Gastrointestinal stromal tumor (GIST) originates from the Interstitial Cells of Cajal, the pacemaker cells that produce the slow mechanical muscle contractions responsible for moving food through the digestive tract. Most GISTs have a mutation in either the c-KIT gene or the Platelet-Derived Growth Factor Receptor (PDGFR) gene. Periodically either the BRAF or the NF-1 gene is identified as being mutated in GIST patients who lack c-kit or PDGFRA mutations. GIST tumors without a KIT, PDGFRA, BRAF, or NF-1 mutation are described as being Wildtype (WT), likening them to the phenotype found in the general population. KIT and PDGFRA-mutant GIST patients frequently have a very good response to Imatinib (Gleevec). This has not proven to be the case with WT GIST.
KIT/PDGFR mutations are gene defects for growth factor receptors located on the cell surface; these mutations cause the cell growth switch to stay on all of the time. These cells are said to have an activating oncogene that can be likened to having a stuck accelerator on a car. Wildtype GISTs do not possess the defective KIT or PDGFRA activating oncogene. Instead, WT GIST tumors are frequently missing a key protein called Succinate Dehydrogenase (SDH) and are referred to as being SDH-deficient. (Conversely, patients who have KIT/PDGFR-mutated GIST are SDH-positive, meaning that they do not have impaired SDH function.) Pediatric GIST patients (those diagnosed at less than 20 years of age) are Wildtype for KIT and PDGFRA mutations.
The SDH gene is located inside the mitochondria of the cell. It is instrumental in converting nutrients to the energy needed by the body. A deficiency of the SDH enzyme results in an accumulation of succinate during the energy conversion cycle. A build-up of succinate causes aberrant build-up of hypoxia-inducible factor (HIF), a situation referred to as pseudohypoxia. The downstream consequences include an accumulation of the growth factors VEGF and EGFR, leading to the oncogenic problem. SDH-deficiency can be likened to having broken brakes on a car.
Wildtype GIST Clinic patients fall into three categories.
1. The first group classification stains SDH-positive on immunohistochemistry (SDH IHC+), meaning that the SDH protein is present. Tumor samples of the patients in this group present with a mixed cell histology, meaning that there is a lot of variation in the look of the cells. The primary tumors can originate in the stomach, the duodenum, or the intestine. These patients tend to be diagnosed at age of 40 or above. Normal presentation is the development of GIST tumors without incidence of paragangliomas or pulmonary chondromas. These patients are described as being SDH-positive.
2. The second group classification stains SDH-negative on immunohistochemistry (SDH IHC-) without an identified SDH gene mutation, deletion, or duplication seen. These patients are usually female and all have had stomach primary tumors. Some have paragangliomas, and some have paragangliomas as well as pulmonary chondromas. This is the youngest group, on average, with a median age at diagnosis of 14 years. These patients are described as being SDH-deficient.
3. The third group classification also stains SDH-negative on immunohistochemistry (SDH IHC-) but by contrast they have an identified SDH gene defect. These patients can also present with paragangliomas and chondromas. They are typically somewhat older at diagnosis than those in the previous group, with a median age of 25. These patients are classified as being SDH-deficient.
Patients with Carney-Stratakis Dyad stain negative on immunohistochemistry (SDH IHC-) with an identifiable SDH gene mutation, deletion, or duplication. Dyad patients are at risk for development of GIST tumors and/or paragangliomas. There appears to be equal male:female predominance.
Carney Triad patients tumors are also SDH-deficient upon immunohistochemistry (SDH IHC-), however do not present with an as yet identified SDH mutation, deletion, or duplication. Triad patients are at risk for development of all three types of tumors (GISTs, paragangliomas, and pulmonary chondromas). 90% of these patients are female.
SDH-status terminology can be confusing. Immunohistichemistry (IHC) testing refers to the process of applying a reagent to a biological tissue in order to determine the the absence or presence of a protein as indicated by a color-producing reaction. SDH IHC testing results indicate whether or not a patient is classified as being SDH-deficient. Testing for an SDH gene mutation is not the same as immunohisochemistry testing for the SDH protein. SDH-deficient patients may or may not have an accompanying identifiable SDH gene mutation.
WT GIST terminology is quickly evolving. Currently, those diagnosed before the age of 20 are considered to be Pediatric GIST patients. Patients diagnosed after the age of 20 years of age who do not bear a KIT, PDGFRa, BRAF, or NF-1 mutation (regardless of whether or not they have an SDH mutation) are described as having Pediatric-like GIST. Most recently, the term SDH-deficient GIST is being utilized by researchers and specialists in the field.