Gain-of-function PDGFRA mutations, earlier reported in gastrointestinal stromal tumors, are common in small intestinal inflammatory fibroid polyps. A study of 60 cases

Abstract

The inflammatory fibroid polyp is a rare benign lesion occurring throughout the digestive tract. It usually forms a solitary mass, characterized by a proliferation of fibrovascular tissue infiltrated by a variable number of inflammatory cells. The etiology of this lesion is unknown and conflicting histogenetic theories have been proposed. Recently, mutations in platelet-derived growth factor receptor (PDGFRA) and PDGFRA expression were reported in gastric inflammatory fibroid polyps. In this study, PDGFRA exons 12, 14, and 18 were screened for activating mutations in 60 small intestinal inflammatory fibroid polyps. In addition, the PDGFRA expression was evaluated immunohistochemically. Mutations in PDGFRA were identified in 33 of 60 (55%) cases, whereas 95% expressed PDGFRA. There were 26 deletions, three deletion-insertions, duplication, and single nucleotide substitution in exon 12, and a single nucleotide substitution and deletion in exon 18. The majority (n ¼ 23) of exon 12 deletions were 1837_1851del leading to S566_E571delinsR. However, 1835_1852delinsCGC leading to the same S566_E571delinsR, were found in two tumors. Three inflammatory fibroid polyps had 1836_1850del leading to S566_E571delinsK. A complex deletion-insertion affecting a similar region (1837_1856delinsGATT-GATGATC) and leading to S566_I573delinsRIDDL was identified once. In addition, duplication and single nucleotide substitution were found 5 0 to the common inflammatory fibroid polyp mutational 'hot spot'. These mutations consist of 1808_1828dup leading to I557_E563dup, and 1821T4A resulting in 561V4D substitution. A 2664A4T and 2663_2674del leading to 842D4V and D842_H845del, respectively, were identified in exon 18. Similar gain-of-function PDGFRA mutations reported in gastrointestinal stromal tumors have been considered to be a driving pathogenetic force. This study showed consistent expression and common mutational activation of PDGFRA in small intestinal inflammatory fibroid polyps as in their gastric counterparts, and these lesions should be considered PDGFRA-driven benign neoplasms. We also suggest that these polyps may develop from earlier described PDGFRA-positive mesenchymal cells distributed along the villus membrane after oncogenic PDGFRA activation.

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.…”

“…No physiological counterpart has hitherto been described for IFPs, although it has been suggested that they may develop from PDGFRA‐positive mesenchymal cells found along the villus membrane in the small intestine 2, 4. Conversely, GISTs as a whole are commonly considered to be related to interstitial cells of Cajal (ICCs) 5.…”

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.…”