Mutational characteristics of gastrointestinal stromal tumors: A single-center analysis of 302 patients

Abstract

Gastrointestinal stromal tumors (GISTs) represent a spectrum of tumors characterized by variable behaviors and activating mutations in KIT proto-oncogene, receptor tyrosine kinase (KIT) or platelet derived growth factor receptor α (PDGFRA) genes. However, whether genotype analysis should be regarded as a prognostic indicator remains unclear. In the present study, clinicopathological data and the mutation phenotypes of KIT and PDGFRA genes were assessed in a series of 302 patients with GISTs at a single center. Univariate and multivariate Cox regression analyses were performed to identify the clinicopathological and mutational factors associated with relapse-free survival (RFS) in patients who had undergone complete primary GIST resection. KIT and PDGFRA mutations were identified in 233 (77.2%) and 30 (9.9%) cases, respectively. The following clinicopathological parameters were significantly associated with a shorter RFS: Male, non-gastric tumor origin, larger tumor size (>5 cm), high mitotic activity (>5/50 high-power fields), necrosis and epithelioid morphology. Tumors at non-gastric sites, with high National Institutes of Health risk classification, high World Health Organization (WHO) grade and KIT deletion involving codons 557/558/559 exhibited a significantly higher risk of progression. In the Cox regression model, KIT deletion involving codons 557/558/559, non-gastric origin and high WHO grade were independent indicators of RFS. The adverse prognosis associated with KIT deletions involving codons 557/558/559 was also observed for gastric GISTs. Conversely, spindle morphology, KIT exon 11 substitution and PDGFRA exon 18 mutation were associated with a longer RFS and lower rate of relapse. Furthermore, the coexistence of KIT exon 11 deletion and exon 13 duplication was observed in one tumor, with adverse prognostic features. Heterogeneity affecting morphology, immunostaining and genotype was identified in 4 cases. In addition, the presence of succinate dehydrogenase-deficient GIST was found in 5 cases (3.6%). In conclusion, the tumor genotype with regard to KIT and PDGFRA mutations exhibited prognostic significance for the risk of GIST progression and may be helpful for the optimization of tailored adjuvant therapy.

Keywords: KIT; PDGFRA; gastrointestinal stromal tumors; heterogeneity; mutation.

Figure 1.

Spectrum of KIT and PDGFRA mutations in 302 cases of GISTs. (A) Distribution of KIT and PDGFRA mutations. KIT exon 11 deletion was the most common genotype (36.4%, n=110) among the GISTs. Less frequent mutations included KIT exon 11 substitution (26.2%, n=79) and PDGFRA exon 18 substitution (7.3%, n=22). KIT exon 17 substitution, PDGFRA exon 12 substitution and exon 14 substitution were rare genotypes. (B) Counts of KIT exon 11 codons affected by deletion, duplication and substitution are depicted. Deletions and substitutions frequently involved codons 557–560, whereas duplication was observed in codons 572–580. (C-F) One patient with a GIST exhibited the coexistence of KIT exon 11 deletion and exon 13 duplication. The specimen of this patient presented (C) epithelioid and (D) spindle morphology and high mitotic activity (arrows). Hematoxylin and eosin staining (magnification, ×400). In this patient, the (E) in-frame deletion of KIT exon 11 (codons 553–558) and (F) in-frame insertion of exon 13 (one base pair insertion between codons 642 and 643) were detected. KIT, KIT proto-oncogene, receptor tyrosine kinase; PDGFRA, platelet derived growth factor receptor α; GIST, gastrointestinal stromal tumor.

Figure 2.

Heterogeneity of GISTs in one patient (case 1). Case 1A, a GIST at the greater curvature of the stomach, showed spindle cell and in distinct storiform morphology, with the strong expression of CD117, DOG1 and CD34 and the presence of KIT exon 11 substitution (p.V560D, arrow). By contrast, case 1B, a GIST at the lesser curvature of the stomach, had epithelioid morphology with uniform nuclei and cytoplasmic vacuoles. The tumor was positive for DOG1 and CD34 but negative for CD117. Mast cells served as an internal positive control. No mutation involving KIT exon 11 was detected in case 1B. Images show H&E, CD117, DOG1 and CD34 staining (magnification, ×200). GIST, gastrointestinal stromal tumor; DOG1, discovered on GIST-1; KIT, KIT proto-oncogene, receptor tyrosine kinase; H&E, hematoxylin and eosin.

Figure 3.

Heterogeneity of GISTs in a second patient (case 6). Hypercellular and pleomorphic histology was visible in the specimen of case 6A, a gastric GIST. Multinucleated giant cells and pathological mitoses (arrow) were observed. The tumor in case 6A was positive for CD117 and DOG1 but negative for CD34. Endothelial cells served as an internal positive control. Case 6B, a GIST between the stomach and spleen, exhibited a conventional spindle cell morphology, with the presence of myxoid stroma and the strong expression of CD117, DOG1 and CD34. KIT codon 579 was deleted in case 6A, whereas a KIT exon 11 substitution (p.W557G, arrow) existed in case 6B. Images show H&E, CD117, DOG1 and CD34 staining (magnification, ×200). GIST, gastrointestinal stromal tumor; DOG1, discovered on GIST-1; KIT, KIT proto-oncogene, receptor tyrosine kinase; H&E, hematoxylin and eosin.

Figure 4.

Estimates of RFS in patients with GISTs by Kaplan-Meier survival analysis with log-rank tests. (A) Male sex, (B) non-gastric origin, (C) tumor size >5 cm, (D) mitotic count >5/50 HPF and (E) necrosis were associated with a lower RFS rate. (F) Compared with spindle and mixed morphology, the epithelioid subtype was significantly associated with a shorter RFS. According to the (G) National Institutes of Health and (H) WHO classifications, patients classified as high risk and high grade (3b/5/6a/6b) had significantly lower RFS rates. KIT deletions involving codons 557/558/559 significantly reduced the RFS rates of patients with (I) GISTs and (J) gastric GISTs compared with those of patients with other KIT mutations or WT KIT. (K) KIT exon 11 substitution indicated a significantly improved RFS for patients with GISTs. (L) Patients with PDGFRA exon 18 mutations had a higher RFS rate, although the difference from that of patients with other PDGFRA mutations was not statistically significant. RFS, relapse-free survival; GIST, gastrointestinal stromal tumor; HPF, high-power fields; WHO, World Health Organization; KIT, KIT proto-oncogene, receptor tyrosine kinase; WT, wild-type; PDGFRA, platelet derived growth factor receptor α.