Retrospective Analyses of PD-L1, LAG-3, TIM-3, OX40L Expressions and MSI Status in Gastroenteropancreatic Neuroendocrine Neoplasms.

We investigated expressions of PD-L1, LAG-3, TIM-3, and OX40L as immune checkpoint proteins, and MSI (repetitive short-DNA-sequences due to defective DNA-repair system) status were analyzed with immunohistochemistry from tissue blocks. Of 83 patients, PD-L1 expression was observed in 18.1% (n = 15) of the patients. None of the patients exhibited LAG-3 expression. TIM-3 expression was 4.9% (n = 4), OX40L was 22.9% (n = 19), and 8.4% (n = 7) of the patients had MSI tumor. A low-to-intermediate positive correlation was observed between PD-L1 and TIM-3 expressions (rho: 0.333, p < 0.01). Although PD-L1 expression was higher in grade 3 NET/NEC, MSI status was prominent in grade 1/2 NET.

Long noncoding RNA HOTAIR is upregulated in an aggressive subgroup of gastrointestinal stromal tumors (GIST) and mediates the establishment of gene-specific DNA methylation patterns.

Aberrant alterations of DNA methylation are common events in oncogenesis. The origin of cancer-associated epigenetic defects is of interest for mechanistic understanding of malignant transformation and-in the long run-therapeutic modulation of DNA methylation in a locus-specific manner. Given the ability of certain long noncoding RNAs to operate as an interface between DNA and the epigenetic modification machinery which can interact with DNA methyltransferases, we hypothesized-considering HOTAIR as an example-that this transcript may contribute to gene specificity of DNA methylation. Using gastrointestinal stromal tumors (GISTs, n = 67) as a model, we confirmed upregulation of HOTAIR in tumors with high risk of recurrence and showed high abundance of the transcript in GIST cell lines. HOTAIR knockdown in GIST-T1 cells triggered transcriptional response of genes involved in the organization and disassembly of the extracellular matrix and, notably, induced global locus-specific alterations of DNA methylation patterns. Hypomethylation was induced at a total of 507 CpG sites, whereas 382 CpG dinucleotides underwent gain of methylation upon HOTAIR depletion. Importantly, orchestrated gain or loss of methylation at multiple individual CpG sites was shown for cancer-related DPP4, RASSF1, ALDH1A3, and other targets. Collectively, our data indicate that HOTAIR enables target specificity of DNA methylation in GIST and is capable of dual (hypo- and hypermethylation) regulation by a yet to be defined mechanism. The results further suggest the feasibility of manipulating DNA methylation in a targeted manner and are of interest in the context of epigenetic cancer therapy.

[Gastrointestinal leiomyoma with interstitial cells of Cajal: mimicker of gastrointestinal stromal tumor].

Objective: To study clinical and pathologic characteristics of leiomyomas of the gastrointestinal tract, and to investigate the distribution characteristics of interstitial cells of Cajal ( ICCs ) in gastrointestinal leiomyomas. Methods: One hundred and forty-seven cases of leiomyomas of gastrointestinal tract were collected at the Second Affiliated Hospital of Zhengzhou University from June 2012 to June 2017. Clinical and pathologic findings were analyzed, combined with immunohistochemistry, Alcian blue-osafranin staining and molecular study. Results: The age of patients ranged from 13-82 years with mean age of 52 years. Male to female ratio was about 1∶2. Histologically, all tumors were composed of ovoid to spindle cells arranged in short intersecting fascicles. All tumors were diffusely and strongly positive for smooth muscle antibodies, desmin and h-caldesmon by immunohistochemical staining. A prominent interspersed subpopulation of elongated/dendritic-like cells with CD117 and DOG1 positivity (accounting for 1% to 30% of all tumor cells) and negative for Alcian blue-osafranin staining was identified in all esophageal leiomyomas, 16 of 20 (80%) gastric leiomyomas and 3 of 12 small bowel leiomyomas, but none in colonic/rectal leiomyomas. Mutational analysis in 16 cases showed absence of mutation in exons 9, 11, 13 or 17 of C-KIT and exons 12 or 18 of PDGFRA. Conclusions: ICCs are identified in esophageal and gastric leiomyomas, as well as in small percentage of intestinal leiomyomas. Such findings may bring significant diagnostic pitfalls for misdiagnosis as gastrointestinal stromal tumor. Careful attention to the distribution of CD117 and DOG1 positive cells and molecular mutation analysis of C-KIT and PDGFRA may be necessary to establish the correct diagnosis.

Surgical Pathology of Gastrointestinal Stromal Tumors: Practical Implications of Morphologic and Molecular Heterogeneity for Precision Medicine.

Gastrointestinal stromal tumor (GIST), the most common mesenchymal neoplasm of the gastrointestinal tract, exhibits diverse histologic and clinical manifestations. With its putative origin in the gastrointestinal pacemaker cell of Cajal, GIST can arise in association with any portion of the tubular gastrointestinal tract. Morphologically, GISTs are classified as spindled or epithelioid, though each of these subtypes encompasses a broad spectrum of microscopic appearances, many of which mimic other histologic entities. Despite this morphologic ambiguity, the diagnosis of GIST is aided in many cases by immunohistochemical detection of KIT (CD117) or DOG1 expression. The natural history of GIST ranges from that of a tumor cured by surgical resection to that of a locally advanced or even widely metastatic, and ultimately fatal, disease. This clinicopathologic heterogeneity is paralleled by an underlying molecular diversity: the majority of GISTs are associated with spontaneous activating mutations in KIT, PDGFRA, or BRAF, while additional subsets are driven by genetic lesions-often inherited-of NF1 or components of the succinate dehydrogenase enzymatic complex. Specific gene mutations correlate with particular anatomic or morphologic characteristics and, in turn, with distinct clinical behaviors. Therefore, prognostication and treatment are increasingly dictated not only by morphologic clues, but also by accompanying molecular genetic features. In this review, we provide a comprehensive description of the heterogenous molecular underpinnings of GIST, including implications for the practicing pathologist with regard to morphologic identification, immunohistochemical diagnosis, and clinical management.

[Clinicopathologic and molecular characteristics of malignant gastrointestinal neuroectodermal tumors].

Objective: To investigate the clinicopathologic and molecular characteristics, diagnostic, differential diagnostic and prognostic features of malignant gastrointestinal neuroectodermal tumor. Methods: Two cases of malignant gastrointestinal neuroectodermal tumor were retrieved; the clinical and radiologic features, histomorphology, immunophenotype, molecular genetics and prognosis were analyzed and the relevant literature reviewed. Results: Case 1 was a 57-year-old male, presented with recurrent abdominal pain and melena. Pelvic imaging showed a circumscribed thickening of the wall of a small intestinal segment, and a malignant lymphoma was favored. Case 2 was a 24-year-old male, presented with recurrent small intestinal malignancy. Imaging demonstrated multiple masses in the peritoneal and pelvic cavities, and a malignant gastrointestinal stromal tumor with multiple metastases was suspected. Grossly both tumors were located mainly in the muscularis propria of small intestine. Case 1 showed a single 5.5 cm tumor; and case 2 consisted of two tumors measuring 4 cm and 6 cm respectively. Microscopic examination of both tumors showed small round blue, but focally spindled or clear tumor cells in solid pattern. The tumor cells had scanty cytoplasm, indistinctive nucleoli and brisk mitoses. Osteoclast-like giant cells were dispersed within the stroma. In case 1 rosette-like and pseudo-papillary growth patterns were noted, and in case 2 there were variable-sized hemorrhagic cysts. By immunohistochemistry, both tumors showed strong and diffuse expression of SOX10 and S-100, and focal to diffuse expression of neuroendocrine markers (CD56 or synaptophysin). Case 2 exhibited focal reactivity to pan-cytokeratin. Both tumors lacked expression of markers associated with gastrointestinal stromal tumor, smooth muscle tumor, melanoma (HMB45 or Melan A), dendritic cell tumor and Ewing sarcoma. Fluorescence in situ hybridization analysis demonstrated EWSR1 rearrangement in both tumors and the next generation sequencing confirmed EWSR1-ATF1 gene fusion in case 2. At follow-up of 16 months, case 1 was recurrence or metastasis free; whereas case 2 showed multiple recurrences and metastases within 19 months although stable disease was transiently achieved when treated with combinations of multidrug and targeted chemotherapy. Conclusions: Malignant gastrointestinal neuroectodermal tumor is a rare and aggressive soft tissue sarcoma with a predilection for small intestine. It has distinctive morphologic, immunohistochemical and molecular characteristics and needs to be distinguished from other small blue round and spindle cell tumors that occur in the gut. Careful attentions to its characteristic histomorphology with the judicious use of immunohistochemistry and molecular genetics can help to distinguish this tumor from its many mimickers.

Clinicopathological Significance of RhoA Expression in Digestive Tract Cancer: A Systematic Review and Meta-Analysis.

BACKGROUND: RhoA protein expression has been reported in different types of cancer. We performed an up-to-date meta-analysis to evaluate the clinicopathological characteristics of RhoA protein expression in patients with gastrointestinal cancer. METHODS: We searched in several databases, including MEDLINE (PubMed) and China National Knowledge Infrastructure, to identify studies examining the association between RhoA protein and cancer. The quality of the included studies was assessed. Cochrane Collaboration's Software Review Manager 5.3 was utilized to test the heterogeneity, overall effect, and publication bias of the combined studies. The reported odds ratio and 95% confidence interval (CI) were calculated by using fixed and random effects models depending on the heterogeneity of the included studies. RESULTS: A total of 15 studies met the inclusion criteria of the meta-analysis. RhoA expression was significantly higher in gastrointestinal cancer than in normal tissues. RhoA protein expression in digestive system neoplasms was significantly associated with tumor clinical staging, metastatic status and differentiated degree. However, no association with gender was found. RhoA mRNA expression was no associated with clinicopathological significance. CONCLUSIONS: Current evidence supports the conclusion that RhoA expression is associated with clinical staging, metastatic status, and differentiated degree in digestive system neoplasms. RhoA expression may play an important role in the carcinogenesis and metastasis of gastrointestinal cancer.

RNA quality in fresh-frozen gastrointestinal tumor specimens-experiences from the tumor and healthy tissue bank TU Dresden.

The term "pre-analytics" summarizes all procedures concerned with specimen collection or processing as well as logistical aspects like transport or storage of tissue specimens. All or these variables as well as tissue-specific characteristics affect sample quality. While certain parameters like warm ischemia or tissue-specific characteristics cannot be changed, other parameters can be assessed and optimized. The aim of this study was to determine RNA quality by assessing the RIN values of specimens from different organs and to assess the influence of vacuum preservation. Samples from the GI tract, in general, appear to have lower RNA quality when compared to samples from other organ sites. This may be due to the digestive enzymes or bacterial colonization. Processing time in pathology does not significantly influence RNA quality. Tissue preservation with a vacuum sealer leads to preserved RNA quality over an extended period of time and offers a feasible alternative to minimize the influence of transport time into pathology.

Predictive value of immunohistochemistry in pre-malignant lesions of the gastrointestinal tract.

Immunohistochemistry can be an important adjunct to histopathology for the diagnosis of pre-malignant lesions of the gastrointestinal tract and in patient risk stratification. The purpose of this review is to provide information and guidance on the usefulness of immunohistochemical markers that facilitate the diagnosis of dysplasia and help to predict risk for the development of carcinoma in pre-malignant lesions of the gastrointestinal tract. Particular emphasis is given to the role of immunohistochemistry in the assessment of epithelial dysplasia in the setting of Barrett's esophagus and inflammatory bowel disease; supplementary immunohistochemistry for subtyping adenomas of the stomach and ampulla and serrated polyps of the colon and rectum; and ancillary markers of squamous neoplasia of the anal canal.

Genotyping and immunohistochemistry of gastrointestinal stromal tumors: An update.

Gastrointestinal stromal tumors (GISTs) were originally thought to harbor either KIT or platelet-derived growth factor receptor A (PDGFRA) mutations only. However, more recent discoveries have highlighted additional, less common oncogenic driver mutations including NF1, BRAF, and succinate dehydrogenase (SDH) mutations. Genotyping GISTs has become more important since not all genotypes respond equally to FDA-approved tyrosine kinase inhibitors. GIST is a paradigm for personalized cancer therapy. Recent studies demonstrate how immunohistochemistry can be used both to diagnose GIST and to screen for specific mutations. DOG1 is particularly useful in the diagnosis of KIT-negative GIST, including tumors with PDGFRA mutations, which can also potentially be identified by immunohistochemistry for PDGFRA. SDHB immunohistochemistry is useful in characterizing GISTs with SDHA-D mutations, whereas SDHA immunohistochemistry is able to identify SDHA mutant GISTs.

[C-KIT in gastrointestinal stromal tumors and associated malignancies: A Study in a population with genetic isolation]. / C-kit en tumores estromales gastrointestinales y neoplasias asociadas: estudio en población con aislamiento genético.

INTRODUCTION: Gastrointestinal stromal tumors (GIST) are the most common mesenchymal tumors of the gastrointestinal tract. Numerous studies have reported the association between GIST and other neoplasms. OBJECTIVES: The aim of this study was to investigate the possible association between GIST and other tumors in a genetically isolated population. METHODS: A retrospective study was conducted of patients with GIST between 2002 and 2009 at our center. Epidemiological, pathological and family data in patients with GIST alone (group A) were compared with those in patients with GIST associated with other neoplasms (group B). A possible common genetic mechanism was investigated between GIST and associated malignancies by testing the detection of the immunohistochemical marker, CD117, in all tumors. RESULTS: Twenty-two patients with GIST were identified, 10 in group A (45%) and 12 in group B (55%). In group B, the associated tumor was malignant in 6 patients (50%) and benign in another 6 (50%). Of the 22 patients with GIST, 8 (36%) had a family history of malignancies. Of these 8 patients, 7 (87.5%) were in group B (p=0.03) and 3 (37.5%) showed the same pathological type of neoplasm as their relatives. All GIST were positive for CD117 whereas associated malignancies were negative for this marker. CONCLUSION: We did not find immunohistochemical positivity for CD117 in malignancies associated with GIST. Given the special characteristics of the study population, the association between GIST and associated malignancies may be incidental.

[Intra-abdominal soft tissue tumors. What needs to be known to reach the diagnosis with the help of immunohistochemistry, FISH and molecular biology]. / Tumeurs des tissus mous intra-abdominales. Ce qu'il faut savoir pour parvenir à un diagnostic en s'aidant de l'immunohistochimie, de la FISH, et de la biologie moléculaire.

Connective tissue tumors located inside the abdomen are a rare heterogeneous group of tumors, except for gastro-intestinal stromal tumors. They may be benign, malignant, or intermediate in terms of biologic potential. Pathologists have to remember the list of all the lesions possibly involved, with their immunohistochemical characteristics, and to know which molecular analyses are needed, with which expected results, and by which team they can be performed. The main tumor types are discussed with diagnostic tools and treatment consequences.

Tumor markers in colorectal cancer, gastric cancer and gastrointestinal stromal cancers: European group on tumor markers 2014 guidelines update.

Biomarkers currently play an important role in the detection and management of patients with several different types of gastrointestinal cancer, especially colorectal, gastric, gastro-oesophageal junction (GOJ) adenocarcinomas and gastrointestinal stromal tumors (GISTs). The aim of this article is to provide updated and evidence-based guidelines for the use of biomarkers in the different gastrointestinal malignancies. Recommended biomarkers for colorectal cancer include an immunochemical-based fecal occult blood test in screening asymptomatic subjects ≥50 years of age for neoplasia, serial CEA levels in postoperative surveillance of stage II and III patients who may be candidates for surgical resection or systemic therapy in the event of distant metastasis occurring, K-RAS mutation status for identifying patients with advanced disease likely to benefit from anti-EGFR therapeutic antibodies and microsatellite instability testing as a first-line screen for subjects with Lynch syndrome. In advanced gastric or GOJ cancers, measurement of HER2 is recommended in selecting patients for treatment with trastuzumab. For patients with suspected GIST, determination of KIT protein should be used as a diagnostic aid, while KIT mutational analysis may be used for treatment planning in patients with diagnosed GISTs.

Detection of human JCPyV and BKPyV in diffuse large B-cell lymphoma of the GI tract.

Previous studies have demonstrated that infection with human polyomavirus, such as JCPyV and BKPyV, might be associated with various human tumors. However, an association between human JCPyV and BKPyV infection and diffuse large B-cell lymphoma (DLBCL) has not been reported. The purpose of this study was to examine DLBCLs of the gastrointestinal tract for evidence of human polyomavirus infection. Nested PCR and DNA sequencing were employed for viral DNA detection and viral genotype identification. In addition, two viral proteins, the large tumor antigen (LT) and the major structural protein (VP1), were detected by immunohistochemistry (IHC). Human JCPyV and BKPyV DNA was detected in 14 out of 16 tissue samples (87.5%), whereby nine cases were infected with JCPyV and five cases were infected with BKPyV. Both archetypal and rearranged genotypes of JCPyV and BKPyV were detected in the tissues. LT was detected in 11 tissue samples (68.75%). However, VP1 was not detected in any of the tissue samples. The presence of human JCPyV and BKPyV DNA and protein in DLBCL tissues of gastrointestinal tract were first reported in this study. The current results provide evidence of a possible association between human JCPyV and BKPyV infection and DLBCL.

Nordic guidelines 2014 for diagnosis and treatment of gastroenteropancreatic neuroendocrine neoplasms.

BACKGROUND: The diagnostic work-up and treatment of patients with neuroendocrine neoplasms (NENs) has undergone major recent advances and new methods are currently introduced into the clinic. An update of the WHO classification has resulted in a new nomenclature dividing NENs into neuroendocrine tumours (NETs) including G1 (Ki67 index ≤ 2%) and G2 (Ki67 index 3-20%) tumours and neuroendocrine carcinomas (NECs) with Ki67 index > 20%, G3. Aim. These Nordic guidelines summarise the Nordic Neuroendocrine Tumour Group's current view on how to diagnose and treat NEN-patients and are meant to be useful in the daily practice for clinicians handling these patients.

The usefulness of preoperative 18FDG positron-emission tomography and computed tomography for predicting the malignant potential of gastrointestinal stromal tumors.

BACKGROUND: Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the gastrointestinal tract. The tumor size and mitotic count, typical risk category factors, are difficult to determine preoperatively. This study aimed to evaluate the usefulness of preoperative 18F-fluoro-2-deoxyglucose positron-emission tomography/computed tomography (18FDG-PET/CT) for predicting the malignant potential of GISTs by analyzing the correlation between the maximum standardized uptake value (SUVmax) and postoperative factors. METHODS: Thirty consecutive patients underwent surgery after preoperative 18FDG-PET/CT and were diagnosed with pathologically confirmed GIST. The tumor size, mitotic count, MIB-1 index and National Institutes of Health (NIH) risk category were compared with SUVmax. RESULTS: Significant correlations between SUVmax and tumor size and NIH risk category were determined. The sensitivity and specificity of SUVmax for predicting the risk of malignancy were 85.7 and 62.5%, respectively. The optimal cut-off value for SUVmax was 3.0 between patients classified into low-risk and high-risk malignancy groups. There was no significant correlation between SUVmax and mitotic count or MIB-1 index. Multivariate analysis indicated that SUVmax was the only predictive risk factor in the high-risk malignancy group. CONCLUSIONS: 18FDG-PET/CT is useful for assessing the malignant potential and bioactivity of GISTs. When SUVmax is >3.0, the tumor must be resected even if it measures <2 cm, because of its high malignant potential.

Incidental GIST after appendectomy in a pediatric patient: a first instance and review of pediatric patients with CD117 confirmed GISTs.

A 7-year-old boy underwent uncomplicated laparoscopic appendectomy for acute appendicitis. Incidentally, he was found to have a spindle cell tumor with CD117 immunopositivity, consistent with gastrointestinal stromal tumor (GIST) in the appendix. Although commonly reported in adults, pediatric GISTs are rare gastrointestinal malignancies that occur in only 1.4-2.7% of children and adolescents. Due to the paucity of reports, data are insufficient to adequately characterize tumor behavior, recurrence, and survival. We present the first case of pediatric GIST in the appendix. In addition, a review of the literature for CD117 confirmed pediatric GISTs was conducted to summarize its clinical features and current treatment options.

Extracellular domain c-kit mutation with duplication of Ser501Ala502 found in gastrointestinal stromal tumors is more imatinib- and nilotinib-sensitive than that with duplication of Ala502Tyr503.

The great majority of gastrointestinal stromal tumors (GISTs) have gain-of-function mutations of the c-kit gene, which encodes KIT receptor tyrosine kinase. Most of the mutations are located at exon 11, but some are at exon 9 or at other exons. Mutation types at exon 11 vary, while most mutations at exon 9 are a particular duplication of Ala502Tyr503 (KIT-Dup-Ala502Tyr503). Recently a duplication of Ser501Ala502 (KIT-Dup-Ser501Ala502) at exon 9 has been reported in two cases of pediatric mastocytosis and one case of adult mast cell leukemia. Although KIT-Dup-Ser501Ala502 had not been reported in GISTs, we found two GIST cases possessing the mutation in 45 GIST cases with exon 9 c-kit gene mutations, among a total of approximately 500 GIST cases examined. In this report, we briefly summarize clinicopathological findings of the two cases, and characterize the biology of the mutation. When autophosphorylation of KIT-Dup-Ser501Ala502 was examined by transient transfection of c-kit cDNA with Dup-Ser501Ala502 into CHO-K1 cells, KIT-Dup-Ser501Ala502 was ligand-independently activating. The inhibitory effect of selective tyrosine kinase inhibitors, imatinib and nilotinib, on KIT-Dup-Ser501Ala502 was examined and compared with that of KIT-Dup-Ala502Tyr503. Imatinib efficiently inhibited constitutive activation of KIT-Dup-Ser501Ala502 at a concentration of 0.1 µM, whereas it inhibited that of KIT-Dup-Ala502Tyr503 at a concentration of 10 µM. Constitutive activation of KIT-Dup-Ser502Ala503 was not inhibited by nilotinib even at a concentration of 10 µM but that of KIT-Dup-Ala501Tyr502 was almost completely inhibited at a concentration of 1 µM. The results suggest that imatinib and nilotinib could be more effective on GISTs with KIT-Dup-Ser501Ala502 than those with KIT-Dup-Ala502Tyr503. In fact, a patient with KIT-Dup-Ser501Ala502 showed long-term stable disease with administration of the usual dose of 400 mg imatinib. Although mutation sites of KIT-Dup-Ser501Ala502 and KIT-Dup-Ala502Tyr503 are closely located, imatinib- and nilotinib-sensitive KIT-Dup-Ser501Ala502 are distinguishable from KIT-Dup-Ala502Tyr503.

GI tract tumors with melanocytic differentiation.

Gastrointestinal (GI) tract tumors with melanocytic differentiation may present significant diagnostic challenges both for the pathologist and the clinician. This comprehensive review discusses the relatively common as well as rare entities that have melanocytic differentiation in the GI tract. Clinical, histologic, immunohistochemical and molecular features are discussed along with prognosis and differential diagnosis.

Diagnostic significance of DOG-1 and PKC-θ expression and c-Kit/PDGFRA mutations in gastrointestinal stromal tumours.

OBJECTIVE: To investigate discovered on gastrointestinal stromal tumor (GIST)-1 (DOG-1) and protein kinase C-θ (PKC-θ) expression in a series of GISTs and determine the sensitivity, specificity, and diagnostic value of these two antigens. METHODS: Immnunohistochemistry (IHC) was used to detect CD117, DOG-1, PKC-θ, CD34, Ki-67, α-smooth muscle actin (SMA), S100, and Desmin expression in 147 GISTs and 51 non-GISTs. c-Kit gene (exons 9, 11, 13, and 17) and platelet-derived growth factor receptor-alpha (PDGFRA) gene (exons 12 and 18) mutations were also detected. RESULTS: About 94.5% GISTs were CD117 positive, 96% were DOG-1 positive, and 90.5% were PKC-θ positive. DOG-1 had a specificity of 100%, while CD117 and PKC-θ had a specificity of 90% and 80%, respectively. There was no significant difference between DOG-1 and PKC-θ expressions when compared to CD117 expression. In 30 out of 42 (71.5%) GISTs, a c-Kit gene mutation was found, and in 3 out of 42 cases (7%), PDGFRA was mutated. Wild-type c-Kit/PDGFRA genes accounted for 21.5% (9/42). Most c-Kit gene mutations were found to be located at exon 11, mainly as in-frame deletions. Mutations in exon 9 were all missense mutations. Most PDGFRA gene mutations were found in exon 18, codon 842. c-Kit gene mutations in exons 13 and 17, and the PDGFRA gene mutation in exon 12 were not detected. CONCLUSIONS: Compared to CD117, DOG-1 is a biomarker with higher sensitivity and specificity. The combination of CD117 and DOG-1 can be used to improve the diagnosis of GIST. Although PKC-θ has a lower specificity than DOG-1, it can be a useful biomarker, especially in CD117(-) and/or DOG-1(-) cases.

Clinical significance of insulin-growth factor 1 and insulin-growth factor 1 receptor expression in gastrointestinal stromal tumors.

BACKGROUND/AIMS: Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors in the gastrointestinal tract and are mostly driven by KIT and PDGFRA-activation mutations. However, other signaling pathways are involved in pathogenesis and proliferation of GISTs. This study investigates the prognostic significance of insulin-like growth factor 1 (IGF1) and IGF1 receptor (IGF1R) and the role of succinate dehydrogenase subunit B (SDHB) in GISTs. METHODOLOGY: Immunohistochemistry (IHC) for IGF1, IGF1R and SDHB was performed in total of 165 GISTs. RESULTS: The overexpression of IGF1 was evident in tumors with high mitotic count, large tumor size and was correlated with high risk of malignant behavior. IGF1R overexpression was correlated with IGF overexpression, high mitotic count and high risk of malignant behavior. Loss of expression for SDHB was found in only 2 gastric GISTs. CONCLUSIONS: The overexpression of IGF1 and IGF1R can be useful marker to predict relapse and aggressive behavior in GISTs and has prognostic implications.