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

Abstract

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.

PDGFRA-mutant syndrome

“…Sporadic PDGFRA-mutant GISTs are known to be linked to a gastric location. 5,26 Interestingly, this happens even in the case of germline PDGFRA mutations, a context where other PDGFRA-driven tumors (inflammatory fibroid polyps and fibrous tumors if considered separately) arise also in the bowel (as shown here and in refs. 9 and 10).…”

“…5,6 PDGFRA exon-14 mutations occur in o 1% of GISTs 26 and, to the best of our knowledge, have very rarely been reported in inflammatory fibroid polyps. 27 P653L PDGFRA mutation is hitherto unreported.…”

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

“…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.…”

“…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.…”

Gastric GISTs: Analysis of c-Kit, PDGFRA and BRAF mutations in relation to prognosis and clinical pathological characteristics of patients – A GIRCG study

“…7,15,18,21,31 The higher PDGFRA mutation frequency observed in gastric GISTs is in accordance with the better prognosis observed for this type of tumor. 12,30,32 Our study revealed the potential prognostic relevance of the type and position of KIT mutations in untreated resected gastric GISTs, in addition to classic pathological criteria such as dimension, mitosis, Miettinen risk stratification, ulceration and necrosis. Tumors with mutations (especially deletions), affecting codons 557, 558 or 559 of KIT exon 11 would appear to be a distinct subset of gastric GISTs with malignant clinical Table 3 Results from univariable analysis using the Cox proportional hazards model.…”