRA-mutated GISTs display epithelioid or mixed (predominantly epithelioid) phenotypes. 7,8 Intriguingly, data on the correlation of the histological subtype with the clinical outcome have been inconsistent. The presence of an epithelioid/mixed morphology/ component in GISTs was associated with malignant behavior in GISTs in several studies.…”

mentioning

confidence: 99%

“…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.…”

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confidence: 99%

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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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“…2,20,21 PDGFRA-mutated GISTs show a preference for gastric location, epithelioid morphology, variable or absent KIT expression by immunohistochemistry (IHC), and a more indolent clinical behavior. 21,22 In about 10% of patients, no detectable mutation is identified in either KIT or PDGFRA. In particular, GISTs that occur in pediatric or neurofibromatosis type I patients are nearly always wild type (ie not mutated) for both genes.…”

Section: Review Of Kit and Pdgfra Biologymentioning

confidence: 99%

Targeted therapy of cancer: new roles for pathologists in identifying GISTs and other sarcomas

Antonescu

2008

Modern Pathology

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Once a poorly understood pathologic entity, gastrointestinal stromal tumor (GIST) has emerged in recent years as a distinct oncologic-molecular paradigm that is now a leading model for kinase-targeted therapies in oncology. Most GISTs are KIT-expressing and KIT signaling-driven mesenchymal tumors, many of which have KIT-activating mutations. A small subset of GIST show activating mutations in PDGFRA, encoding a related member of the type III receptor tyrosine kinase family. The revelation of KIT expression as a diagnostic signature of GIST has not only revolutionized the pathologic criteria in classifying GIST, but also shed light on the histogenesis of these tumors. The similarities in KIT immunoreactivity and ultrastructural appearance between GISTs and the intestinal pacemaker, the interstitial cells of Cajal (ICC), suggested that GISTs derive from or differentiate toward the ICC lineage. KIT plays a significant role in proliferation, survival, and differentiation of hematopoietic stem cells, mast cells, melanocytes, and interstitial cells of Cajal; activating KIT mutations have been identified in tumors affecting most of these cell lineages. This review will include a summary of the biology behind the specific targeted therapies, emphasizing the central role of KIT and PDGFRA oncogenic mutations in GISTs and their clinical and pathologic correlates. The role of KIT immunohistochemistry vs mutation testing will be discussed, with an insight into the indications for KIT/PDGFRA genotyping in GIST. The morphologic and molecular changes that appear with imatinib treatment, such as response and acquired imatinib resistance, are being discussed. The success GIST story based on targeted molecular paradigm may be applied in other imatinib-responsive sarcoma, such as dermatofibrosarcoma protuberans.

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Association of Platelet-Derived Growth Factor Receptor α Mutations with Gastric Primary Site and Epithelioid or Mixed Cell Morphology in Gastrointestinal Stromal Tumors

Cited by 151 publications

References 15 publications

Gastrointestinal stromal tumors: what do we know now?

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

Targeted therapy of cancer: new roles for pathologists in identifying GISTs and other sarcomas

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