Gastrointestinal stromal tumours (GISTs) negative for KIT (CD117 antigen) immunoreactivity

Dębiec‐Rychter, Maria; Wasąg, Bartosz; Stul, Michel; Wever, Ivo De; Oosterom, Allan Van; Hagemeijer, Anne; Sciot, Raf

doi:10.1002/path.1546

Cited by 181 publications

(159 citation statements)

References 20 publications

Supporting

Mentioning

142

Contrasting

Unclassified

Order By: Relevance

“…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%

“…8 The presence of such PDGFRA mutations has been linked to gastric location of tumor, epithelioid morphology and lack of KIT expression in some cases. [3][4][5]18 More recently, missense mutation in PDGFRA TK1 (exon 14) leading to N659K amino-acid substitution was reported in one gastric GIST. 2 Although subsequently two more tumors with such a PDGFRA mutation were reported, 18 little is known about frequency and clinicopathologic profile of GISTs carrying this type of PDGFRA mutation.…”

mentioning

confidence: 99%

“…However, in some cases KIT immunoreactivity is weak or undetectable. [2][3][4][5] Activation of KIT by its ligand leads to downstream phosphorylation of substrate proteins and subsequently activates networks of signal transduction pathways that regulate cell proliferation, survival, apoptosis, motility and other important cell functions. 6 Mutually exclusive gain-of-function KIT or PDGFRA (platelet-derived growth factor receptor a) mutations have been documented in a majority of GISTs and are believed to be a major force in their pathogenesis.…”

mentioning

confidence: 99%

See 2 more Smart Citations

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

Lasota

Stachura

Miettinen

2006

Laboratory Investigation

124

View full text Add to dashboard Cite

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.

show abstract

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

See 1 more Smart Citation

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

Lasota

Stachura

Miettinen

2006

Laboratory Investigation

124

View full text Add to dashboard Cite

show abstract

“…9,41,42 These markers are highly selective for GISTs over other mesenchymal tumors. Further, as discussed below, both genotypes are associated with cytogenetic changes that are distinctive for GIST.…”

Section: Platelet-derived Growth Factor Receptor-amentioning

confidence: 99%

“…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

View full text Add to dashboard Cite

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.

show abstract