Table 2.
Summary of data on the clinical and molecular characteristics of hereditary GISTs
| Subtype/syndrome | Primary molecular abnormality | Clinicopathological features | Potential therapies/clinical notes | References |
|---|---|---|---|---|
| SDHx (HPPS) | Germline pathogenic variants in the SDHx genes, SDHA/B/C/D germline mutations | Early age at diagnosis; often multifocal; possible lymph node involvement; increased tendency to metastasize; coexistence of paraganglioma/pheochromocytoma and other neoplasms (including RCC) | Importance of genetic testing; possibility of cascade testing in the family | [40, 46] |
| Carney–Stratakis syndrome | Germline pathogenic variants or deletions in SDHB/SDHC/SDHD | Autosomal dominant inheritance; both sexes; onset in childhood/ adolescence; multiple paragangliomas and multifocal gastric GISTs | Genetic testing; differentiation from Carney triad; possible SDHC epimutations | [91, 92] |
| Germline KIT PV | Germline KIT pathogenic variants | Rare; multiple GISTs; possible skin hyperpigmentation; also reported in families with mastocytosis | No clear genotype–phenotype correlation; limited data | [93, 94] |
| Germline PDGFRA PV | Germline PDGFRA pathogenic variants | Very rare; multiple GISTs; incomplete penetration; phenotype: thickening of the facial skin, broad hands/feet, premature tooth loss | Limited data; characteristic clinical phenotype | [82, 83] |
| GIST in the context of NF1 | Inactivation of the NF1 gene → activation of the RAS pathway | Incidence of NF1: ~ 1:4000–5000; ~ 50% de novo mutations; GIST in about 7% of patients; usually the small intestine; multifocality; low mitotic activity; spindle cell morphology; indolent course; no KIT/PDGFRA/BRAF/SDH mutations | Surgery for localized disease; resistance to imatinib and other TKIs; possible palliative treatment; observation for slow-growing tumors; potential approaches: MEK inhibitors (e.g., selumetinib – no studies in NF1 GISTs); participation in clinical trials to be considered | [90] |
GIST gastrointestinal stromal tumors, HPPS hereditary paraganglioma-pheochromocytoma syndrome, PDGFRA platelet-derived growth factor receptor alpha, PV pathogenic variant, RCC renal cell carcinoma, SDH succinate dehydrogenase, TKIs tyrosine kinase inhibitors