Telocytes as possible precursors of PDGFRA-mutant gastrointestinal mesenchymal tumors—rejoinder

We read with interest the reply by Manley et al to our letter supporting telocytes (TCs) as possible precursors of gastrointestinal mesenchymal tumors [1], [2]. We would like to clarify that the tumors we think derive from TCs along with inflammatory fibroid polyps (IFPs) are actually PDGFRA-mutant gastrointestinal stromal tumors (GISTs), that is, “genuine” GISTs (concurring to form this tumor group together with the other GIST subtypes, distinguished by diverse pathogenetic mechanisms, which likewise feature distinctive morphology and clinical features). Therefore, in this regard, the definition “PDGFRA-mutant polyps arising sporadically and syndromically within the stomach and diagnosed as GISTs,” ascribed to us by Manley and colleagues, is inaccurate. Actually, PDGFRA-mutant GISTs are in most cases not polypoid, rather constituting intramural masses, with clear-cut histologic and immunophenotypical features [3]. We have recently produced morphogenetic evidence of the origin of these tumors, along with typical IFPs, from TCs, exploiting the opportunity offered by the concurrent presence of a prominent TC hyperplasia [4]. In the same article, we proposed to define IFP as “telocytoma” because this term conveys both the neoplastic and histotypic natures of these tumors. Conversely, tumors typical of PDGFRA-mutant syndrome whose nosology is less straightforward are the fibrous tumors defined as GISTs by De Raedt and colleagues [5] and described also by Carney and Stratakis [6] and by ourselves [7]. These tumors not only do not exhibit morphologic features typical of GISTs but also do not express CD117 and DOG1; in addition, they have been found mostly in the small intestine, unlike PDGFRA-mutant GISTs, which show a strong predilection for the stomach. We have previously discussed in depth this issue, supporting these “fibrous tumors” as a possible variant of IFP [7]. In conclusion, in our opinion, PDGFRA mutations can determine 3 types of lesions in the gastrointestinal tract: (1) typical PDGFRA-mutant GIST, (2) typical IFP (telocytoma) and its variant formerly defined as “fibrous tumors”, and (3) TC hyperplasia. Of note, the latter and the “fibrous tumors” variant of IFP (telocytoma) hitherto have been described exclusively in germline PDGFRA mutant settings, that is, in PDGFRA-mutant syndrome.