Inflammatory fibroid polyps harbour mutations in the platelet‐derived growth factor receptor alpha (PDGFRA) gene

Abstract

Inflammatory fibroid polyps (IFPs) are mesenchymal tumours which arise in the submucosa and mucosa of the gastrointestinal tract. To date, the pathogenesis is unknown and IFPs are considered reactive and non-neoplastic lesions. Investigating a series of 23 IFPs, we made the observation that the tumours consistently express PDGFRA. To further elucidate the pathogenetic role of PDGFRA, we performed mutational analyses of exons 10, 12, 14, and 18. As IFPs are characterized by an inflammatory infiltrate rich in eosinophils, we used fluorescence in situ hybridization in a subset of tumours to investigate a possible FIP1L1-PDGFRA translocation which is known as the cause of hypereosinophilic syndrome (HES). Sixteen IFPs (70%) harboured activating mutations in exons 12 and 18, respectively: V561D (n = 1), R560SDelta561-567 (n = 1), Delta559-561D591H (n = 1), S566RDelta567-571 (n = 3), D842V (n = 7), D842I (n = 1), Delta842-845 (n = 1), and Delta845-848 (n = 1). These mutations equal pathogenic mutations detected in gastrointestinal stromal tumours previously. Activating mutations in exons 10 and 14 were not noted. None of the cases revealed the FIP1L1-PDGFRA translocation. Considering the remarkable number of activating mutations detected in our series, we conclude that the vast majority of IFPs harbour gain-of-function mutations in the PDGFRA gene. The presence of PDGFRA mutations questions the reactive nature of IFPs and raises the possibility of a neoplastic process.

Telocytes are the physiological counterpart of inflammatory fibroid polyps and PDGFRA‐mutant GISTs

“…Consequently, by analogy with what has been inferred from ICCH in germline KIT ‐mutant settings regarding the relationship between ICC and KIT ‐mutant GIST, TC can be considered the physiological counterpart of IFP. Consistently, it is noticeable that a subtype of TC, differing from the other GI TCs because of its lack of CD34 expression, has been described in the axes of intestinal villi both in humans and mice27 and that intestinal IFPs, unlike gastric ones, are often CD34‐ 1, 2…”

“…Immunohistochemically, the lesional mesenchymal cells express CD34 and platelet‐derived growth factor receptor alpha (PDGFRA). Most IFPs bear PDGFRA mutations 1, 2. A subset of GI stromal tumours (GISTs), accounting for 6%‐7% of the total, also harbours PDGFRA mutations, similar to IFPs 3.…”

PDGFRA-mutant syndrome

“…PDGFRA mutations are reported in about 74% and 55% of gastric and small-intestinal inflammatory fibroid polyps, respectively, 7,8 and in 6-7% of GISTs. 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.…”

“…4 However, GISTs are not the only gastrointestinal PDGFRA-mutant tumors; in fact, shortly after the INF/NF3b genotype was described, PDGFRA mutations were also found in inflammatory fibroid polyps. [5][6][7][8] More recently, CD34 + fibrous tumors of uncertain classification (henceforth simply referred to as 'fibrous tumors') have been reported in a germline PDGFRA-mutated context, constituting another possible PDGFRAmutant tumor. 9 Although GISTs and inflammatory fibroid polyps can sometimes be multiple and/or syndromic, [9][10][11][12][13][14] germline PDGFRA mutations have rarely been described, with only two familial examples.…”

Gastrointestinal tract spindle cell lesions—just like real estate, it's all about location

“…Inflammatory fibroid polyps have been reported in a family in which three generations of women have had these 'Devon polyposis' lesions. 41,42 These polyps were believed to be reactive in the past, but they are now known to have mutations in the platelet-derived growth factor receptor alpha (PDGFRA) gene, 43 a feature that they share with a subset of GISTs. However, in constrast to GISTs, inflammatory fibroid polyps are always benign.…”