Cases Of GIST Research Articles

Abstract 1767: Molecular subclassification of gastrointestinal stromal tumors by genomic backgrounds

Abstract Gastrointestinal stromal tumors (GISTs) are the most common gastrointestinal mesenchymal tumors. While about 10% of GISTs are known to be developed from the KIT or PDGFRA gain-of-function mutations, the rest, which is the majority of GISTs, is so-called as wild-type GISTs. There are attempts to make subclassification of wild-type GISTs in syndromic or non-syndromic group as promising for understanding of heterogeneity or treatment strategy. Genomic states of succinate dehydrogenase B (SDHB) and neurofibromatosis type 1 (NF1) have been raised as candidates for subclassification of wild-type GISTs. In this presentation, we will discuss our recent three cases of wild-type GISTs, carrying germline pathogenic variants in SDHB or NF1. Two cases with SDHB germline pathogenic variants showed stomach GISTs with good clinical course, the maintained performance status and long survival nevertheless of the recurrence. The other case with an NF1 germline pathogenic variant showed multiple GISTs in small intestine which was controlled surgically and the late onset of other clinical symptoms of NF1. These cases might clinically suggest potential prognostic and predictive markers in genomic alterations of SDHB or NF1 for the cases with wild-type GISTs. Citation Format: Hideki Yamamoto, Eiji Nakada, Seiji Kawano, Fumino Kato, Chika Fukano, Mashu Futagawa, Yusaku Urakawa, Risa Ohsumi, Sayaka Ueno, Hiroyuki Yanai, Akira Hirasawa. Molecular subclassification of gastrointestinal stromal tumors by genomic backgrounds [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1767.

A Case of Recurrent Gastrointestinal Stromal Tumor with Chondroid Differentiation

Abstract Introduction/Objective Gastrointestinal stromal tumors (GIST) comprise 0.1% to 3% of gastrointestinal neoplasms but are the most common mesenchymal tumors in the gastrointestinal tract. They originate from the interstitial cells of Cajal and most frequently arise in the stomach. However, chondroid differentiation of GIST is extremely rare with less than ten cases reported in the literature. We present a case of a 58-year-old female with recurrent GIST post-imatinib therapy. Methods/Case Report The patient was originally diagnosed with GIST seven years prior when she visited the Emergency Department after a syncopal episode and was incidentally found to have a 11 x 8.5 x 7 cm gastric mass based on abdominal CT scan. She underwent biopsy that showed spindle cell lesion staining positively for DOG1 and CD117 and negatively for desmin, consistent with GIST. She subsequently underwent partial gastrectomy with pathology showing high grade spindle cell type GIST with focal bizarre epithelioid cells and necrosis. Molecular testing identified the tumor to have a c-KIT mutation. Based on large tumor size and risk of recurrence, she was treated with imatinib for three years. Two years after completion of imatinib therapy, her surveillance imaging showed a mass compatible with recurrence measuring 11.8 x 11.7 x 6.7 cm. Additionally, imaging identified a mass in her mid abdomen that was biopsied and showed metastatic GIST supported by immunophenotype. The patient undewent a second partial gastrectomy and the mass on gross examination showed a heterogeneous cut surface displaying some solid and necrotic areas that appears to have invaded adjacent adipose tissue. Histomorphological features showed a spindle component with necrosis and a focus of chondroid differentiation. Tumor cells were immunopositive for DOG1 and CD117. The chondroid component did not stain for either marker. Results (if a Case Study enter NA) NA Conclusion There have been few reported cases of GIST with chondroid differentiation. Moreover, a previous study found three of 35 patients who showed phenotypic alteration post-imatinib therapy with changes ranging from tubulopapillary to epithelioid morphology. However, there has been no case with chondroid differentiation after imatinib therapy reported. This case illustrates the variable response of GIST to imatinib and its possible transformation because of the therapy. To better understand the prognosis of GIST with chondroid differentiation, more cases should be identified, reported, and monitored closely.

Assessing prognostic factors of long-term survival after surgery for colorectal gastrointestinal stromal tumours.

Due to their rarity, the management of colorectal gastrointestinal stromal tumours (CR GISTs) is still under debate. The aim of this study was to assess prognostic factors. We performed a retrospective review of patients who underwent surgery with curative intent for CR GIST at our centre from 2002 to 2019. Factors associated with overall (OS) and recurrence-free survival (RFS) were analysed. Fifty-six patients were included [median age 63 years, 29 (52%) female, 30 (54%) Miettinen high-risk, 40 (71%) with rectal GIST]. Nineteen (34%) patients received perioperative (neoadjuvant and/or adjuvant) imatinib. All cases of colonic GIST had an R0 resection, compared with 28 (70%) of rectal GISTs. After a median follow-up of 97 months (interquartile range 48-155 months), 14 (25%) deaths and 14 (25%) recurrences occurred. In the high-risk cohort, factors associated with improved RFS were R0 resection (OR 0.19, 95% CI 0.1-0.5, p = 0.002) and perioperative imatinib (OR 0.33, 95% CI 0.42-0.97, p = 0.04). Patients who had received perioperative imatinib had longer RFS (60% vs. 11% at 5 years, p = 0.006) but not OS. In rectal GISTs, 5-year OS was 85% for R0 and 70% for R1 resections (p = 0.164) and 5-year RFS was 85% for R0 and 12% for R1 resection (p < 0.001). When stratifying patients by perioperative imatinib, there were no differences in OS or RFS in the R0 or R1 groups. Perioperative imatinib and R0 resection were associated with improved RFS in high-risk patients with CR GIST. In patients with rectal GIST, R1 resection was associated with worse RFS irrespective of perioperative imatinib treatment.

PATIENT MANAGEMENT TACTICS AT DIFFERENT STAGES OF GASTROINTESTINAL STROMAL TUMORS (GIST).

The aim: To analyze the results of treatment even in limited groups of patients. Materials and methods: Clinical cases of GIST based on the materials of the surgical clinic of the Central Municipal Hospital in Uzhgorod (Transcarpathian region) were discussed. Clinical, ultrasound and CT monitoring was provided. CT dynamics were assessed according to RECIST 1.1. Conclusions: Only surgery resection is enough in case of the "small" tumor originated from the stomach. Otherwise, in case of locally-widespread GIST it is expedient to refrain from radical surgical intervention. High-grade GIST was verified by the IHC examination with mutation of the KIT gene in exon 11. Imatinib mesylate 400 mg PO daily was prescribed. More than 1-year follow-up result: firstly more than 50% reduction of the tumor size with subsequent stabilization of the disease. Minimally invasive processes allow surgical interventions and do not require aggressive adjuvant therapy. The presence of a giant GIST is a serious diagnostic and treatment challenge. Only management of the patient by a multidisciplinary team allows to resolve diagnostic and treatment contradictions, to create the prospect of achieving complete or partial remission and long-term survival.

GASTROINTESTINAL STROMAL TUMOUR – EXPERIENCE OF A PERIPHERAL TERTIARY CARE INSTITUTE

Introduction- GIST is a generally a rare tumour but it is most common mesenchymal malignancy of gastrointestinal tract . this malignancy originates from the interstitial cells of Cajal, the pacemakers of GI tract. Management of GIST is associated with difculties at diagnosis, proper immunohistochemical categorisation, completeness surgical excision,resistance to available TKIs. Aim of this study was to share the experience of treating GIST case AIMS - Methods- s from a peripherally located tertiary level hospital . In this retrospective observational study all the histology and immunohistochemistry proved cases of GIST attending Department of Radiotherapy of Midnapore Medical College between 2016 to 2017 were accrued and evaluated. 12 Cases were evaluated for their Result - demographic character, clinical presentation , treatment history, response pattern. M:F ratio was 1.4:1.Age range was 37 years to 58 years. Eleven cases were postoperative and 1 case was advanced inoperable. All the cases were positive for KIT stains .All the patients received treatment with Tyrosine Kinase inhibitor Imatinib Mesylate. At the end of 2 yrs of treatment and follow up 10 patients were disease free , two patients developed progression of disease. Introduction of Imatinib Mesylate and other TKIs have Conclusion - revolutionised the management of GISTs. Still the management is associated different obstacles like early diagnosis, proper immunohistochemical and genotypic categorisation, resistance to available TKIs , lack of large scale studies . Further long term studies with larger study population is needed to improve the treatment outcome of patients suffering from this mysterious disease.

494. GIANT GASTROINTESTINAL STROMAL TUMOR OF THE ESOPHAGUS: REPORT OF TWO CASES

Abstract Gastrointestinal stromal tumor (GIST) accounts for 1-3% of all gastrointestinal tumors. Most of GIST occurs in the stomach and small intestine, but GIST from the esophagus is relatively rare at about 2-5%. Surgical resection is the treatment of choice, but no routine procedure has been established. We report two cases of esophageal GIST that underwent surgical resection. [Case 1] A 75-year-old woman. She was diagnosed with an 11 cm-sized submucosal tumor was found in the esophagus by upper gastrointestinal endoscopy. Histopathological examination showed that the tumor was GIST. The patient's postoperative course was uneventful and the patient was discharged home in good condition on the 22nd postoperative day. [Case 2] A 58-year-old man. He was diagnosed a 9 cm-sized elevated lesion in the by CECT. The tumor suspected esophageal cancer sarcoma, we underwent esophagectomy. Finally, histopathological examination revealed that the tumor was GIST. His postoperative course was uneventful and he was discharged on the 19th postoperative day. [Case 1 result] Postoperative adjuvant chemotherapy with imatinib was failed, but the follow-up period continued without recurrence. [Case2 result] Postoperative adjuvant chemotherapy with imatinib was introduced. Contrast-enhanced CT 6 months after surgery revealed multiple liver metastases. 2nd line chemotherapy with sunitinib is still ongoing. [Discussion] Surgical treatment is the first choice for esophageal GIST, but no standard surgical procedure has been established. In the past, esophagectomy similar to esophageal cancer was often performed, but thoracoscopic local resection may be selected in recent years. Even in the case of giant esophageal GIST as like this two cases, if the general condition is stable and preoperative treatment is possible, it is possible to choose to perform preoperative neoadjuvant chemotherapy.

Study from Tertiary Care Centre Elucidating the Role of CD 117 &amp; DOG 1 Antibodies in Diagnosis of Gastrointestinal Stromal Tumors

Introduction: Gastrointestinal stromal tumors are the most common mesenchymal tumors in the gastrointestinal tract. The diagnosis of GISTs becomes much more accurate by using IHC (CD117/DOG1) and molecular analysis (KIT/PDGFRA), both of which constitute the gold standard of diagnosis in GISTs. Aim: The study was conducted in a tertiary care hospital in western India between January, 2019 to June 2020 to evaluate clinic pathological correlation &amp; agreement between CD117 and DOG1 antibodies that are employed in diagnosis of GIST. Material &amp; Methods: The cases were selected on the basis of inclusion &amp; exclusion criteria defined and thereafter a panel of CD117, DOG1 and other antibodies was applied to diagnose GIST from other mesenchymal tumors of gastrointestinal tract. Results: The average age of the patient was 53.5 years with male preponderance was noted. (M:F=1.66). The clinical complaints included: GI Bleeding (50%), Abdominal pain (30%), lump abdomen (20%).Most common site for GIST was gastric (50%) followed small intestine (40%), mesentry-omentum (7.50%) and colon (2.50%). Spindle cell morphology (75.00%) was the most common histomorphological subtype. DOG1 antibody diagnosed 97.50 % cases of GIST and CD117 diagnosed 92.50% cases of GIST. DOG1 expressed high staining ratio score in 95% cases while CD117 had high staining ratio score in 87.50% cases. Mostly stronger intensity of immunostaining was observed with DOG1 while CD117 expressed variable intensity of immunostaining. Also, CD117 expressed variable immunostaining amongst different histomorphological variants and risk groups. While immunostaining with DOG1 was not significantly variable. The results demonstrated that DOG-1 was found to be a superior marker with higher sensitivity and specificity as compared to CD117, specificity (100% versus 96.43%) and sensitivity (97.5% versus 92.5%). Conclusion: The immunohistochemistry panel should be applied in stepwise manner over “morphologically suspicious” cases Mesenchymal Tumours of GIT to diagnose and rule out GIST with first panel being CD117 and DOG1. DOG-1 was found to be a superior marker with higher sensitivity and specificity as compared to CD117. Cases negative for all the antibodies should definitely be referred for molecular analysis to detect other mutations of GIST (kit/PDGFRA negative wild type GIST). Keywords: GIST, CD 117, DOG 1 antibody

Efficacy of SCF drug conjugate targeting c-KIT in gastrointestinal stromal tumor

BackgroundGastrointestinal stromal tumor (GIST) is a rare type of cancer that occurs in the gastrointestinal tract. The majority of GIST cases carry oncogenic forms of KIT, the receptor for stem cell factor (SCF). Small molecule kinase inhibitor imatinib is effective in prolonging the survival of GIST patients by targeting KIT. However, drug resistance often develops during the therapeutic treatment. Here, we produced a SCF-emtansine drug conjugate (SCF-DM1) with favorable drug efficacy towards GIST cells.MethodsRecombinant human SCF (rhSCF) was expressed in E. coli cells and further purified with Ni–NTA Sepharose and Phenyl Sepharose. It was then conjugated with DM1, and the conjugated product SCF-DM1 was evaluated using in vitro cell-based assays and in vivo xenograft mouse model.ResultsSCF-DM1 was effective in inhibiting imatinib-sensitive and -resistant GIST cell lines and primary tumor cells, with IC50 values of < 30 nM. It induced apoptosis and cell cycle arrest in GIST cells. In xenograft mouse model, SCF-DM1 showed favorable efficacy and safety profiles.ConclusionsrhSCF is a convenient and effective vector for drug delivery to KIT positive GIST cells. SCF-DM1 is an effective drug candidate to treat imatinib-sensitive and -resistant GIST.

Descriptive epidemiology of soft tissue sarcomas and gastrointestinal stromal tumors in Thailand

This study aimed to analyze burden of STS and GIST in population and survival rate which represented the current situation of treatment in Thailand. The data was collected from five population-based cancer registries around the country for the period 2001 through 2015. The Segi world standard population was used to calculated age-standardized incidence rates (ASR). Standardized rate ratios (SRR) were used to compare populations. Joinpoint Trend Analysis was used to assess changes in incidence. STATA was used to examine patient survival rates. During the study period, 4080 cases of STS and 457 cases of GIST were reported. The ASR of STS and GIST was 2.14/100,000 person-years and 0.22/100,000 person-years, respectively. The most common histological types of STS were unspecified sarcoma (24.8%), leiomyosarcoma (19.0%) and liposarcoma (11.4%). The overall ASR of STS in Thailand was relatively low compared to Western countries. The five-year survival rate was 62.6% for STS and 63.4% for GIST, which was comparable to the rates reported in other countries. This is the first report of STS and GIST from PBCRs in Thailand. Based on current healthcare service, an overall survival rates of STS and GIST are comparable to those reported from others.

Abstract 660: Predicting imatinib responses in exon 18 PDGFRA-mutant GIST

Abstract Gastrointestinal stromal tumor (GIST) is the most common GI sarcoma and frequently harbor oncogenic mutations in KIT or platelet derived growth factor receptor alpha (PDGFRA) receptor tyrosine kinases. While type II tyrosine kinase inhibitors (TKIs) revolutionized the treatment of KIT-mutant GIST, they are thought to be ineffective for many PDGFRA-mutant GIST cases. Over 80% of PDGFRA mutations in GIST occur in exon 18 and patients with the most common mutation, D842V, are resistant to imatinib and other type II TKIs, leading to poor outcomes. However, beyond D842V, numerous other PDGFRA exon 18 mutations have been observed. From curated data of a large cohort of PDGFRA-mutant GISTs, we have identified nearly 50 unique PDGFRA exon 18 mutations, including both point mutations and complex indels. Although it is largely unknown how these mutations respond to imatinib, currently most, if not all, PDGFRA exon 18 mutations are assumed to be imatinib resistant. Using cell models, we tested some of the most commonly observed mutations in this cohort. Contrary to dogma, we observed that some exon 18 mutations tested were imatinib sensitive. We also observed that imatinib sensitivity seemed to be dependent on the properties of the residue in the 842-codon position, which encodes a key auto-inhibitory residue. We then hypothesized that imatinib sensitivity of every known or future reported PDGFRA exon 18 mutation might be predicted based on the 842 residue. To test the predictive potential of the 842 residue, we created mutagenic libraries that included every amino acid substitution at the 842 position. We expressed each mutation in Ba/F3 cells and assessed imatinib sensitivity via immunoblotting for phosphorylated-PDGFRA. Overall, 40% of tested mutations were sensitive to imatinib, further debunking the belief that all PDGFRA exon 18 mutations are imatinib resistant. In agreement with our hypothesis, we found that any hydrophobic residue at the 842 position conferred imatinib resistance (IC50 &amp;gt; 100nM), and all other amino acids tested to date were imatinib sensitive (IC50 &amp;lt; 100nM). Based on these data alone, over 55% of the 50 unique mutations identified from our PDGFRA-mutant GIST patient cohort would be predicted to be imatinib sensitive, demonstrating the importance of understanding the biochemical properties of various exon 18 mutations to predict treatment outcomes. Our predictive model would help identify patients with PDGFRA exon 18 mutations that could benefit from using front-line imatinib as an alternative to avapritinib, which has been recently approved for first-line treatment for all PDGFRA exon 18 mutant GIST. Imatinib, which has been used clinically for over 20 years, has a superior safety and tolerability profile compared to avapritinib. This paradigm shifting approach has the potential to transform patient care and outcomes by optimizing the sequencing of TKIs for PDGFRA-mutant GIST patients. Citation Format: Homma M. Khosroyani, Lillian R. Klug, Johanna Falkenhorst, Sebastian Bauer, Michael C. Heinrich. Predicting imatinib responses in exon 18 PDGFRA-mutant GIST [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 660.

Malignant extragastrointestinal stromal tumor: A challenging diagnosis due to unusual presentation

Gastrointestinal stromal tumors are the most common mesenchymal tumors of gastrointestinal tract which comprise <1% of all primary gastrointestinal malignancies. These tumors show mutations in the KIT gene or platelet-derived growth factor receptor-A gene and usually stains positively for CD117. Very few cases of extragastrointestinal GIST (EGIST) have been reported in literature which originate from omentum and mesentery as per our knowledge. Here, we report a case of EGIST arising from omentum with no connection to gastrointestinal tract organs in a 60-year-old woman who presented with abdominal pain for 2–3 months. Intraoperative findings showed the presence of multiple globular masses and nodules in the peritoneal cavity. Microscopically, the spindled tumor cells were arranged in interlacing fashion. Immunohistochemistry showed positivity for CD117 and negativity for smooth muscle actin (SMA). Thus, EGIST should always be considered as a differential diagnosis for nodular mesenteric masses.

Clinico Pathologic Features and Prognostic Grouping of Gastrointestinal Stromal Tumors (GISTS) in Peshawar: an Institutional Perspective

Background: Gastrointestinal stromal tumours (GISTS) are uncommon gastrointestinal tumours. The prognosis is heavily influenced by the histopathologic features of resection specimens, which have not been investigated extensively in our community. Objective of the current study was to assess the histopathologic features of GISTs in our community, as well as how they affect their prognosis, based on what we found. Methodology: In this study, 60 cases of GISTs were included that were found and treated at Peshawar's Khyber Teaching Hospital from Jan, 2018 to December, 2020. Results: The patients' ages varied from 18 to 71 years. The stomach was the most common location for primary GISTs, accounting for 57.7% of cases.75% of the patients had spindle cell morphology, and 53.8 percent of them had a poor prognosis. It was shown that intestinal GISTs had a higher grade (70%) and were more likely to be in the elevated-risk prognosis groups than stomach gastrointestinal stromal tumor,(43 percent). However, there is no statistical difference found. Although GISTs are rare gastro-intestinal tumors, initial discovery and recognition of unfavorable histology properties are important for effective treatment. In stomach the GISTs is prevalent. However, intestinal gastrointestinal stromal tumors are shown to be more prevalent and more likely to be linked to poor prognostic factors. Moreover, further large-scale investigations are needed to confirm this conclusion. Keywords: Intestinal-GISTs, Stomach-GISTs, Peshawar, Gastrointestinal stromal tumors,

Immunohistochemical features of gastrointestinal stromal tumors and their role for differential diagnosis and prognosis

The aim. To clarify all most important immunohistochemical features of gastrointestinal stromal tumors with different histological patterns and analyze the role of expression of Ki-67, MMP-9, VEGF and p16ink4A as a predictive markers of tumor progression.&#x0D; Materials and methods. The study is based on analysis of 100 primary GISTs for description of their morphological features and 36 GISTs taken from this 100 for study of prognostic markers.&#x0D; Results. All spindle cell GISTs have shown diffuse expression of CD117 in tumor cells. The levels of CD117 expression varied from strong expression (3+) until mild expression (1+). Strong expression were seen in 75,8 % of spindle cell GISTs. Epithelioid GISTs demonstrated heterognous moderate or mild expression of CD117. All primary epithelioid GISTs from patients that had relapse of tumor in period from 1 till 3 years demonstrated focal mild expression of CD 117 in tumor cells. Expression of DOG-1 were seen in all 100 cases of GISTs, that were included in our study. The strong expression of DOG-1 (3+) were seen in all 45 GISTs that had low mitotic rate (≤5 mitoses per 50HPF) and not associated with their histological pattern. GISTs with high mitotic rate demonstrated heterogeneous expression of DOG-1 in tumors: moderate expression (2+) with patchy areas of strong expression (3+). Expression of CD56 was not found in spindle cell GISTs, but single tumor cells of epithelioid GISTs that had high mitotic rate demonstrated expression of this marker. The average expression of p16ink4A were higher in tumors that gave relapses compared with tumors without relapses (50,3 % versus 5,7 % respectively, U-test=16.5; p≤0,01).The average expression of MMP-9 also were significantly higher in GISTs that gave relapses: 63,2 % compared with 13,4 % in GISTs without relapse (U-test=16; p≤0 ,01).The strong VEGF expression was found in 66,7 % of GISTs that had relapses and only in 8,3 % of GISTs without relapses. 50 % of GISTs without relapses was negative for VEGF. Finally, the average expression of Ki-67 were 13,4 % in GISTs with relapses and 8,7 % in GISTs without them (U-test=16; p≤0,01).&#x0D; Conclusion. We highly recommend using DOG-1 for epithelioid GISTs. Additionally in epithelioid GISTs can be used CD56 that can give focal positive reaction in some tumour cells. The following minimal panel of markers for differential diagnosis of spindled GISTs from other mesenchymal tumors of gastrointestinal tract is proposed: CD117, DOG-1 and SMA, where the first too markers will demonstrated the moderate or strong diffuse expression and SMA can be occasionally positive in some tumor cells. p16ink4A, ki-67, VEGF and MMP-9 can be used as additional prognostic markers in GISTs.

The occurrence of gastrointestinal stromal tumors with second malignancies – Case series of a single institution experience

IntroductionGastrointestinal stromal tumors (GISTs) may coexist with different types of malignancies, either synchronously or metachronously. The aim of this study was to characterize the clinical and histopathological features of GIST coexisting with other neoplasms. MethodsA retrospective analysis of 76 GISTs cases diagnosed at our institution between January 2003 and March 2020 was performed. A subgroup of cases with concomitant second malignancy was selected. The clinical and pathologic records were reviewed. Results18 out of 76 patients (23.7%) with GISTs were diagnosed with the second neoplasms. In 11 cases GISTs were diagnosed metachronously to the second malignancy, whereas 7 cases of GIST were synchronous. The most common concomitant neoplasms were breast cancer and gastric cancer. The concomitant GIST were located mainly in small intestine (52.6%). 14 GISTs were classified as very low or low-risk (77.8%), 3 as moderate risk (16.7%) and 1 as high risk tumors (5.6%). ConclusionThe coexistence of GIST with other malignancies may be more common, than it has been considered. As the most of concomitant GISTs occurs metachronously to the second malignancy, studying of this phenomenon requires a long-term follow-up.

Histopathological Spectrum in Pancreaticoduodenectomy Specimens: Fifteen Year Study from a Tertiary Care Centre in North India

Abstract Introduction/Objective The periampullary region is histologically complex owing to the confluence of three different kinds of epithelia (duodenal, pancreatic, biliary) harbouring four types of cancers. Although anatomical proximity warrants a common surgical approach, overall survival depends largely on the type of surgical indication. Malignant epithelial tumors are the predominant indications, accompanied by a myriad of benign tumors and tumor-like lesions. We reviewed our archival pancreaticoduodenectomies to analyze the spectrum of these lesions. Methods All pancreaticoduodenectomy specimens received in Department of Pathology, from 2005–2019 (15 years) were analyzed for histological spectrum. Results A total of 786 pancreaticoduodenectomies were received with an overall M:F= 2.3:1 and age range 17–91 years. Of these, 94.4% were neoplastic (742 cases) and 5.6% were non-neoplastic. Benign neoplastic lesions (19 cases, 2.4%) included adenomyoma (7 cases, 0.9%), solid-cystic pseudopapillary tumor of pancreas (5 cases, 0.6%), intraductal papillary mucinous neoplasm (2 cases, 0.3%) and one case each of serous cystadenoma, mucinous cystic neoplasm, dermoid cyst, gangliocytic paraganglioma and Peutz-Jeghers polyp. Ampullary adenocarcinoma was the predominant malignant epithelial lesion (609 cases, 77.5%) followed by distal CBD cancer (43 cases, 5.5%), pancreatic head cancer (20 cases, 2.5%), neuroendocrine tumors (22 cases, 2.8%), carcinoma gallbladder (5 cases, 0.6%) and one case of ampullary adenosquamous carcinoma (0.1%). Non-epithelial tumors included 9 cases of GIST (1.1%), 3 of carcinosarcoma and one case each of leiomyosarcoma and lymphoma. Non-neoplastic lesions (3.2%) included 22 cases of chronic pancreatitis and one case each of xanthogranulomatous pancreatitis, lymphoplasmacytic slcerosing pancreatitis and xanthogranulomatous cholecystitis. Ectopic pancreas was rare (2 cases, 0.3%) and 16 cases (2%) were negative for any specific pathology. Conclusion This is the largest data on histological spectrum of pancreaticoduodenectomies from India. The malignant lesions form the major bulk (94%), however benign lesions also account for a substantial percentage of surgical indications. Among malignant lesions, ampullary cancers outreach far above pancreatic cancers in the Indian subcontinent.

Primary Appendiceal Gastrointestinal Stromal Tumor: A Case of an Incidental Tumor

Abstract Introduction/Objective Gastrointestinal stromal tumors (GISTs) are rare with an approximate prevalence of 2%. Though rare, they are the most common mesenchymal neoplasm of the gastrointestinal tract. They commonly occur in the stomach (50-60%), small intestine (20-30%), large intestine and esophagus (&amp;lt;10%). GISTs arising in the appendix are very rare, with less than 20 cases reported in the English literature to date. The clinical presentation varies from appendicitis-like symptoms to incidental findings on imaging, during surgery for other diseases or at autopsy. The differential diagnosis of GIST from other stromal tumors is often difficult on hematoxylin and eosin (H&amp;E) examination alone. The use of immunohistochemistry (IHC) plays a key role in confirming the diagnosis. GISTs can be graded based on a four-tier risk stratification system, including high, intermediate, low and very low risk, taking size tumor and mitotic activity into consideration. Most of the previously reported cases of primary appendiceal GIST were low or very low risk but one case of malignant GIST arising in the appendix has been reported. Methods We present the case of a 65-year-old male with a slightly thickened appendix and fluid in the distal aspect incidentally found on computer tomography (CT) scan for diverticulitis workup. An appendectomy with adequate was performed. The gross specimen revealed a 0.2-0.4 cm thick wall with no gross perforations or masses. Histologically, the tumor measured 0.8 cm and was composed of spindle cells with no nuclear atypia and absent to low mitotic activity. The IHC profile of the tumor was positive for CD117, DOG1 and CD34. A diagnosis of Gastrointestinal stromal tumor, low grade was rendered. Conclusion We endeavor to highlight the importance of considering GIST in the differential diagnosis in patients with nonspecific symptoms and/or atypical image findings of the appendix especially in ruling out a possible malignant GIST.

Abstract 3005: Comprehensive profile of platelet derived growth factor receptor alpha (PDGFRA) mutations in gastrointestinal stromal tumors

Abstract Gastrointestinal stromal tumors (GIST) most commonly harbor oncogenic mutations in KIT tyrosine kinase, which can be targeted by the tyrosine kinase inhibitor, imatinib. However, a subset of GIST, approximately 10% of cases, instead contain mutations in a related kinase, PDGFRA. Historically, advanced PDGFRA-mutant GIST patients have had poor prognosis, primarily because the majority of these tumors are driven by the activating mutation PDGFRA D842V, which is strongly resistant to imatinib and other kinase inhibitors approved for GIST. This amino acid, D842, is within the activation loop of PDGFRA, which contains conserved motifs that change conformation depending on an active or inactive state of the kinase domain. The PDGFRA D842V mutation leads to the loss of polar interactions in the activation loop, which then stabilize the active confirmation of the kinase. Imatinib, a type II kinase inhibitor, binds only to inactive conformation of KIT and PDGFRA. This makes imatinib and other type II kinase inhibitors incapable of binding to the PDGFRA D842V-mutant receptor. The lack of effective treatments for this mutation in particular led to the development of novel kinase inhibitors to target PDGFRA, such as avapritinib (BLU-285), a type I kinase inhibitor which is capable of binding the active conformation and has been shown to potently inhibit PDGFRA D842V in vitro and in the clinic. However, our understanding of the biochemical effect of avapritinib and other PDGFRA inhibitors against all known primary and secondary PDGFRA mutations is still unknown. We have collected clinical data from over 200 PDGFRA-mutant GIST patients, the largest database of its kind to date. We found that over half of all these GIST bear D842V mutations, but nearly 50 unique mutations make up the mutations seen in the remaining GIST cases. Using in vitro models, we profiled the sensitivity of avapritinib and other novel inhibitors such as crenolanib, ripretinib (DCC-2618), and AZD3229 against many of the observed PDGFRA mutations. We also used three-dimensional modeling in silico to demonstrate the consequences of PDGFRA activating mutations on kinase function and drug binding. We also modeled and characterized novel secondary mutations in PDGFRA seen in drug resistant tumors. From our results, we have curated a comprehensive data set that can be used to inform clinicians about possible treatment options for PDGFRA-mutant GIST, and also provide implications for treatments of other PDGFRA-mutant cancers. Citation Format: Homma Khosroyani, Lillian R. Klug, Ajia Town, Jonas Lategahn, Johanna Falkenhorst, Susanne Grunewald, Thomas Mühlenberg, Christiane Ehrt, Eve Wardelmann, Wolfgang Hartmann, Hans-Ulrich Schildhaus, Sascha Jung, Paul Czodrowski, Abbas Agaimy, Piotr Rutkowski, Daniel Rauh, Sebastian Bauer, Michael C. Heinrich. Comprehensive profile of platelet derived growth factor receptor alpha (PDGFRA) mutations in gastrointestinal stromal tumors [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3005.

Laparoscopic sleeve gastrectomy performed in a morbidly obese patient with gastrointestinal stromal tumor: a case report and literature review

BackgroundGastrointestinal stromal tumor (GIST) is the most frequent submucosal tumor, and with advancements of diagnostic modalities, the incidence of GIST cases diagnosed have increased. Similarly, prevalence of morbid obesity has also rapidly increased over the past decade. Notably, the incidence of GIST in obese patients was reported to be more frequent as compared to the general population. Despite local resection being the first choice for GIST treatment, extensive surgery should also be considered depending on the tumor size and location. Laparoscopic sleeve gastrectomy (LSG), the most popular bariatric procedure, could also be a concomitant treatment option for both morbid obesity and GIST when the tumor is contained within LSG the excision range. There are, however, few reports about LSG planned for GIST preoperatively.Case presentationA morbidly obese 46-year-old Japanese male (body weight of 105.4 kg, body mass index (BMI) of 36.6 kg/m2) was diagnosed with an intramural GIST in the gastric fundus. Because of his extreme visceral fat dominated obesity (visceral fat area of 386 cm2), in addition to the size and location of the tumor, we determined that it would be difficult to perform local resection. We planned LSG as a concomitant treatment for both GIST and morbid obesity. After the preoperative examination and 6 months of weight control, the patient lost enough weight to undergo LSG safely. Keeping enough distance away from the tumor, which we observed with an endoscope, we performed LSG to successfully resect the tumor. The patient was discharged uneventfully. Weight loss was successful as his BMI was 21.0 kg/m2 at 3 months post-surgery.ConclusionWe successfully performed LSG in a morbidly obese patient with a large GIST. This is the largest GIST concomitantly resected with LSG reported within current literature.

Transanal Endoscopic Microsurgery (TEM) for rectal GI stromal tumor

BackgroundTransanal endoscopic microsurgery (TEM) is effective in treating adenomas and select early rectal cancers. Our objective is to evaluate TEM in treating early rectal GISTs. MethodsPatients were identified in a prospective database with pathology confirmed rectal GIST prior to TEM over 10 years. Demographic, pathologic, operative and follow-up data was analysed and presented with descriptive statistics. Results7 cases of rectal GIST were treated with TEM with a follow-up time of 31 months (0–71). Median tumor distance from the anal verge was 4 cm (2.5–6) and median tumor size was 3 cm (2–5.7). Negative margins were achieved in 4/7 patients. Those with positive margins were treated with repeat TEM or imatinib. 1 patient had local recurrence successfully treated by TEM. ConclusionsOverall, TEM is safe for locally excising GISTs. As rectal GISTs are rare, a multicenter registry may better elucidate outcomes with this treatment.

Molecular and Clinicopathological Features of Gastrointestinal Stromal Tumors in Vietnamese Patients.

BackgroundGastrointestinal stromal tumors (GISTs) are the most frequent mesenchymal neoplasms of the gastrointestinal tract. Management of GIST patients is currently based on clinicopathological features and associated genetic changes. However, the detailed characteristics and molecular genetic features of GISTs have not yet been described in the Vietnamese population.MethodsWe first identified 155 patients with primary GIST who underwent surgery with primary curative intent between 2011 and 2014 at University Medical Center at Ho Chi Minh City, Vietnam. We evaluated the clinicopathological features and immunohistochemical reactivity to p53 and Ki-67 in these patients. Additionally, KIT genotyping was performed in 100 cases.ResultsThe largest proportion of GISTs was classified as high-risk (43.2%). Of the 155 GISTs, 52 (33.5%) were positive for Ki-67, and 58 (37.4%) were positive for p53. The expression of Ki-67 and p53 were correlated with mitotic rate, tumor size, risk assessment, and tumor stage. Out of 100 GIST cases, KIT mutation was found in 68%, of which 62 (91.2%) were found in exon 11, two (2.9%) in exon 9, and four (5.8%) in exon 17. No mutation in exon 13 was identified. Additionally, KIT mutations did not correlate with any clinicopathological features.ConclusionsThe expression of Ki-67 and p53 were associated with high-risk tumors. Mutations in exon 11 were the most commonly found, followed by exon 17 and exon 9. Additionally, KIT mutation status was not correlated with any recognized clinicopathological features.