scholarly journals O6-methylguanine DNA methyltransferase and glucose transporter 2 in foregut and hindgut gastrointestinal neuroendocrine neoplasms

2020 ◽  
Author(s):  
Hirofumi Watanabe ◽  
Yuto Yamazaki ◽  
Fumiyoshi Fujishima ◽  
Komoto Izumi ◽  
Masayuki Imamura ◽  
...  
Keyword(s):  
Therapeutic Efficacy ◽  
Dna Methyltransferase ◽  
Glucose Transporter ◽  
Neuroendocrine Neoplasm ◽  
Neuroendocrine Neoplasms ◽  
Ki 67 ◽  
Methylguanine Dna Methyltransferase ◽  
Glucose Transporter 2 ◽  
Polymerase Chain ◽  
Neuroendocrine Carcinomas

Abstract Background: Streptozocin (STZ) is used for treating both pancreatic (PanNET) and gastrointestinal (GI-NET) neuroendocrine tumors but its therapeutic efficacy is relatively low in GI-NETs. Therefore, it has become pivotal to select GI-NET patients who could benefit from STZ treatment. STZ is transported via the glucose transporter 2 (GLUT2) into the cells and the loss of O6-methylguanine DNA methyltransferase (MGMT) also increases its therapeutic efficacy. Therefore, GLUT2 high and MGMT low status could be the surrogate markers of STZ. Methods: In this study, we examined the MGMT and GLUT2 status in gastrointestinal neuroendocrine neoplasm (NEN). We studied 84 NEN cases: 33 foregut and 37 hindgut GI-NETs and 14 gastrointestinal neuroendocrine carcinomas (GI-NECs). Results: In GI-NETs, MGMT scores of ≥2 and ≥3 were 77% (54/70) and 56% (39/70), respectively, and GLUT2 scores of ≥4 and ≥6 were 30% (21/70) and 4.3% (3/70), respectively. Methylation-specific polymerase chain reaction revealed that MGMT promoter methylation was detected only in 2/14 GI-NECs but none of the included GI-NETs. GLUT2 (GLUT2 score) and MGMT immunoreactivity (MGMT and H-scores) were both significantly correlated with Ki-67 labeling index (GLUT2 score: P = 0.0045, ρ = -0.4570; MGMT score: P = 0.0064, ρ = -0.4399; H-score: P = 0.0110, ρ = -0.4135) and MGMT immunoreactivity were significantly correlated with GLUT2 immunoreactivity (MGMT score: P = 0.0198; H-score, P = 0.0004, ρ = 0.5483) in hindgut NETs, but not in foregut NETs. However, discrepancies from the above correlation between GLUT2 and MGMT immunoreactivity were detected in several GI-NET cases which could be potential candidates for STZ therapy. Conclusion: The evaluation of MGMT and GLUT2 status could provide an important information in planning STZ therapy in GI-NET patients.

scholarly journals O6-methylguanine DNA methyltransferase and glucose transporter 2 in foregut and hindgut gastrointestinal neuroendocrine neoplasms

BMC Cancer ◽  
2020 ◽  
Vol 20 (1) ◽  
Author(s):  
Hirofumi Watanabe ◽  
Yuto Yamazaki ◽  
Fumiyoshi Fujishima ◽  
Komoto Izumi ◽  
Masayuki Imamura ◽  
...  
Keyword(s):  
Therapeutic Efficacy ◽  
Dna Methyltransferase ◽  
Glucose Transporter ◽  
Neuroendocrine Neoplasm ◽  
Neuroendocrine Neoplasms ◽  
Ki 67 ◽  
Methylguanine Dna Methyltransferase ◽  
Glucose Transporter 2 ◽  
Polymerase Chain ◽  
Neuroendocrine Carcinomas

Abstract Background Streptozocin (STZ) is used for treating both pancreatic (PanNET) and gastrointestinal (GI-NET) neuroendocrine tumors but its therapeutic efficacy is relatively low in GI-NETs. Therefore, it has become pivotal to select GI-NET patients who could benefit from STZ treatment. STZ is transported via the glucose transporter 2 (GLUT2) into the cells and the loss of O6-methylguanine DNA methyltransferase (MGMT) also increases its therapeutic efficacy. Therefore, GLUT2 high and MGMT low status could be the surrogate markers of STZ. Methods In this study, we examined the MGMT and GLUT2 status in gastrointestinal neuroendocrine neoplasm (NEN). We studied 84 NEN cases: 33 foregut and 37 hindgut GI-NETs and 14 gastrointestinal neuroendocrine carcinomas (GI-NECs). Results In GI-NETs, MGMT scores of ≥2 and ≥ 3 were 77% (54/70) and 56% (39/70), respectively, and GLUT2 scores of ≥4 and ≥ 6 were 30% (21/70) and 4.3% (3/70), respectively. Methylation-specific polymerase chain reaction revealed that MGMT promoter methylation was detected only in 2/14 GI-NECs but none of the included GI-NETs. GLUT2 (GLUT2 score) and MGMT immunoreactivity (MGMT and H-scores) were both significantly correlated with Ki-67 labeling index (GLUT2 score: P = 0.0045, ρ = − 0.4570; MGMT score: P = 0.0064, ρ = − 0.4399; H-score: P = 0.0110, ρ = − 0.4135) and MGMT immunoreactivity were significantly correlated with GLUT2 immunoreactivity (MGMT score: P = 0.0198; H-score, P = 0.0004, ρ = 0.5483) in hindgut NETs, but not in foregut NETs. However, discrepancies from the above correlation between GLUT2 and MGMT immunoreactivity were detected in several GI-NET cases which could be potential candidates for STZ therapy. Conclusion The evaluation of MGMT and GLUT2 status could provide an important information in planning STZ therapy in GI-NET patients.

scholarly journals O6-methylguanine DNA methyltransferase and glucose transporter 2 in foregut and hindgut gastrointestinal neuroendocrine neoplasms

2020 ◽  
Author(s):  
Hirofumi Watanabe ◽  
Yuto Yamazaki ◽  
Fumiyoshi Fujishima ◽  
Komoto Izumi ◽  
Masayuki Imamura ◽  
...  
Keyword(s):  
Therapeutic Efficacy ◽  
Dna Methyltransferase ◽  
Glucose Transporter ◽  
Neuroendocrine Neoplasm ◽  
Neuroendocrine Neoplasms ◽  
Ki 67 ◽  
Methylguanine Dna Methyltransferase ◽  
Glucose Transporter 2 ◽  
Polymerase Chain ◽  
Neuroendocrine Carcinomas

Abstract Background: Streptozocin (STZ) is used for treating both pancreatic (PanNET) and gastrointestinal (GI-NET) neuroendocrine tumors but its therapeutic efficacy is relatively low in GI-NETs. Therefore, it has become pivotal to select GI-NET patients who could benefit from STZ treatment. STZ is transported via the glucose transporter 2 (GLUT2) into the cells and the loss of O6-methylguanine DNA methyltransferase (MGMT) also increases its therapeutic efficacy. Therefore, GLUT2 high and MGMT low status could be the surrogate markers of STZ. Methods: In this study, we examined the MGMT and GLUT2 status in gastrointestinal neuroendocrine neoplasm (NEN). We studied 84 NEN cases: 33 foregut and 37 hindgut GI-NETs and 14 gastrointestinal neuroendocrine carcinomas (GI-NECs). Results: In GI-NETs, MGMT scores of ≥2 and ≥3 were 77% (54/70) and 56% (39/70), respectively, and GLUT2 scores of ≥4 and ≥6 were 30% (21/70) and 4.3% (3/70), respectively. Methylation-specific polymerase chain reaction revealed that MGMT promoter methylation was detected only in 2/14 GI-NECs but none of the included GI-NETs. GLUT2 (GLUT2 score) and MGMT immunoreactivity (MGMT and H-scores) were both significantly correlated with Ki-67 labeling index (GLUT2 score: P = 0.0045, ρ = -0.4570; MGMT score: P = 0.0064, ρ = -0.4399; H-score: P = 0.0110, ρ = -0.4135) and MGMT immunoreactivity were significantly correlated with GLUT2 immunoreactivity (MGMT score: P = 0.0198; H-score, P = 0.0004, ρ = 0.5483) in hindgut NETs, but not in foregut NETs. However, discrepancies from the above correlation between GLUT2 and MGMT immunoreactivity were detected in several GI-NET cases which could be potential candidates for STZ therapy. Conclusion: The evaluation of MGMT and GLUT2 status could provide an important information in planning STZ therapy in GI-NET patients.

scholarly journals O 6-Methylguanine DNA Methyltransferase and Glucose Transporter 2 in Foregut and Hindgut Gastrointestinal Neuroendocrine Neoplasms

2020 ◽  
Author(s):  
Hirofumi Watanabe ◽  
Yuto Yamazaki ◽  
Fumiyoshi Fujishima ◽  
Komoto Izumi ◽  
Masayuki Imamura ◽  
...  
Keyword(s):  
Therapeutic Efficacy ◽  
Dna Methyltransferase ◽  
Glucose Transporter ◽  
Neuroendocrine Neoplasm ◽  
Neuroendocrine Neoplasms ◽  
Ki 67 ◽  
Methylguanine Dna Methyltransferase ◽  
Glucose Transporter 2 ◽  
Polymerase Chain ◽  
Neuroendocrine Carcinomas

Abstract Background: Streptozocin (STZ) is used for treating both pancreatic (PanNET) and gastrointestinal (GI-NET) neuroendocrine tumors but its therapeutic efficacy is relatively low in GI-NETs. Therefore, it has become pivotal to select GI-NET patients who could benefit from STZ treatment. STZ is transported via the glucose transporter 2 (GLUT2) into the cells and the loss of O6-methylguanine DNA methyltransferase (MGMT) also increases its therapeutic efficacy. Therefore, GLUT2 high and MGMT low status could be the surrogate markers of STZ. Methods: In this study, we examined the MGMT and GLUT2 status in gastrointestinal neuroendocrine neoplasm (NEN). We studied 84 NEN cases: 33 foregut and 37 hindgut GI-NETs and 14 gastrointestinal neuroendocrine carcinomas (GI-NECs). Results: In GI-NETs, MGMT scores of ≥2 and ≥3 were 77% (54/70) and 56% (39/70), respectively, and GLUT2 scores of ≥4 and ≥6 were 30% (21/70) and 4.3% (3/70), respectively. Methylation-specific polymerase chain reaction revealed that MGMT promoter methylation was detected only in 2/14 GI-NECs but in none of GI-NETs. GLUT2 (GLUT2 score) and MGMT immunoreactivity (MGMT and H-scores) were both significantly correlated with Ki-67 labeling index (GLUT2 score: P = 0.0045, ρ = -0.4570; MGMT score: P = 0.0064, ρ = -0.4399; H-score: P = 0.0110, ρ = -0.4135) and MGMT immunoreactivity were both significantly correlated with GLUT2 immunoreactivity (MGMT score: P = 0.0198; H-score, P = 0.0004, ρ = 0.5483) in hindgut NETs, but not in foregut NETs. However, discrepancies from the above correlation between GLUT2 and MGMT immunoreactivity were detected in several GI-NET cases which could be potential candidates for STZ therapy. Conclusion: The evaluation of MGMT and GLUT2 status could provide an important information in planning STZ therapy in GI-NET patients.

scholarly journals Neuroendocrine neoplasms of the lung: a pathology update

2021 ◽  
Author(s):  
Jasna Metovic ◽  
Marco Barella ◽  
Giuseppe Pelosi
Keyword(s):  
Neuroendocrine Differentiation ◽  
Predictive Biomarkers ◽  
Neuroendocrine Neoplasm ◽  
Diagnostic Tools ◽  
Neuroendocrine Neoplasms ◽  
Ki 67 ◽  
Blue Book ◽  
Starting Point ◽  
Resection Specimen ◽  
Neuroendocrine Carcinomas

Summary Purpose Neuroendocrine tumors and neuroendocrine carcinomas in the lung are distinct and separate entities featuring neuroendocrine differentiation, for which an accurate classification is clinically warranted. Materials and methods Three perspectives were addressed: (i) diagnostic tools, with the terminology to be used in either resection specimen or small-sized material; (ii) the so-called carcinoid tumors with elevated proliferation rates (mitotic and/or Ki-67 activity); (iii) predictive biomarkers based on immunohistochemical characterization. Results We herein provide a pathology update on lung neuroendocrine neoplasm classification that will appear in the forthcoming 5th edition of the WHO Blue Book, including a short discussion about biomarkers, which are presently given full consideration in clinical practice. Conclusion The WHO classification on lung neuroendocrine neoplasms is the cornerstone to provide the best clinical management of patients and is the starting point for any investigative insight.

scholarly journals Mixed Neuroendocrine/Non-neuroendocrine Neoplasm (MiNEN) of the Ovary Arising from Endometriosis: Molecular Pathology Analysis in Support of a Pathogenetic Paradigm

2021 ◽  
Author(s):  
Roberta Maragliano ◽  
Laura Libera ◽  
Ileana Carnevali ◽  
Valeria Pensotti ◽  
Giovanna De Vecchi ◽  
...  
Keyword(s):  
Large Cell ◽  
Neuroendocrine Neoplasm ◽  
Molecular Profile ◽  
Neuroendocrine Neoplasms ◽  
Fish Analysis ◽  
Sequencing Analysis ◽  
Endometrioid Carcinoma ◽  
Preneoplastic Lesions ◽  
Ovarian Endometriosis ◽  
Neuroendocrine Carcinomas

AbstractPrimary ovarian neuroendocrine neoplasms (Ov-NENs) are infrequent and mainly represented by well-differentiated forms (neuroendocrine tumors — NETs — or carcinoids). Poorly differentiated neuroendocrine carcinomas (Ov-NECs) are exceedingly rare and only few cases have been reported in the literature. A subset of Ov-NECs are admixed with non-neuroendocrine carcinomas, as it occurs in other female genital organs, as well (mostly endometrium and uterine cervix), and may be assimilated to mixed neuroendocrine/non-neuroendocrine neoplasms (MiNENs) described in digestive and extra-digestive sites. Here, we present a case of large cell Ov-NEC admixed with an endometrioid carcinoma of the ovary, arising in the context of ovarian endometriosis, associated with a uterine endometrial atypical hyperplasia (EAH). We performed targeted next-generation sequencing analysis, along with a comprehensive immunohistochemical study and FISH analysis for TP53 locus, separately on the four morphologically distinct lesions (Ov-NEC, endometrioid carcinoma, endometriosis, and EAH). The results of our study identified molecular alterations of cancer-related genes (PIK3CA, CTNNB1, TP53, RB1, ARID1A, and p16), which were present with an increasing gradient from preneoplastic lesions to malignant proliferations, both neuroendocrine and non-neuroendocrine components. In conclusion, our findings underscored that the two neoplastic components of this Ov-MiNEN share a substantially identical molecular profile and they progress from a preexisting ovarian endometriotic lesion, in a patient with a coexisting preneoplastic proliferation of the endometrium, genotypically and phenotypically related to the ovarian neoplasm. Moreover, this study supports the inclusion of MiNEN in the spectrum ovarian and, possibly, of all gynecological NENs, among which they are currently not classified.

scholarly journals Molecular Pathology of Well-Differentiated Pulmonary and Thymic Neuroendocrine Tumors: What Do Pathologists Need to Know?

2021 ◽  
Vol 32 (1) ◽  
pp. 154-168 ◽  
Author(s):  
Marco Volante ◽  
Ozgur Mete ◽  
Giuseppe Pelosi ◽  
Anja C. Roden ◽  
Ernst Jan M. Speel ◽  
...  
Keyword(s):  
Neuroendocrine Tumors ◽  
Young Patients ◽  
Carcinoid Tumors ◽  
Neuroendocrine Neoplasms ◽  
Grey Zone ◽  
Cell Hyperplasia ◽  
Ki 67 ◽  
Familial Form ◽  
Well Differentiated ◽  
Neuroendocrine Carcinomas

AbstractThoracic (pulmonary and thymic) neuroendocrine tumors are well-differentiated epithelial neuroendocrine neoplasms that are classified into typical and atypical carcinoid tumors based on mitotic index cut offs and presence or absence of necrosis. This classification scheme is of great prognostic value but designed for surgical specimens, only. Deep molecular characterization of thoracic neuroendocrine tumors highlighted their difference with neuroendocrine carcinomas. Neuroendocrine tumors of the lung are characterized by a low mutational burden, and a high prevalence of mutations in chromatin remodeling and histone modification-related genes, whereas mutations in genes frequently altered in neuroendocrine carcinomas are rare. Molecular profiling divided thymic neuroendocrine tumors into three clusters with distinct clinical outcomes and characterized by a different average of copy number instability. Moreover, integrated histopathological, molecular and clinical evidence supports the existence of a grey zone category between neuroendocrine tumors (carcinoid tumors) and neuroendocrine carcinomas. Indeed, cases with well differentiated morphology but mitotic/Ki-67 indexes close to neuroendocrine carcinomas have been increasingly recognized. These are characterized by specific molecular profiles and have an aggressive clinical behavior. Finally, thoracic neuroendocrine tumors may arise in the background of genetic susceptibility, being MEN1 syndrome the well-defined familial form. However, pathologists should be aware of rarer germline variants that are associated with the concurrence of neuroendocrine tumors of the lung or their precursors (such as DIPNECH) with other neoplasms, including but not limited to breast carcinomas. Therefore, genetic counseling for all young patients with thoracic neuroendocrine neoplasia and/or any patient with pathological evidence of neuroendocrine cell hyperplasia-to-neoplasia progression sequence or multifocal disease should be considered.

scholarly journals Clinicopathological heterogeneity between primary and metastatic sites of gastroenteropancreatic neuroendocrine neoplasm

2020 ◽  
Vol 15 (1) ◽  
Author(s):  
Huiying Shi ◽  
Chen Jiang ◽  
Qin Zhang ◽  
Cuihua Qi ◽  
Hailing Yao ◽  
...  
Keyword(s):  
Tumor Metastasis ◽  
Immunohistochemical Analysis ◽  
Metastatic Tumor ◽  
Neuroendocrine Neoplasm ◽  
Neuroendocrine Neoplasms ◽  
Ki 67 ◽  
Who Grade ◽  
Index Variation ◽  
The Difference ◽  
Metastatic Sites

Abstract Background Chromogranin A (CgA), synaptophysin (Syn) and the Ki-67 index play significant roles in diagnosis or the evaluation of the proliferative activity of gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs). However, little is known about whether these biological markers change during tumor metastasis and whether such changes have effect on prognosis. Methods We analyzed 35 specimens of both primary and metastatic tumor from 779 patients who had been diagnosed as GEP-NENs at Wuhan Union Hospital from August 2011 to October 2019. The heterogeneity of CgA, Syn and Ki-67 index was evaluated by immunohistochemical analysis. Results Among these 779 patients, the three most common sites of NENs in the digestive tract were the pancreas, rectum and stomach. Metastases were found in 311 (39.9%) patients. Among the 35 patients with both primary and metastatic pathological specimens, differences in the Ki-67 level were detected in 54.3% of the patients, while 37.1% showed a difference in CgA and only 11.4% showed a difference in Syn. Importantly, due to the difference in the Ki-67 index between primary and metastatic lesions, the WHO grade was changed in 8.6% of the patients. In addition, a Kaplan–Meier survival analysis showed that patients with Ki-67 index variation had a shorter overall survival (p = 0.0346), while neither Syn variation nor CgA variation was related to patient survival (p = 0.7194, p = 0.4829). Conclusions Our data indicate that primary and metastatic sites of GEP-NENs may exhibit pathological heterogeneity. Ki-67 index variation is closely related to the poor prognosis of patients with tumor metastasis, but neither Syn variation nor CgA variation is related to patient prognosis. Therefore, clinicopathologic evaluation of the primary tumor and metastatic sites could be helpful for predicting the prognosis.

scholarly journals The Correlations Between the Expression of SSTR2, SSTR5 Proteins and Clinicopathological Parameters as well as Prognosis of Gastric Neuroendocrine Neoplasms

2020 ◽  
Author(s):  
Yanwei Ye ◽  
Chuangfeng Xiao ◽  
Yingze Li ◽  
YiMing Shan ◽  
Jie Li ◽  
...  
Keyword(s):  
Somatostatin Receptor ◽  
Tumor Grade ◽  
Neuroendocrine Neoplasm ◽  
Clinicopathological Parameters ◽  
Neuroendocrine Neoplasms ◽  
P Value ◽  
Ki 67 ◽  
Positive Group ◽  
Expression Rate ◽  
Normal Stomach

Abstract Background： Somatostatin receptor 2, 5 (SSTR2, SSTR5) were seldom investigated in gastric neuroendocrine neoplasms (G-NENs). The purpose of the study was to elucidate the expression of SSTR2, SSTR5 in G-NENs and related clinical significance.Methods： 66 paraffin-embedded specimens were obtained from The first affiliated hospital of Zhengzhou university. The expression of SSTR2 and SSTR5 was detected by immunohistochemistry. The expression of SSTR2, SSTR5 and the clinicopathological characteristics, related immunohistochemical molecules and prognosis of gastric neuroendocrine neoplasm were analyzed statistically.Results： The expression rate of SSTR2 protein in G-NENs tissues and normal stomach tissues was 48.5% and 25.0%, respectively (P=0.046); the expression rate of SSTR5 protein in G-NENs tissues and normal stomach tissues was 65.2% and 25.0% , respectively (P=0.018). The expression of SSTR2 was positively correlated with the expression of Ki-67, SSTR5 and tumor grade (P-value was 0.032, 0.002, and 0.005, respectively); the expression of SSTR5 was positively correlated with the expression of SSTR2, Ki-67, CD-56 and tumor grade (P-value was 0.032, 0.011, 0.008, 0.028, respectively). In the SSTR2-positive group, SSTR5, CD-56, Ki-67 were closely related to the prognosis of patients with G-NENs. In the SSTR5-positive group, tumor grade, SSTR2, CD-56, Ki-67 were closely related to the prognosis of patients with G-NENs. Multi-factor analysis showed that SSTR2 and SSTR5 were independent prognostic factors for patients with G-NENs. Conclusion. High expression of SSTR2 and SSTR5 protein was related to the tumorigenesis of G-NENs. SSTR2 and SSTR5 were associated with the prognosis and might improve the prognosis of G-NENs.

scholarly journals Evaluation of MGMT gene methylation in neuroendocrine neoplasms

2021 ◽  
Author(s):  
Rosa Della Monica ◽  
Mariella Cuomo ◽  
Roberta Visconti ◽  
Annabella di Mauro ◽  
Michela Buonaiuto ◽  
...  
Keyword(s):  
Dna Methyltransferase ◽  
Alkylating Agents ◽  
Methylation Status ◽  
Neuroendocrine Neoplasms ◽  
Mgmt Methylation ◽  
Gene Methylation ◽  
Mgmt Gene ◽  
Methylguanine Dna Methyltransferase ◽  
Specific Pcr ◽  
Well Differentiated

Unresectable neuroendocrine neoplasms (NENs) often poorly respond to standard therapeutic approaches. Alkylating agents, in particular temozolomide, commonly used to treat high-grade brain tumors including glioblastomas, have recently been tested in advanced or metastatic NENs, where they showed promising response rates. In glioblastomas, prediction of response to temozolomide is based on the assessment of the methylation status of the MGMT gene, as its product, O-6-methylguanine-DNA methyltransferase, may counteract the damaging effects of the alkylating agent. However, in NENs, such a biomarker has not been validated yet. Thus, we have investigated MGMT methylation in 42 NENs of different grades and from various sites of origin by two different approaches: in contrast to methylation-specific PCR (MSP), which is commonly used in glioblastoma management, amplicon bisulfite sequencing (ABS) is based on high resolution next-generation sequencing and interrogates several additional CpG sites compared to those covered by MSP. Overall, we found MGMT methylation in 74% (31/42) of the NENs investigated. A higher methylation degree was observed in well-differentiated tumors and in tumors originating in the gastrointestinal tract. Comparing MSP and ABS results, we demonstrate that the region analyzed by the MSP test is sufficiently informative of the MGMT methylation status in NENs, suggesting that this predictive parameter could routinely be interrogated also in NENs

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