Paediatric and adolescent wild-type syndromic GISTs

Gastrointestinal stromal tumours (GISTs) lacking KIT or PDGFRA mutations account for approximately 10–15% of all cases. Given their extreme rarity, centralised pathological diagnosis is strongly recommended.

SDH-deficient GISTs

Approximately 30-40% of KIT and PDGFRA WT-GIST are driven by a defect in the succinate dehydrogenase (SDH) complex. SDH complex consists of four different subunits (A, B, C, D) and it is involved in the mitochondrial respiratory chain, which regulates both cellular oxygenation and metabolism.

SDH-deficient GISTs are marked by the loss of SDH-B expression and characterized by the over-expression of the insulin growth factor 1 receptor (IGF1R).

They show distinctive clinical and pathological features, including a younger age at diagnosis, a prevalence in female and a mixed epithelioid and spindle cell morphology. The stomach is a common primary site, there is a tendency toward lymph nodal involvement and natural history tend to be indolent, even if often metastatic upfront.

SDH-B deficient GISTs can be both sporadic, including most paediatric as well as a proportion of young adult GISTs, or syndromic, when they occur in the context of hereditary and non-hereditary syndromes such as the Carney triad or Carney-Stratakis syndrome.

  • Carneys Triad Syndrome (CTS) is a non-hereditary tumour syndrome characterized by the presence of at least two of the following: GIST, pulmonary chondroma, and/or functioning extra-adrenal paraganglioma. CTS patients, female for the vast majority, do not have SDH germline mutations, but SDH-deficiency may be mediated by allelic losses in SDH. CTS is not very common in SDH-deficient GIST patients and, overall, it is an extremely rare syndrome with less than 50 cases currently reported in literature.
  • Carney-Stratakis syndrome (CSS) is a rare hereditary syndrome combining gastric GIST and paraganglioma, often at multiple sites. The disease is driven by a loss-of-function germline mutation in SDH subunits B, C, or D. In contrast with CTS, CSS patients split equally between male and female.

Non SDH-deficient GISTs

BRAF V600E mutation can be detected in approximately 5-10% of the subgroup of the remaining KIT/PDGFRA wild-type GIST, but not SDH-deficient. They tend to arise in small intestine and seem to be associated with a better outcome.

  • Quadruple-negative GISTs” are defined as KIT/PDGFRA/BRAF/SDH wild-type GIST. NF1 gene mutations can be often detected in quadruple-negative GISTs and are commonly constitutional, suggesting that a significant proportion of patients with apparently sporadic quadruple-negative GISTs are affected by an underlying neglected neurofibromatosis type 1 syndrome.
  • Neurofibromatosis type 1 syndrome is a condition characterized by café-au-lait spots, iris Lisch nodules, axillary and inguinal freckling, and multiple neurofibromas, caused by mutations in the tumor suppressor NF1 gene. The signs and symptoms of this condition can vary widely among affected people. Syndromic GISTs arising in association with tend to be multicentric and predominantly located in the small bowel.

Return to PAWS-GIST