Mutation testing, at least for the
KIT and
PDGFRA genes, is recommended when TKIs, such as imatinib, sunitinib, and regorafenib, are to be used.
KIT mutations (present in 80 % of primary GISTs) are commonest in exon 11 (65 %), followed by exon 9 (8 %), and are rarely found in exons 13 and 17. Most GISTs caused by
KIT exon 11 or 13 mutations are naïve to imatinib.
KIT exon 9 mutations are associated with a nongastric location, clinicopathologically aggressive features, and hyposensitivity to imatinib. GISTs with
KIT exon 17 mutations are rare and some of them (e.g., D816V) are resistant to imatinib.
PDGFRA mutations (present in 10 % of primary GISTs) are common in tumors of the stomach and have epithelioid features as well as indolent behaviors. The commonest mutation of
PDGFRA, D842V, is associated with resistance to imatinib, sunitinib, and regorafenib. Approximately 10 % of GISTs are negative for
KIT and
PDGFRA mutations; these are referred to as wild-type GISTs. Wild-type GISTs are heterogeneous in genotype and may include mutations in
HRAS,
NRAS,
BRAF,
NF1 or the SDH complex (Table
1). Wild-type GISTs may be considered insensitive to imatinib. A mutation analysis may add prognostic information for GIST patients, especially for some specific subtypes, and genotyping can provide critical biomarkers to predict the activity of TKIs. Pathology reports may include, at least, the pathological diagnosis of GIST, tumor origin, presence of preoperative or intraoperative rupture, histological type, maximal size (cm), mitotic index (area of 5 mm
2), surgical margin, immunohistochemical findings (KIT, DOG1, CD34, desmin, S100, Ki67), presence of pathological necrosis, risk stratification, and
KIT and
PDGFRA mutations.
Table 1
Mutations and clinicopathological features
KIT
| All exons | 80 % | All sites | |
8 | | Rare | Small bowel | Yes, intermediate |
9 | Insertion of AY 502–503 | 5–10 % | Small bowel, colon, spindle, aggressive |
11 | Deletions, missense mutations, insertions | 60–70 % | All sites | Yes |
Deletion of codon 557 or 558 | | Aggressive, poor prognosis |
Internal tandem duplication | | Benign features, clinically indolent, female, stomach |
13 | K642E | 1 % | All sites | Yes |
17 | D820Y, N822K, Y823D | 1 % | All sites | No for D816V |
PDGFRA
| All exons | 10 % | Epithelioid, clinically indolent | |
12 | Missense mutations | 1–2 % | All sites | Yes |
14 | N659K | <1 % | Stomach, epithelioid | Yes |
18 | D842V | 10–5 % | Stomach, mesentery, omentum, epithelioid | No for D842V |
Wild-type | | 10–15 % | All sites | Probably no |
BRAF
| | V600E | Rare | |
SDHA/SDHB/SDHC/SDHD mutations | | | ~2 % | Carney–Stratakis syndromea; stomach, multiple, immunohistochemically SDHB negative |
Juvenile GIST; stomach, clinically indolent, multiple, immunohistochemically SDHB negative |
Loss of SDH expression | | | Carney triadb; stomach, clinically indolent, juvenile onset, immunohistochemically SDHB negative |
HRAS, NRAS mutation | | | <1 % | |
NF1 mutation | | | 1–2 % | Small bowel, clinically indolent, multiple, spindle |
There are several subsets of GISTs with features distinct from those of conventional
KIT- or
PDGFRA-mutated GISTs, including pediatric GIST, neurofibromatosis type 1 associated GIST (NF1-GIST), Carney–Stratakis syndrome, the Carney triad, and familial GISTs (Table
1):
1.
Pediatric GISTs, which are predominantly found in the female stomach, are frequently associated with predominant epithelioid features, lymph node metastasis, and mutations in the SDH complex. These tumors are sometimes multicentric and/or multinodular, and typically progress slowly.
SDH-mutated GISTs are thought to be insensitive to imatinib, but sunitinib may work to some extent [
10,
18].
2.
NF1–GISTs are marked by wild-type and multicentric tumors, are predominantly located in the small intestine, and are relatively indolent in terms of clinical and pathological features. NF1–GISTs are insensitive to imatinib.
3.
Carney–Stratakis syndrome is caused by germline loss-of-function mutations in SDH genes, including subunits A, B, C, and D, and is characterized by a dyad of gastric GIST and paraganglioma.
4.
The Carney triad is typically marked by gastric GISTs, paraganglioma, and pulmonary chondromas and may be accompanied by an epigenetic loss of SDH expression.
5.
Familial GISTs with germline mutations in either the
KIT gene or the
PDGFRA gene present as autosomal dominant traits and are associated with the presence of multiple GISTs in the gastrointestinal tract that are found in relatively young individuals [
19].