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  • Review Article
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Towards a new classification of gastroenteropancreatic neuroendocrine neoplasms

Nature Reviews Clinical Oncology volume 13, pages 691–705 (2016)Cite this article

Subjects

Key Points

  • Neuroendocrine neoplasms (NENs) constitute a heterogeneous group of tumours that are each associated with varying clinical presentations, a different likelihood of progression, and a distinct prognosis

  • The 2010 WHO classification of NENs stratifies disease into NEN grade 1, NEN grade 2, neuroendocrine carcinoma (NEC) grade 3; this classification forms the basis of current treatment guidelines

  • Molecular profiling of tissue specimens is increasingly performed in clinical practice and provides information on genetic aberrations of potential therapeutic relevance; although with limited clinical value to date

  • The 'driver' mutations in gastroenteropancreatic NENs, which might be important targets for new therapies, remain to be identified; however, the PI3K/AKT/mTOR axis has been identified as a key oncogenic signalling pathway

  • NENs can be treated using mTOR inhibitors (rapalogs including everolimus and temsirolimus), but resistance eventually develops via escape mechanisms that warrant further investigation in order to develop novel therapeutic strategies

  • The 2010 WHO classification will continue to guide the management of NENs; however, information from molecular profiling of tumours, 'liquid biopsies' (including circulating mRNA measurements), and molecular imaging might improve patient outcomes

Abstract

Gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) constitute a heterogeneous group of tumours associated with variable clinical presentations, growth rates, and prognoses. To improve the management of GEP-NENs, the WHO developed a classification system that enables tumours to be graded based on markers of cell proliferation in biopsy specimens. Indeed, histopathology has been a mainstay in the diagnosis of GEP-NENs, and the WHO grading system facilitates therapeutic decision-making; however, considerable intratumoural heterogeneity, predominantly comprising regional variations in proliferation rates, complicates the evaluation of tumour biology. The use of molecular imaging modalities to delineate the most-aggressive cell populations is becoming more widespread. In addition, molecular profiling is increasingly undertaken in the clinical setting, and genomic studies have revealed a number of chromosomal alterations in GEP-NENs, although the 'drivers' of neoplastic development have not been identified. Thus, our molecular understanding of GEP-NENs remains insufficient to inform on patient prognosis or selection for treatments, and the WHO classification continues to form the basis for management of this disease. Nevertheless, our increasing understanding of the molecular genetics and biology of GEP-NENs has begun to expose flaws in the WHO classification. We describe the current understanding of the molecular characteristics of GEP-NENs, and discuss how advances in molecular profiling measurements, including assays of circulating mRNAs, are likely to influence the management of these tumours.

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Figure 1: The evolution of molecular classification systems for cancers.
Figure 2: Menin a major regulator of signalling in neuroendocrine neoplasms (NEN).
Figure 3: Points of interaction between the PI3K/AKT/mTOR and RAS/RAF/MEK/MAPK pathways.

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Acknowledgements

The authors thank Xia Chu of the University of Uppsala, Sweden, for his assistance in developing Fig. 2.

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Authors and Affiliations

  1. Department of Surgery, Yale University School of Medicine, 333 Cedar Street, New Haven, 06519, Connecticut, USA

    Mark Kidd & Irvin Modlin

  2. Department of Endocrine Oncology, Uppsala University Hospital, Entrance 40, 5th floor, Uppsala, SE-751 85, Sweden

    Kjell Öberg

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I.M. is a consultant to Wren Laboratories, a subsidiary of Clifton Life Sciences. M.K. and K.Ö. declare no competing interests.

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Kidd, M., Modlin, I. & Öberg, K. Towards a new classification of gastroenteropancreatic neuroendocrine neoplasms. Nat Rev Clin Oncol 13, 691–705 (2016). https://doi.org/10.1038/nrclinonc.2016.85

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