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Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal neoplasms of the gastrointestinal tract, frequently characterized by mutations in the KIT or PDGFRA genes. This case report details the complex clinical course of a 71-year-old female with a history of HIV and metastatic GIST presenting with acute abdominal symptoms indicative of perforated viscus. Initial imaging revealed a massive pneumoperitoneum and a large abdominal mass, necessitating immediate surgical intervention. The patient underwent multiple surgeries, including bowel resections and colostomy creation, to address the extensive tumor burden and complications. Postoperatively, she required intensive care management, including mechanical ventilation, vasopressor support, and hemodialysis for acute kidney injury. Pathological examination confirmed metastatic GIST with extensive mesenteric and omental involvement. Immunohistochemical staining was positive for CD117 (c-KIT) and DOG-1. Despite aggressive surgical and supportive measures, the patient's condition highlighted the significant challenges in managing advanced GIST with perforation. This case highlights the importance of a multidisciplinary approach, integrating surgical, medical, and intensive care to optimize outcomes. The prognosis of GIST varies widely, with localized tumors having favorable outcomes following resection, while metastatic cases often face a poorer prognosis despite advances in targeted therapies. This case exemplifies the critical need for personalized treatment plans and ongoing research to improve the management and prognosis of GIST patients.

Classic colon carcinomas are defined as adenocarcinomas, characterized by groups of medium/large cells with basophilic and polymorphous nuclei and an eosinophilic elongated cytoplasm, that rearrange on glandular structures. Signs of poor prognosis include high tumor budding, lymphovascular and perineural invasion, poor differentiation, positive margins, and CDX2 loss. Less frequent colon carcinoma subtypes are: mucinous, medullary, signet-ring cell, squamous cell, small cell and undifferentiated carcinoma, among others. In the following case report, we present a 65-year-old woman with a T2N0Mx colon carcinoma with a remarkable papillary and follicular histological appearance. The immunohistochemical stains confirmed an intestinal origin (CDX2+) and excluded a thyroid, gynecological, and urological metastasis, with tumor cells negative for GATA3, PAX8, TTF-1, and thyroglobulin. There was no loss of mismatch repair proteins and p53 showed a wild-type staining. next generation sequencing showed a platelet-derivated growth factor receptor alpha (PDGFRA) mutation. To the best of our knowledge, there have been only two examples of primary papillary colon carcinoma reported in the literature, and neither of them with a PDGFRA mutation. We describe one tumor and discuss its pathological features. [ABSTRACT FROM AUTHOR]

Background The patient selection for optimal adjuvant therapy in gastrointestinal stromal tumors (GISTs) is provided by nomogram based on tumor size, mitotic index, tumor location, and tumor rupture. Although mutational status is not currently used to risk assessment, tumor genotype showed a prognostic influence on natural history and tumor relapse. Innovative measures, such as KIT/PDGFRA -mutant-specific variant allele frequency (VAF) levels detection from next-generation sequencing (NGS), may act as a surrogate of tumor burden and correlate with prognosis and overall survival of patients with GIST, helping the choice for adjuvant treatment. Patients and Methods This was a multicenter, hospital-based, retrospective/prospective cohort study to investigate the prognostic role of KIT or PDGFRA -VAF of GIST in patients with radically resected localized disease. In the current manuscript, we present the results from the retrospective phase of the study. Results Two-hundred (200) patients with GIST between 2015 and 2022 afferent to 6 Italian Oncologic Centers in the EURACAN Network were included in the study. The receiver operating characteristic (ROC) curves analysis was used to classify "low" vs. "high" VAF values, further normalized on neoplastic cellularity (nVAF). When RFS between the low and high nVAF groups were compared, patients with GIST with KIT/PDGFRA nVAF > 50% showed less favorable RFS than patients in the group of nVAF ≤ 50% (2-year RFS, 72.6% vs. 93%, respectively; P =.003). The multivariable Cox regression model confirmed these results. In the homogeneous sub-population of intermediate-risk, patients with KIT -mutated GIST, the presence of nVAF >50% was statistically associated with higher disease recurrence. Conclusion In our study, we demonstrated that higher nVAF levels were independent predictors of GIST prognosis and survival in localized GIST patients with tumors harboring KIT or PDGFRA mutations. In the cohort of intermediate-risk patients, nVAF could be helpful to improve prognostication and the use of adjuvant imatinib. [ABSTRACT FROM AUTHOR]

Abstract Background Metanephric stromal tumors (MST) are rare benign renal tumors that mainly occur in infants and children. Approximately 72% of MST in children have the B-Raf proto-oncogene serine/threonine kinase (BRAF) V600E mutation. To date, only five cases of adult MSTs have been reported and no clear genetic alterations have been found. Case presentation We report a case of MST in a 45-year-old woman who complained of left lower back pain for a week, accompanied by hypertension (150/79 mmHg). Magnetic resonance imaging (MRI) showed an abnormally enhanced nodule (1.1 cm in the middle of the left kidney), which was histopathologically consistent with an MST. The BRAF V600E mutation was not detected in tumor cells using PCR and next-generation sequencing (NGS). However, a platelet-derived growth factor receptor alpha (PDGFRA) mutation was detected in this case using NGS. The patient showed no recurrence or metastasis nine months after partial nephrectomy, and her blood pressure was consistently normal. Conclusion This is the first report of alterations in PDGFRA in MSTs. This result advances our knowledge of genetic variations in adult MSTs, which may have different gene alterations from MSTs in children.

Background: Metanephric stromal tumors (MST) are rare benign renal tumors that mainly occur in infants and children. Approximately 72% of MST in children have the B-Raf proto-oncogene serine/threonine kinase (BRAF) V600E mutation. To date, only five cases of adult MSTs have been reported and no clear genetic alterations have been found. Case presentation: We report a case of MST in a 45-year-old woman who complained of left lower back pain for a week, accompanied by hypertension (150/79 mmHg). Magnetic resonance imaging (MRI) showed an abnormally enhanced nodule (1.1 cm in the middle of the left kidney), which was histopathologically consistent with an MST. The BRAF V600E mutation was not detected in tumor cells using PCR and next-generation sequencing (NGS). However, a platelet-derived growth factor receptor alpha (PDGFRA) mutation was detected in this case using NGS. The patient showed no recurrence or metastasis nine months after partial nephrectomy, and her blood pressure was consistently normal. Conclusion: This is the first report of alterations in PDGFRA in MSTs. This result advances our knowledge of genetic variations in adult MSTs, which may have different gene alterations from MSTs in children. [ABSTRACT FROM AUTHOR]

Gastrointestinal stromal tumour (GIST) is the most common sarcoma and can be seen in any part of the gastrointestinal tract. The effect of tyrosine kinase inhibitors varies with mutation status in receptor tyrosine kinase KIT and in platelet-derived growth factor receptor A (PDGFRA). This case presents a 61-year-old man, diagnosed with an 11-cm GIST located at the stomach with a high risk of recurrence. The patient showed intolerance to imatinib shortly after introduction and subsequently progressed on sunitinib and nilotinib. The patient started fourth-line treatment with sorafenib with an impressive response to a point at which metastases intra-abdominally and in the liver could be resected. After surgery, sorafenib was restarted. Due to toxicity, sorafenib dose was reduced over time. The dose was insufficient to control the disease since a new recurrence was detected. Mutation analyses revealed a GIST harbouring a deletion of codon p.I843_D846del, located at PDGFRA exon 18, right next to the codon D842 where mutations are known leading to imatinib resistance. In this case, the GIST was highly sensitive to sorafenib, and the response was dose related. It is mandatory to perform mutation analyses on primary tumour and at recurrence in the decision-making of the correct treatment for the patient. In March 2021, the patient had been in treatment with sorafenib for 12.5 years and was still without signs of recurrence. A multidisciplinary approach was essential for the long-term survival of the patient in this case.

Platelet-derived growth factor receptor A (PDGFRA) mutations occur in approximately 10–15% of gastrointestinal stromal tumors (GISTs). These tumors with PDGFRA mutations have a different pathogenesis, clinical characteristics, and treatment response compared to tumors with receptor tyrosine kinase protein (KIT) mutations (60–70%). Many clinical studies have investigated the use of tyrosine kinase inhibitors mainly in patients with KIT mutations; however, there is a lack of attention to the PDGFRA-mutated molecular subtype. The main effective inhibitors of PDGFRA are ripretinib, avapritinib, and crenolanib, and their mechanisms and efficacy in GIST (as confirmed in clinical trials) are described in this review. Some multi-targeted tyrosine kinase inhibitors with inhibitory effects on this molecular subtype are also introduced and summarized in this paper. This review focuses on PDGFRA-mutated GISTs, introduces their clinical characteristics, downstream molecular signaling pathways, and existing resistance mechanisms. We focus on the most recent literature that describes the development of PDGFRA inhibitors and their use in clinical trials, as well as the potential benefits from different combination therapy strategies. [ABSTRACT FROM AUTHOR]

Simple Summary: Gastrointestinal stromal tumors represent the most common mesenchymal tumor of the canine gastrointestinal tract. Activating mutations in c-KIT and PDGFRA genes are considered the key molecular drivers of human gastrointestinal stromal tumors pathogenesis and are used to predict the response to Receptor tyrosine kinase inhibitors. However, in veterinary medicine, the significance of these mutations in canine gastrointestinal stromal tumors has not been sufficiently explored yet. The aim of this study is to investigate the mutational status of c-KIT and PDGFRA, by PCR and sequencing, in 17 canine gastrointestinal stromal tumors. Mutations of c-KIT were detected in 47% of cases; in one case, PDGFRA mutation was also identified. Although follow-up data were not available for all specimens, based on the information collected, we observed at the time of diagnosis the presence of metastases in cases with c-KIT mutation. In conclusion, this study provides evidence for the presence of c-KIT and PDGFRA mutations in canine gastrointestinal stromal tumors and suggests a potential association of c-KIT mutation with the more aggressive biological behavior of the tumor. Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the canine gastrointestinal tract and are diagnosed by the immunohistochemical expression of the receptor tyrosine kinase (RTK) KIT. Activating mutations of the proto-oncogenes c-KIT and PDGFRA drive GIST oncogenesis and are used to predict the response to RTK-inhibitors in human oncology. Currently, the frequency and significance of these mutations in canine GIST have not been adequately explored. Therefore, we investigated the mutational status of c-KIT (exons 9, 11 and 13) and PDGFRA (exons 12 and 18) genes by PCR followed by fragment analysis for c-KIT deletions and PCR followed by screening with DHPLC and direct sequencing confirmation for single nucleotide variations in 17 formalin-fixed paraffin-embedded canine GISTs confirmed by KIT immunopositivity. c-KIT mutations were detected in 47% of cases, with a mutation detection rate significantly higher (p = 0.0004, Fisher's exact test) and always involving exon 11. A PDGFRA gene mutation (exon 18) was identified in one case. Even if follow-up data were not available for all cases, four cases with documented abdominal metastases displayed c-KIT mutations. These data confirm that c-KIT exon 11 mutations occur frequently in canine GISTs, and identify the presence of a PDGFRA mutation similar to human GISTs. This study also suggests a potential association of c-KIT mutation with more aggressive biological behavior. [ABSTRACT FROM AUTHOR]

Objective: To investigate the correlation of KIT and PDGFRA mutation status with immunohistochemistry (IHC) and clinicopathological features in the primary, recurren tor metastatic gastrointestinal stromal tumors (GIST). Methods: A total of 167 primary GIST including 22 recurrent or metastatic GIST were tested for CD117, DOG1, CD34 and Ki-67 by IHC, and KIT gene exon 9, 11, 13, 17and PDGFRA gene exon12, 18 were analyzed by Sanger sequencing. Results: The frequencies of KIT and PDGFRA mutation in 167 primary GIST were 83.8%(140/167) and 3.0% (5/167), respectively. The mutation frequencies of KIT gene exon 11, exon 9 and exon 17 were 74.9% (125/167),8.4% (14/167) and 0.6% (1/167). Five primary GIST harbored PDGFRA mutations in exon 18,and 4 tumors had D842V mutation. Genetic mutations in KIT gene included point mutations (34.3%,48/140), deletion mutations (40.7%,57/140), duplication mutations (3.6%,5/140), and complicated mutations (deletion-insertion,12.1%,17/140).For GIST with KIT gene exon 11 mutation, Ki-67 index was significantly higher in tumors with non-point mutation than those with point mutations (P=0.0052). In 22 recurrent or metastatic GIST, double-exon mutation on KIT gene were found in 9 cases and 6 case were with mutation in both exon 11 and 17, 2 in exon 11 and 13,and one in exon 9 and 13.In 22 cases with recurrent or metastatic GIST, patients with double KIT exon mutations had a longer median progression-free survival (PFS)(108 months) than those with wild type gene (PFS, 30 months),and single exon mutation (PFS, 60 months)(P=0.0299 and P=0.0111), while no significant difference were observed regarding Ki-67, CD117, DOG1, CD34 expression,tumor size and nuclear mitosis between them. Conclusions: KIT mutations in primary GIST occur more often in exon 11. For primary GIST with KIT exon 11 mutations, Ki-67 index is higher in lesions with non-point mutation than those with point mutation,indicating poor biological beha-vior. In recurrence or metastatic GIST, cases harbor the double KIT exon mutations account for 9/22 and possess a better PFS than those with wild type and singe KIT exon 11 mutation.

Platelet-derived growth factor receptor A (PDGFRA) mutations occur in approximately 10–15% of gastrointestinal stromal tumors (GISTs). These tumors with PDGFRA mutations have a different pathogenesis, clinical characteristics, and treatment response compared to tumors with receptor tyrosine kinase protein (KIT) mutations (60–70%). Many clinical studies have investigated the use of tyrosine kinase inhibitors mainly in patients with KIT mutations; however, there is a lack of attention to the PDGFRA-mutated molecular subtype. The main effective inhibitors of PDGFRA are ripretinib, avapritinib, and crenolanib, and their mechanisms and efficacy in GIST (as confirmed in clinical trials) are described in this review. Some multi-targeted tyrosine kinase inhibitors with inhibitory effects on this molecular subtype are also introduced and summarized in this paper. This review focuses on PDGFRA-mutated GISTs, introduces their clinical characteristics, downstream molecular signaling pathways, and existing resistance mechanisms. We focus on the most recent literature that describes the development of PDGFRA inhibitors and their use in clinical trials, as well as the potential benefits from different combination therapy strategies.

Purpose: To explore molecular alterations and their correlation with the survival of patients with glioblastoma (GBM) with corpus callosum (CC) involvement (ccGBM).Methods: Electronic medical records were reviewed for glioma patients tested for molecular alterations and treated at our hospital between January 2016 and July 2020. ccGBM was compared to GBM without CC involvement (non-ccGBM) to identify differences in molecular alterations. Clinical outcomes and survival were compared between ccGBM and non-ccGBM patients, as well as among patients with ccGBM with different molecular alteration statuses. ccGBM was also compared to diffuse midline glioma (DMG) to clarify their correlation in molecular alterations, the progression-free survival (PFS), and overall survival (OS).Results: Thirty ccGBM and 88 non-ccGBM patients were included. PDGFRA amplification (PDGFRAamp, 33.3 vs. 9.1%, P = 0.004) and missense mutation (PDGFRAmut, 20.0 vs. 3.4%, P = 0.011) both had higher incidences in ccGBM than in non-ccGBM. PDGFRA alteration was associated with the occurrence of ccGBM (OR = 4.91 [95% CI: 1.55–15.52], P = 0.007). ccGBM with PDGFRAamp resulted in a shorter median PFS (8.6 vs. 13.5 months, P = 0.025) and OS (12.4 vs. 17.9 months, P = 0.022) than non-ccGBM with PDGFRAnon-amp. ccGBM with PDGFRAamp combined with PDGFRAmut (PDGFRAamp-mut) had a shorter median PFS (7.6 vs. 8.9 months, P = 0.022) and OS (9.6 vs. 17.8 months, P = 0.006) than non-ccGBM with wild-type PDGFRA and no amplification (PDGFRA-w, non-amp). Compared to ccGBM with PDGFRA-w, non-amp, ccGBM with PDGFRAamp and PDGFRAamp-mut both had a shorter median PFS and OS (P < 0.05). The hazard ratios (HRs) of PDGFRAamp for PFS and OS in ccGBM were 3.08 (95% CI: 1.02–9.35, P = 0.047) and 5.07 (1.52–16.89, P = 0.008), respectively, and the HRs of PDGFRAamp-mut for PFS and OS were 13.16 (95% CI: 3.19–54.40, P < 0.001) and 16.36 (2.66–100.70, P = 0.003). ccGBM may have similar incidences of PDGFRAamp or mut (PDGFRAamp/mut) as DMG, and they also had similar median PFS (10.9 vs. 9.0 months, P = 0.558) and OS (16.8 vs. 11.5 months, P = 0.510).Conclusion:PDGFRA alterations are significantly associated with the occurrence and poor prognosis of ccGBM. ccGBM with PDGFRAamp/mut may be classified as a single subtype of GBM that has a similar survival rate to DMG. PDGFR inhibitors may be a promising treatment method for ccGBM.

Gastrointestinal stromal tumour (GIST) is the most common sarcoma and can be seen in any part of the gastrointestinal tract. The effect of tyrosine kinase inhibitors varies with mutation status in receptor tyrosine kinase KIT and in platelet-derived growth factor receptor A (PDGFRA). This case presents a 61-year-old man, diagnosed with an 11-cm GIST located at the stomach with a high risk of recurrence. The patient showed intolerance to imatinib shortly after introduction and subsequently progressed on sunitinib and nilotinib. The patient started fourth-line treatment with sorafenib with an impressive response to a point at which metastases intra-abdominally and in the liver could be resected. After surgery, sorafenib was restarted. Due to toxicity, sorafenib dose was reduced over time. The dose was insufficient to control the disease since a new recurrence was detected. Mutation analyses revealed a GIST harbouring a deletion of codon p.I843_D846del, located at PDGFRA exon 18, right next to the codon D842 where mutations are known leading to imatinib resistance. In this case, the GIST was highly sensitive to sorafenib, and the response was dose related. It is mandatory to perform mutation analyses on primary tumour and at recurrence in the decision-making of the correct treatment for the patient. In March 2021, the patient had been in treatment with sorafenib for 12.5 years and was still without signs of recurrence. A multidisciplinary approach was essential for the long-term survival of the patient in this case. [ABSTRACT FROM AUTHOR]

Purpose: To explore molecular alterations and their correlation with the survival of patients with glioblastoma (GBM) with corpus callosum (CC) involvement (ccGBM). Methods: Electronic medical records were reviewed for glioma patients tested for molecular alterations and treated at our hospital between January 2016 and July 2020. ccGBM was compared to GBM without CC involvement (non-ccGBM) to identify differences in molecular alterations. Clinical outcomes and survival were compared between ccGBM and non-ccGBM patients, as well as among patients with ccGBM with different molecular alteration statuses. ccGBM was also compared to diffuse midline glioma (DMG) to clarify their correlation in molecular alterations, the progression-free survival (PFS), and overall survival (OS). Results: Thirty ccGBM and 88 non-ccGBM patients were included. PDGFRA amplification (PDGFRAamp , 33.3 vs. 9.1%, P = 0.004) and missense mutation (PDGFRAmut , 20.0 vs. 3.4%, P = 0.011) both had higher incidences in ccGBM than in non-ccGBM. PDGFRA alteration was associated with the occurrence of ccGBM (OR = 4.91 [95% CI: 1.55–15.52], P = 0.007). ccGBM with PDGFRAamp resulted in a shorter median PFS (8.6 vs. 13.5 months, P = 0.025) and OS (12.4 vs. 17.9 months, P = 0.022) than non-ccGBM with PDGFRAnon-amp. ccGBM with PDGFRAamp combined with PDGFRAmut (PDGFRAamp-mut) had a shorter median PFS (7.6 vs. 8.9 months, P = 0.022) and OS (9.6 vs. 17.8 months, P = 0.006) than non-ccGBM with wild-type PDGFRA and no amplification (PDGFRA-w, non-amp). Compared to ccGBM with PDGFRA-w, non-amp , ccGBM with PDGFRAamp and PDGFRAamp-mut both had a shorter median PFS and OS (P < 0.05). The hazard ratios (HRs) of PDGFRAamp for PFS and OS in ccGBM were 3.08 (95% CI: 1.02–9.35, P = 0.047) and 5.07 (1.52–16.89, P = 0.008), respectively, and the HRs of PDGFRAamp-mut for PFS and OS were 13.16 (95% CI: 3.19–54.40, P < 0.001) and 16.36 (2.66–100.70, P = 0.003). ccGBM may have similar incidences of PDGFRAamp or mut (PDGFRAamp/mut) as DMG, and they also had similar median PFS (10.9 vs. 9.0 months, P = 0.558) and OS (16.8 vs. 11.5 months, P = 0.510). Conclusion: PDGFRA alterations are significantly associated with the occurrence and poor prognosis of ccGBM. ccGBM with PDGFRAamp/mut may be classified as a single subtype of GBM that has a similar survival rate to DMG. PDGFR inhibitors may be a promising treatment method for ccGBM. [ABSTRACT FROM AUTHOR]

Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the canine gastrointestinal tract and are diagnosed by the immunohistochemical expression of the receptor tyrosine kinase (RTK) KIT. Activating mutations of the proto-oncogenes c-KIT and PDGFRA drive GIST oncogenesis and are used to predict the response to RTK-inhibitors in human oncology. Currently, the frequency and significance of these mutations in canine GIST have not been adequately explored. Therefore, we investigated the mutational status of c-KIT (exons 9, 11 and 13) and PDGFRA (exons 12 and 18) genes by PCR followed by fragment analysis for c-KIT deletions and PCR followed by screening with DHPLC and direct sequencing confirmation for single nucleotide variations in 17 formalin-fixed paraffin-embedded canine GISTs confirmed by KIT immunopositivity. c-KIT mutations were detected in 47% of cases, with a mutation detection rate significantly higher (p = 0.0004, Fisher’s exact test) and always involving exon 11. A PDGFRA gene mutation (exon 18) was identified in one case. Even if follow-up data were not available for all cases, four cases with documented abdominal metastases displayed c-KIT mutations. These data confirm that c-KIT exon 11 mutations occur frequently in canine GISTs, and identify the presence of a PDGFRA mutation similar to human GISTs. This study also suggests a potential association of c-KIT mutation with more aggressive biological behavior.

Introduction: The benefit of the tyrosine kinase inhibitor (TKI) imatinib mesylate in metastatic Gastrointestinal Stromal Tumors (GIST) leads to improved progression-free survival (PFS) and overall survival (OS). Clinical trials of adjuvant imatinib have provided data on the utility in management of primary GIST. There still remains uncertainty regarding the optimal duration of therapy.Areas covered: Here, we review the literature on the pivotal clinical trials evaluating adjuvant imatinib: ACOSOG Z9000/Z9001, EORTC 62024, Scandinavian Sarcoma Group XVIII, and PERSIST-5. The data from these studies that were analyzed included the patient population, length of therapy, and outcomes.Expert opinion: Clinical trial data demonstrate that adjuvant imatinib delays recurrence and appears to improve survival when taken for 3 years in high-risk patients; treatment for 5 years has been found to be safe, although difficult for patients to maintain adherence. These studies all incorporated slightly different patient populations based upon eligibility criteria for risk of recurrence, but support the use in patients with intermediate to high risk of disease recurrence. Data from these studies does not support treating those with low risk of recurrence or imatinib-insensitive mutations. [ABSTRACT FROM AUTHOR]

Background: Gastrointestinal stromal tumors are the most common mesenchymal tumors of the stomach and small bowel. Their myriad morphology sometimes renders the diagnosis very challenging. Case presentation: The 57 years old man was admitted to hospital for a gastric mass found in a routine physical examination. Gastroscopy examination showed scattered mucosa congestion and edema, there were no ulcer or mass. Computed tomography scan uncovered a round shadow in the right upper abdominal cavity, closely related to the gastric antrum. The patient underwent tumor resection and partial gastrectomy. On gross examination of the specimen the tumor was 7 cm × 5 cm × 5 cm and the cut surface was greyish white with multifocal small cysts. Microscopically, there are two sharply separated morphologic pattern. One side was hypocellular with short spindle cell randomly distributed in sclerosing stroma in which are some branched staghorn-like vessels, mimicking solitary fibrous tumor. The other side was cellular with loose bundle-like growth of spindle cells in fibromyxoid stroma with lymphocytes infiltration, mimicking inflammatory myofibroblastic tumor. The number of mitosis was less than 5 per 5 mm2 field. There was no necrosis. Immunophenotypically, the spindle cells were focally CD117 weakly positive and Dog1 positive. They were negative for S100, MDM2, ALK, CK-pan, CD34, CDK4, STAT6, SMA, desmin. SDHB expression was intact. Gene sequencing revealed PDGFRA exon 18 mutation (D842V). The final diagnosis was gastrointestinal stromal tumor, low risk. The patient was followed up with 10 months after operation, no recurrence or metastasis was found. Conclusion: We present an unusual case of gastrointestinal stromal tumor harboring PDGFRA p.D842 mutation with unusual morphology. Our case expanded the morphological spectrum of those tumors, recognizing this rare morphological variation of the tumor would avoid misdiagnosis and inappropriate treatment.

A 21‐year‐old female presented with a 5‐year history of an erythematous papule on her right breast. The biopsy showed a dense, dermal nodular infiltrate, extending focally into the subcutaneous tissue. The infiltrate was composed predominantly of pleomorphic cells with bi‐lobed, multi‐lobed, horseshoe, or ring‐shaped nuclei. There was a smaller subset of monomorphous cells characterized by a round, reniform, or elongated single‐lobed nucleus. Accompanying cells included few foamy histiocytes, lymphocytes, and numerous scattered eosinophils. No necrosis, vascular invasion, or ulceration was present. The pleomorphic and monomorphic granular cells were positive for Giemsa stain as well as for tryptase, CD117, CD68, CD2, and CD30 immunohistochemistry and negative for S100, CD1a, myeloperoxidase, lysozyme, and CD56. Clinical examination was negative for any additional similar lesions and serum tryptase was within normal limits. The bone marrow was not biopsied. In addition, fluorescent in situ hybridization revealed multiple clones with loss of number 5 chromosome and PDGFRA and HRAS mutations. The lesion did not recur or progress after a 6‐year clinical follow‐up. To our full knowledge, we report the first case of pleomorphic mastocytoma with loss of chromosome 5 and PDGFRA and HRAS mutations. [ABSTRACT FROM AUTHOR]

Epithelioid gastrointestinal stromal tumors (GISTs) are rare and may be confused with other tumors with epithelioid morphology. Therefore, herein, we collected 12 epithelioid GIST samples and summarized their morphological and immunohistochemical characteristics. Through genetic testing, we explored the correlation between morphology and gene mutations. The results showed that eight tumors showed focal or diffuse myxoid stromal changes with less cohesively arranged rhabdoid tumor cells; among these, five showed platelet-derived growth factor receptor alpha gene (PDGFRA) mutations. Signet ring cells with sclerosing stroma and receptor tyrosine kinase type III gene (KIT) mutations were present in two cases, which might be a KIT mutation-associated growth pattern in epithelioid GISTs. Succinate dehydrogenase gene (SDH) mutations were detected in three cases. Simultaneously, PDGFRA mutations were detected in two cases, and the Kirsten rat sarcoma viral oncogene homolog gene (KRAS) mutation was detected in another case. SDH-subunit B (SDHB) expression was partially weak and strongly diffuse in two cases with concurrent PDGFRA and SDHD mutations, respectively. The coexistence of PDGFRA and SDHD mutations may have affected SDHB expression. Altogether, we concluded that PDGFRA mutations may play an important role in co-mutant GIST pathogenesis. • This study summarizes the morphological and genetic features of epithelioid gastrointestinal stromal tumors (GISTs). • The growth pattern of signet ring cells with sclerosing stroma was correlated with KIT mutations in epithelioid GISTs. • SDH mutations were detected in three cases, but SDHB showed focally weak or strong diffuse immunostaining. • The coexistence of PGDFRA or KRAS mutation might have affected the SDHB in GISTs with SDH mutation [ABSTRACT FROM AUTHOR]

Copyright of Der Pathologe is the property of Springer Nature and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Aims Rhabdoid morphology resembling that of the aggressive paediatric rhabdoid tumours occurs in various malignancies usually lacking characteristic SMARCB1 ( INI1) loss. Little is known about the clinicopathological and molecular characteristics of the rhabdoid phenotype in gastrointestinal stromal tumours ( GISTs). Methods and results Six gastric rhabdoid GISTs were examined by immunohistochemistry, KIT and platelet-derived growth factor receptor-α gene ( PDGFRA) mutation analysis, and comparative genomic hybridization ( CGH). All tumours expressed KIT, PDGFRA, DOG-1, and SMARCB1 (two of six with a mosaic pattern). Five of six tumours harboured PDGFRA mutations (D842V in four; N659K in one), and one case was wild type for KIT/ PDGFRA and succinate dehydrogenase ( SDH) A-negative and SDHB-negative by immunohistochemistry. CGH revealed aberrations typical of GISTs (−1p, −14, and −22q in three, five, and three cases, respectively), with a mean of 1.7 aberrations in the epithelioid component and 2.7 in the rhabdoid component. None showed progression (mean follow-up of 25 months). Conclusions Rhabdoid gastric GISTs are associated with epithelioid morphology and PDGFRA mutations. They harbour CGH aberrations that are typical of ordinary GISTs in both tumour components. The presence of additional genetic alterations in the rhabdoid areas indicates evolution from the epithelioid components, and possible genetic and biological progression. On the basis of our series and previous reports, rhabdoid morphology in GISTs presumably does not imply aggressiveness. [ABSTRACT FROM AUTHOR]

Purpose: The duodenum as primary site for gastrointestinal stromal tumors (GISTs) is rare and mitotic rate, tumor size, type of mutation and number of chromosomal aberrations have prognostic implications. Methods: We analyzed the outcome of 13 patients with duodenal GISTs who underwent surgical tumor resection. Either segmental duodenectomy or pylorus-preserving duodenopancreatectomy was performed. The tumors were histopathologically examined and the risk of progression was assessed based on tumor size and mitotic count. Additionally, mutation analysis of the KIT and PDGFRA receptor tyrosine kinase genes and comparative genomic hybridization (CGH) were performed in all cases. Results: Eight patients underwent segmental duodenectomy and five patients were treated with pylorus-preserving duodenopancreatectomy. None of the five GISTs with low or no risk for malignancy according to the Miettinen classification developed tumor progress. In contrast, five of eight cases (62.5%) with high-risk tumors revealed tumor progress, and four of these patients died (50%). The median overall survival for all patients was 66 months, and the median disease-free survival 41 months. The operative procedure and type of mutation did not correlate with long-term survival. CGH analysis displayed −15q in 12/13 tumors, and −1p in 11/13 cases as characteristic chromosomal aberrations for intestinal origin. Notably, −22q was present in three of four cases with tumor progress. Conclusions: Both segmental duodenectomy and pylorus-preserving duodenopancreatectomy are appropriate options to treat duodenal GIST and should be implemented depending on resectability and the patient's performing state. The Miettinen classification and CGH findings correlate with the clinical course. [ABSTRACT FROM AUTHOR]

Gastrointestinal stromal tumors (GISTs) are rare tumors of mesenchymal origin that develop along the gastrointestinal tract. Over ten years ago, their management dramatically changed following the discovery of an activating mutation of the KIT oncogene, which led to the use of small molecule inhibitors to therapeutically target these mutant kinases. Patients with advanced GIST, who were once a subset of sarcoma with poor prognosis due to their lack of chemosensitivity, may now survive more than 5 years following treatment with tyrosine kinase inhibitors (TKI) such as imatinib mesylate (IM) and sunitinib malate (SU). After ten years of active clinical and preclinical research, it has become clear that, although relatively homogeneous compared to other solid malignancies, there is still some heterogeneity in GISTs and most notably in regard to response to therapy. Here, we review the current data regarding molecular prediction of response in this disease. [ABSTRACT FROM AUTHOR]

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Purpose. This study analyzed the relationship between treatment outcome and kinase mutational status in Korean patients with advanced gastrointestinal stromal tumors (GISTs). Experimental Design. Clinical data were collected from 113 consecutive patients with metastatic or unresectable GISTs treated with imatinib from June 2001 through June 2005 at five institutions in Korea. KIT exons 9, 11, 13, and 17 and PDGFRA exons 12 and 18 were examined. Results. The median patient age was 57 years (range, 31-82 years). The overall response rate was 67.2%. KIT mutations were found in exon 11 (n = 92, 81.4%) and exon 9 (n = 10, 8.8%). One patient had a PDGFRA exon 18 mutation. The overall mutation rate was 91.2%. Response rates were 68.4%, 50.0%, and 80.0% in patients with KIT exon 11 mutations, KIT exon 9 mutations, and no kinase mutations, respectively. With a median follow-up of 49.0 months, the median progression-free survival (PFS) time was 42.0 months and median overall survival (OS) time was not reached. PFS and OS times did not differ significantly according to KIT genotype. Conclusion. This study was unable to find an association between KIT mutational status and clinical outcome of imatinib in Korean patients with advanced GISTs. There was a trend toward better outcomes for patients with wild-type KIT or exon 11 mutations compared with exon 9 mutations, although this was not statistically significant. Compared with previous studies in western populations, these results suggest that ethnic differences may influence the relationship between KIT genotype and clinical outcome to imatinib. [ABSTRACT FROM AUTHOR]

Introduction: Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the digestive tract., Presentation of Case: 54-year-old woman with a history of phyllodes tumor of the left breast he patient was admitted to our hospital for management of retroperitoneal soft tissue tumor, attached to the fourth portion of the duodenum, opposite the head of the pancreas. The patient underwent a large excision of the tumor, the duodenojejunal flexure, and the third and fourth portions of the duodenum along with the head of the pancreas. The histopathological examination confirmed the presence of a spindlecell mesenchymal proliferation. These cells do not express CD117, but they express DOG1. A PDGFRA mutation was identified later. The final diagnosis was duodenal GIST., Discussion: few cases of GIST in the fourth portion of the duodenum had been reported in the literature. PDGFRA mutation is identified as GISTs tumorigenesis to 15% of cases, and the diagnosis of GISTs is not based solely on the expression of the protein Kit., Conclusion: the molecular biology examinations are very helpful in the direction of the correct diagnosis in case of negative staining for CD117., Competing Interests: The authors declared no potential conflicts of interests with respect to research, authorship and/or publication of the article., (© 2022 Published by Elsevier Ltd on behalf of IJS Publishing Group Ltd.)

Pediatric high-grade glioma (HGG, WHO Grade III and IV) is a devastating brain tumor with a median survival of less than two years. PDGFRA is frequently mutated/ amplified in pediatric HGG, but the significance of this finding has not been fully characterized. We hypothesize that alterations of PDGFRA will promote distinct prognostic and treatment implications in pediatric HGG. In order to characterize the impact of PDGFR pathway alterations, we integrated genomic data from pediatric HGG patients (n=290) from multiple pediatric datasets and sequencing platforms. Integration of multiple human datasets showed that PDGFRA mutation, but not amplification, was associated with older age in pediatric HGG (P= <0.0001). In multivariate analysis, PDGFRA mutation was correlated with worse prognosis (P = 0.026), while PDGFRA amplification was not (P = 0.11). By Kaplan-Meier analysis, non-brainstem HGG with PDGFRA amplification carried a worse prognosis than non-brainstem HGG without PDGFRA amplification (P = 0.021). There were no pediatric patients with PDGFRA-amplified HGG that survived longer than two years. Additionally, we performed paired molecular profiling (germline / tumor / primary cell culture) and targeting of an infant thalamic HGG with amplification and outlier increased expression of PDGFRA. Dasatinib inhibited proliferation most effectively. In summary, integration of the largest genomic dataset of pediatric HGG to date, allowed us to highlight that PDGFRA mutation is found in older pediatric patients and that PDGFRA amplification is prognostic in non-brainstem HGG. Future precision-medicine based clinical trials for pediatric patients with PDGFRA-altered HGG should consider the optimized delivery of dasatinib.

The first 15 years of management of gastrointestinal stromal tumor (GIST) have led to 3 lines of therapy for metastatic disease: imatinib, sunitinib, and regorafenib. In the adjuvant setting, imatinib is usually given for 3 years postoperatively to patients with higher-risk primary tumors that are completely resected. In this review, issues regarding GIST adjuvant therapy are discussed. It is hoped this review will help the reader understand the present standard of care to improve upon it in years to come., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Gastrointestinal stromal tumor (GIST) is the most frequent mesenchymal tumor of the gastrointestinal tract and one of the most frequent sarcoma. Mutually exclusive KIT and PDGFRA mutations are central events in GIST pathogenesis, and their understanding is crucial because specific treatment targeting oncogenic KIT and PDGFRA activation (especially imatinib) has become available. The most frequent PDGFRA mutation (D842V) is associated with primary resistance to imatinib. Data related to regorafenib efficacy in PDGFRA -mutated GIST are lacking. We report here a case report of a prolonged response with regorafenib in a patient with a PDGFRA- mutated GIST., Competing Interests: Financial & competing interests disclosure The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. No writing assistance was utilized in the production of this manuscript.