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Most high-grade neuroendocrine tumours of the lung are likely to secondarily develop from pre-existing carcinoids: innovative findings skipping the current pathogenesis paradigm

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Abstract

Among lung neuroendocrine tumours (Lung-NETs), typical carcinoid (TC) and atypical carcinoid (AC) are considered separate entities as opposed to large cell neuroendocrine carcinoma (LCNEC) and small cell lung carcinoma (SCLC). By means of two-way clustering analysis of previously reported next-generation sequencing data on 148 surgically resected Lung-NETs, six histology-independent clusters (C1 → C6) accounting for 68% of tumours were identified. Low-grade Lung-NETs were likely to evolve into high-grade tumours following two smoke-related paths. Tumour composition of the first path (C5 → C1 → C6) was coherent with the hypothesis of an evolution of TC to LCNEC, even with a conversion of SCLC-featuring tumours to LCNEC. The second path (C4 → C2–C3) had a tumour composition supporting the evolution of AC to SCLC-featuring tumours. The relevant Ki-67 labelling index varied accordingly, with median values being 5%, 9% and 50% in the cluster sequence C5 → C1 → C6, 12% in cluster C4 and 50–60% in cluster C2–C3. This proof-of-concept study suggests an innovative view on the progression of pre-existing TC or AC to high-grade NE carcinomas in most Lung-NET instances.

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Acknowledgments

This work is dedicated to the memory of Carlotta, an extraordinarily lively girl who died untimely of cancer in the prime of her life.

Funding

Fabrizio Bianchi (FB), Aldo Scarpa (AS), Sara Pilotto (SP), Emilio Bria (EB) and Marco Volante (MV) were supported by grants from the Italian Association for Cancer Research (AIRC) as follows: FB, MFAG17568; AS, 5x1000 18182; SP and EB, MFAG14282; and MV, MFAG17568, 5x1000 18182 and IG19238. SP was also supported by a fellowship award of the International Association for Lung Cancer (IASLC).

Author information

Author notes

  1. Giuseppe Pelosi and Fabrizio Bianchi have contributed equally to the work.

Authors and Affiliations

  1. Department of Oncology and Hemato-Oncology, Università degli Studi di Milano, Milan, Italy

    Giuseppe Pelosi

  2. Inter-Hospital Pathology Division, Science & Technology Park, IRCCS MultiMedica, Milan, Italy

    Giuseppe Pelosi

  3. Servizio Interaziendale di Anatomia Patologica, Polo Scientifico e Tecnologico, IRCCS MultiMedica, Via Gaudenzio Fantoli 16/15, 20138, Milan, Italy

    Giuseppe Pelosi

  4. ISBREMIT, Regenerative Medicine and Innovative Therapies, IRCCS Casa Sollievo della Sofferenza, Institute for Stem-Cell Biology, San Giovanni Rotondo, FG, Italy

    Fabrizio Bianchi & Elisa Dama

  5. ARC-NET Research Centre and Section of Pathology of the Department of Diagnostics and Public Health, University and Hospital Trust of Verona, Verona, Italy

    Michele Simbolo, Andrea Mafficini & Aldo Scarpa

  6. Department of Pathology and Laboratory Medicine, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy

    Angelica Sonzogni

  7. Department of Medicine, Section of Medical Oncology, University and Hospital Trust of Verona, Verona, Italy

    Sara Pilotto & Emilio Bria

  8. Department of Medical Sciences and Division of Pneumology, San Giuseppe Hospital, IRCCS MultiMedica, Milan, Italy

    Sergio Harari

  9. Department of Oncology, City of Health and Science, University of Turin and Pathology Unit Molinette Hospital, Turin, Italy

    Mauro Papotti

  10. Department of Oncology, University of Turin and Pathology Unit San Luigi Hospital, Orbassano, Turin, Italy

    Marco Volante

  11. Department of Surgical, Medical, Molecular Pathology and Critical Area, University of Pisa, Pisa, Italy

    Gabriella Fontanini

  12. Department of Surgical and Diagnostic Sciences (DISC), University of Genova and IRCCS San Martino-IST University Hospital, Genoa, Italy

    Luca Mastracci

  13. Laboratory of Vascular Biology and Angiogenesis, Science & Technology Park, IRCCS MultiMedica, Milan, Italy

    Adriana Albini

  14. Department of Cardiothoracic and Vascular Sciences, Pathological Anatomy Section, University of Padua Medical School, Padua, Italy

    Fiorella Calabrese

Authors
  1. Giuseppe Pelosi
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  2. Fabrizio Bianchi
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  3. Elisa Dama
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  4. Michele Simbolo
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  5. Andrea Mafficini
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  6. Angelica Sonzogni
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  7. Sara Pilotto
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  8. Sergio Harari
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  9. Mauro Papotti
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  10. Marco Volante
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  11. Gabriella Fontanini
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  12. Luca Mastracci
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  13. Adriana Albini
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  14. Emilio Bria
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  15. Fiorella Calabrese
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  16. Aldo Scarpa
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Contributions

GP conceived and designed the study, drafted and finalised the manuscript and shared all statistical analyses; FB carried out clustering analysis, supervised all statistical procedures, shared the study design and contributed to draft and finalise the manuscript; ED performed univariate and multivariate statistical analysis; MS and AM identified the gene signature from the original files; AnSo, SP, SH, MP, MV, GF, LM, AA, FC and EB critically revised the manuscript; AS critically revised and finalised the manuscript. All authors approved the submitted version.

Corresponding author

Correspondence to Giuseppe Pelosi.

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The authors declare that they have no conflict of interest.

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Supplemental Figure 1.

A. Supervised clustering analysis of gene alterations across the entire spectrum of Lung-NETs. Different tumours and types of genetic alterations are colour coded as per the legend. TC stands for typical carcinoid, AC for atypical carcinoid, LCNEC for large cell neuroendocrine carcinoma and SCLC for small cell lung carcinoma. B. Survival analysis by Kaplan-Meier plot of tumours stratified by histologic subtyping. (GIF 9 kb)

High resolution image (TIFF 11272 kb)

Supplemental Figure 2.

High-grade NET consistent with SCLC in the cluster C1 (A) showed an intra-tumour compartmentalization of the Ki-67 immunostaining with an intimate admixture of proliferating and non-proliferating tumour cells within the same tumour case. This distribution of tumour cells ruled out a collision tumour and was in agreement with the evolution of a pre-existing carcinoid to high-grade SCLC-like NET (B). (GIF 24 kb)

High resolution image (TIFF 4656 kb)

Supplemental Figure 3

Unsupervised cluster analysis on the data set published by Rekhtman et al. (see reference #8), regarding NGS analysis of a large series of LCNEC of the lung. (GIF 7 kb)

High resolution image (TIFF 9292 kb)

Supplemental Table 1

(DOCX 70 kb)

Supplemental Table 2

(DOCX 63 kb)

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Pelosi, G., Bianchi, F., Dama, E. et al. Most high-grade neuroendocrine tumours of the lung are likely to secondarily develop from pre-existing carcinoids: innovative findings skipping the current pathogenesis paradigm. Virchows Arch 472, 567–577 (2018). https://doi.org/10.1007/s00428-018-2307-3

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  • DOI: https://doi.org/10.1007/s00428-018-2307-3

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