A common classification framework for neuroendocrine neoplasms: an International Agency for Research on Cancer (IARC) and World Health Organization (WHO) expert consensus proposal

Abstract

The classification of neuroendocrine neoplasms (NENs) differs between organ systems and currently causes considerable confusion. A uniform classification framework for NENs at any anatomical location may reduce inconsistencies and contradictions among the various systems currently in use. The classification suggested here is intended to allow pathologists and clinicians to manage their patients with NENs consistently, while acknowledging organ-specific differences in classification criteria, tumor biology, and prognostic factors. The classification suggested is based on a consensus conference held at the International Agency for Research on Cancer (IARC) in November 2017 and subsequent discussion with additional experts. The key feature of the new classification is a distinction between differentiated neuroendocrine tumors (NETs), also designated carcinoid tumors in some systems, and poorly differentiated NECs, as they both share common expression of neuroendocrine markers. This dichotomous morphological subdivision into NETs and NECs is supported by genetic evidence at specific anatomic sites as well as clinical, epidemiologic, histologic, and prognostic differences. In many organ systems, NETs are graded as G1, G2, or G3 based on mitotic count and/or Ki-67 labeling index, and/or the presence of necrosis; NECs are considered high grade by definition. We believe this conceptual approach can form the basis for the next generation of NEN classifications and will allow more consistent taxonomy to understand how neoplasms from different organ systems inter-relate clinically and genetically.

SATB2 in neuroendocrine neoplasms: strong expression is restricted to well‐differentiated tumours of lower gastrointestinal tract origin and is most frequent in Merkel cell carcinoma among poorly differentiated carcinomas

“…The parotid tumour failed to express TTF‐1 or CK20, and showed null pattern staining for p53 and total Rb. As with the lung tumour, the results of p53 and total Rb immunostaining suggest biallelic inactivation of these tumour suppressors, which is the genetic hallmark of small‐cell lung cancer and is frequently encountered in other visceral NECs but is not typical of Merkel cell carcinoma . The uterine cervical tumour was, again, TTF‐1‐negative and CK20‐negative, and showed null pattern p53 and wild‐type pattern total Rb staining.…”

“…This pattern would be typical of an adenocarcinoma, in which p53 inactivation is frequent and Rb inactivation is uncommon. A subset of NECs, including many large‐cell NECs of lung origin and extrapulmonary visceral NECs, bear genetic signatures similar to that of the non‐NECs that arise at that site . The vaginal tumour was TTF‐1‐negative, was modestly positive for CK20 (H‐score of 83), and showed p53 null pattern staining.…”

Experience and future perspectives on the use of the Papanicolaou Society of Cytopathology Terminology System for reporting pancreaticobiliary cytology

“…Further studies aiming at the impact of such subclassification among IPMNs may warrant a specific place for this oncocytic variant inside the Neoplastic: Other category. For neuroendocrine tumors, the recent guidelines for classification and grading may also have an impact on the cytological categorization of such lesions . It has been proposed that neuroendocrine tumors should be graded in three tiers, with mitotic count ideally expressed as mitoses per mm 2 area, counted in up to 10 mm 2 .…”

Advances in the cytologic diagnosis of gastroenteropancreatic neuroendocrine neoplasms

“…NECs have high proliferative activity and include small‐cell, large‐cell, and mixed neuroendocrine and non‐neuroendocrine types. Most recently, expert opinion is that grade is not necessary for neuroendocrine carcinomas, because they are all high grade . In contrast, NETs have a 3‐tier grading system (grades 1‐3) based on proliferative activity (Table ).…”

“…The second relatively minor change in the 2017 WHO classification is that the Ki67 index range for grade 1 was changed to <3% from ≤2%. Although a 3‐tiered grading of tumors from the 2010 WHO classification system is currently the used for nonpancreatic gastrointestinal neuroendocrine neoplasms (Table ), the system will be revised in the anticipated fifth edition of the WHO Classification of Gastrointestinal Tumors , and there is a consensus proposal to extend the same classification framework to neuroendocrine neoplasms of all anatomic sites …”