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  • Review article
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Neuroendocrine neoplasms of the lung and gastrointestinal system: convergent biology and a path to better therapies

Nature Reviews Clinical Oncology volume 20, pages 16–32 (2023)Cite this article

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Abstract

Neuroendocrine neoplasms (NENs) can develop in almost any organ and span a spectrum from well-differentiated and indolent neuroendocrine tumours (NETs) to poorly differentiated and highly aggressive neuroendocrine carcinomas (NECs), including small-cell lung cancer (SCLC). These neoplasms are thought to primarily derive from neuroendocrine precursor cells located throughout the body and can also arise through neuroendocrine transdifferentiation of organ-specific epithelial cell types. Hence, NENs constitute a group of tumour types that share key genomic and phenotypic characteristics irrespective of their site of origin, albeit with some organ-specific differences. The establishment of representative preclinical models for several of these disease entities together with analyses of human tumour specimens has provided important insights into crucial aspects of their biology with therapeutic implications. In this Review, we provide a comprehensive overview of the current understanding of NENs of the gastrointestinal system and lung from clinical and biological perspectives. Research on NENs has typically been siloed by the tumour site of origin, and a cross-cutting view might enable advances in one area to accelerate research in others. Therefore, we aim to emphasize that a better understanding of the commonalities and differences of NENs arising in different organs might more effectively inform clinical research to define therapeutic targets and ultimately optimize patient care.

Key points

  • Neuroendocrine neoplasms are categorized as either neuroendocrine tumours (NETs) or neuroendocrine carcinomas (NECs) characterized by markedly different proliferative rates.

  • Slow-growing NETs share key biological characteristics across different sites of origin.

  • NECs are aggressive cancers that almost always have inactivation of the tumour-suppressor genes TP53 and RB1.

  • NECs across sites of origin have been subtyped based on overlapping sets of key transcription factors.

  • Despite fundamental biological similarities, both NETs and NECs have some characteristics, including mutational spectra, that are reflective of their organ of origin.

  • Further understanding of these differences and commonalities could accelerate therapeutic research for patients with neuroendocrine neoplasms.

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Fig. 1: Common trajectories of metastatic spread for lung and gastrointestinal NENs.
Fig. 2: Histology of neuroendocrine neoplasms.
Fig. 3: Prevalent genetic mutations in NENs.
Fig. 4: Transcriptional subtypes and developmental models of SCLC, LCNEC and GEP-NECs.
Fig. 5: Application of patient-derived models of NENs.

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Acknowledgements

The work of C.M.R. is supported by the US NIH National Cancer Institute (NCI) grants R35 CA263816 and U24 CA213274. Generation of the data for Fig. 3 was supported in part by the Marie-Josée and Henry R. Kravis Center for Molecular Oncology and the NCI Cancer Center Core Grant P30 CA008748. The authors gratefully acknowledge S. Tischfield and the members of the Molecular Diagnostics Service in the Department of Pathology at the Memorial Sloan Kettering Cancer Center for their assistance in drafting the figures for this manuscript.

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Authors and Affiliations

  1. Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA

    Kenta Kawasaki, Álvaro Quintanal-Villalonga & Charles M. Rudin

  2. Cancer Biology and Genetics Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA

    Kenta Kawasaki

  3. Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA

    Natasha Rekhtman

  4. Druckenmiller Center for Lung Cancer Research, Memorial Sloan Kettering Cancer Center, New York, NY, USA

    Charles M. Rudin

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The authors contributed equally to all aspects of the article.

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Correspondence to Álvaro Quintanal-Villalonga or Charles M. Rudin.

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Competing interests

C.M.R. has consulted regarding oncology drug development for AbbVie, Amgen, AstraZeneca, D2G, Daiichi Sankyo, Epizyme, Genentech/Roche, Ipsen, Jazz, Kowa, Lilly, Merck and Syros, and serves on the scientific advisory boards of Bridge Medicines, Earli, and Harpoon Therapeutics. The other authors declare no competing interests.

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Kawasaki, K., Rekhtman, N., Quintanal-Villalonga, Á. et al. Neuroendocrine neoplasms of the lung and gastrointestinal system: convergent biology and a path to better therapies. Nat Rev Clin Oncol 20, 16–32 (2023). https://doi.org/10.1038/s41571-022-00696-0

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