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Neuroendocrine neoplasia of the gastrointestinal tract revisited: towards precision medicine

Abstract

Over the past 5 years, a number of notable research advances have been made in the field of neuroendocrine cancer, specifically with regard to neuroendocrine cancer of the gastrointestinal tract. The aim of this Review is to provide an update on current knowledge that has proven effective for the clinical management of patients with these tumours. For example, for the first time in the tubular gastrointestinal tract, well-differentiated high-grade (grade 3) tumours and mixed neuroendocrine–non-neuroendocrine neoplasms (MiNENs) are defined in the WHO classification. This novel classification enables efficient identification of the most aggressive well-differentiated neuroendocrine tumours and helps in defining the degree of aggressiveness of MiNENs. The Review also discusses updates to epidemiology, cell biology (including vesicle-specific components) and the as-yet-unresolved complex genetic background that varies according to site and differentiation status. The Review summarizes novel diagnostic instruments, including molecules associated with the secretory machinery, novel radiological approaches (including pattern recognition techniques), novel PET tracers and liquid biopsy combined with DNA or RNA assays. Surgery remains the treatment mainstay; however, peptide receptor radionuclide therapy with novel radioligands and new emerging medical therapies (including vaccination and immunotherapy) are evolving and being tested in clinical trials, which are summarized and critically reviewed here.

Key points

  • Neuroendocrine neoplasms (NENs) are made up of two separate groups, well-differentiated, termed neuroendocrine tumour (NET), and poorly differentiated, termed neuroendocrine carcinoma (NEC).

  • WHO 2019 classification of gut NENs grades NETs as grade 1 to grade 3 based on tumour morphology, tumour cell proliferation measured in terms of the Ki67 proliferation index and/or the mitotic count, whereas NECs are by definition grade 3.

  • The genetic landscape of gut NETs is poorly understood and mainly involves chromosomal alterations combined with epigenetic changes.

  • Novel diagnostic approaches include neuroendocrine tissue markers, liquid biopsy for multigene detection, radiomics with computer-assisted diagnosis for CT and MRI, PET and novel endoscopy approaches including operational video capsule endoscopy.

  • Novel therapies include tyrosine kinase inhibitors, immunotherapy, vaccination, surgical debulking and locoregional treatments.

  • Research effort should target the personalized management of patients with NEN exploring the relationship between genetic background, NEN development and tumour response to therapy.

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Fig. 1: Neuroendocrine cell secretion properties, control and neuroendocrine neoplasia.
Fig. 2: The relationship between size of primary neuroendocrine neoplasia and metastasis.

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Acknowledgements

The authors acknowledge the support of internal university grant (Università Cattolica line D.1 2017-R412500403) to G.R. and the WILL Foundation and generous donation in memoriam “Sören Piepgras” to B.W. We are grateful to C. Klersy, Clinical Epidemiology and Biometry, IRCCS Fondazione Policlinico San Matteo, Pavia, Italy, for generous and skilled statistical work on published databases and to M. Sigal, Department of Molecular Biology, Max Planck Institute for Infection Biology, Berlin, Germany, T. Penzkofer, Department of Radiology, Charité - Universitätsmedizin Berlin, Germany, L. Hammerich, Department of Medicine, Charité - Universitätsmedizin Berlin, Germany and R. Baum, THERANOSTICS Centre for Molecular Radiotherapy and Molecular Imaging, Zentralklinik Bad Berka, Germany for critical revision and helpful suggestions.

Review criteria

A search for original articles published between 1980 and 2019 focusing on neuroendocrine neoplasms was performed in MEDLINE and PubMed. The search terms used were “carcinoids”, “endocrine tumours”, “neuroendocrine tumours”, “neuroendocrine carcinoma” AND “gastrointestinal tract”, as well as AND “epidemiology”, “genetics”, “molecular biology”, “imaging”, “medical therapy”, “surgery” and “PRRT”. Also, a specific search was done on “gastrointestinal tract” AND “neuroendocrine cells” AND “SNARE proteins”, “secretion”, “signal transduction”, “development “, “organoid”, “single cell RNA”, “transcription factors” and “lineage specification”. All papers identified were English-language, full-text papers. We also searched the reference lists of identified articles for further papers.

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Correspondence to Guido Rindi.

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Rindi, G., Wiedenmann, B. Neuroendocrine neoplasia of the gastrointestinal tract revisited: towards precision medicine. Nat Rev Endocrinol 16, 590–607 (2020). https://doi.org/10.1038/s41574-020-0391-3

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