Syndromic gastrointestinal stromal tumors

Abstract

Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal neoplasms of gastrointestinal tract. They feature heterogeneous triggering mechanisms, implying relevant clinical differences. The vast majority of GISTs are sporadic tumors. Rarely, however, GIST-prone syndromes occur, mostly depending on heritable GIST predisposing molecular defects involving the entire organism. These conditions need to be properly identified in order to plan appropriate diagnostic, prognostic and therapeutic procedures.Clinically, GIST-prone syndromes must be thought of whenever GISTs are multiple and/or associated with accompanying signs peculiar to the background tumorigenic trigger, either in single individuals or in kindreds. Moreover, syndromic GISTs, individually considered, tend to show distinctive features depending on the underlying condition. When applicable, genotyping is usually confirmatory.In GIST-prone conditions, the prognostic features of each GIST, defined according to the criteria routinely applied to sporadic GISTs, combine with the characters proper to the background syndromes, defining peculiar clinical settings which challenge physicians to undertake complex decisions. The latter concern preventive therapy and single tumor therapy, implying possible surgical and molecularly targeted options.In the absence of specific comprehensive guidelines, this review will highlight the traits characteristic of GIST-predisposing syndromes, with particular emphasis on diagnostic, prognostic and therapeutic implications, which can help the clinical management of these rare diseases.

Classification of gastrointestinal stromal tumor syndromes

“…Usually, patients with PDGFRA-mutated GISTs tend not to have metastases to lymph nodes. Specifically in PDGFRAmutant syndromal GISTs, there is a strong female predominance (Ricci 2016). Contrasting somewhat the finding in kindreds affected by germline KIT mutation, patients with PDGFRA germline mutations never have diffuse hyperplasia of interstitial cells of Cajal, instead of having only focal hyperplasia (Chompret et al 2004).…”

“…In fact, to date more than 31 families and 6 individuals have been found to have germline mutations in KIT, most often in exon 11 but also in exons 8, 9, 13 and 17 (Ricci 2016). Consistent with its oncogenic function, the inheritance pattern in these families is autosomal-dominant, and the youngest reported age of GIST diagnosis is 15, with median age of 40-50 (Li et al 2005, Kleinbaum et al 2008.…”

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

“…We herein report a detailed morphological and immunophenotypical analysis of the diffuse stromal proliferation described in the GI wall in PDGFRA ‐mutant syndrome7 and of its relationship with IFP and GIST, by exploiting the exceptional opportunity offered by its remarkable manifestation, together with the presence of these tumours, in an individual from a kindred previously published by the authors 9…”

“…However, to date, no ICCH has been detected either in human germline PDGFRA ‐mutants or in mice generated for the conditional expression of mutant PDGFRA , arguing against a relationship between ICCs and PDGFRA ‐driven GISTs. Conversely, GI stromal cell hyperplasia has been described in these conditions, especially at submucosal level 7, 8, 9, 10…”

Malignant melanoma of sun-protected sites: a review of clinical, histological, and molecular features

“…There are no reports of KIT germline mutations leading to melanoma, despite nearly 40 individuals or kindreds with identified KIT mutations associated with gastrointestinal stromal tumors. 56,58,59 Since exposure to UV radiation is unlikely to be a source of mutagenesis, there have been several attempts took to look at other environmental risk factors for the development of acral or mucosal melanoma. Two case-control studies identified previous trauma as having significant associations with acral melanoma.…”