Skip to main content

Advertisement

SpringerLink
Log in

Clinical impact of mixed pulmonary carcinoma and carcinoid: the driver from their mono-clonal origin

  • Original Article
  • Published:
Virchows Archiv Aims and scope Submit manuscript

Abstract

The combination of neuroendocrine/non neuroendocrine lung tumors (CNNELT) mentioned in the last edition of the World Health Organization (WHO) of Thoracic Tumors refers to small cell carcinoma (SCLC) or large cell neuroendocrine carcinoma (LCNEC) mixed with any other non-small cell lung carcinoma (NSCLC). Typical Carcinoid (TC)/Atypical Carcinoid (AC) combined with NSCLC is not included among this category. However, case reports of TC/AC combined with NSCLC have been described. We previously reported 2 cases of lung adenocarcinoma (LUA) mixed with carcinoid sharing mutations in both components supporting the hypothesis of a clonal origin. We extended our analysis to other four cases of mixed NSCLC-carcinoid by performing targeted-DNA and RNA-based NGS analysis in both primary and their paired lymph nodes metastasis. In all cases, LUA and AC components shared at least 1 common mutation (KRAS driver mutation p.Gly12Val in cases 1 and 3, AKAP13-RET fusion in case 2, and missense KRAS driver mutation p.Gly12Ala in case 4, reinforcing the hypothesis of a clonal origin. Moreover, the same mutation was detected in the metastasis constituted only by AC (cases 2 and 4). Although it is a rare malignancy in the lung, mixed LUA and TC/AC could be included among the histotypes for which a deep molecular characterization of both components is needed to identify the presence of potential druggable genetic alterations.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  1. Travis WD, Beasley M, Cree I et al (2021) Lung neuroendocrine neoplasms. In: WHO classification of tumors Editorial Board (ed) Thoracic Tumours. Lyon. IARC Press

    Google Scholar 

  2. Rindi G, Mete O, Uccella S et al (2022) Overview of the 2022 WHO classification of neuroendocrine neoplasms. Endocr Pathol 33(1):115–154. https://doi.org/10.1007/s12022-022-09708-2

    Article  PubMed  CAS  Google Scholar 

  3. La Rosa S, Simbolo M, Franzi F et al (2018) Combined adenocarcinoma-atypical carcinoid of the lung. Targeted next-generation sequencing (NGS) suggests a monoclonal origin of the two components. Diagn Histopath 24:3,120–3,123. https://doi.org/10.1016/j.mpdhp.2018.02.002

    Article  Google Scholar 

  4. Parente P, Rossi A, Sparaneo A et al (2021) Mixed pulmonary adenocarcinoma and atypical carcinoid: a report of two cases of a non-codified entity with biological profile. Front Mol Biosci 3(8):784876. https://doi.org/10.3389/fmolb.2021.784876

    Article  CAS  Google Scholar 

  5. Metovic J, Barella M, Bianchi F et al (2021) Morphologic and molecular classification of lung neuroendocrine neoplasms. Virchows Arch 478(1):5–19. https://doi.org/10.1007/s00428-020-03015-z

    Article  PubMed  PubMed Central  Google Scholar 

  6. Miyanaga A, Masuda M, Motoi N et al (2020) Whole-exome and RNA sequencing of pulmonary carcinoid reveals chromosomal rearrangements associated with recurrence. Lung Cancer 145:85–94. https://doi.org/10.1016/j.lungcan.2020.03.027

    Article  PubMed  Google Scholar 

  7. Derks JL, Rijnsburger N, Hermans BCM et al (2021) Clinical-pathologic challenges in the classification of pulmonary neuroendocrine neoplasms and targets on the horizon for future clinical practice. J Thorac Oncol 16(10):1632–1646. https://doi.org/10.1016/j.jtho.2021.05.020

    Article  PubMed  CAS  Google Scholar 

  8. Alcala N, Leblay N, Gabriel AAG et al (2019) Integrative and comparative genomic analyses identify clinically relevant pulmonary carcinoid groups and unveil the supra-carcinoids. Nat Commun 10(1):3407. https://doi.org/10.1038/s41467-019-11276-9

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  9. Cavazza A, Toffanetti R, Ferrari G et al (2001) Combined neoplasia of the lung: description of a case of adenocarcinoma mixed with typical carcinoid. Pathologica 93(3):216–220

    PubMed  CAS  Google Scholar 

  10. Olofson AM, Tafe LJ (2018) A case of a primary lung cancer comprised of adenocarcinoma and atypical carcinoid tumor with both components harboring BRAF p.V600E mutation. Exp Mol Pathol 104:26–28. https://doi.org/10.1016/j.yexmp.2017.12.004

    Article  PubMed  CAS  Google Scholar 

  11. Okazaki M, Sano Y, Soga Y et al (2015) Combined atypical carcinoid tumour and squamous cell carcinoma of the lung. Intern Med 54:1385–1388. https://doi.org/10.2169/internalmedicine.54.3846

    Article  PubMed  Google Scholar 

  12. Owens CL, Fraire AE (2011) Combined carcinoid tumor and squamous cell carcinoma of lung: expanding the spectrum of combined tumors of lung. Int J Surg Pathol 19:273–275. https://doi.org/10.1177/1066896910397883

    Article  PubMed  Google Scholar 

  13. Inoue C, Konosu-Fukaya S, Murakami K et al (2022) Coexistence of carcinoid tumor and adenocarcinoma of the lung; morphological, immunohistochemical and genetic analyses, a case report. Diagn Pathol 17(1):25

    Article  PubMed  PubMed Central  Google Scholar 

  14. Nagamatsu Y, Iwasaki Y, Omura H et al (2012) A case of resected synchronous multiple primary lung cancer comprising adenocarcinoma and carcinoid (cancer-in-cancer). Gen Thorac Cardiovasc Surg 60(8):518–521. https://doi.org/10.1007/s11748-012-0029-z

    Article  PubMed  Google Scholar 

  15. Abbi KKS, Hameed MK, Jiang Y et al (2014) Pulmonary collision tumor consisting of adenocarcinoma and typical carcinoid-a case report and review of literature. Am J Ther 21(6):e234–e238. https://doi.org/10.1097/MJT.0b013e318293b0b0

    Article  PubMed  Google Scholar 

  16. Sen F, Borczuk AC (1998) Combined carcinoid tumor of the lung: a combination of carcinoid and adenocarcinoma. Lung Cancer 21(1):53–58. https://doi.org/10.1016/S0169-5002(98)00042-7

    Article  PubMed  CAS  Google Scholar 

  17. Lloyd RV, Osamura RY, Klöppel G et al (2017) WHO classification of tumours of endocrine organs. IARC, Lyon

    Google Scholar 

  18. Klimstra DS, Klöppel G, La Rosa S et al (2019) WHO classification of tumours of digestive system tumours, 5th edn. IARC, Lyon

    Google Scholar 

  19. La Rosa S, Sessa F, Uccella S (2016) Mixed neuroendocrine-nonneuroendocrine neoplasms (MiNENs): unifying the concept of a heterogeneous group of neoplasms. Endocr Pathol 27(4):284–311. https://doi.org/10.1007/s12022-016-9432-9

    Article  PubMed  CAS  Google Scholar 

  20. Acker F, Stratmann J, Aspacher L et al (2021) KRAS Mutations in squamous cell carcinomas of the lung. Front Oncol 11:788084

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  21. Philpott C, Tovell H, Frayling IM et al (2017) The NF1 somatic mutational landscape in sporadic human cancers. Hum Genomics 11:13. https://doi.org/10.1186/s40246-017-0109-3

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  22. Swarts DRA, Ramaekers FCS, Speel EJM (1826) Molecular and cellular biology of neuroendocrine lung tumors: evidence for separate biological entities. Biochim Biophys Acta - Rev Cancer 2012:255–271. https://doi.org/10.1016/j.bbcan.2012.05.001

    Article  CAS  Google Scholar 

  23. Vogt A, Schmid S, Heinimann K et al (2017) Multiple primary tumours: challenges and approaches, a review. ESMO Open 2(2):1–11. https://doi.org/10.1136/esmoopen-2017-000172

    Article  Google Scholar 

Download references

Acknowledgments

“Fig. 4 was re-adapted from the manuscript by Parente et al. Front Mol Biosci. 2021 Dec 3;8:784876 (Figs. 2 and 5), http://creativecommons.org/licenses/by/4.0/”. We thank Dr. Chiara Di Giorgio (Fondazione IRCC Casa Sollievo della Sofferenza; San Giovanni Rotondo) for editing this manuscript for English language.

Author information

Author notes

  1. Paolo Graziano and Paola Parente contributed equally to this work.

Authors and Affiliations

  1. Pathology Unit, Fondazione IRCCS Casa Sollievo della Sofferenza, Viale Cappuccini, sn, 71013, San Giovanni Rotondo, FG, Italy

    Paolo Graziano, Paola Parente, Diego Urbano & Giuseppe Di Maggio

  2. Laboratory of Oncology, Fondazione IRCCS Casa Sollievo della Sofferenza, Viale Cappuccini, sn, 71013, San Giovanni Rotondo, FG, Italy

    Flavia Centra, Teresa Balsamo & Lucia Anna Muscarella

  3. 1st Pathology Division, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Giacomo Venezian, 1, 20133, Milano, MI, Italy

    Massimo Milione & Giovanni Centonze

  4. Pathology Unit, Department of Oncology, University of Turin at San Luigi Hospital, Turin, Italy

    Marco Volante

  5. Pathology Unit, Azienda USL-IRCCS di Reggio Emilia, Via Giovanni Amendola, 2, 42122, Reggio Emilia, RE, Italy

    Alberto Cavazza

  6. Oncology Unit, Fondazione IRCCS Casa Sollievo della Sofferenza, Viale Cappuccini, sn, 71013, San Giovanni Rotondo, FG, Italy

    Concetta Di Micco

  7. Pathology Unit, Fondazione Poliambulanza Hospital Institute, Via Leonida Bissolati, 57, 25124, Brescia, BS, Italy

    Giulio Rossi

  8. Oncology Center of Excellence, Therapeutic Science & Strategy Unit, IQVIA, Via Fabio Filzi, 29, 20124, Milano, MI, Italy

    Antonio Rossi

Authors
  1. Paolo Graziano
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Paola Parente
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Flavia Centra
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Massimo Milione
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Giovanni Centonze
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Marco Volante
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Alberto Cavazza
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Diego Urbano
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Giuseppe Di Maggio
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Teresa Balsamo
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Concetta Di Micco
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Giulio Rossi
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Antonio Rossi
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Lucia Anna Muscarella
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Conceptualization: Paola Parente (PP) and Lucia Anna Muscarella (LAM); methodology: Paolo Graziano (PG), PP, Flavia Centra (FC), Massimo Milione (MM), Giovanni Centonze (GC), Marco Volante (MV) Alberto Cavazza (AC), Diego Urbano (DU) Giuseppe Di Maggio (GDM) Teresa Balsamo (TB), Concetta Di Micco (CDM), Giulio Rossi (GR), Antonio Rossi (AR), and LAM; validation: MM, MV, AC, GR, and AR; formal analysis: PG, PP, and LAM; investigation FC, GC, DU, GDM, TB, and CDM; data curation: PP and LAM ; writing—original draft preparation: PG, PP, and LAM; writing— review and editing: MM, MV, GR, and AR; supervision: GR and PG. All Authors read and approved the final manuscript.

Corresponding author

Correspondence to Paola Parente.

Ethics declarations

Ethics approval and consent to participate

The clinical–pathological information and the biological material used in this study were collected following the Declaration of Helsinki.

Competing interests

The authors declare no competing interests.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

ESM 1

(DOCX 21 kb)

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Graziano, P., Parente, P., Centra, F. et al. Clinical impact of mixed pulmonary carcinoma and carcinoid: the driver from their mono-clonal origin. Virchows Arch 484, 37–46 (2024). https://doi.org/10.1007/s00428-023-03663-x

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00428-023-03663-x

Keywords

Search

Navigation