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 Well Differentiated Grade 3 Neuroendocrine Tumors of the Digestive Tract: A Narrative Review

2020 ◽  
Vol 9 (6) ◽  
pp. 1677
Author(s):  
Anna Pellat ◽  
Romain Coriat
Keyword(s):  
Digestive Tract ◽  
Neuroendocrine Tumors ◽  
Peptide Receptor Radionuclide Therapy ◽  
Small Sample ◽  
World Health ◽  
Neuroendocrine Neoplasms ◽  
Ki 67 ◽  
Metastatic Setting ◽  
Well Differentiated ◽  
Grade 3

The 2017 World Health Organization (WHO) classification of neuroendocrine neoplasms (NEN) of the digestive tract introduced a new category of tumors named well-differentiated grade 3 neuroendocrine tumors (NET G−3). These lesions show a number of mitosis, or a Ki−67 index higher than 20% with a well-differentiated morphology, therefore separating them from neuroendocrine carcinomas (NEC) which are poorly differentiated. It has become clear that NET G−3 show differences not only in morphology but also in genotype, clinical presentation, and treatment response. The incidence of digestive NET G−3 represents about one third of NEN G−3 with main tumor sites being the pancreas, the stomach and the colon. Treatment for NET G−3 is not yet standardized because of lack of data. In a non-metastatic setting, international guidelines recommend surgical resection, regardless of tumor grading. For metastatic lesion, chemotherapy is the main treatment with similar regimen as NET G−2. Sunitinib has also shown some positive results in a small sample of patients but this needs confirmation. Peptide receptor radionuclide therapy (PRRT) and immunotherapy could be future available treatments after ongoing studies. The goal of this review was to sum up the latest data on the epidemiology and management of digestive NET G−3.

scholarly journals Digestive Well-Differentiated Grade 3 Neuroendocrine Tumors: Current Management and Future Directions

Cancers ◽  
2021 ◽  
Vol 13 (10) ◽  
pp. 2448
Author(s):  
Anna Pellat ◽  
Anne Ségolène Cottereau ◽  
Lola-Jade Palmieri ◽  
Philippe Soyer ◽  
Ugo Marchese ◽  
...  
Keyword(s):  
Neuroendocrine Tumors ◽  
Functional Imaging ◽  
World Health ◽  
Neuroendocrine Neoplasms ◽  
Tumor Site ◽  
Ki 67 ◽  
Future Directions ◽  
Metastatic Setting ◽  
Well Differentiated ◽  
Grade 3

Digestive well-differentiated grade 3 neuroendocrine tumors (NET G-3) have been clearly defined since the 2017 World Health Organization classification. They are still a rare category lacking specific data and standardized management. Their distinction from other types of neuroendocrine neoplasms (NEN) not only lies in morphology but also in genotype, aggressiveness, functional imaging uptake, and treatment response. Most of the available data comes from pancreatic series, which is the most frequent tumor site for this entity. In the non-metastatic setting, surgical resection is recommended, irrespective of grade and tumor site. For metastatic NET G-3, chemotherapy is the main first-line treatment with temozolomide-based regimen showing more efficacy than platinum-based regimen, especially when Ki-67 index <55%. Targeted therapies, such as sunitinib and everolimus, have also shown some positive therapeutic efficacy in small samples of patients. Functional imaging plays a key role for detection but also treatment selection. In the second or further-line setting, peptide receptor radionuclide therapy has shown promising response rates in high-grade NEN. Finally, immunotherapy is currently investigated as a new therapeutic approach with trials still ongoing. More data will come with future work now focusing on this specific subgroup. The aim of this review is to summarize the current data on digestive NET G-3 and explore future directions for their management.

scholarly journals Neuroendocrine neoplasms of the pancreas: diagnosis and pitfalls

2021 ◽  
Author(s):  
Björn Konukiewitz ◽  
Moritz Jesinghaus ◽  
Atsuko Kasajima ◽  
Günter Klöppel
Keyword(s):  
Neuroendocrine Tumors ◽  
Chromogranin A ◽  
Molecular Profile ◽  
Neuroendocrine Neoplasms ◽  
Histological Differentiation ◽  
Pancreatic Neuroendocrine Neoplasms ◽  
Poorly Differentiated ◽  
Well Differentiated ◽  
Diagnostic Pitfalls ◽  
Neuroendocrine Carcinomas

AbstractCommon to neuroendocrine neoplasms of the pancreas is their expression of synaptophysin, chromogranin A, and/or INSM1. They differ, however, in their histological differentiation and molecular profile. Three groups can be distinguished: well-differentiated neuroendocrine neoplasms (neuroendocrine tumors), poorly differentiated neuroendocrine neoplasms (neuroendocrine carcinomas), and mixed neuroendocrine-non-neuroendocrine neoplasms. However, the expression of synaptophysin and, to a lesser extent, also chromogranin A is not restricted to the neuroendocrine neoplasms, but may also be in a subset of non-neuroendocrine epithelial and non-epithelial neoplasms. This review provides the essential criteria for the diagnosis of pancreatic neuroendocrine neoplasms including diagnostic clues for the distinction of high-grade neuroendocrine tumors from neuroendocrine carcinomas and an algorithm avoiding diagnostic pitfalls in the delineation of non-neuroendocrine neoplasms with neuroendocrine features from pancreatic neuroendocrine neoplasms.

Modern approaches to the treatment of gastric neuroendocrine tumors

2016 ◽  
Vol 21 (3) ◽  
pp. 165-168
Author(s):  
Ivan N. Peregorodiev ◽  
V. Y Bokhian ◽  
I. S Stilidi ◽  
V. V Delektorskaya
Keyword(s):  
Neuroendocrine Tumors ◽  
Activity Index ◽  
Morphological Type ◽  
Neuroendocrine Neoplasms ◽  
Type I ◽  
Wide Range ◽  
High Proliferative Activity ◽  
Well Differentiated ◽  
The One ◽  
Neuroendocrine Carcinomas

Gastrointestinal neuroendocrine tumors (GI-NETs) include a wide range of tumors with different variants of the course of the disease. At the one end of the clinical spectrum there are highly differentiated type I GI-NETs, with five-year survival rate over 95%, at the another end there are low-differentiated neuroendocrine carcinoma (large-, smallcell cancers) representing a tumor with extremely poor prognosis. Therapeutic approaches to different types of tumors are different. It is necessary to distinguish the treatment of well-differentiated neuroendocrine neoplasms (I and II clinical-morphological type) and low-differentiated neuroendocrine carcinomas. At the same time, it should be noted how different is the treatment of well-differentiated neuroendocrine tumors with high proliferative activity index (III clinico-morphological type of tumor) and low-differentiated neuroendocrine carcinomas (large-, small-cell cancers).

Characterization of a novel entity of high-grade well-differentiated colorectal neuroendocrine tumors.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e15696-e15696
Author(s):  
Salman Rafi Punekar ◽  
Lena Masri-Lavine ◽  
Cristina Hajdu ◽  
Elliot Newman ◽  
Daniel Jacob Becker
Keyword(s):  
Carcinoid Tumor ◽  
Neuroendocrine Tumors ◽  
National Registry ◽  
Cox Proportional Hazards ◽  
Small Cell ◽  
Carcinoid Tumors ◽  
Low Grade ◽  
High Grade ◽  
Ki 67 ◽  
Well Differentiated

e15696 Background: Small studies suggest that a new pathologic entity of high-grade (by Ki-67 or mitotic index) well-differentiated (by histologic features) neuroendocrine tumors (NETs) exist throughout the GI tract, but the prognosis and characteristics of affected patients are unknown. We sought to further characterize the prognosis and demographics of patients with high-grade (HG) well-differentiated (WD) colorectal NET. Materials and Methods: We used the Surveillance Epidemiology and End Results (SEER) database to study patients with NETs of the colon and rectum diagnosed from 2000 to 2015. We identified patient demographics, clinical and tumor characteristics, and studied associations with tumor grade. We compared overall survival (OS) between patients with low-grade (LG)(grade 1-2) well-differentiated (ICD-0-3 = carcinoid), high-grade (grade 3-4) well-differentiated, and high-grade poorly-differentiated NETs (ICD-0-3 = small cell neuroendocrine). We used logistic regression to detect associations with grade and Cox proportional hazards models to examine predictors of survival. Results: We identified 5,894 cases with colorectal carcinoid tumor (5780 [98.1%] LG and 114 [1.9%] HG); the cohort was 68% white, 48% male, and had a median age of 54. Patients diagnosed with HG carcinoid tumors were more likely to be of older age (OR 2.23; 95% CI 1.19-4.19 for age 60-69 vs < 50) and unmarried (OR 1.56; 95% CI 1.02-2.38), and less likely to be diagnosed after 2010 (OR 0.09; 95% CI 0.06-0.15). OS for patients with HG carcinoids (median 36 m; 95% CI 13-92) fell in between OS for those with HG small cell NETs (median 7 m; 95% CI 6-8), and LG carcinoid tumor (median not reached, > 120 m). Among patients with carcinoid tumors, black patients (HR 1.31; 95% CI 1.03-1.67, older patients (HR 3.60; 95% CI 2.50-5.19 for age 60-69 vs < 50), unmarried patients (HR 1.52; 95% CI 1.24-1.87), and those with HG features (HR 3.85; 95% CI 2.88-5.15) had worse survival. Conclusions: We defined a subset of high-grade well-differentiated NETs, more commonly diagnosed in older, unmarried patients, with a prognosis between that of high grade small cell NETs and low grade carcinoid tumors. Our analysis adds the first national registry study to the literature in support of a new classification of non-pancreatic high-grade well differentiated NETs.

Erratum to: KI-67 heterogeneity in well differentiated gastro-entero-pancreatic neuroendocrine tumors: when is biopsy reliable for grade assessment?

Endocrine ◽  
2017 ◽  
Vol 57 (3) ◽  
pp. 503-503
Author(s):  
Federica Grillo ◽  
Luca Valle ◽  
Diego Ferone ◽  
Manuela Albertelli ◽  
Maria Pia Brisigotti ◽  
...  
Keyword(s):  
Neuroendocrine Tumors ◽  
Pancreatic Neuroendocrine Tumors ◽  
Ki 67 ◽  
Well Differentiated ◽  
Grade Assessment

scholarly journals Expression of the phosphorylated variant of the AKT1-kinase (p-AKT1) in well-differentiated pancreatic neuroendocrine tumors: immunohistochemical evaluation

2018 ◽  
Vol 46 (4) ◽  
pp. 314-322
Author(s):  
V. V. Delektorskaya ◽  
O. N. Solov'eva ◽  
G. Yu. Chemeris ◽  
Yu. I. Patyutko
Keyword(s):  
Liver Metastases ◽  
Neuroendocrine Tumors ◽  
Treatment Effectiveness ◽  
Disease Free Survival ◽  
Immunohistochemical Analysis ◽  
Pancreatic Neuroendocrine Tumors ◽  
Ki 67 ◽  
New Treatment ◽  
Well Differentiated ◽  
High Level

Background:Well-differentiated pancreatic neuroendocrine tumors (pNETs) represent a group of rare epithelial neoplasms with a highly variable clinical course. AKT1 is one of the most frequently activated protein kinases in pNETs, which promotes the tumor growth and is of interest as a prognostic factor and a target for new treatment approaches.Aim:To study the expression of the phosphorylated variant of AKT1-kinase (p-AKT1) in primary pNETs and their liver metastases and to correlate the results with various clinical and pathological parameters and the disease prognosis.Materials and methods:P-AKT1 expression was studied by the immunohistochemical analysis of the primary lesions and liver metastases in 52 pNETs patients.Results:A high level of cytoplasmic and/or nuclear immunoreactivity was detected in 24/52 of the primary pNETs (46.2%) and in 16/27 of their liver metastases (59.3%). p-AKT1 expression was observed in 3 (21.4%) of NET grade (G) 1, in 14 (46.7%) of NET G2, and in 7 (87.5%) of NET G3. p-AKT1 expression was more frequently identified in pNET G3 category and increased during the tumor progression in metachronous liver metastases, as compared to the corresponding primary tumor. In addition, p-AKT1 positivity was significantly associated with an increase of grade from G1 to G3 (p = 0.004), the Ki-67 index (p = 0.029), the pTNM stage (p = 0.0008), perineural invasion (p = 0.031) and a decrease in disease-free survival (p = 0.05).Conclusion:The results suggest that p-АКТ1 plays an important role in the pathogenesis of pNETs and may be an additional criterion for assessment of the prognosis and treatment effectiveness in this type of tumors.

scholarly journals INSM1 Is a Highly Specific Marker of Neuroendocrine Differentiation in Primary Neoplasms of the Gastrointestinal Tract, Appendix, and Pancreas

2020 ◽  
Vol 153 (6) ◽  
pp. 811-820 ◽  
Author(s):  
Kelsey E McHugh ◽  
Sanjay Mukhopadhyay ◽  
Erika E Doxtader ◽  
Christopher Lanigan ◽  
Daniela S Allende
Keyword(s):  
Goblet Cell ◽  
Neuroendocrine Differentiation ◽  
Neuroendocrine Neoplasms ◽  
Specific Marker ◽  
Low Grade ◽  
Ki 67 ◽  
Neuroendocrine Markers ◽  
Primary Neoplasms ◽  
Poorly Differentiated ◽  
Well Differentiated

Abstract Objectives INSM1 has been described as a sensitive and specific neuroendocrine marker. This study aims to compare INSM1 with traditional neuroendocrine markers in gastrointestinal neuroendocrine neoplasms. Methods Retrospective review (2008-2018) was used to retrieve paraffin-embedded tissue from 110 gastrointestinal neuroendocrine neoplasms and controls that was subsequently stained with INSM1, synaptophysin, chromogranin, CD56, and Ki-67. Results INSM1 was positive in 16 of 17 (94.1%) gastric, 17 of 18 (94.4%) pancreatic, 13 of 18 (72.2%) small bowel, 17 of 21 (81.0%) colonic, and 26 of 36 (72.2%) appendiceal tumors. INSM1 was positive in 58 of 70 (82.9%) well-differentiated neuroendocrine tumors, 17 of 20 (85.0%) poorly differentiated neuroendocrine carcinomas, 8 of 11 (72.7%) low-grade goblet cell adenocarcinomas (grade 1), and 6 of 9 (66.7%) high-grade goblet cell adenocarcinomas (grade 2/3). INSM1 sensitivity for neuroendocrine neoplasms (80.9%) was less than that of synaptophysin (99.1%), chromogranin (88%), and CD56 (95.3%); specificity was higher (95.7% vs 86.0%, 87.3%, and 86.0%, respectively). Conclusions INSM1 is a useful marker of neuroendocrine differentiation in gastrointestinal neuroendocrine and mixed neuroendocrine neoplasms. Compared with traditional neuroendocrine markers, INSM1 is less sensitive but more specific.

scholarly journals Prediction of Progression-Free Survival in Patients With Advanced, Well-Differentiated, Neuroendocrine Tumors Being Treated With a Somatostatin Analog: The GETNE-TRASGU Study

2019 ◽  
Vol 37 (28) ◽  
pp. 2571-2580 ◽  
Author(s):  
Alberto Carmona-Bayonas ◽  
Paula Jiménez-Fonseca ◽  
Ángela Lamarca ◽  
Jorge Barriuso ◽  
Ángel Castaño ◽  
...  
Keyword(s):  
Neuroendocrine Tumors ◽  
Failure Time ◽  
Somatostatin Analogs ◽  
Progression Free Survival ◽  
Accelerated Failure Time Model ◽  
Endocrine Tumors ◽  
First Line ◽  
Ki 67 ◽  
Free Survival ◽  
Well Differentiated

PURPOSE Somatostatin analogs (SSAs) are recommended for the first-line treatment of most patients with well-differentiated, gastroenteropancreatic (GEP) neuroendocrine tumors; however, benefit from treatment is heterogeneous. The aim of the current study was to develop and validate a progression-free survival (PFS) prediction model in SSA-treated patients. PATIENTS AND METHODS We extracted data from the Spanish Group of Neuroendocrine and Endocrine Tumors Registry (R-GETNE). Patient eligibility criteria included GEP primary, Ki-67 of 20% or less, and first-line SSA monotherapy for advanced disease. An accelerated failure time model was developed to predict PFS, which was represented as a nomogram and an online calculator. The nomogram was externally validated in an independent series of consecutive eligible patients (The Christie NHS Foundation Trust, Manchester, United Kingdom). RESULTS We recruited 535 patients (R-GETNE, n = 438; Manchester, n = 97). Median PFS and overall survival in the derivation cohort were 28.7 (95% CI, 23.8 to 31.1) and 85.9 months (95% CI, 71.5 to 96.7 months), respectively. Nine covariates significantly associated with PFS were primary tumor location, Ki-67 percentage, neutrophil-to-lymphocyte ratio, alkaline phosphatase, extent of liver involvement, presence of bone and peritoneal metastases, documented progression status, and the presence of symptoms when initiating SSA. The GETNE-TRASGU (Treated With Analog of Somatostatin in Gastroenteropancreatic and Unknown Primary NETs) model demonstrated suitable calibration, as well as fair discrimination ability with a C-index value of 0.714 (95% CI, 0.680 to 0.747) and 0.732 (95% CI, 0.658 to 0.806) in the derivation and validation series, respectively. CONCLUSION The GETNE-TRASGU evidence-based prognostic tool stratifies patients with GEP neuroendocrine tumors receiving SSA treatment according to their estimated PFS. This nomogram may be useful when stratifying patients with neuroendocrine tumors in future trials. Furthermore, it could be a valuable tool for making treatment decisions in daily clinical practice.

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