Inherited Neuroendocrine Neoplasms

Mete, Özgür; Hannah‐Shmouni, Fady; Kim, Raymond H.; Stratakis, Constantine A.

doi:10.1007/978-3-030-54391-4_18

Cited by 9 publications

(8 citation statements)

References 187 publications

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“…The new section on NENs in non-endocrine organs includes a broad discussion of well-differentiated neuroendocrine tumors (NETs) that occur in the gastrointestinal tract, lung, upper airways, urogenital system, breast, and skin (Table 2). While these are not always the source of clinically relevant hormone excess, they can be associated with hereditary syndromes and thus may be multifocal disorders, both within a given organ/system or in other sites [33]. The features of poorly differentiated NECs in all sites, like in the pancreas, result in a classification as small cell and large cell types, as well as Merkel cell carcinoma that is distinct.…”

Section: Question 1: Are There Any Nomenclature Changes or Any New Di...mentioning

confidence: 99%

“…Most of the syndromes involve multiple organs. It is now recognized that these syndromes are associated with precursor lesions that allow the expert pathologist to make the diagnosis based on morphology [145,172], and in some situations, molecular immunohistochemistry allows confirmation of the exact diagnosis [33].…”

Section: Question 11: What Are Spinal Middle Ear Neuroendocrine Tumor...mentioning

confidence: 99%

“…Patients with MEN1 and MEN4, hyperparathyroidismjaw tumor syndrome, CDC73-related familial isolated hyperparathyroidism, and SDH-deficient tumor syndromes can be diagnosed using molecular immunohistochemistry to document loss of a tumor suppressor [33]. Stains for menin (Fig.…”

Section: Question 11: What Are Spinal Middle Ear Neuroendocrine Tumor...mentioning

confidence: 99%

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Overview of the 2022 WHO Classification of Neuroendocrine Neoplasms

et al. 2022

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In this review, we detail the changes and the relevant features that are applied to neuroendocrine neoplasms (NENs) in the 2022 WHO Classification of Endocrine and Neuroendocrine Tumors. Using a question-and-answer approach, we discuss the consolidation of the nomenclature that distinguishes neuronal paragangliomas from epithelial neoplasms, which are divided into well-differentiated neuroendocrine tumors (NETs) and poorly differentiated neuroendocrine carcinomas (NECs). The criteria for these distinctions based on differentiation are outlined. NETs are generally (but not always) graded as G1, G2, and G3 based on proliferation, whereas NECs are by definition high grade; the importance of Ki67 as a tool for classification and grading is emphasized. The clinical relevance of proper classification is explained, and the importance of hormonal function is examined, including eutopic and ectopic hormone production. The tools available to pathologists for accurate classification include the conventional biomarkers of neuroendocrine lineage and differentiation, INSM1, synaptophysin, chromogranins, and somatostatin receptors (SSTRs), but also include transcription factors that can identify the site of origin of a metastatic lesion of unknown primary site, as well as hormones, enzymes, and keratins that play a role in functional and structural correlation. The recognition of highly proliferative, well-differentiated NETs has resulted in the need for biomarkers that can distinguish these G3 NETs from NECs, including stains to determine expression of SSTRs and those that can indicate the unique molecular pathogenetic alterations that underlie the distinction, for example, global loss of RB and aberrant p53 in pancreatic NECs compared with loss of ATRX, DAXX, and menin in pancreatic NETs. Other differential diagnoses are discussed with recommendations for biomarkers that can assist in correct classification, including the distinctions between epithelial and non-epithelial NENs that have allowed reclassification of epithelial NETs in the spine, in the duodenum, and in the middle ear; the first two may be composite tumors with neuronal and glial elements, and as this feature is integral to the duodenal lesion, it is now classified as composite gangliocytoma/neuroma and neuroendocrine tumor (CoGNET). The many other aspects of differential diagnosis are detailed with recommendations for biomarkers that can distinguish NENs from nonneuroendocrine lesions that can mimic their morphology. The concepts of mixed neuroendocrine and non-neuroendocrine (MiNEN) and amphicrine tumors are clarified with information about how to approach such lesions in routine practice. Theranostic biomarkers that assist patient management are reviewed. Given the significant proportion of NENs that are associated with germline mutations that predispose to this disease, we explain the role of the pathologist in identifying precursor lesions and applying molecular immunohistochemistry to guide genetic testing.

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Section: Question 1: Are There Any Nomenclature Changes or Any New Di...mentioning

confidence: 99%

Section: Question 11: What Are Spinal Middle Ear Neuroendocrine Tumor...mentioning

confidence: 99%

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Overview of the 2022 WHO Classification of Neuroendocrine Neoplasms

et al. 2022

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Section: Introductionmentioning

confidence: 99%

“…Most pulmonary and thymic neuroendocrine tumors (carcinoid tumors) are associated with sporadic disease; thus, only a small fraction is currently linked to germline susceptibility [ 74 ]. The age of the patient at time of diagnosis, personal, and/or family history for inherited endocrine tumor syndromes or tumors that may be seen in association with various neuroendocrine neoplasms, cytomorphological findings, and molecular immunohistochemical biomarkers are all important parameters that might prompt diagnosticians to search for a potential underlying germline disease in neuroendocrine neoplasia [ 74 ]. Similar to other anatomic sites, the accurate distinction of paragangliomas (non-epithelial neuroendocrine neoplasms of paraganglia) from their epithelial counterparts is of significance since primary pulmonary and mediastinal paragangliomas are more frequently associated with germline alterations [ 75 ] compared with thoracic (pulmonary and thymic) neuroendocrine tumors.…”

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confidence: 99%

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

et al. 2021

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Thoracic (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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