Clinicopathological heterogeneity between primary and metastatic sites of gastroenteropancreatic neuroendocrine neoplasm

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.

Download Full-text

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

10.21203/rs.3.rs-66797/v1 ◽

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.

Download Full-text

Tumor Macroscopic Morphology Is an Important Prognostic Factor in Predicting Chemotherapeutic Efficacy and Clinical Outcomes of Patients With Colorectal Neuroendocrine Neoplasms, One Multicenter Retrospective Cohort Study

Frontiers in Endocrinology ◽

10.3389/fendo.2021.801741 ◽

2021 ◽

Vol 12 ◽

Author(s):

Zhijie Wang ◽

Ke An ◽

Rui Li ◽

Qian Liu

Keyword(s):

Prognostic Factor ◽

Locally Advanced ◽

Progression Free Survival ◽

Tnm Stage ◽

Stage Ii ◽

Neuroendocrine Neoplasm ◽

Neuroendocrine Neoplasms ◽

Ki 67 ◽

Dismal Prognosis ◽

Poorly Differentiated

Background and AimsLocally advanced and metastatic colorectal neuroendocrine neoplasm (NEN) is a rare disease with a dismal prognosis. We aimed to explore the value of the macroscopic morphology of NENs in the management of TNM stage II-IV colorectal NENs, which has not been fully elucidated in previous reports.MethodsWe retrospectively enrolled 125 eligible patients with TNM stage II-IV colorectal NENs who were diagnosed between 2000 and 2020 from three Chinese hospitals. All were categorized into either protruding or ulcerative NEN groups through endoscopic evaluation of their macroscopic morphology. Clinicopathological data were collected and compared between the two groups. Survival analysis was performed to assess the survival outcomes between the two groups.ResultsA total of 77 and 48 patients had protruding and ulcerative NENs, respectively. Patients with ulcerative NENs had a larger median tumor size (P<0.001) and higher median Ki-67 index (P<0.001), and a larger proportion of these patients had grade G3 disease (P=0.001) and poorly differentiated neoplasms (P=0.001), as well as higher frequencies of T3 and T4 tumors (P=0.006) than patients with protruding NENs. In addition, patients with ulcerative NENs showed a much lower response to first-line chemotherapy [50% (95% CI: 27.3% - 72.7%) versus 20% (95% CI: 3.1% - 36.9%), P=0.03] and a worse 3-year progression-free survival (PFS) rate [19.7% (95% CI: 7.2% - 32.2%) versus 49.5% (95% CI: 37.5% - 61.5%), P=0.001] and 3-year overall survival (OS) rate [30.7% (95% CI: 15.6% - 45.8%) versus 76.9% (95% CI: 66.5% - 87.3%), P<0.001] than those with protruding NENs. The multivariate analysis results indicated that the macroscopic shape of NENs was an independent prognostic factor affecting both PFS (HR = 1.760, 95% CI: 1.024 – 3.026, P = 0.04) and OS (HR = 2.280, 95% CI: 1.123 – 4.628, P = 0.02).ConclusionsUlcerative NENs were more malignant and chemotherapy resistant than protruding NENs. Tumor macroscopic morphology is a valuable prognostic factor for stage II-IV colorectal NENs.

Download Full-text

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

10.21203/rs.3.rs-48471/v2 ◽

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.

Download Full-text

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

BMC Cancer ◽

10.1186/s12885-020-07579-6 ◽

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.

Download Full-text

Neuroendocrine neoplasms of the lung: a pathology update

memo - Magazine of European Medical Oncology ◽

10.1007/s12254-021-00681-w ◽

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.

Download Full-text

Gastric Mixed Neuroendocrine-Nonneuroendocrine Neoplasm: A rare case report

Medical Science and Discovery ◽

10.36472/msd.v8i4.528 ◽

2021 ◽

Vol 8 (4) ◽

pp. 291-293

Author(s):

Mecdi Gurhan Balci ◽

Mahir Tayfur

Keyword(s):

Histopathological Examination ◽

Epigastric Pain ◽

Correct Diagnosis ◽

Neuroendocrine Cells ◽

Neuroendocrine Neoplasm ◽

Neuroendocrine Neoplasms ◽

Ki 67 ◽

Rare Case Report ◽

Atypical Cells ◽

Strong Staining

Objective: The incidence of gastric neuroendocrine neoplasms is less than 1%. They are seen as combined tumors with non-neuroendocrine neoplasms at a rate of approximately 7%. This study aims to share the case of mixed neuroendocrine and non-neuroendocrine cancer with the literature. Case: Endoscopic biopsies were taken from the tumoral mass detected in the gastric cardia region at endoscopy in a 60-year-old male patient that has complaints of weight loss and epigastric pain. Histopathological examination revealed malignant tumor infiltration that consisting of neuroendocrine cells with large nuclei and narrow cytoplasm in some areas and adenoid structures composed of atypical cells with pleomorphic large nuclei in some areas. Strong staining was observed in neuroendocrine areas with neuroendocrine markers such as synaptophysin and Chromogranin. Ki-67 proliferative index and mitotic activity were high in neuroendocrine neoplasm areas. The case was reported as a high-grade neuroendocrine-non neuroendocrine mixed neoplasm. Conclusion: Gastric Mixed Neuroendocrine-Nonneuroendocrine neoplasms are rare cases and correct diagnosis and grading are important in the treatment and patient follow-up protocol.

Download Full-text

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

10.21203/rs.3.rs-48471/v3 ◽

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

Download Full-text

Ki-67 Labeling Index Variability Between Surgically Resected Primary and Metastatic Hepatic Lesions of Gastroenteropancreatic Neuroendocrine Neoplasms

International Journal of Surgical Pathology ◽

10.1177/1066896921990715 ◽

2021 ◽

pp. 106689692199071

Author(s):

Takaaki Furukawa ◽

Masato Ozaka ◽

Manabu Takamatsu ◽

Yutaka Takazawa ◽

Kentaro Inamura ◽

...

Keyword(s):

Hepatic Metastases ◽

Tumor Grade ◽

Primary Lesion ◽

Primary Site ◽

Labeling Index ◽

Neuroendocrine Neoplasms ◽

Ki 67 ◽

Gastroenteropancreatic Neuroendocrine Neoplasms ◽

Hepatic Lesions ◽

Metastatic Sites

Background. A higher Ki-67 labeling index is associated with a poorer prognosis in gastroenteropancreatic neuroendocrine neoplasms. It has also been proposed that the Ki-67 labeling index may increase during disease progression from the primary site to metastatic sites. Although biopsy specimens are used to measure the Ki-67 labeling index, heterogeneity in lesions is thought to affect the assessment of the Ki-67 labeling index. To overcome tumor heterogeneity, we evaluated the variability in the Ki-67 labeling index between primary lesions and hepatic metastases by analyzing only surgically resected specimens. Methods. We conducted a single-center retrospective study to analyze the variability in the Ki-67 labeling index and the change in tumor grade between the primary site and metastatic hepatic sites in 19 patients diagnosed with gastroenteropancreatic neuroendocrine neoplasms at the Cancer Institute Hospital of the Japanese Foundation for Cancer Research from 1998 to 2018. Both the primary site and metastatic hepatic sites were surgically resected. Results. Among the 19 patients with gastroenteropancreatic neuroendocrine neoplasms, 12 patients (63%) showed higher levels of the Ki-67 labeling index at metastatic hepatic sites than at the primary site. The median Ki-67 labeling index levels for the primary lesion and metastatic hepatic lesions were 5% and 10%, respectively. The Ki-67 labeling index levels were significantly elevated in the metastatic hepatic lesions compared to the primary lesion ( P = .002). Conclusions. This study addressed the heterogeneity of the Ki-67 labeling index by analyzing only surgically resected specimens. We observed a statistically significant increase in the Ki-67 labeling index in hepatic metastases compared to the primary lesion.

Download Full-text

Clinical relevance of different WHO grade 3 pancreatic neuroendocrine neoplasms based on morphology

Endocrine Connections ◽

10.1530/ec-17-0388 ◽

2018 ◽

Vol 7 (2) ◽

pp. 355-363 ◽

Cited By ~ 9

Author(s):

Xu Han ◽

Xuefeng Xu ◽

Hongyun Ma ◽

Yuan Ji ◽

Dansong Wang ◽

...

Keyword(s):

Vascular Invasion ◽

Who Classification ◽

Univariate Analysis ◽

Tnm Staging ◽

Mitotic Count ◽

Biological Behavior ◽

Neuroendocrine Neoplasms ◽

Ki 67 ◽

Who Grade ◽

Pancreatic Neuroendocrine Neoplasms

Purpose Emerging evidence suggests G3 pancreatic neuroendocrine neoplasms (pNENs) present heterogeneous morphology and biology. The 2017 WHO classification has introduced a new category of well-differentiated pancreatic neuroendocrine tumors (WD-pNETs) G3, compared with poorly differentiated pancreatic neuroendocrine carcinomas (PD-pNECs) G3. We aim to analysis the demographics and outcomes of patients with resectable 2017 WHO G3 pNENs to facilitate the distinction between two entities. Methods The multi-institutional retrospective cohort involving 57 surgically treated patients affected by 2017 WHO G3 pNENs were morphologically identified and clinically analyzed. Patients having WD-pNETs G3 and those having PD-pNECs G3 were compared. Results Thirty patients had WD-pNETs and 27 patients had PD-pNECs. The distributions of Ki-67 and mitotic count in patients with PD-pNECs or WD-pNETs showed remarkable disparities. ROC indicated cut-off value of Ki-67 was 45. PD-pNECs were more common in patients with elevated Ki-67 and mitotic count, advanced AJCC TNM stage, vascular invasion, regional lymph-node metastases, elevated NSE and decreased CgA levels compared with WD-pNETs (P < 0.05). The association between 2017 WHO G3 grade and TTR was statistically significant (P < 0.05). Univariate analysis indicated OS rates were associated with morphologic differentiation (WD-pNETs vs PD-pNECs), Ki-67, TNM staging, synchronous distant metastases, initial treatments, vascular invasion, regional lymph nodes metastases, mitotic count and age (P < 0.05). Multivariate analyses illustrated Ki-67, differentiation, TNM staging and vascular invasion were independent predictors (P < 0.05). Conclusions PD-pNECs G3 presented malignant biological behavior and dismal outcome compared with WD-pNETs G3. These findings challenge 2010 WHO classification and suggest the categorization can be improved by refined tumor grading.

Download Full-text

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

10.21203/rs.3.rs-48471/v1 ◽

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.

Download Full-text