Chinese Pedigree with Hereditary Gastrointestinal Stromal Tumors: A Case Report and Literature Review.

Familial gastrointestinal stromal tumor (GIST) is a rare autosomal dominant genetic disorder with only a few affected families reported to date. Here, we report a case of familial GISTs harboring a novel germline mutation within exon 18 of KIT. A 58-year-old male patient presented with gastric subepithelial lesions accompanied by cutaneous hyperpigmentation, which were subsequently diagnosed as multinodular GISTs. Endoscopic surgery was initially conducted to remove the larger lesions, and pathological examinations were then conducted for the diagnosis of GISTs. Family history revealed that some other family members had similar cutaneous pigmentations. Whole-exome sequencing was used to search for potential driver mutations, and Sanger sequencing was used for mutation validation. A novel primary driver mutation of KIT (c.G2485C, p.A829P) was detected in these hereditary GISTs, which has been reported in some targeted chemotherapy-resistant GISTs. Cell models were subsequently established for the rapid screening of candidate drugs and exploring potential mechanisms. This mutation could lead to cell proliferation and imatinib resistance by ligand-independent activation of KIT; however, ripretinib administration was identified as an applicable targeted therapy for this mutation. The mutation activated the JAK/STAT3 and MAPK/ERK pathways, which could be inhibited by ripretinib administration. To the best of our knowledge, this is the first report of the KIT-A829P mutation in familial GISTs, complementing the pathogenesis of familial GISTs and providing valuable information for the precision treatment of this disease.

Small Gastric Stromal Tumors: An Underestimated Risk.

BACKGROUND AND OBJECTIVES: Small gastrointestinal stromal tumors (GISTs) are defined as tumors less than 2 cm in diameter, which are often found incidentally during gastroscopy. There is controversy regarding the management of small GISTs, and a certain percentage of small GISTs become malignant during follow-up. Previous studies which used Sanger targeted sequencing have shown that the mutation rate of small GISTs is significantly lower than that of large tumors. The aim of this study was to investigate the overall mutational profile of small GISTs, including those of wild-type tumors, using whole-exome sequencing (WES) and Sanger sequencing. METHODS: Thirty-six paired small GIST specimens, which were resected by endoscopy, were analyzed by WES. Somatic mutations identified by WES were confirmed by Sanger sequencing. Sanger sequencing was performed in an additional 38 small gastric stromal tumor samples for examining hotspot mutations in KIT, PDGFRA, and BRAF. RESULTS: Somatic C-KIT/PDGFRA mutations accounted for 81% of the mutations, including three novel mutation sites in C-KIT at exon 11, across the entire small gastric stromal tumor cohort (n = 74). In addition, 15% of small GISTs harbored previously undescribed BRAF-V600E hotspot mutations. No significant correlation was observed among the genotype, pathological features, and clinical classification. CONCLUSIONS: Our data revealed a high overall mutation rate (~96%) in small GISTs, indicating that genetic alterations are common events in early GIST generation. We also identified a high frequency of oncogenic BRAF-V600E mutations (15%) in small GISTs, which has not been previously reported.

Efficacy of endoscopic ultrasound in the evaluation of small gastrointestinal stromal tumors.

BACKGROUND: Gastrointestinal stromal tumors (GISTs) with a diameter of < 2 cm are called small GISTs. Currently, endoscopic ultrasound (EUS) is widely used as a regular follow-up method for GISTs, which can also provide a preliminary basis for judging the malignancy potential of lesions. However, there are no studies on the accuracy of EUS to assess the malignant potential of small GISTs. AIM: To evaluate the efficacy of EUS in the diagnosis and risk assessment of small GISTs. METHODS: We collected data from patients with small GISTs who were admitted to Shengjing Hospital of China Medical University between October 2014 and July 2019. The accurate diagnosis and risk classifications of patients were based on the pathological assessment according to the modified National Institute of Health criteria after endoscopic resection or laparoscopic surgery. Preoperative EUS features (marginal irregularity, cystic changes, homogeneity, ulceration, and strong echogenic foci) were retrospectively analyzed. The assessment results based on EUS features were compared with the pathological features. RESULTS: A total of 256 patients (69 men and 187 women) were enrolled. Pathological results included 232, 16, 7, and 1 very low-, low-, intermediate-, and high-risk cases, respectively. The most frequent tumor location was the gastric fundus (78.1%), and mitoses were calculated as > 5/50 high power field in 8 (3.1%) patients. Marginal irregularity, ulceration, strong echo foci, and heterogeneity were detected in 1 (0.4%), 2 (0.8%), 22 (8.6%), and 67 (65.1%) patients, respectively. However, cystic changes were not detected. Tumor size was positively correlated with the mitotic index (P < 0.001). Receiver operating curve analysis identified 1.48 cm as the best cut-off value to predict malignant potential (95% confidence interval: 0.824-0.956). EUS heterogeneity with tumor diameters > 1.48 cm was associated with higher risk classification (P < 0.05). CONCLUSION: Small GISTs (diameters > 1.48 cm) with positive EUS features should receive intensive surveillance or undergo endoscopic surgery. EUS and dissection are efficient diagnostic and therapeutic approaches for small GISTs.

Comprehensive review of diagnostic modalities for early chronic pancreatitis.

Chronic pancreatitis (CP) is a progressive condition caused by several factors and characterised by pancreatic fibrosis and dysfunction. However, CP is difficult to diagnose at an early stage. Various advanced methods including endoscopic ultrasound based elastography and confocal laser endomicroscopy have been used to diagnose early CP, although no unified diagnostic standards have been established. In the past, the diagnosis was mainly based on imaging, and no comprehensive evaluations were performed. This review describes and compares the advantages and limitations of the traditional and latest diagnostic modalities and suggests guidelines for the standardisation of the methods used to diagnose early CP.