Myxoid epithelioid gastrointestinal stromal tumor (GIST) with mast cell infiltrations: A subtype of GIST with mutations of platelet-derived growth factor receptor alpha gene

Sakurai, Shunsuke; Hasegawa, Tadashi; Sakuma, Yoshiki; Takazawa, Yutaka; Motegi, Atsushi; Nakajima, Takashi; Saito, Ken; Fukayama, Masashi; Shimoda, Tadakazu

doi:10.1016/j.humpath.2004.07.008

Cited by 87 publications

(70 citation statements)

References 27 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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“…Very little is known about the possible role of non-mutated MCs infiltrating GIST tumor masses. Pronounced MC infiltration has been described in myxoid epithelioid GISTs, a subtype characterized by low/negative c-Kit expression, whose tumorigenesis depends instead on Pdgfra mutations (Sakurai et al, 2004), suggesting that preserved c-Kit function in MCs is a prerequisite for their tumor-promoting activity.…”

Section: Gain-of-function Mutationsmentioning

confidence: 99%

Tumor-intrinsic and -extrinsic roles of c-Kit: mast cells as the primary off-target of tyrosine kinase inhibitors

et al. 2010

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c-Kit tyrosine kinase receptor and its ligand stem cell factor have multiple functions during development, whereas in adulthood they are mostly needed for stem cell (SC) maintenance and mast cell (MC) biology. c-Kit plays an essential tumor-cell-intrinsic role in many types of cancer, either providing the tumorigenic force when aberrantly activated or conferring stem-like features characterizing the most aggressive variants. A tumorcell-extrinsic role occurs through c-Kit-dependent accessory cells (such as MCs) that infiltrate tumors and deeply influence their progression. c-Kit-targeted therapy with tyrosine kinase inhibitors (TKIs) may ideally work against both tumor and stromal cells. Here, we summarize the tumor-intrinsic and -extrinsic roles of c-Kit in cancer and discuss TKIs with their on-and off-targets, with a special emphasis on MCs as paradigmatic c-Kit-dependent accomplices for tumor progression.

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“…The postimatinib samples showed a high score 7,8,22 of The residual cellularity, again spindle in shape, was (g) immunoreactive for PDGFRA and (h) very weakly for KIT.…”

Section: Short Reportmentioning

confidence: 99%

Imatinib response in two GIST patients carrying two hitherto functionally uncharacterized PDGFRA mutations: An imaging, biochemical and molecular modeling study

Dileo

Pricl

Tamborini

et al. 2010

Intl Journal of Cancer

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Beside the well known “in vivo” and “in vitro” Imatinib resistant D842V mutation in PDGFRA receptor, very few are the information concerning the “in vivo” Imatinib activity with respect to the other PDGFRA mutations for which only “in vitro” data are available. Two patients carrying PDGFRA mutations in exons 18 (involving residues DIMH842‐845) and 12 (V561D), respectively, were treated with Imatinib at a dose of 400 mg/day. According to Response Evaluation Criteria in Solid Tumors criteria, after a median treatment of 7 months both patients showed clinical partial response, and underwent surgery of the minimal residual disease. Tumor response was confirmed pathologically. In both patients, analyses of PDGFRA performed on pre‐ and/or post‐treatment material were compared to affinity data of the mutated receptor towards the inhibitor. Molecular modeling evidence was found to be consistent with sensitivity of mutated PDGFRA receptors to Imatinib. Thus, the “in vivo” evidence that these two mutations of PDGFRA are sensitive to Imatinib was confirmed by a multidimensional approach comprising “in silico” experiments that, in association to molecular and biochemical analyses, constitutes a powerful tool to predict Imatinib sensitivity, clinically beneficial in the treatment of these tumors with molecularly targeted therapies.

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Myxoid epithelioid gastrointestinal stromal tumor (GIST) with mast cell infiltrations: A subtype of GIST with mutations of platelet-derived growth factor receptor alpha gene

Cited by 87 publications

References 27 publications

Gastrointestinal stromal tumors: what do we know now?

Gastrointestinal stromal tumors: what do we know now?

Tumor-intrinsic and -extrinsic roles of c-Kit: mast cells as the primary off-target of tyrosine kinase inhibitors

Imatinib response in two GIST patients carrying two hitherto functionally uncharacterized PDGFRA mutations: An imaging, biochemical and molecular modeling study

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