CD117-negative Gastrointestinal Stromal Tumors Research Articles

To improve the understanding of CD117-negative gastrointestinal stromal tumor

Gastrointestinal stromal tumor (GIST) is the most common mesenchymal tumor of the digestive tract. The diagnosis of GIST relies mainly on clinicopathological features, tumor cell morphology and immunohistochemical marker CD117 (c-Kit). However, some tumors (about 3%-4%) have clinicopathological features of GIST but do not express CD117. To determine whether these lesions are true GIST, it is necessary to raise awareness of CD117-negative GIST. This article discusses the immunohistochemical features, gene mutations, prognosis and efficacy of targeted drugs of CD117-negative GIST. Research results suggest that CD117-negative GIST lacks KIT expression but has typical clinical, histopathological and cytogenetic features. These tumors have KIT and/or PDGFRA mutations, or are wild type. Because most KIT-negative GISTs contain PDGFRA or KIT mutation, pathologists and oncologists should not exclude GIST diagnosis based on negative immunohistochemical staining of KIT. It is known that approximately 30% of PDGFRA mutations may be sensitive to imatinib, and patients with such tumors may benefit from imatinib, so imatinib treatment should not be empirically denied in these patients.

Clinical Diagnosis of Gastrointestinal Stromal Tumor (GIST): From the Molecular Genetic Point of View.

Gastrointestinal stromal tumors (GISTs) originating from the interstitial cells of Cajal are mesenchymal tumors of the gastrointestinal tract and have been found to harbor c-KIT mutations and KIT (CD117) expression since 1998. Later, PDGFRA mutations, SDH alterations, and other drive mutations were identified in GISTs. In addition, more and more protein markers such as DOG1, PKCθ were found to be expressed in GISTs which might help clinicians diagnose CD117-negative GISTs. Therefore, we plan to comprehensively review the molecular markers and genetics of GISTs and provide clinicians useful information in diagnostic and therapeutic strategies of GISTs. Twenty years after the discovery of KIT in GISTs, the diagnosis of GISTs became much more accurate by using immunohistochemical (IHC) panel (CD117/DOG1) and molecular analysis (KIT/PDGFRA), both of which constitute the gold standard of diagnosis in GISTs. The accurately molecular diagnosis of GISTs guides clinicians to precision medicine and provides optimal treatment for the patients with GISTs. Successful treatment in GISTs prolongs the survival of GIST patients and causes GISTs to become a chronic disease. In the future, the development of effective treatment for GISTs resistant to imatinib/sunitinib/regorafenib and KIT/PDGFRA-WT GISTs will be the challenge for GISTs.

Expression and its clinical significance of immunological markers in tumor tissues of 338 patients with gastrointestinal stromal tumor

Objective To analyze the expressions and clinical significance of CD117, CD34, smooth muscle actin (SMA), DOG-1 and desmin in tumor tissues of patients with gastrointestinal stromal tumor (GIST). Methods From May 2008 to December 2016, 338 GIST patients were enrolled and the clinicopathological characteristics were recorded. The expressions of CD117, CD34, SMA, DOG-1 and desmin in tumor tissues of the enrolled patients were detected by immunohistochemistry. Chi-square test and rank-sum test were performed for statistical analysis. Results Among 338 GIST patients, cases positive for CD117, CD34, SMA, DOG-1 and desmin were 332 (98.2%), 308 (91.1%), 133 (39.3%), 322 (95.3%) and 48 (14.2%), respectively. There were significant differences in CD34 expression among tumors with different maximum diameter, risk grade and primary site (Z=-3.085, -3.064, χ2=57.110; all P<0.05). The difference in CD117 expression among different nationalities was statistically significant (χ2=10.641, P<0.05). The differences in desmin expression among tumors with different maximum diameter, risk grade and mitotic counting were statistically significant (Z=-2.343, -2.625 and -2.005, all P<0.05). Among all 338 GIST patients, six cases for CD117 were negative, five of them for CD34 were positive, three SMA positive and five DOG-1 positive. The co-expression positive rates of CD117 with CD34, SMA, DOG-1 were 89.6%(303/338), 38.5%(130/338), 93.8%(317/338) and 14.2%(48/338), respectively. Conclusions CD117 is an essential immunological marker for the diagnosis of GIST. For CD117-negative GIST patients, CD34, SMA, DOG-1 and desmin are helpful in improving the accuracy of GIST diagnosis and differentiated diagnosis. Key words: Immunohistochemistry; Diagnosis; Gastrointestinal stromal tumor; Clinicopathological characterestics; Immune markers

Diagnostic difficulties in c-kit negative gastrointestinal stromal tumors: report of four cases

Introduction: The gastrointestinal stromal tumors (GIST) are dominated by KIT and PDGFRA mutation. The immunohistochemical detection of CD117, a protein express by KIT gene, is essential for the diagnosis and those that are negative always represented a diagnostic challenge Case reports: In this article we present a series of 4 cases of CD117 negative GIST tumors, diagnosed and surgically resected in Fundeni Clinical Institute and an overview of the histogenesis, diagnostic problems and management of c-kit negative GIST. All patients were males and the tumors were located in the stomach and small bowel. Conclusion: It is important for the pathologists to beware of the fact that a CD117 negative in the context of a typical morphological appearance does not exclude a GIST tumor and also the oncologist must be aware not to exclude the therapy with imatinib based on the negativity of CD117.

Analysis of mutation of the c-Kit gene and PDGFRA in gastrointestinal stromal tumors.

The aim of the present study was to investigate mutation status of the c-Kit gene (KIT) and PDGFRA in patients with a gastrointestinal stromal tumor (GIST). In total, 93 patients with a GIST were included in the study, in which polymerase chain reaction amplification and gene sequencing were used to detect the sequences of exons 9, 11, 13 and 17 in KIT and exons 12 and 18 in PDGFRA. KIT mutations were detected in 64 cases (68.82%), of which exon 11 mutations were detected in 56 cases (60.22%), exon 13 mutations were detected in three cases (3.23%) and one case (1.08%) was shown to have a mutation in exon 17. The most common mutation in exon 11 was a deletion, which accounted for 55.36% (31/56) of the cases, followed by a point mutation observed in 26.79% (15/56) of the cases, while an insertion (tandem repeats) was identified in 14.29% (8/56) of the cases, and 3.57% (2/56) of the exon 11 mutations were deletions associated with a point mutation. The majority of the mutations were heterozygous, with only a few homozygous mutations. Mutational analysis revealed the mutations to be more concentrated in the classic hot zone at the 5'-end, followed by the tandem repeat frame at the 3'-end. In four cases, a mutation was detected in exon 18 of PDGFRA, of which one was associated with a mutation in KIT. The remaining three cases (10.34%, 3/29) were not associated with mutations in KIT and accounted for 37.5% (3/8) of the CD117-negative GIST cases. Therefore, the majority of the GIST cases were characterized by mutations in KIT or PDGFRA, which were directly associated with the disease. Pairs of different mutations in the same exon of KIT, or KIT mutations coupled with pairs of mutations in PDGFRA, were detected in a small number of patients. Imatinib is a small molecule tyrosine kinase inhibitor and is the first line targeted treatment for GIST, resulting in markedly improved survival rates. Thus, gene mutation genotyping may provide inspiration and guidance for imatinib-based targeted cancer therapy.

Determination of muscle differentiation markers SMA and MSA in CD117-positive and CD117-negative gastrointestinal stromal tumors of different malignant potential

Determination of muscle differentiation markers SMA and MSA in CD117-positive and CD117-negative gastrointestinal stromal tumors of different malignant potential

Gastric glomus tumor with prominent polytypic plasmacytosis: case report and review of literature

Glomus tumor is a rare benign mesenchymal tumor, mostly found in acral skin or superficial soft tissues, but it can occur in other locations. Glomus tumors in different locations share similar histological and immunohistochemical characteristics, although some aberrant features can be identified. We report a case of 41 year-old male with gastric glomus tumor, preoperatively diagnosed as CD117 negative gastrointestinal stromal tumor. Apart from the rare location, glomus tumor showed some other unusual features – peritumoral polytypic plasmacytosis and florid mesothelial hyperplasia. Although gastric glomus tumors are rare, they should be included in differential diagnosis of submucosal gastric tumors.

Predictive value of KIT immunohistochemical staining for KIT mutations in patients with gastrointestinal stromal tumors (GIST): A systematic review.

30 Background: Immunohistochemical staining for KIT (CD117) is used as part of diagnostic tool for GIST. Approximately 95% of GIST are known to be positive for CD117. Studies have shown that not all CD117-positive GIST carry KIT mutations nor does CD117 negativity rule out KIT or PDGFRA mutations. We performed a systematic review to investigate the positive and negative predictive values of KIT immunostaining for KIT mutations in GIST. Methods: A Medline search of the MeSH terms “KIT mutation” and “GIST” and “prevalence” yielded 54 articles from year 1999 to 2011. English language studies on GIST with data available for KIT immunostaining as well as KIT gene mutations were included. Studies lacking data on either CD117 positivity or KIT mutations were excluded. Immunostaining was done using Dako polyclonal rabbit antibody or PKCh monoclonal mouse antibody in eligible studies. Denaturing high-pressure liquid chromatography (DHPLC) was used to screen mutations in majority of eligible studies, and ABI Prism Genetic Analyzer to sequence DNA. Results: 6 studies including 708 CD117-positive GIST patients were eligible for analysis of positive predictive value of KIT immunostaining for KIT mutations and 5 studies including 47 CD117-negative GIST patients for negative predictive value. Many studies were excluded due to insufficient data on CD117 positivity or KIT mutational analysis. 72.8% of CD117-positive GIST tumors carried KIT mutations (exon 11 62.2%, exon 9 10.2%, exon 13 1.8% and exon 17 1%), and 4.1% harbored PDGFRA mutations. In contrast, 74.5% of CD117-negative GIST tumors did not have KIT mutations. 25.5% of CD117-negative GIST harbored KIT exon 11 mutations (no mutations in exon 9, 13 or 17 were observed). In addition, 30% of CD117-negative GIST were found to have PDGFRA mutations. Conclusions: PDGFRA mutations were found to be 7 times more common in CD117-negative than in CD117-positive GIST (30% vs. 4.1%). Over half (55.5%) of CD117-negative GIST carried KIT exon 11 or PDGFRA mutations. We recommend mutational analysis in all tumors clinically suspected of GIST and that are CD117-negative for two reasons: 1. in order to make a diagnosis, and 2. to help tailor therapy.

Clinicopathologic features and immunophenotypes of CD117-negative gastrointestinal stromal tumor

To study the immunophenotype and c-kit or platelet derived growth factor receptor alpha (PDGFRA) gene mutations in CD117-negative gastrointestinal stromal tumors (GISTs). Ten cases of GISTs with typical histologic features but no CD117 expression were retrieved from the archival of Department of Pathology, Peking Union Medical College Hospital, China. The cases were further evaluated for the presence of c-kit exons 9, 11, 13 and 17 mutations and PDGFRA exons 12 and 18 mutations. DNA was extracted from the paraffin-embedded tumor tissue. The PCR products were sequenced directly for the mutations. An immunohistochemical study for CD117, CD34, smooth muscle actin, desmin, S-100 protein, WT-1 and DOG-1 was also performed. Eight of the 10 cases had the mutation tests completed. C-kit mutation in exon 9 was detected in only one case. Amongst the 10 cases studied, CD34 was expressed in 9 cases. Smooth muscle actin was focally positive in 2 cases. None of them expressed desmin or S-100 protein. DOG-1 and WT-1 were diffusely positive in 5 and 4 cases, respectively. In addition, DOG1 was diffusely but weakly positive in 1 case and focally expressed in 2 cases. Three cases were focally positive for WT-1. Pathologic diagnosis of CD117-negative GISTs can be facilitated with the application of a panel of immunohistochemical markers, including DOG-1 and WT-1.

Correlation of Kinase Genotype and Clinical Outcome in the North American Intergroup Phase III Trial of Imatinib Mesylate for Treatment of Advanced Gastrointestinal Stromal Tumor: CALGB 150105 Study by Cancer and Leukemia Group B and Southwest Oncology Group

Imatinib mesylate is standard treatment for patients who have advanced gastrointestinal stromal tumor (GIST), but not all patients benefit equally. In previous studies, GIST genotype correlated with treatment outcome and optimal imatinib dosing. We examined the relationship between kinase genotype and treatment outcome for 428 patients enrolled on the North American phase III study SWOG S0033/CALGB 150105 and treated with either 400 mg or 800 mg daily doses of imatinib. The presence of KIT exon 11-mutant genotype (n = 283) correlated with improved treatment outcome when compared with KIT exon 9-mutant (n = 32) and wild-type (WT; n = 67) genotypes for objective response (complete response [CR]/partial response [PR], 71.7% v 44.4% [P = .007]; and 44.6% [P = .0002], respectively); time to tumor progression (TTP; median 24.7 months v 16.7 and 12.8 months, respectively); and overall survival (OS; median 60.0 months v 38.4 and 49.0 months, respectively). The survival outcomes for patients with exon 9-mutant, exon 11-mutant or WT GIST were not affected by imatinib dose. However, there was evidence of improved response rates for patients with exon 9-mutant tumors treated with imatinib 800 mg versus 400 mg (CR/PR, 67% v 17%; P = .02). Patients who had CD117-negative GIST had similar TTP but inferior OS compared with patients who had CD117-positive disease, which suggests that patients who have CD117-negative GIST may benefit from imatinib treatment. In addition, we identified novel but rare mutations of the KIT extracellular domain (exons 8 and 9). We confirmed the favorable impact of KIT exon 11 genotype when compared with KIT exon 9 and wild-type genotype for patients with advanced GIST who are treated with imatinib.

Ultrastructural features and platelet-derived growth factor receptor A gene mutations in CD117-negative gastrointestinal stromal tumor

To explore the ultrastructural features and mutation status of platelet-derived growth factor receptors A (PDGFRA) and c-kit in gastrointestinal stromal tumors that were immunohistochemically negative for CD117 antigen. Six cases of gastrointestinal stromal tumors that were CD117 immunostain negative were studied by electron microscopy. Direct PCR sequencing was used to investigate the mutation status of c-kit gene exons 9, 11, 13, 17 and PDGFRA gene exons 12 and 18. The ultrastructural features of all 6 cases were similar to those of the interstitial cell of Cajal (ICC). None of the 6 cases were found to have c-kit gene mutations. However, three tumors were found to harbor PDGFRA exon 18 activating mutations, including two tumors having an Asp-->Val842 missense mutation and one having an Arg-->Ser841 missense mutation. PDGFRA mutations may provide an important alternative molecular mechanism for the development of gastrointestinal stromal tumor.

Status and clinical implication of c-kit and PDGFRA mutations in 165 cases of gastrointestinal stromal tumor (GIST)

To investigate the status of c-kit and PDGFRA mutations of GIST in a the large sample of Chinese patients. One hundred and sixty-five cases were evaluated for the presence of c-kit and PDGFRA mutations. Exon 9, 11, 13, 17 of c-kit and exon 12, 18 of PDGFRA were analyzed by PCR amplification and direct sequencing. Immunohistochemical demonstrations of KIT (CD117) were seen in 94% of the cases (155/165). Overall, c-kit mutations were identified in 76.1% (118/155) of CD117 positive cases: 67.1% (104/155) involving exon 11, 7.1% (11/155) involving exon 9, 1.3% (2/155) involving exon 13 and 0.6% (1/155) involving exon 17. The c-kit exon 11 mutations were mostly heterogeneous and clustered in the classic "hot spot" at the 5' end of the exon, including in-frame deletion and point mutation. The second "hot spots" were internal tandem duplications (ITD) at the 3' end of the exon, which were associated with female patient, older age, stomach location and low mitotic counts. The exon 9 mutations correlated with a distinct subset of GISTs involving the small bowel of young male patients. A new point mutation of L641P was identified in exon 13. PDGFRA mutations were present in 50% (5/10) of CD117-negative GISTs, all involving exon 18 with the majority of mutations being D842V. One novel in-frame deletion of IMHD mutation at codon 843 - 846 with S847T was identified. GISTs with PDGFRA mutations were often larger tumors arising from the omentum/mesentery of young male patients with high risk of aggressive behavior. The vast majority of GISTs in this study harbored c-kit and PDGFRA mutations, there were non-random relations between the gene mutation patterns and the locations of GISTs. It appears that Chinese GIST patients have some unique mutation patterns. It is necessary to evaluate the gene mutations status of GISTs to guide target therapy.

Analysis of CD117-negative gastrointestinal stromal tumors

To identify the gastrointestinal stromal tumors (GISTs) that are negative for CD117 expression by immunohistochemistry and to characterize their malignant potential. A total of 108 primary mesenchymal tumors of the gastrointestinal tract were screened to select CD117-negative tumors, from which KIT (exons 9, 11, 13, and 17) and PDGFRA (exons 10, 12, 14, and 18) were sequenced to identify GISTs. Tumor recurrence and distant metastasis were used as the criteria of malignancy. The result showed that approximately 25% (29/108) of the gastrointestinal mesenchymal tumors were negative for CD117 and approximately 6% (7/108) of the tumors were CD117-negative GISTs. All these CD117-negative tumors had a mutated KIT and a wild-type PDGFRA. All CD117-negative GISTs with mutations at codons 557/558 of KIT had mitotic counts >10/50 high power field, and 75% (3/4) of them showed multiple recurrence or distant metastasis. CD117-negative KIT mutated GISTs account for approximately 6% of the gastrointestinal mesenchymal tumors. Tumor recurrence or distant metastasis correlates to both the KIT mutations at codons 557/558 and the mitotic counts, but not to the tumor size.