The classification of neuroendocrine neoplasms of the lung and digestive system according to WHO, 5th edition: similarities, differences, challenges, and unmet needs.

Neuroendocrine neoplasms (NENs) are a group of disease entities sharing common morphological, ultrastructural and immunophenotypical features, yet with distinct biological behavior and clinical outcome, ranging from benign to frankly malignant. Accordingly, a spectrum of therapeutic options for each single entity is available, including somatostatin analogues (SSA), mTOR-inhibitors, peptide receptor radionuclide therapy (PRRT), non-platinum and platinum chemotherapy. In the last few decades, several attempts have been made to better stratify these lesions refining the pathological classifications, so as to obtain an optimal correspondence between the scientific terminology and, the predictive and prognostic features of each disease subtype, and achieve a global Classification encompassing NENs arising at different anatomical sites. The aim of this review was to analyze, compare and discuss the main features and issues of the latest WHO Classifications of NENs of the lung and the digestive system, in order to point out the strengths and limitations of our current understanding of these complex diseases.

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

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.

Diagnosis of digestive system tumours.

The WHO Classification of Tumours provides the international standards for the classification and diagnosis of tumours. It enables direct comparisons to be made between different countries. In the new fifth edition, the series has gone digital with the launch of a website as well as a series of books, known widely as the WHO Blue Books. The first volume to be produced is on the classification of Digestive System tumours, replacing the successful 2010 version. It has been rewritten and updated accordingly. This article summarises the major diagnostic innovations that have occurred over the last decade and that have now been incorporated in the classification. As an example, it incorporates the recently proposed classification of neuroendocrine tumours, based on the recognition that neuroendocrine tumours and carcinomas differ substantially in the genetic abnormalities that drive their growth, findings relevant to treatment selection and outcome prediction. Several themes have emerged during the production process. One is the importance of the progression from hyperplasia to dysplasia to carcinoma in the evolution of the malignant process. Advances in imaging techniques and endoscopy have resulted in enhanced access to precancerous lesions in the gastrointestinal and biliary tract, necessitating both changes in classification schema and clinical practice. Diagnosis of tumours is no longer the sole purview of pathologists, and some patients now receive treatment before tissue is obtained, based on clinical, radiological and liquid biopsy results. This makes the classification relevant to many disciplines involved in the care of patients with tumours of the digestive system.

Recent Advances in Digestive Tract Tumors: Updates From the 5th Edition of the World Health Organization "Blue Book".

CONTEXT.­: The World Health Organization Classification of Tumours: Digestive System Tumors, 5th edition, was published in 2019 and shows several impactful changes as compared with the 4th edition published in 2010. Changes include a revised nomenclature of serrated lesions and revamping the classification of neuroendocrine neoplasms. Appendiceal goblet cell adenocarcinoma is heavily revised, and intrahepatic cholangiocarcinoma is split into 2 subtypes. New subtypes of colorectal carcinoma and hepatocellular carcinoma are described. Precursor lesions are emphasized with their own entries, and both dysplastic and invasive lesions are generally recommended to be graded using a 2-tier system. Hematolymphoid tumors, mesenchymal tumors, and genetic tumor syndromes each have their own sections in the 5th edition. New hematolymphoid lesions include monomorphic epitheliotropic intestinal T-cell lymphoma; duodenal-type follicular lymphoma; intestinal T-cell lymphoma, not otherwise specified; and indolent T-cell lymphoproliferative disorder of the gastrointestinal tract. This paper will provide an in-depth look at the changes in the 5th edition as compared with the 4th edition. OBJECTIVE.­: To provide a comprehensive, in-depth update on the World Health Organization classification of digestive tumors, including changes to nomenclature, updated diagnostic criteria, and newly described entities. DATA SOURCES.­: The 5th edition of the World Health Organization Classification of Tumours: Digestive System Tumours, as well as the 4th edition. CONCLUSIONS.­: The World Health Organization has made many key changes in its newest update on tumors of the digestive system. Pathologists should be aware of these changes and incorporate them into their practice as able or necessary.

Gastrointestinal tissue-based molecular biomarkers: a practical categorisation based on the 2019 World Health Organization classification of epithelial digestive tumours.

Molecular biomarkers have come to constitute one of the cornerstones of oncological pathology. The method of classification not only directly affects the manner in which patients are diagnosed and treated, but also guides the development of drugs and of artificial intelligence tools. The aim of this article is to organise and update gastrointestinal molecular biomarkers in order to produce an easy-to-use guide for routine diagnostics. For this purpose, we have extracted and reorganised the molecular information on epithelial neoplasms included in the 2019 World Health Organization classification of tumours. Digestive system tumours, 5th edn.

A review of changes to and clinical implications of the eighth TNM classification of hepatobiliary and pancreatic cancers.

Hepatobiliary and pancreatic cancers have poor outcomes. Clinical staging is useful for predicting survival and selecting treatment options. The 8th edition of tumor-node metastasis (TNM) was published in 2016 and came into effect from 2018. Regarding liver cancer (hepatocellular carcinoma), tumour size and vascular invasion were more emphasized adding numbers. Tumour size was included for intrahepatic cholangiocarcinoma. T2 for gallbladder cancer was divided into two categories based on the side of invasion, and lymph node metastasis was classified according to the number of lymph nodes, not the site. The N category for perihilar cholangiocarcinoma was changed to the same as that for gallbladder cancer (total number of regional lymph nodes). The depth of tumour invasion using cut-off values of 5 and 12 mm was adopted as the T category for distal cholangiocarcinoma. The N category was also changed (the total number of regional lymph nodes). Regarding cancer of the ampulla of Vater, the T category was classified in more detail and the N category was also changed to the total number of regional lymph nodes. T1 for pancreatic cancer was separated into T1 subcategories (T1a, T1b and T1c) based on cut-off values of 5 and 10 mm. T1-T3 were classified with cut-off values of ≤2 cm, >2 to 4 cm and >4 cm. Furthermore, the N category was changed to the total number of regional lymph nodes. Although there are limitations due to treatment decisions only being based on imaging interpretation, this classification predicts the prognosis of patients more accurately than the previous edition.

Lung and digestive neuroendocrine neoplasms. From WHO classification to biomarker screening: Which perspectives?

The recent classifications of lung and digestive neuroendocrine neoplasms (NENs) make a fundamental distinction between well- and poorly-differentiated neoplasms. Well-differentiated NENs are termed carcinoids in the lung and neuroendocrine tumors in the gastroenteropancreatic sphere; their risk of malignancy is highly variable; histological grading is used to stratify patients into prognostically significant groups. Poorly-differentiated NENs are termed neuroendocrine carcinoma in both the lung and the digestive sphere; they constantly are of high grade of malignancy; two types are recognized on the basis of tumor cell morphology, the small cell and the large cell types. Recent studies have largely uncovered the genetic landscape of several subsets of well-differentiated NENs (lung, pancreas, small intestine) and of poorly-differentiated NENs. Some molecular markers may help to the differential diagnosis between highly proliferative neuroendocrine tumors and neuroendocrine carcinomas, especially in the pancreas. In well-differentiated tumors, MGMT status is proposed as a predictive marker of the response to temozolomide, but remains to be validated. In poorly-differentiated neoplasms, large cell neuroendocrine carcinoma has been shown to be a heterogeneous category, with some cases presenting the same molecular signature than small cell carcinoma and others the same signature than adenocarcinomas of the same body site. Rb protein has been recently shown to be a potential marker of response to platinum salts in neuroendocrine carcinoma. Much remains to be done to translate the rapid progress in the molecular understanding of NENS into diagnostic, prognostic or predictive markers.

Aspects regarding nomenclature, classification and pathology of neuroendocrine neoplasms of the digestive system - a review.

Neuroendocrine neoplasms (NENs) of the digestive system are composed of cells with a neuroendocrine phenotype. These tumors produce and secrete peptide hormones and biogenic amines and they are called neuroendocrine neoplasms because of the marker proteins that they share with the neural cell system. The classification and nomenclature used to designate NENs have undergone changes over the past decades due to the accumulation of evidence related to the biological characteristics and their evolution. The European Neuroendocrine Tumor Society (ENETS) proposed a classification system based on the tumor grading and staging according to their localization. The latest internationally recognized NEN classification was published by the World Health Organization (WHO) in 2010. In accordance with the 2010 WHO criteria, the determination of the NEN malignancy potential is based on grading, depending on the mitotic activity and the Ki67 proliferation index, as well as on the tumor TNM stage. It is worth emphasizing that the terms neuroendocrine tumor (NET) and neuroendocrine carcinoma (NEC), without reference to grading or differentiation, are inadequate for prognostic assessment or the therapy determination, being inappropriate in pathology reports. The functional status of the tumor is based on the clinical findings but not on the pathological data or immunohistochemically profile. Despite the inability to establish a single system of sites, these are common features to establish the basis of most systems, documentation of these features allowing for greater reliability in the pathology reporting of these neoplasms.

Prognostic significance of pretreatment plasma fibrinogen level in patients with digestive system tumors: a meta-analysis.

High pretreatment levels of plasma fibrinogen have been widely reported to be a potential predictor of prognosis in digestive system tumors; however, the conclusions are not consistent. Therefore, we performed a meta-analysis to comprehensively assess the prognostic roles of high pretreatment plasma fibrinogen levels in digestive system tumors. We searched for eligible studies in the PubMed, Embase, and Web of Science electronic databases for publications from the database inception to 1 September 2017. The endpoints of interest included overall survival, disease-free survival, and recurrence-free survival. We investigated the relationship between fibrinogenemia and overall survival in colorectal cancer (10 studies), gastric cancer (6), pancreatic cancer (6), hepatocellular carcinoma (7), and esophageal squamous cell carcinoma (10); the pooled results indicated that fibrinogenemia was significantly related to a worse overall survival (hazard ratio (HR) 1.73; 95% confidence interval (CI) 1.52, 1.97; P <0.001; HR 1.71; 95% CI 1.28, 2.28; P <0.001; HR 1.57; 95% CI 1.13, 2.17; P = 0.007; HR 1.89; 95% CI 1.57, 2.27; P <0.001, and HR 1.67; 95% CI 1.35, 2.07; P <0.001). Taken together, an increased pretreatment plasma fibrinogen level was related to worse survival in digestive system tumors, indicating that it could be a useful prognostic marker in these types of tumors.

Unusual Sites of High-Grade Neuroendocrine Carcinomas: A Case Series and Review of the Literature.

BACKGROUND Neuroendocrine tumors (NETs) encompass a diverse group of varying clinicopathological entities arising from cells of the endocrine and nervous systems. The presentation of these unique tumors can range from occult disease discovered incidentally to hyperactive, metastatic secretory tumors. NETs most commonly originate in the gastrointestinal and respiratory tract, although they may occur at any site in the body due to the wide distribution of neuroendocrine cells. Their classification system is complex and continues to evolve, and the current system uses histological grade in defining these subtypes. Neuroendocrine carcinomas (NECs), or high-grade, poorly-differentiated NETs, are the most aggressive subtype. Surgical resection remains the primary treatment modality and may be curative, thus early diagnosis is paramount. Management of advanced NETs remains both a diagnostic and therapeutic challenge; however, advances in our understanding of these unique neoplasms as well as an evolving classification system has led to the development of adjunctive therapeutic approaches aimed to minimize morbidity and improve patient outcomes. CASE REPORT We present 6 cases of unusual sites of high-grade neuroendocrine carcinomas involving the cervix, gallbladder, oesophagus, ovary, prostate, and urinary bladder. CONCLUSIONS Our case series highlights the heterogenous and aggressive nature of this subtype of NETs as well as their diagnostic and therapeutic difficulties. We also review the evolution of the NET classification system and its impact on the management of these malignancies.

[Pathology of the R1 classification in visceral cancer surgery]. / Pathologie der R1-Klassifikation in der viszeralonkologischen Chirurgie.

The completeness of tumor removal is described in the residual tumor classification (R classification). The R category of a surgical specimen reflects the effects of treatment, influences further treatment decisions and is associated with patient survival. Thorough pathological examination of all resection planes, including the circumferential margin, is necessary for accurate classification.

Digestive neuroendocrine neoplasms: A 2016 overview.

Digestive neuroendocrine neoplasms (DNENs) have an incidence of 2.39 per 100,000 inhabitants per year, and a prevalence of 35 cases per 100,000; the gap between these rates is to be referred to the relatively long survival that characterizes the majority of these tumors, which can be thus considered as chronic oncological diseases. Up to 80% of patients are stage IV since the first diagnosis, presenting a 5-yr overall survival rate of 35%-55% and a twice higher mortality than limited disease. DNENs express somatostatin receptors in more than 80% of cases, detected through immunohistochemistry or functional imaging tests (FITs). This feature identifies patients who may benefit from "cold" somatostatin analogs (SSAs) or peptide receptors radionuclide therapy, although SSAs are sometimes used also with a negative uptake at FITs. The therapeutic options have been recently increased after the identification of molecular pathways involved in DNENs pathogenesis, and the subsequent use of targeted therapies (i.e., Everolimus and Sunitinib) for these neoplasms. This review offers an overview about pancreatic and small bowel NENs, critically underlining the issues that still need to be clarified and the future perspectives to be investigated.

Digestive neuroendocrine tumors: reclassifying of 26 cases according to 2010 who classification.

BACKGROUND: The classification of digestive neuroendocrine tumors is difficult due to their heterogeneity and rareness. AIMS: Reclassify the digestive neuroendocrine tumors according  to  the  WHO-2010 classification .  Methods: A retrospective study included   26 patients having digestive neuroendocrine     tumors ,  is achieved  in our  Pathology  Laboratory  of the Military Hospital of  Tunis between 2000 and 2013. RESULTS: The mean age of patients was 49.64 years. The Sex ratio was  1.36. It was 6 gastric tumors, 5 small intestine tumors , 5 pancreatic tumors, 5  appendix tumors , one hypatic tumor, one  gall bladder  tumor , one rectal tumor and one colon tumor. According to the WHO -2000 classification, tumors are categorised into 11 well differentiated  endocrine tumors, 13 well differentiated  endocrine carcinoma  and 2 poorly differentiated carcinoma . According to the WHO -2010 classification, tumors were re-evaluated as  16 neuroendocrine tumors grade 1, 6 neuroendocrine tumors grade 2 and 4 neuroendocrine carcinoma . CONCLUSION: There was a concordance between the two classifications in 93% of cases. The WHO -2010 classification may allow a  better classification for the digestive neuroendocrine tumors, however there are some histological categories that remained difficult to classify.

Digestive neuroendocrine tumors: reclassifying of 26 cases according to 2010 who classification.

BACKGROUND: The classification of digestive neuroendocrine tumors is difficult due to their heterogeneity and rareness. AIMS: Reclassify the digestive neuroendocrine tumors according  to  the  WHO-2010 classification .  Methods: A retrospective study included   26 patients having digestive neuroendocrine     tumors ,  is achieved  in our  Pathology  Laboratory  of the Military Hospital of  Tunis between 2000 and 2013. RESULTS: The mean age of patients was 49.64 years. The Sex ratio was  1.36. It was 6 gastric tumors, 5 small intestine tumors , 5 pancreatic tumors, 5  appendix tumors , one hypatic tumor, one  gall bladder  tumor , one rectal tumor and one colon tumor. According to the WHO -2000 classification, tumors are categorised into 11 well differentiated  endocrine tumors, 13 well differentiated  endocrine carcinoma  and 2 poorly differentiated carcinoma . According to the WHO -2010 classification, tumors were re-evaluated as  16 neuroendocrine tumors grade 1, 6 neuroendocrine tumors grade 2 and 4 neuroendocrine carcinoma . CONCLUSION: There was a concordance between the two classifications in 93% of cases. The WHO -2010 classification may allow a  better classification for the digestive neuroendocrine tumors, however there are some histological categories that remained difficult to classify.

The 2010 WHO classification of digestive neuroendocrine neoplasms: a critical appraisal four years after its introduction.

This paper briefly illustrates the basis, rules of application, and present outcome of the current World Health Organization (WHO) classification for neuroendocrine neoplasms. Established in 2010 upon the proposal from the European Neuroendocrine Tumor Society (ENETS), the WHO 2010 fostered some definitional changes (most notably the use of neuroendocrine tumor (NET) instead of carcinoid) and indicated the tools of grading and staging. Specific rules for its application were also defined. The data generated from the use of WHO 2010 classification substantially endorsed its rules and prognostic efficacy. In addition, the application demonstrated some issues, among which are the possible re-definition of the cutoff for grading G1 vs G2, as well as the possible identification of cases with somewhat different clinical behavior within the G3 neuroendocrine cancer class. Overall, since the recent introduction of WHO 2010 grading and staging, it appears wise to keep the current descriptors to avoid unnecessary confusion and to generate comparable data. Homogenous data on large series are ultimately needed to solve such issues.

[Neuroendocrine tumors of digestive system: morphologic spectrum and cell proliferation (Ki67 index)].

This review deals with the analysis of up-to-date concepts ofdiferent types of human neuroendocrine tumors of the digestive system. It summarizes the information on the specifics of recent histological classifications and criteria of morphological diagnosis accounting histological, ultrastructural and immunohistochemical parameters. Current issues of the nomenclature as well as various systems of grading and staging are discussed. In the light of these criteria the results of the own research clinical value of the determination of cell proliferation in primary and metastatic gastroenteropancreatic neuroendocrine neoplasms on the basis of evaluation of the Ki67 antigen expression are also presented.

[Aero-digestive tract squamous intra-epithelial neoplasia]. / Néoplasie intra-épithéliale épidermoïde des voies aéro-digestives supérieures.

Aero-digestive tract squamous intra-epithelial neoplasia is a disease whose genetic and epigenetic features lead to clinical signs and well codified histologic features. This publication aims to review the molecular alterations which have been identified in these lesions, to clarify the clinical manifestations and to discuss the proposed histological classification.