KIT mutation in a naïve succinate dehydrogenase‐deficient gastric GIST

Abstract

Up to 85% of gastrointestinal stromal tumors (GIST) harbor mutually exclusive mutations in the KIT or the PDGFRA gene. Among others, known as wild type GIST, succinate dehydrogenase (SDH)‐deficient tumors develop due to genetic or epigenetic alterations in any of four SDH genes. Herein, we present a unique case of SDH‐deficient GIST with an unusual heterogeneous SDHA and SDHB staining pattern and mutations detected in the SDHA and KIT gene. A 50‐year‐old patient presented with a 5 cm large gastric tumor with a multinodular/plexiform growth pattern, mixed epithelioid and spindle cell morphology, and focal pronounced nuclear atypia with hyperchromasia and high mitotic activity. Immunohistochemically, CD117 and DOG‐1 were positive. SDHB and SDHA stains showed loss of expression in some of the nodules, whereas others presented with an unusually weak patchy positivity. Molecular analysis revealed a point mutation in exon 5 of the SDHA gene and a mutation in exon 11 of the KIT gene. We hypothesize that based on the allele frequency of SDHA and KIT mutations the tumor is best regarded as SDH‐deficient GIST in which the SDHA mutation represents the most likely driver mutation. The identified KIT mutation raises the distinct possibility that the KIT mutation is a secondary event reflecting clonal evolution. This is the first case of a treatment naïve GIST harboring a somatic SDHA and a KIT mutation, challenging the dogma that oncogenic mutations in treatment naïve GIST are mutually exclusive.

A multidisciplinary approach in the diagnostic challenge of GIST

“…Small and large intestine GISTs usually consist of spindle cells arranged in sheets or storiform-like patterns, but sometimes may have epithelioid cells. SDH-deficient tumors are often epithelioid and patients with SDH-deficient GISTs are younger than those with tyrosine kinase receptor gene mutant tumors ( 30 ). Extracellular acidophilic globules composed of collagen [skenoid periodic acid-Schiff (PAS)-positive fibers] may be observed and are usually associated with non-aggressive intestinal tumors ( 9 ).…”

KIT Mutation in Gastric Gastrointestinal Stromal Tumor in a Patient With Familial Paraganglioma Syndrome Type 4

“…1 The vast majority of GISTs are sporadic and occur in older adults. 2 In approximately 5% of cases, there is an association with a genetic or idiopathic multi-tumor syndrome, including type 1 neurofibromatosis, familial GIST syndrome, Carney-Stratakis syndrome, and Carney triad. 3 GIST tumors can be subclassified into succinate dehydrogenase (SDH)-competent and SDH-deficient groups.…”

“…3 GIST tumors can be subclassified into succinate dehydrogenase (SDH)-competent and SDH-deficient groups. 2 The SDH enzyme complex is located in the inner mitochondrial membrane and connects the oxidation of succinate to fumarate in the Krebs cycle to the reduction of coenzyme Q in the mitochondrial electron transport chain. 4 It is composed of four subunits (SDH A to D).…”

“…Other SDH-competent GISTs include tumors with NF1, BRAF mutations, or other rare mutations in ARID1A, ARID1B, CBL, FGFR1, NRAS, HRAS, KRAS, MAX, MEN1, and PIK3CA as well as novel gene fusions (KIT-PDGFRA and ETV6-NTRK3). 2 The SDH-deficient GIST group includes the majority of pediatric GISTs, some sporadic adult cases, and GIST syndromes including the Carney triad and Carney-Stratakis-Syndrome. 2 The Carney triad consists of gastric GIST, paraganglioma, and pulmonary chondroma and is seen mainly in girls and young women.…”

“…2 The SDH-deficient GIST group includes the majority of pediatric GISTs, some sporadic adult cases, and GIST syndromes including the Carney triad and Carney-Stratakis-Syndrome. 2 The Carney triad consists of gastric GIST, paraganglioma, and pulmonary chondroma and is seen mainly in girls and young women. 7 GISTs associated with the Carney triad show the loss of expression of SDHB by immunohistochemistry caused by epigenetic silencing of the SDHC gene through promoter hypermethylation.…”