Intermediate Risk Gastrointestinal Stromal Tumors Research Articles

Deep learning predicts patients outcome and mutations from digitized histology slides in gastrointestinal stromal tumor

Risk assessment of gastrointestinal stromal tumor (GIST) according to the AFIP/Miettinen classification and mutational profiling are major tools for patient management. However, the AFIP/Miettinen classification depends heavily on mitotic counts, which is laborious and sometimes inconsistent between pathologists. It has also been shown to be imperfect in stratifying patients. Molecular testing is costly and time-consuming, therefore, not systematically performed in all countries. New methods to improve risk and molecular predictions are hence crucial to improve the tailoring of adjuvant therapy. We have built deep learning (DL) models on digitized HES-stained whole slide images (WSI) to predict patients’ outcome and mutations. Models were trained with a cohort of 1233 GIST and validated on an independent cohort of 286 GIST. DL models yielded comparable results to the Miettinen classification for relapse-free-survival prediction in localized GIST without adjuvant Imatinib (C-index=0.83 in cross-validation and 0.72 for independent testing). DL splitted Miettinen intermediate risk GIST into high/low-risk groups (p value = 0.002 in the training set and p value = 0.29 in the testing set). DL models achieved an area under the receiver operating characteristic curve (AUC) of 0.81, 0.91, and 0.71 for predicting mutations in KIT, PDGFRA and wild type, respectively, in cross-validation and 0.76, 0.90, and 0.55 in independent testing. Notably, PDGFRA exon18 D842V mutation, which is resistant to Imatinib, was predicted with an AUC of 0.87 and 0.90 in cross-validation and independent testing, respectively. Additionally, novel histological criteria predictive of patients’ outcome and mutations were identified by reviewing the tiles selected by the models. As a proof of concept, our study showed the possibility of implementing DL with digitized WSI and may represent a reproducible way to improve tailoring therapy and precision medicine for patients with GIST.

Racial differences in prognostic role of white blood cell ratios in gastrointestinal stromal tumors.

e23507 Background: Gastrointestinal stromal tumors (GIST) are rare mesenchymal tumors with an estimated 3,300 to 6,000 new cases per year in the United States. Per SEER database, significant racial disparity exists with an incidence rate twice as high for African Americans as compared to Whites. Currently, parameters used in stratification of disease risk can only be determined by postoperative histopathological evaluation. Cancer-related inflammation is linked to different stages of tumor development so markers found in peripheral blood have been studied as surrogates. We present a study comparing the predictive prognostic ability of preoperative serum inflammatory markers in primary untreated GIST and highlight the differences between Black and White patients. Methods: This is a retrospective analysis of 149 patients who underwent operative resection of primary untreated GIST. Preoperative blood samples were used for the analysis. Patients were excluded if they showed clinical signs of infection during time of pre-operative blood sampling or had non-GIST synchronous malignancy. Clinicopathological data was obtained from patient chart review and logistic regression models were used to evaluate data. There is ongoing next-generation sequencing data analysis. Results: 149 patients were included: 80 (53.7%) Black, 43 (28.9%) White, 26 (17.5%) were other. The mean values for neutrophil to lymphocyte ratio (NLR), platelet to lymphocyte ratio (PLR), and monocyte to lymphocyte ratio (MLR) were 3.62 (SD 3.07), 191.55 (SD 119.15), and 0.47 (SD 0.49) respectively. On univariate analysis NLR and PLR were significant prognostic indicators of high and intermediate risk GISTs per the National Institute of Health (NIH) categories [NLR p = 0.008, PLR p = 0.007]. Upon subgroup analysis, NLR and PLR showed the highest statistical significance for predictors of high and intermediate risk GISTs among the Black patient population [NLR odds ratio (OR) 2.685; 95% confidence interval (CI) 0.976-7.381; p = 0.05 and PLR OR 1.792; 95% CI 1.054-3.049; p = 0.031]. The same was not shown to be true for the White patient population. 11 out 149 patients progressed since diagnosis of which 8 were Black and 3 White. 7 were in the high risk category, 3 in low risk and 1 in intermediate risk with an overall mean NLR and PLR 5.25 and 244 respectively. The average time to progression was noted to 28 months. Conclusions: The NLR and PLR are easily obtainable and cost-effective indexes which have the prognostic ability to serve as surrogates for high and intermediate risk GISTs. They appear to be more predictive in the Black patient population than in White. Further study is warranted for incorporation into risk stratification systems.

Clinicopathological features and prognosis of gastrointestinal stromal tumors with KIT/PDGFRA gene "homozygous mutation": a multicenter retrospective cohort study

Objective: To investigate the clinicopathological features of gastrointestinal stromal tumor (GIST) with KIT/PDGFRA "homozygous mutation", the efficacy of targeted therapy and the prognosis. Methods: A retrospective cohort study and propensity score matching were used. "Homozygous mutation" was defined as the detection of KIT/PDGFRA gene status of GIST by Sanger sequencing, which showed that there was only mutant gene sequence in the sequencing map, lack of wild-type sequence or the peak height of mutant gene sequence was much higher than that of wild-type gene sequence (> 3 times). "Heterozygous mutation" was defined as the mutant gene sequences coexisted with wild type gene sequences, and the peak height was similar (3 times or less). The clinicopathological data and follow-up information of 92 GIST patients with KIT/PDGFRA "homozygous mutation" were collected from 4 hospitals in Shanghai from January 2008 to May 2021 (Renji Hospital, Shanghai Jiaotong University School of Medicine: 70 cases; Zhongshan Hospital, Fudan University: 14 cases; Changhai Hospital, Naval Military Medical University: 6 cases and Ruijin Hospital, Shanghai Jiaotong University School of Medicine: 2 cases). Patients with perioperative death, other malignancies, and incomplete clinicopathological information were excluded. The clinicopathological features of the patients and the efficacy of targeted drug therapy were observed and analyzed. The efficacy was evaluated using Choi criteria, which were divided into complete response (CR), partial response (PR), stable disease (SD) and progressive disease (PD). In addition, a total of 230 patients with high-risk GIST with "heterozygous mutation" in exon 11 of KIT gene and 117 patients with recurrent or metastatic GIST with "heterozygous mutation" in exon 11 of KIT gene were included. The propensity score matching method was used to match GIST patients with "heterozygous" and "homozygous" mutations in exon 11 of KIT gene (1∶1) for survival analysis. The disease-free survival (DFS) between two groups of high-risk GIST patients who underwent complete surgical resection were compared. And progression-free survival (PFS) in patients with recurrent or metastatic GIST were compared. Results: Of the 92 GIST cases with KIT/PDGFRA "homozygous mutation", 58 were males and 34 were females, with a median onset age of 62 (31-91) years. Primary GIST 83 cases. Primary high-risk GIST (53 cases), metastatic GIST (21 cases) and recurrent GIST (9 cases) accounted for 90.2% (83/92). There were 90 cases of KIT gene"homozygous mutation" (exon 11 for 88 cases, exon 13 for 1 case, exon 17 for 1 case), and 2 cases of PDGFRA gene "homozygous mutation" (exon 12 for 1 case, exon 18 for 1 case). The median follow-up time was 49 (8-181) months. Among the 61 cases of primary localized GIST undergoing complete surgical resection, 2 cases were intermediate-risk GIST, 5 cases were low-risk GIST, and 1 case was very low-risk GIST, of whom 1 case of intermediate-risk GIST received 1-year adjuvant imatinib mesylate (IM) therapy after operation, and no tumor recurrence developed during the follow-up period. The remaining 53 cases were high-risk GIST, and follow-up data were obtained from 50 cases, of whom 22 developed tumor recurrence during follow-up. Of 9 patients directly receiving neoadjuvant targeted therapy (IM or avapritinib), 5 had complete imaging follow-up data, and the evaluation of efficacy achieved PR. Of all the 92 GIST cases with KIT/PDGFRA "homozygous mutation", 50 (54.4%) had tumor metastasis or tumor recurrence or progression during follow-up, and 12 (13.0%) died of the tumor. Survival analysis combined with propensity score showed that in 100 cases of high-risk GISTs with complete resection, GISTs with "homozygous mutation" in exon 11 of KIT gene had shorter disease-free survival (DFS) than GISTs with "heterozygous mutation" in exon 11 of KIT gene (median DFS: 72 months vs. 148 months, P=0.015). In 60 cases of recurrent or metastatic GISTs with KIT gene exon 11 mutation, IM was used as the first-line treatment, and the progression-free survival (PFS) of GISTs with "homozygous mutation" was shorter compared to GISTs with "heterozygous mutation" (median PFS: 38 months vs. 69 months, P=0.044). The differences were statistically significant. Conclusions: "Homozygous mutation" in KIT/PDGFRA gene is associated with the progression of GIST. The corresponding targeted therapeutic drugs are still effective for GIST with KIT/PDGFRA gene "homozygous mutation". Compared with GIST patients with "heterozygous mutation" in KIT exon 11, GIST patients with "homozygous mutation" in KIT exon 11 are more likely to relapse after surgery and to develop resistance to IM. Therefore, it is still necessary to seek more effective treatment methods for this subset of cases.

Diagnostic Role of 18F-Fluorodeoxyglucose Positron Emission Tomography in Gastric Mesenchymal Tumors.

There have been no comparative studies investigating the results of 18F-fluorodeoxyglucose (FDG)-positron emission tomography (PET) in patients with gastric mesenchymal tumors, including leiomyomas, leiomyosarcomas, schwannomas, and gastrointestinal stromal tumors (GISTs). We retrospectively reviewed the data of 142 patients with pathologically diagnosed gastric mesenchymal tumors treated at 11 institutions. We analyzed the correlation between the maximum standardized uptake value (SUVmax) evaluated using fluorodeoxyglucose-positron emission tomography (FDG-PET) and the tumor size. The correlation between the SUVmax and mitotic index was also investigated in GISTs. The SUVmax (mean ± standard deviation) was 0.5 ± 0.6 in very low-risk GISTs (n = 42), 2.1 ± 0.7 in low-risk GISTs (n = 26), 4.9 ± 0.8 in intermediate-risk GISTs (n = 22), 12.3 ± 0.8 in high-risk GISTs (n = 20), 1.0 ± 1.0 in leiomyomas (n = 15), 6.9 ± 1.2 in schwannomas (n = 10), and 3.5 in a leiomyosarcoma (n = 1). The SUVmax of GISTs with an undetermined risk classification was 4.2 ± 1.3 (n = 8). Linear associations were observed between the SUVmax and tumor size in GISTs, leiomyomas, and schwannomas. The SUVmax of GISTs with a high mitotic index was significantly higher than that of GISTs with a low mitotic index (9.6 ± 7.6 vs. 2.4 ± 4.2). In conclusion, we observed positive correlations between the SUVmax and tumor size in GISTs, leiomyomas, and schwannomas. The SUVmax also positively correlated with the mitotic index and risk grade in GISTs. Schwannomas showed a higher FDG uptake than GISTs and leiomyomas.

High expression of proenkephalin is associated with favorable outcomes in patients with gastrointestinal stromal tumors.

PurposeThe aim of this study was to elucidate the prognostic value of proenkephalin (PENK) in gastrointestinal stromal tumors (GISTs).Patients and methodsWe collected data on 268 eligible postoperative patients diagnosed with GIST between January 1, 2002, and December 31, 2011. PENK expression was detected in GIST tissues classified using the United States National Institutes of Health (NIH) risk classification system. The associations between high PENK expression and the clinicopathological characteristics were assessed. Overall survival (OS) and recurrence-free survival (RFS) were estimated by Kaplan–Meier analysis, and the log-rank test was used to compare the differences between groups. Univariate and multivariate Cox regression analyses were conducted to assess the prognostic value of PENK in GIST patients.ResultsHigh PENK expression was more common in the low- and intermediate-risk GIST groups compared with the high-risk group (P<0.05). Additionally, PENK expression was associated with tumor size, mitosis count per 50 high-power fields, and tumor rupture (P<0.05). Kaplan–Meier analysis revealed that high PENK expression was associated with superior OS and RFS, while low PENK expression was associated with worse OS and RFS. Furthermore, PENK was shown to be an independent predictor of OS and RFS in the overall population (for OS, hazard ratio [HR], 1.596, 95% confidence interval [CI], 1.006–2.914, P<0.001; for RFS, HR, 1.910, 95% CI, 0.977–3.089, P<0.001).ConclusionPENK expression in GIST is closely associated with NIH risk grade and prognosis, indicating that PENK may act as a tumor suppressor and may serve as a new biomarker for predicting prognosis in postoperative GIST patients.

Effect of long non-coding RNA AOC4P on gastrointestinal stromal tumor cells

ObjectiveIn this research, we explored the effect of long non-coding RNA (lncRNA) AOC4P on gastrointestinal stromal tumor (GIST) cells.Materials and methodsThe expression of lncRNA AOC4P in tissues was detected by real-time PCR (RT-PCR). The epithelial–mesenchymal transition (EMT)-related proteins in tissues were analyzed by Western blot. The experiment included negative control group (CN), silence AOC4P group (si AOC4P), and silence negative control group (si CT). RT-PCR, MTT, Scratch, Transwell, and Annexin V-FITC methods were used to detect the expression of lncRNA AOC4P, cell proliferation, cell migration ability, cell invasion ability, and apoptosis, respectively. The EMT-related proteins including TGF-β, ZEB1, Vimentin, Snail, and E-cadherin were analyzed by Western blot.ResultsThe expression of lncRNA AOC4P and the expression of EMT-related proteins in high-risk GISTs were higher than that in low- and intermediate-risk GISTs (P<0.05). It was revealed that cell proliferative migration and invasive ability in si AOC4P group was decreased than that in CN and si CT groups (P<0.05), and cell apoptosis in si AOC4P group was higher than that in si CT group. The results of Western blot demonstrated that the expression of TGF-β1, ZEB1, Vimentin, and Snail in si AOC4P group were lower than that in si CT and CN group (P<0.05), and the expression of E-cadherin in si AOC4P group was higher than that in si CT and CN group (P<0.05).

Postoperative imatinib in patients with intermediate risk gastrointestinal stromal tumor.

To determine whether imatinib adjuvant treatment improved recurrence-free survival (RFS) in gastrointestinal stromal tumor (GIST) with intermediate risk. Patients who had undergone complete tumor resection with intermediate risk were enrolled. A total of 99 patients received imatinib adjuvant therapy and 93 patients only received observation. The RFS in patients who received adjuvant therapy was superior to RFS in control group (p =0.004). GIST with location of intestine or rectum and GIST with exon 11 deletion mutation had longer RFS. Adjuvant imatinib improves RFS of GIST with intermediate risk of recurrence, particularly in GIST with intestinal and rectal location or c-kit gene exon 11 deletion mutation.

Efficacy analysis of adjuvant therapy with imatinib for gastric intermediate-risk gastrointestinal stromal tumor.

e23510 Background: Accumulating evidence suggests that patients with high-risk gastrointestinal stromal tumor (GIST) can significantly benefit from adjuvant therapy with imatinib. However, the effect of this therapy in intermediate-risk GIST patients, particularly within gastric, has yet to be well demonstrated. Herein, we explored the efficacy of adjuvant imatinib in patients with gastric intermediate-risk GIST (GIGIST). Methods: The clinicopathologic and follow-up data on 93 GIGIST cases diagnosed from January 2005 to December 2016 at Union Hospital, Wuhan China were analyzed retrospectively. Univariate and multivariate analyses were performed to assess the prognostic factors for GIGIST. The patients were divided into three subgroups (Table) according to the multivariate analysis results to evaluate the efficacy of adjuvant imatinib. Results: We examined 43 male and 50 female patients with a median age of 60 years (range, 21-84 years). All patients underwent complete resection, and 42 (45%) patients were prescribed adjuvant imatinib 400 mg/day after surgery. The median adjuvant therapy period was 16 months (range, 12-72 months). The majority of the patients (86% [n = 80]) underwent followed-up for a median period of 46 months (range, 6-120 months). The 1-, 3-, and 5-year recurrence-free survival (RFS) rates in the whole group were 100.0%, 91.5% and 88.5%, respectively. Multivariate analysis revealed that the mitotic count (P = 0.040, relative risk (RR) = 6.078 [95% confidence interval (CI), 0.541-68.274]) and neutrophil-lymphocyte ratio (NLR; P = 0.036, RR = 6.102 [95% CI 0.782-47.632]) were prognostic risk factors for RFS. Adjuvant imatinib markedly increased the RFS rates in patients with a mitotic count greater than 2/50 high-power fields (HPF) and an NLR greater than 2.3 but not in the other two subgroups. Conclusions: GIGIST has a favorable overall prognosis. Patients with a mitotic count greater than 2/50 HPF and an NLR greater than 2.3 were identified as an advantageous group for adjuvant imatinib and targeted therapy longer than 1 year is strongly recommended to increase the RFS rate. Subgroup Mitotic count NLR Number of patients 1 ≤2 HPF Any value 28 2 > 2 to ≤10 HPF ≤2.3 28 3 > 2 to ≤10 HPF > 2.3 24

Retrospective analysis of 85 cases of intermediate-risk gastrointestinal stromal tumor

Background & AimsA significant benefit of imatinib adjuvant therapy for patients with high risk gastrointestinal stromal tumors (GIST) has been confirmed. However, the effect of imatinib adjuvant therapy for intermediate-risk GIST has not been well studied. In this article, we compare differences of recurrence-free survival (RFS) rates between patients with intermediate-risk GIST who accepted imatinib adjuvant therapy and those who did not.MethodA retrospective study of intermediate-risk GIST was conducted in the First Affiliated Hospital of Zhengzhou University, China. The pathology reports of 112 patients who had been treated by surgery showed intermediate-risk GIST. The treatment and control groups were designed according to the administration of imatinib adjuvant therapy (≥1 year). Survival and recurrence data were collected and RFS of each group was calculated.ResultsEighty fivepatients with intermediate-risk GIST were followed up. Thirty of them (treatment group) accepted imatinib adjuvant therapy over 1 year. Through comparing the RFS of the two groups, we established that there was no statistically significant difference in RFS rates (P=0.940).ConclusionThere is no significant benefit for patients with intermediate-risk GIST to accept imatinib adjuvant treatment.

Prognostic significance of KIT exon 11 deletion mutation in intermediate-risk gastrointestinal stromal tumor.

Benefit of adjuvant imatinib therapy following curative resection in patients with intermediate-risk gastrointestinal stromal tumor (GIST) is unclear. GIST-specific exon mutations, in particular exon 11 deletions, have been shown to be prognostic. We hypothesize that specific KIT mutations may improve risk stratification in patients with intermediate-risk GIST, identifying a subgroup of patients who may benefit from adjuvant therapy. In total, 142 GIST patients with complete clinicopathologic and mutational data from two sites were included. Risk classification was based on the modified National Institute of Health (NIH) criteria. In this cohort, 74% (n = 105) of patients harbored a KIT mutation; 61% (n = 86) were found in exon 11 of which nearly 70% were KIT exon 11 deletions (n = 60). A total of 18% (n = 25) of cases were classified as having intermediate-risk disease. Univariate analysis confirmed tumor size, mitotic index, nongastric origin, presence of tumor rupture and modified NIH criteria were adversely prognostic for relapse-free survival (RFS). Among KIT/PDGFRA mutants, KIT exon 11 deletions had a significantly worse prognosis (hazard ratio 2.31; 95% confidence interval, 1.30-4.10; P = 0.003). Multivariate analysis confirmed KIT exon 11 deletion (P = 0.003) and clinical risk classification (P < 0.001) as independent adverse prognostic factors for RFS. Intermediate-risk patients harboring KIT exon 11 deletions had RFS outcomes similar to high-risk patients. The presence of KIT exon 11 deletion mutation in patients with intermediate-risk GIST is associated with an inferior clinical outcome with RFS similar to high-risk patients.

Surgery of upper GI gastrointestinal stromal tumors: our experience, prognostic analysis.

To review our treatment experience of gastrointestinal stromal tumors (GISTs) of the upper gastrointestinal tract and identify the prognostic factors that influence tumor recurrence. Data of 46 consecutive patients with upper GI GISTs who underwent surgery from 1988 to 2011 were reviewed. The overall and disease-free survival rates and influence of clinicopathologic variables on disease-free survival rate were evaluated. The median age was 64 years (range, 20-86 years). R0 resections were performed in 43 (93.5%) patients. With a median follow-up time of 33 months (1-275 months), there were 5 (10.9%) recurrences and 2 mortalities in the high-risk group. The overall survival and recurrence-free survival rates at 5 years were 92.1% and 84.6%, respectively. Male gender, tumor size of >10 cm, high numbers of mitotic figures, R1 resection, high risk according to the Joensuu criteria, and a Ki-67 index of >10% were associated with a poor prognosis. Surgical resection of low- and intermediate-risk GISTs has excellent results. High counts of mitotic figures, male gender, incomplete resection, large tumor size, and a high Ki-67 index are associated with a poor prognosis.

Promoter methylation of PCDH10 by HOTAIR regulates the progression of gastrointestinal stromal tumors

HOTAIR, a long non-coding RNA (lncRNA), plays a crucial role in tumor initiation and metastasis by interacting with the PRC2 complex and the modulation of its target genes. The role of HOTAIR in gastrointestinal stromal tumors (GISTs) is remains unclear. Herein we investigate the mechanism of HOTAIR in the genesis and promotion of GISTs. The expression of HOTAIR was found to be higher in surgically resected high-risk GISTs than that in low- and intermediate-risk GISTs. Using GIST-T1 and GIST882 cells, we demonstrated that HOTAIR repressed apoptosis, was associated with cell cycle progression, and controlled the invasion and migration of GIST cells. Using a gene expression microarray and lists of HOTAIR-associated candidate genes, we suggested that protocadherin 10 (PCDH10) is a key molecule. PCDH10 expression was significantly decreased in GIST-T1 and GIST882 cells, possibly as a consequence of hypermethylation. We observed that HOTAIR induced PCDH10 methylation in a SUZ12-dependent manner. In this study, we found that the malignant character of GISTs was initiated and amplified by PCDH10 in a process regulated by HOTAIR. In summary, our findings imply that PCDH10 and HOTAIR may be useful markers of disease progression and therapeutic targets.

Surgical Management in Patients with Gastrointestinal Stromal Tumors: A Single-Center Experience

Background: We have revisited prognostic outcomes and recurrence patterns in patients with gastrointestinal stromal tumors (GISTs) who underwent complete surgical resection at a single institution. Patients and Methods: Patients who underwent curative surgical treatment were divided into two groups: those with high-risk GISTs (high-risk group) and those with very low-, low-, and intermediate-risk GISTs (lower-risk group). Results: A total of 109 patients who underwent surgery as an initial treatment for GIST were studied. The overall 5- and 10-year survival rates after surgery were 90.3 and 71.1%, respectively. The 5-year survival rate in high-risk group patients was 88.1%, and their overall survival rate did not vary significantly from that of the lower-risk group (5-year survival rate, 91.3%). The recurrence rate in patients with high-risk GISTs gradually increased without reaching a plateau, with a cumulative rate of GIST recurrence of 26.4 and 48.9% at 5 and 10 years after surgical treatment, respectively. Conclusions: Our data suggest that the repeat surgical management in metastatic GIST is of clinical usefulness whatever the risk and improves survival.

Adjuvant therapy with imatinib mesilate in a patient with intermediate risk GIST

The presented case regards a 63-year-old male patient who underwent radical surgery for an intermediate risk gastrointestinal stromal tumor (GIST) and thereafter was treated with imatinib mesilate at a daily dose of 400 mg for one year. Adjuvant therapy for primary GIST has proven benefit in extending relapse free survival in randomised controlled phase III trials; the advantage in overall survival, however, is yet to be proved. Defined risk factors for recurrence are based on GIST size, location, and mitotic rate provide useful guidelines for selecting patients for adjuvant therapy considerations. Nevertheless, it is currently unclear how to select those patients who would benefit the most, which is the optimal dose and treatment duration, and, importantly, if the use of adjuvant imatinib could enhance the chance of cure. The case report will be used as a paradigmatic springboard for further discussion.

Laparoscopic and endoscopic cooperative surgery for gastrointestinal stromal tumor with complete situs inversus: report of a case.

We herein report our experience of performing laparoscopic and endoscopic cooperative surgery for a gastrointestinal stromal tumor with complete situs inversus. A 78-year-old man was referred to our department for treatment of a gastric submucosal tumor. Based on chest X-ray and computed tomography (CT) findings, complete situs inversus was also diagnosed. Upper gastrointestinal endoscopy and imaging showed a 45-mm gastric submucosal tumor in the upper stomach near the esophagogastric junction. We performed local resection of the gastric submucosal tumor by laparoscopic and endoscopic cooperative surgery. Pathological examination revealed that the tumor was an intermediate-risk gastrointestinal stromal tumor, and the patient was discharged on postoperative day 12. The patient is still alive without recurrence or any complications 9 months after surgery.

Primary gastrointestinal stromal tumor of the liver: report of a case

Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the gastrointestinal tract. They can occur anywhere in the gastrointestinal tract, and rarely outside the digestive tract. We herein report a case of primary gastrointestinal stromal tumor that was resected from the liver of a 56-year-old male, which is the sixth description of a primary hepatic gastrointestinal stromal tumor. The tumor was shown to be completely limited within the liver by radiological, intraoperative and pathological examinations. The pathological results demonstrated an intermediate risk gastrointestinal stromal tumor, and immunohistochemical expression of CD117 was positive. Although rare, we suggested that GISTs should be considered in the differential diagnosis of hepatic nodules, and that not all hepatic gastrointestinal stromal tumors should automatically be considered to be metastases from a primary gastrointestinal site.

Gastrointestinal stromal tumor: Our experience

Gastrointestinal stromal tumor: Our experience

A novel germline SDHB mutation in a gastrointestinal stromal tumor patient without bona fide features of the Carney–Stratakis dyad

Gastrointestinal stromal tumors (GISTs) are the most common mesenchyme neoplasms of the gastrointestinal tract. Gain-of-function somatic mutations of the KIT or PDGFRA genes represent the most prevalent molecular alterations in GISTs. In Carney-Stratakis dyad, patients portray germline mutations of the succinate dehydrogenase subunits B (SDHB), C (SDHC) and D (SDHD) and develop multifocal GISTs and multicentric paragangliomas (PGLs). We herein report a novel germline SDHB mutation (c.T282A--Ile44Asn) occurring in a 26 years-old patient diagnosed with a spindle cell intermediate risk GIST that did not present KIT/PDGFRA/BRAF gene mutations. Further analyses revealed loss of the wild-type SDHB allele and complete loss of SDHB expression in the tumor tissue. After genetic screening of other family members, we detected in the patient's mother a SDHB mutation without any clinical/laboratorial evidence of GIST or PGL. Altogether, our findings (germline SDHB mutation with absence of PGL in the index case and of GIST and/or PGL in his mother) raise the possibility that this familiar setting corresponds to an incomplete phenotype of the Carney-Stratakis dyad.

A Novel Correlation between LINE-1 Hypomethylation and the Malignancy of Gastrointestinal Stromal Tumors

Gastrointestinal stromal tumors (GIST) are the most important mesenchymal tumors of the gastrointestinal tract. The vast majority of GISTs exhibit activating mutations of KIT or PDGFRA, but epigenetic alteration of GISTs is largely unknown. In this study, we aimed to clarify the involvement of DNA methylation in GIST malignancy. A total of 106 GIST specimens were studied. Levels of LINE-1 methylation were analyzed using bisulfite pyrosequencing. In addition, methylation of three other repetitive sequences (Alu Yb8, Satellite-α, and NBL2) was similarly analyzed, and CpG island hypermethylation was analyzed using MethyLight. Array-based comparative genomic hybridization (array CGH) was carried out in 25 GIST specimens. LINE-1 hypomethylation was significantly correlated with risk, and high-risk GISTs exhibited significantly lower levels of LINE-1 methylation than low-risk (61.3% versus 53.2%; P = 0.001) or intermediate-risk GISTs (60.8% versus 53.2%; P = 0.002). Hypomethylation of Satellite-α and NBL2 was also observed in high-risk GISTs. By contrast, promoter hypermethylation was relatively infrequent (CDH1, 11.2%; MLH1, 9.8%; SFRP1, 1.2%; SFRP2, 11.0%; CHFR, 9.8%; APC, 6.1%; CDKN2A, 0%; RASSF1A, 0%; RASSF2, 0%) and did not correlate with LINE-1 methylation or risk. Array CGH analysis revealed a significant correlation between LINE-1 hypomethylation and chromosomal aberrations. Our data suggest that LINE-1 hypomethylation correlates significantly with the aggressiveness of GISTs and that LINE-1 methylation could be a useful marker for risk assessment. Hypomethylation may increase the malignant potential of GISTs by inducing accumulation of chromosomal aberrations.

Application and evaluation of biologic potential grading criteria for localized gastrointestinal stromal tumors

To evaluate the implication of Fletcher and Miettinen biologic potential grading criteria in native localized gastrointestinal stromal tumors (GISTs). Two hundred and twenty localized GISTs with complete clinicopathologic and follow-up data were evaluated for their biologic potential by Fletcher and Miettinen grading criteria. The implication of the two grading criteria were compared by survival analysis. Evaluated by Fletcher grading criteria, the overall and disease-free survival rate of high risk GISTs was lower than that of very-low, low and intermediate GISTs; while the overall and disease-free survival rate of very-low, low and intermediate risk GISTs had no statistical diffence. In the high risk GISTs, the overall and disease-free survival rate of small intestinal and rectal GISTs was lower than that of gastric GISTs; while in the intermediate risk GISTs, the disease-free survival rate of small intestinal GISTs was lower than that of gastric GISTs. Evaluated by Miettinen grading criteria, the overall and disease-free survival rate of high risk GISTs was lower than that of very-low, low and intermediate GISTs; while the overall and disease-free survival rate of very-low, low and intermediate risk GISTs had no statistical difference. In the risk subgroup of GISTs, the overall and disease-free survival rate of gastric, small intestinal and rectal GISTs had no statistical difference. Fletcher grading criteria is simple and easy to use; while Miettinen grading criteria for evaluating biological potential by anatomic site is more critical and has important reference implication for the selection of high risk patients for targeted adjuvant treatment.