An analysis of 130 neuroendocrine tumors G3 regarding prevalence, origin, metastasis, and diagnostic features

AbstractLimited data exist on high-grade neuroendocrine tumors (NETs G3) which represent a new category among neuroendocrine neoplasms (NEN). We analyzed NETs G3 in a consultation series regarding prevalence, origin, metastasis, and diagnostic problems. Based on the WHO classification of digestive system tumors, 130 NETs G3 (9%) were identified in 1513 NENs. NET G3 samples were more often obtained from metastatic sites (69%) than NET G1/G2 samples (24%). NET G3 metastases presented most frequently in the liver (74%) and originated from the pancreas (38/90, 42%), followed by the lung (9%), ileum (7%), stomach (3%), rectum (1%), and rare sites (2%) such as the prostate and breast. The primaries remained unknown in 15%. NETs G3 had a median Ki67 of 30% that distinguished them from NECs (60%), though with great overlap. The expression of site-specific markers, p53, Rb1, and SST2 was similar in NETs G3 and NETs G1/G2, except for p53 and Rb1 which were abnormally expressed in 8% and 7% of liver metastases from NET G3 but not from NET G1/G2. NETs G3 were frequently referred as NECs (39%) but could be well distinguished from NECs by normal p53 (92% versus 21%) and Rb1 expression (93% versus 41%) expression. In conclusion, NETs G3 are frequently discovered as liver metastases from pancreatic or pulmonary primaries and are often misinterpreted as NEC. p53 and Rb1 are powerful markers in the distinction of NET G3 from NEC. Rarely, carcinomas from non-digestive, non-pulmonary organs with neuroendocrine features may present as NET G3.

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Classification and Prognostic Stratification of Bronchopulmonary Neuroendocrine Neoplasms

Neuroendocrinology ◽

10.1159/000502776 ◽

2019 ◽

Vol 110 (5) ◽

pp. 393-403 ◽

Cited By ~ 2

Author(s):

Naomi Oka ◽

Atsuko Kasajima ◽

Björn Konukiewitz ◽

Akira Sakurada ◽

Yoshinori Okada ◽

...

Keyword(s):

Disease Free Survival ◽

Mitotic Count ◽

World Health ◽

Neuroendocrine Neoplasms ◽

Prognostic Impact ◽

Ki67 Index ◽

Prognostic Stratification ◽

Net G3 ◽

Health Organization

The accuracy and reproducibility of the World Health Organization (WHO) 2015 classification of bronchopulmonary neuroendocrine neoplasms (BP-NENs) is disputed. The aim of this study is to classify and grade BP-NENs using the WHO 2019 classification of digestive system NENs (DiS-NEN-WHO 2019), and to analyze its accuracy and prognostic impact. Two BP-NEN cohorts from Japan and Germany, 393 tumors (88% surgically resected), were reviewed and the clinicopathological data of the resected tumors (n = 301) correlated to patients’ disease-free survival (DFS). The DiS-NEN-WHO 2019 stratified the 350 tumors into 91 (26%) neuroendocrine tumors (NET) G1, 52 (15%) NET G2, 15 (4%) NET G3, and 192 (55%) neuroendocrine carcinomas (NEC). NECs, but not NETs, were immunohistochemically characterized by abnormal p53 (100%) and retinoblastoma 1 (83%) expression. The Ki67 index, which was on average 4 times higher than mitotic count (p < 0.0001), was prognostically more accurate than the mitotic count. NET G3 patients had a worse outcome than NET G1 (p < 0.01) and NET G2 patients (p = 0.02), respectively. No prognostic difference was detected between NET G3 and NEC patients after 5 year DFS. It is concluded that stratifying BP-NEN patients according to the DiS-NEN-WHO 2019 classification results in 3 prognostically well-defined NET groups, if grading is solely based on Ki67 index. Mitotic count alone may underestimate malignant potential of NETs.

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What is New in 2019 World Health Organization (WHO) Classification of Tumors of the Digestive System: Review of Selected Updates on Neuroendocrine Neoplasms, Appendiceal Tumors, and Molecular Testing

Archives of Pathology & Laboratory Medicine ◽

10.5858/arpa.2019-0665-ra ◽

2020 ◽

Cited By ~ 4

Author(s):

Naziheh Assarzadegan ◽

Elizabeth Montgomery

Keyword(s):

World Health Organization ◽

Digestive System ◽

English Literature ◽

World Health ◽

Response To Treatment ◽

Neuroendocrine Neoplasms ◽

Molecular Testing ◽

Classification Of Tumors ◽

Health Organization

Context.— The 5th edition of the World Health Organization classification of digestive system tumors discusses several advancements and developments in understanding the etiology, pathogenesis, and diagnosis of several digestive tract tumors. Objective.— To provide a summary of the updates with a focus on neuroendocrine neoplasms, appendiceal tumors, and the molecular advances in tumors of the digestive system. Data Sources.— English literature and personal experiences. Conclusions.— Some of the particularly important updates in the 5th edition are the alterations made in the classification of neuroendocrine neoplasms, understanding of pathogenesis of appendiceal tumors and their precursor lesions, and the expanded role of molecular pathology in establishing an accurate diagnosis or predicting prognosis and response to treatment.

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Aberrant Expression of Long Non Coding RNA HOTAIR and De-Regulation of the Paralogous 13 HOX Genes Are Strongly Associated with Aggressive Behavior of Gastro-Entero-Pancreatic Neuroendocrine Tumors

International Journal of Molecular Sciences ◽

10.3390/ijms22137049 ◽

2021 ◽

Vol 22 (13) ◽

pp. 7049

Author(s):

Annabella Di Mauro ◽

Giosuè Scognamiglio ◽

Gabriella Aquino ◽

Margherita Cerrone ◽

Giuseppina Liguori ◽

...

Keyword(s):

Neuroendocrine Tumors ◽

Hox Genes ◽

Predictive Biomarkers ◽

Neuroendocrine Neoplasms ◽

Low Grade ◽

Pancreatic Neuroendocrine Tumors ◽

Aberrant Expression ◽

Molecular Stratification ◽

Tubular Gland ◽

Net G3

Gastro-entero-pancreatic neuroendocrine neoplasms (GEP-NENs) are rare diseases occurring in the gastrointestinal tract and pancreas. They are characterized by the loss of epithelial tubular gland elements, and by the increased expression of neuroendocrine markers. GEP-NENs are subdivided into two histo-pathological types, gastro-entero-pancreatic neuroendocrine tumors (GEP-NETs) and gastro-entero-pancreatic neuroendocrine carcinomas (GEP-NECs). According to WHO 2017 and 2019 classification criteria are graded and staged in four categories, NET-G1, NET-G2, NET-G3, and NEC-G3. The molecular characterization of these tumors can be fundamental for the identification of new diagnostic, prognostic and predictive biomarkers. The main purpose of this study was to analyze the expression of the paralogous 13 HOX genes, normally involved in embryogenic development and frequently deregulated in human cancers, and of the HOX regulating lncRNA HOTAIR in GEP-NENs. The expression of HOX genes is gradually lost in the transition from GEP NET G1 to NET/NEC G3 tumors, while HOTAIR expression, inversely correlated with HOX genes expression and weakly expressed in low-grade GEP NENs, becomes aberrant in NET G3 and NEC G3 categories. Our data highlights their potential role in the molecular stratification of GEP-NENs by suggesting new prognostic markers and potential therapeutic targets.

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Tumor necrosis of primary malignancy affects survival and outcome in patients with liver metastases from neuroendocrine tumors

Zeitschrift für Gastroenterologie ◽

10.1055/s-0037-1612837 ◽

2018 ◽

Vol 56 (01) ◽

pp. E2-E89

Author(s):

G Atanasov ◽

I Tsvetkova ◽

S Benjamin ◽

A Andreou ◽

F Klein ◽

...

Keyword(s):

Liver Metastases ◽

Neuroendocrine Tumors ◽

Tumor Necrosis ◽

Primary Malignancy

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Proposal of a novel H category‐based classification of colorectal liver metastases based on a Japanese nationwide survey

Journal of Hepato-Biliary-Pancreatic Sciences ◽

10.1002/jhbp.920 ◽

2021 ◽

Author(s):

Toru Beppu ◽

Katsunori Imai ◽

Goro Honda ◽

Katsunori Sakamoto ◽

Shin Kobayashi ◽

...

Keyword(s):

Liver Metastases ◽

Colorectal Liver Metastases ◽

Nationwide Survey

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Mixed adenoneuroendocrine carcinoma of the hepatic bile duct: a case report and review of the literature

BMC Gastroenterology ◽

10.1186/s12876-020-01550-2 ◽

2020 ◽

Vol 20 (1) ◽

Author(s):

Sulai Liu ◽

Zhendong Zhong ◽

Meng Xiao ◽

Yinghui Song ◽

Youye Zhu ◽

...

Keyword(s):

Bile Duct ◽

Neuroendocrine Tumors ◽

Radical Surgery ◽

Malignant Tumors ◽

World Health ◽

Ki 67 ◽

Mixed Adenoneuroendocrine Carcinoma ◽

Hilar Bile Duct ◽

Hilar Tumor

Abstract Background The World Health Organization's updated classification of digestive system neuroendocrine tumors in 2010 first proposed the classification of mixed adenoneuroendocrine carcinoma (MANEC). The incidence of biliary malignant tumors with neuroendocrine tumors accounts for less than 1% of all neuroendocrine tumors. Moreover, the incidence of hilar bile duct with MANEC is very rare. Case presentation A 65-year-old female patient came to our hospital for repeated abdominal pain for more than 4 months and skin sclera yellow staining for 1 week. Contrast-enhanced computed tomography imaging and magnetic resonance results suggested a hilar tumor for Bismuth-Corlette Type II. The patient underwent radical surgery for hilar cholangiocarcinoma. Finally, the patient was diagnosed with hilar bile duct MANEC, staged 1 (pT1N0M0) based on the eighth edition of the AJCC. Histopathology showed that the tumor was a biliary tumor with both adenocarcinoma and neuroendocrine carcinoma. No evidence of recurrence and metastasis after 20 months of follow-up. Conclusions We first reported a MANEC that originated in the hilar bile duct. As far as we known, there were few reports of biliary MANEC, and the overall prognosis was poor. We also found that the higher the Ki-67 index, the worse the prognosis of this type of patient. Radical surgery is the most effective treatment.

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A Comparison of Liver-Directed Therapy and Systemic Therapy for the Treatment of Liver Metastases in Patients with Gastrointestinal Neuroendocrine Tumors: Analysis of the California Cancer Registry

Journal of Vascular and Interventional Radiology ◽

10.1016/j.jvir.2020.10.019 ◽

2021 ◽

Author(s):

Jonathan Kessler ◽

Gagandeep Singh ◽

Philip H.G. Ituarte ◽

Rebecca Allen ◽

Sue Chang ◽

...

Keyword(s):

Liver Metastases ◽

Neuroendocrine Tumors ◽

Cancer Registry ◽

Systemic Therapy ◽

California Cancer Registry

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

Endocrine Pathology ◽

10.1007/s12022-021-09668-z ◽

2021 ◽

Vol 32 (1) ◽

pp. 154-168 ◽

Cited By ~ 1

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.

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