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.

Keywords: Carney-Stratakis syndrome; Carney’s triad; Familial GIST; Hereditary GIST; PDGFRA-mutant syndrome; Succinate dehydrogenase; Syndromic GIST; germline mutations.

Fig. 1

Molecular triggers and intracellular pathways involved in syndromic GIST arousal. Syndromic GISTs reported so far hinge upon alterations of one of the following (evidenced with a halo): KIT, PDGFRA, neurofibromin or SDH. KIT and PDGFRA activation initiates a downstream signaling involving multiple pathways: RAS/RAF/MEK/ERK (MAPK) (left, green hue); JAK/STAT3 (centre, blue hue); and PI3K/AKT/mTOR (top right, yellow/brown hue), stimulating oncogenic gene transcription or protein synthesis. In NF1-associated GISTs, tumoral inactivation of the WT neurofibromin impairs its RAS inhibiting effect, resulting in the activation of MAPK cascade downstream to KIT and PDGFRA. Impairment of the SDH enzymatic complex prevents succinate conversion to fumarate. Accumulated succinate inhibits prolyl-hydroxylase; the missed hydroxylation of HIF1-α prevents the degradation of this molecule which, consequently, heterodimerizes with HIF1-β and translocates into the nucleus acting as an oncogenic transcription factor. Furthermore, succinate accumulation inhibits TET DNA hydroxylases resulting in impaired conversion of 5-methylcytosine to 5-hydroxymethylcytosine, required for DNA demethylation, thereby influencing gene expression