Pathology Reporting in Neuroendocrine Neoplasms of the Digestive System: Everything You Always Wanted to Know but Were Too Afraid to Ask

During the 5th NIKE (Neuroendocrine tumors Innovation in Knowledge and Education) meeting, held in Naples, Italy, in May 2019, discussions centered on the understanding of pathology reports of gastroenetropancreactic neuroendocrine neoplasms. In particular, the main problem concerned the difficulty that clinicians experience in extrapolating relevant information from neuroendocrine tumor pathology reports. During the meeting, participants were asked to identify and rate issues which they have encountered, for which the input of an expert pathologist would have been appreciated. This article is a collection of the most rated questions and relative answers, focusing on three main topics: 1) morphology and classification; 2) Ki67 and grading; 3) immunohistochemistry. Patient management should be based on multidisciplinary decisions, taking into account clinical and pathology-related features with clear comprehension between all health care professionals. Indeed, pathologists require clinical details and laboratory findings when relevant, while clinicians require concise and standardized reports. In keeping with this last statement, the minimum requirements in pathology datasets are provided in this paper and should be a baseline for all neuroendocrine tumor professionals.

[1]  A. Vanoli,et al.  Neuroendocrine neoplasms of the appendix, colon and rectum , 2021, Pathologica.

[2]  U. Pastorino,et al.  Ki-67 Index of 55% Distinguishes Two Groups of Bronchopulmonary Pure and Composite Large Cell Neuroendocrine Carcinomas with Distinct Prognosis , 2020, Neuroendocrinology.

[3]  A. Kjaer,et al.  P53, Somatostatin receptor 2a and Chromogranin A immunostaining as prognostic markers in high grade gastroenteropancreatic neuroendocrine neoplasms , 2020, BMC Cancer.

[4]  A. Bellizzi Immunohistochemistry in the diagnosis and classification of neuroendocrine neoplasms: what can Brown do for you? , 2019, Human pathology.

[5]  Peter Schirmacher,et al.  The 2019 WHO classification of tumours of the digestive system , 2019, Histopathology.

[6]  D. Klimstra,et al.  Classification of neuroendocrine neoplasms of the digestive system , 2019 .

[7]  A. Barbieri,et al.  Grading Pancreatic Neuroendocrine Tumors by Ki-67 Index Evaluated on Fine-Needle Aspiration Cell Block Material. , 2019, American journal of clinical pathology.

[8]  He Xiao,et al.  Value of SATB2, ISL1, and TTF1 to differentiate rectal from other gastrointestinal and lung well-differentiated neuroendocrine tumors. , 2019, Pathology, research and practice.

[9]  S. Schulz,et al.  Different somatostatin and CXCR4 chemokine receptor expression in gastroenteropancreatic neuroendocrine neoplasms depending on their origin , 2019, Scientific Reports.

[10]  J. Cates,et al.  Should Ki67 immunohistochemistry be performed on all lesions in multifocal small intestinal neuroendocrine tumours? , 2018, Histopathology.

[11]  Petar Noack,et al.  Accuracy of grading pancreatic neuroendocrine neoplasms with Ki‐67 index in fine‐needle aspiration cellblock material , 2018, Cytopathology : official journal of the British Society for Clinical Cytology.

[12]  Song-Cheol Kim,et al.  Grading by the Ki-67 Labeling Index of Endoscopic Ultrasound–Guided Fine Needle Aspiration Biopsy Specimens of Pancreatic Neuroendocrine Tumors Can Be Underestimated , 2018, Pancreas.

[13]  J. Zedenius,et al.  Regional differences in somatostatin receptor 2 (SSTR2) immunoreactivity is coupled to level of bowel invasion in small intestinal neuroendocrine tumors. , 2018, Neuro endocrinology letters.

[14]  M. Ruchała,et al.  Pasireotide - Mechanism of Action and Clinical Applications. , 2018, Current drug metabolism.

[15]  L. Mazzucchelli,et al.  Mixed Adenoma Well-differentiated Neuroendocrine Tumor (MANET) of the Digestive System: An Indolent Subtype of Mixed Neuroendocrine-NonNeuroendocrine Neoplasm (MiNEN) , 2018, The American journal of surgical pathology.

[16]  A. Vanoli,et al.  Ki67 proliferative index of the neuroendocrine component drives MANEC prognosis. , 2018, Endocrine-related cancer.

[17]  Hong-Jin Kim,et al.  Grading Using Ki-67 Index and Mitotic Rate Increases the Prognostic Accuracy of Pancreatic Neuroendocrine Tumors , 2018, Pancreas.

[18]  W. Ito,et al.  High interlaboratory and interobserver agreement of somatostatin receptor immunohistochemical determination and correlation with response to somatostatin analogs. , 2018, Human pathology.

[19]  R. Luque,et al.  Clinical and functional implication of the components of somatostatin system in gastroenteropancreatic neuroendocrine tumors , 2018, Endocrine.

[20]  Wenchuan Wu,et al.  Clinical relevance of different WHO grade 3 pancreatic neuroendocrine neoplasms based on morphology , 2018, Endocrine connections.

[21]  Xiujun Cai,et al.  Prognostic significance of cytokeratin 19 expression in pancreatic neuroendocrine tumor: A meta-analysis , 2017, PloS one.

[22]  J. Cave,et al.  Clinically Significant Differences in Ki-67 Proliferation Index Between Primary and Metastases in Resected Pancreatic Neuroendocrine Tumors , 2017, Pancreas.

[23]  H. Ono,et al.  Can the Ki-67 Labeling Index in Biopsy Specimens Predict the World Health Organization Grade of Rectal Neuroendocrine Tumors? , 2017, Digestive Diseases.

[24]  A. Vanoli,et al.  KI-67 heterogeneity in well differentiated gastro-entero-pancreatic neuroendocrine tumors: when is biopsy reliable for grade assessment? , 2017, Endocrine.

[25]  P. Illei,et al.  INSM1 Demonstrates Superior Performance to the Individual and Combined Use of Synaptophysin, Chromogranin and CD56 for Diagnosing Neuroendocrine Tumors of the Thoracic Cavity , 2017, The American journal of surgical pathology.

[26]  Laura H. Tang,et al.  Immunohistochemical Characterization of the Origins of Metastatic Well-differentiated Neuroendocrine Tumors to the Liver , 2017, The American journal of surgical pathology.

[27]  T. Morikawa,et al.  Diagnosis, Assessment, and Therapeutic Strategy for Colorectal Mixed Adenoneuroendocrine Carcinoma , 2017, Neuroendocrinology.

[28]  A. Bellizzi,et al.  Increased Grade in Neuroendocrine Tumor Metastases Negatively Impacts Survival , 2017, Annals of Surgical Oncology.

[29]  S. H. Lee,et al.  DAXX/ATRX and MEN1 genes are strong prognostic markers in pancreatic neuroendocrine tumors , 2017, Oncotarget.

[30]  B. Weynand,et al.  Accuracy of Pancreatic Neuroendocrine Tumour Grading by Endoscopic Ultrasound-Guided Fine Needle Aspiration: Analysis of a Large Cohort and Perspectives for Improvement , 2017, Neuroendocrinology.

[31]  S. Fanti,et al.  ENETS Consensus Guidelines for the Standards of Care in Neuroendocrine Tumors: Radiological, Nuclear Medicine and Hybrid Imaging , 2017, Neuroendocrinology.

[32]  M. Pavel,et al.  ENETS Consensus Guidelines for the Standards of Care in Neuroendocrine Tumors , 2017, Neuroendocrinology.

[33]  R. Jensen,et al.  ENETS Consensus Guidelines for the Standards of Care in Neuroendocrine Tumors: Pathology - Diagnosis and Prognostic Stratification , 2017, Neuroendocrinology.

[34]  Minhu Chen,et al.  Somatostatin receptor expression indicates improved prognosis in gastroenteropancreatic neuroendocrine neoplasm, and octreotide long-acting release is effective and safe in Chinese patients with advanced gastroenteropancreatic neuroendocrine tumors , 2017, Oncology letters.

[35]  J. Berlin,et al.  Phase 3 Trial of 177Lu‐Dotatate for Midgut Neuroendocrine Tumors , 2017, The New England journal of medicine.

[36]  W. Weichert,et al.  Somatostatin receptor expression related to TP53 and RB1 alterations in pancreatic and extrapancreatic neuroendocrine neoplasms with a Ki67-index above 20% , 2017, Modern Pathology.

[37]  M. Kloor,et al.  Colorectal mixed adenoneuroendocrine carcinomas and neuroendocrine carcinomas are genetically closely related to colorectal adenocarcinomas , 2017, Modern Pathology.

[38]  N. Fazio,et al.  Heterogeneity of grade 3 gastroenteropancreatic neuroendocrine carcinomas: New insights and treatment implications. , 2016, Cancer treatment reviews.

[39]  P. Ruszniewski,et al.  Gastroenteropancreatic Well-Differentiated Grade 3 Neuroendocrine Tumors: Review and Position Statement. , 2016, The oncologist.

[40]  Xihong Lin,et al.  Association Between Somatostatin Receptor Expression and Clinical Outcomes in Neuroendocrine Tumors , 2016, Pancreas.

[41]  Laura H. Tang,et al.  A Practical Approach to the Classification of WHO Grade 3 (G3) Well-differentiated Neuroendocrine Tumor (WD-NET) and Poorly Differentiated Neuroendocrine Carcinoma (PD-NEC) of the Pancreas , 2016, The American journal of surgical pathology.

[42]  R. Brand,et al.  Alternative Lengthening of Telomeres and Loss of DAXX/ATRX Expression Predicts Metastatic Disease and Poor Survival in Patients with Pancreatic Neuroendocrine Tumors , 2016, Clinical Cancer Research.

[43]  F. Grillo,et al.  Twenty years of gastroenteropancreatic neuroendocrine tumors: is reclassification worthwhile and feasible? , 2016, Endocrine.

[44]  Anthony A. Hyman,et al.  Ki-67 acts as a biological surfactant to disperse mitotic chromosomes , 2016, Nature.

[45]  T. Nagayasu,et al.  Expression of Somatostatin Receptor Type 2A and PTEN in Neuroendocrine Neoplasms Is Associated with Tumor Grade but Not with Site of Origin , 2016, Endocrine Pathology.

[46]  D. Nonaka,et al.  Diagnostic Utility of Orthopedia Homeobox (OTP) in Pulmonary Carcinoid Tumors , 2016, The American journal of surgical pathology.

[47]  F. Sessa,et al.  Mixed Neuroendocrine-Nonneuroendocrine Neoplasms (MiNENs): Unifying the Concept of a Heterogeneous Group of Neoplasms , 2016, Endocrine Pathology.

[48]  P. Ruszniewski,et al.  Anti-tumour effects of lanreotide for pancreatic and intestinal neuroendocrine tumours: the CLARINET open-label extension study , 2016, Endocrine-related cancer.

[49]  M. Sampedro-Núñez,et al.  Presence of sst5TMD4, a truncated splice variant of the somatostatin receptor subtype 5, is associated to features of increased aggressiveness in pancreatic neuroendocrine tumors , 2015, Oncotarget.

[50]  R. Lloyd,et al.  INSM1: A Novel Immunohistochemical and Molecular Marker for Neuroendocrine and Neuroepithelial Neoplasms. , 2015, American journal of clinical pathology.

[51]  R. Fiocca,et al.  Grade Increases in Gastroenteropancreatic Neuroendocrine Tumor Metastases Compared to the Primary Tumor , 2015, Neuroendocrinology.

[52]  M. Daleo,et al.  Discordance of Histologic Grade Between Primary and Metastatic Neuroendocrine Carcinomas , 2015, Annals of Surgical Oncology.

[53]  Michael Goodman,et al.  Calculation of the Ki67 index in pancreatic neuroendocrine tumors: a comparative analysis of four counting methodologies , 2015, Modern Pathology.

[54]  Toby C. Cornish,et al.  Liver metastases of small intestine neuroendocrine tumors: Ki-67 heterogeneity and World Health Organization grade discordance with primary tumors. , 2015, American journal of clinical pathology.

[55]  A. Bellizzi,et al.  A practical method to determine the site of unknown primary in metastatic neuroendocrine tumors. , 2014, Surgery.

[56]  M. V. van Velthuysen,et al.  Grading of Neuroendocrine Neoplasms: Mitoses and Ki-67 Are Both Essential , 2014, Neuroendocrinology.

[57]  M. V. van Velthuysen,et al.  Reliability of Proliferation Assessment by Ki-67 Expression in Neuroendocrine Neoplasms: Eyeballing or Image Analysis? , 2014, Neuroendocrinology.

[58]  A. Krasinskas,et al.  Poorly Differentiated Neuroendocrine Carcinomas of the Pancreas: A Clinicopathologic Analysis of 44 Cases , 2014, The American journal of surgical pathology.

[59]  E. Speel,et al.  Loss of DAXX and ATRX are associated with chromosome instability and reduced survival of patients with pancreatic neuroendocrine tumors. , 2014, Gastroenterology.

[60]  C. Sempoux,et al.  Pancreatic neuroendocrine tumour grading on endoscopic ultrasound‐guided fine needle aspiration: high reproducibility and inter‐observer agreement of the Ki‐67 labelling index , 2013, Cytopathology : official journal of the British Society for Clinical Cytology.

[61]  Toby C. Cornish,et al.  Grading of Well-differentiated Pancreatic Neuroendocrine Tumors Is Improved by the Inclusion of Both Ki67 Proliferative Index and Mitotic Rate , 2013, The American journal of surgical pathology.

[62]  Xiaoyan Zhou,et al.  The Immunohistochemical Expression of Islet 1 and PAX8 by Rectal Neuroendocrine Tumors Should Be Taken into Account in the Differential Diagnosis of Metastatic Neuroendocrine Tumors of Unknown Primary Origin , 2013, Endocrine Pathology.

[63]  A. Bellizzi Assigning Site of Origin in Metastatic Neuroendocrine Neoplasms: A Clinically Significant Application of Diagnostic Immunohistochemistry , 2013, Advances in anatomic pathology.

[64]  T. Smyrk,et al.  Islet-1 Is a Sensitive But Not Entirely Specific Marker for Pancreatic Neuroendocrine Neoplasms and Their Metastases , 2013, The American journal of surgical pathology.

[65]  Laura H. Tang,et al.  Objective Quantification of the Ki67 Proliferative Index in Neuroendocrine Tumors of the Gastroenteropancreatic System: A Comparison of Digital Image Analysis With Manual Methods , 2012, The American journal of surgical pathology.

[66]  Hanlin L. Wang,et al.  Value of Islet 1 and PAX8 in identifying metastatic neuroendocrine tumors of pancreatic origin , 2012, Modern Pathology.

[67]  D. Jain,et al.  PDX-1, CDX-2, TTF-1, and CK7: A Reliable Immunohistochemical Panel for Pancreatic Neuroendocrine Neoplasms , 2012, The American journal of surgical pathology.

[68]  Run Yu,et al.  Ki-67 proliferative index predicts progression-free survival of patients with well-differentiated ileal neuroendocrine tumors. , 2012, Human pathology.

[69]  F. Sessa,et al.  Mixed Adenoneuroendocrine Carcinomas (MANECs) of the Gastrointestinal Tract: An Update , 2012, Cancers.

[70]  A. Sangoi,et al.  PAX8 is expressed in pancreatic well‐differentiated neuroendocrine tumors and in extrapancreatic poorly differentiated neuroendocrine carcinomas in fine‐needle aspiration biopsy specimens , 2011, Cancer cytopathology.

[71]  Michael A. Choti,et al.  DAXX/ATRX, MEN1, and mTOR Pathway Genes Are Frequently Altered in Pancreatic Neuroendocrine Tumors , 2011, Science.

[72]  Andrew H. Beck,et al.  PAX8 expression reliably distinguishes pancreatic well-differentiated neuroendocrine tumors from ileal and pulmonary well-differentiated neuroendocrine tumors and pancreatic acinar cell carcinoma , 2011, Modern Pathology.

[73]  M. Hirsch,et al.  PAX8 Expression in Well-differentiated Pancreatic Endocrine Tumors: Correlation With Clinicopathologic Features and Comparison With Gastrointestinal and Pulmonary Carcinoid Tumors , 2010, The American journal of surgical pathology.

[74]  G. Pelosi,et al.  Somatostatin receptor tissue distribution in lung neuroendocrine tumours: a clinicopathologic and immunohistochemical study of 218 'clinically aggressive' cases. , 2010, Annals of oncology : official journal of the European Society for Medical Oncology.

[75]  C. Lohse,et al.  KIT is an Independent Prognostic Marker for Pancreatic Endocrine Tumors: A Finding Derived From Analysis of Islet Cell Differentiation Markers , 2009, The American journal of surgical pathology.

[76]  Amitabh Srivastava,et al.  Immunohistochemical Staining for CDX-2, PDX-1, NESP-55, and TTF-1 Can Help Distinguish Gastrointestinal Carcinoid Tumors From Pancreatic Endocrine and Pulmonary Carcinoid Tumors , 2009, The American journal of surgical pathology.

[77]  H. Moch,et al.  Islet 1 (Isl1) Expression is a Reliable Marker for Pancreatic Endocrine Tumors and Their Metastases , 2008, The American journal of surgical pathology.

[78]  F. Schmidt Meta-Analysis , 2008 .

[79]  M. Papotti,et al.  Somatostatin receptor type 2A immunohistochemistry in neuroendocrine tumors: a proposal of scoring system correlated with somatostatin receptor scintigraphy , 2007, Modern Pathology.

[80]  C. Capella,et al.  Prognostic and biological significance of cytokeratin 19 in pancreatic endocrine tumours , 2007, Histopathology.

[81]  A. Saqi,et al.  Usefulness of CDX2 and TTF-1 in differentiating gastrointestinal from pulmonary carcinoids. , 2005, American journal of clinical pathology.

[82]  V. Deshpande,et al.  Cytokeratin 19 Is a Powerful Predictor of Survival in Pancreatic Endocrine Tumors , 2004, The American journal of surgical pathology.

[83]  S. Lamberts,et al.  Somatostatin receptors in gastroentero-pancreatic neuroendocrine tumours. , 2003, Endocrine-related cancer.

[84]  L. Aaltonen,et al.  Pathology and genetics of tumours of the digestive system , 2000 .

[85]  S M Powsner,et al.  Clinicians are from Mars and pathologists are from Venus. , 2000, Archives of pathology & laboratory medicine.

[86]  M. Tsuneyoshi,et al.  Malignant smooth muscle tumors of the retroperitoneum and mesentery: A clinicopathologic analysis of 44 cases , 1985, Journal of surgical oncology.

[87]  H. Sorbye,et al.  Predictive and prognostic factors for treatment and survival in 305 patients with advanced gastrointestinal neuroendocrine carcinoma (WHO G3): the NORDIC NEC study. , 2013, Annals of oncology : official journal of the European Society for Medical Oncology.

[88]  G. Petris,et al.  Objective Quantification of the Ki67 Proliferative Index in Neuroendocrine Tumors of the Gastroenteropancreatic System: A Comparison of Digital Image Analysis With Manual Methods , 2013 .

[89]  J. Laissue,et al.  Somatostatin receptor sst1–sst5 expression in normal and neoplastic human tissues using receptor autoradiography with subtype-selective ligands , 2001, European Journal of Nuclear Medicine.

[90]  K. Johnson An Update. , 1984, Journal of food protection.