Abstract
Neuroendocrine neoplasia is described in almost every tissue, either in the pure endocrine organs, the nerve structures or in the so-called diffuse neuroendocrine system. The current nomenclature contains time-honored, widely accepted definitions; however, it is different according to anatomical sites. Diverse definitions may generate confusion and non-standard patient management. The International Agency for Research on Cancer - World Health Organization (IARC-WHO) proposed a framework for universal classification of neuroendocrine neoplasia. Evidence indicates that neuroendocrine cancer is composed by cells with a distinctive phenotype characterized by the expression of general and specific neuroendocrine markers. The neuroendocrine phenotype is indicated as descriptor of a unique cancer category, now recommended for all organs as neuroendocrine neoplasm. Evidence indicates that neuroendocrine neoplasia may be well or poorly differentiated, with diverse incidence and prevalence in different organs. It is proposed that the well-differentiated neoplasm is universally defined as neuroendocrine tumor (NET) and the poorly differentiated as neoplasm neuroendocrine carcinoma (NEC). Evidence indicates that a cancer grading tool based on a proliferation measure by mitotic count, Ki67 % and/or necrosis assessment is useful to predict NET patient behavior. It is proposed to utilize this tool for grading NET universally, with site-specific cut-offs to be defined. It is also acknowledged that significant biological site-specific differences exist. It is recommended that current pathology reports contain this classification together with the current traditional classifiers. This IARC-WHO common classification framework for neuroendocrine neoplasm aims at uniformizing nomenclature toward different organs and at fostering the definition of a similar site-specific gene signature.
Highlights
Endocrine-Related Cancer (2020) 27, R211–R218. It was less than one century ago that Friederich Feyrter proposed the existence of a diffuseendocrine cell system within the human body (Feyrter 1938)
The acid-gastrin-histamine axis is a well-known example of regulatory function supported by neuroendocrine cells at local level
Neuroendocrine cells in the gut develop via a complex gene hierarchy, tightly regulated by local specific physiological stimuli (Gehart et al 2019)
Summary
It was less than one century ago that Friederich Feyrter proposed the existence of a diffuse (neuro)endocrine cell system within the human body (Feyrter 1938). Differentiated NEN displays the highest degree of proliferation rate, is the most aggressive type of neuroendocrine cancer and shares the same risk factors and etiology of non-neuroendocrine cancer when known (e.g. the small cell lung cancer strongly associates with smoking similar to other types of bronchogenic carcinoma). The poorly differentiated high grade NEN has a high degree of gene abnormality most often involving classical drivers including TP53 and Rb (Rekhtman et al 2016, Konukiewitz et al 2017, Shamir et al 2019) This genetic background was consistently found in mixed neuroendocrine, non-neuroendocrine cancers pointing to a common genetic and lineage origin for both components (Jesinghaus et al 2017, Woischke et al 2017). Similar to other cancer types (e.g. adenocarcinoma, squamous cell carcinoma), NEN are recognized as a category variant that has its own specific features (the neuroendocrine phenotype) and can be found almost everywhere in the body. It is expected that site-specific genetic signatures may exist for NEN classes in various organs
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