Skip to main content

Advertisement

SpringerLink
Log in

Primary lung adenocarcinoma in three adolescent patients affected by bone sarcomas

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

Abstract

Pediatric primary lung carcinomas are extremely rare. Apart from known associations with congenital adenomatoid malformations, cases of primary lung adenocarcinomas after prolonged treatments of pediatric malignancy have been reported. We describe the morphological and molecular features of three cases of lung adenocarcinoma developed in adolescents aged 8 to 17 years during progression of their bone osteosarcoma or Ewing sarcomas. The morphological features overlapped those of adult lung adenocarcinoma including in situ, minimally invasive, and invasive forms. EGFR gene mutations were found in all three cases by targeted next-generation sequencing. The two patients with Ewing sarcoma had no progression of their lung cancer and no further progression of the metastatic bone tumor after additional chemo- and radio-therapy. Conversely, the osteosarcoma patient refused further treatments after thoracic surgery for metastatic osteosarcoma and locally advanced adenocarcinoma and died 2 years later of widespread distant metastases. Our results indicate that primary lung cancer might originate in pediatric patients during prolonged adjuvant therapies for primary bone neoplasm, and this possibility should be considered in the presence of suspected lung disease progression to correctly monitor the primary tumor evolution and define the appropriate therapeutic strategy at each time point. If appropriately treated, second primary lung cancer may not affect the patients’ prognosis. The pathogenetic mechanisms of these rare lung adenocarcinomas are not clear, but the presence of EGFR mutations in all three cases indicates an oncogene addiction of the lung tumor, rather than a direct cancerogenic effect of the sarcoma-related treatment.

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

Similar content being viewed by others

References

  1. Hartman GE, Shochat SJ (1983) Primary pulmonary neoplasms of childhood: a review. Ann Thorac Surg 36:108–119

    Article  CAS  Google Scholar 

  2. Travis WD, Linnoila RI, Horowitz M, Becker RL Jr, Pass H, Ozols R, Gazdar A (1988) Pulmonary nodules resembling bronchioloalveolar carcinoma in adolescent cancer patients. Mod Pathol 1:372–377

    CAS  PubMed  Google Scholar 

  3. Kayton ML, He M, Zakowski MF, Moreira AL, Lau C, Chou AJ, Merchant M, Merola PR, Wexler LH, la Quaglia MP, Travis WD, Ladanyi M (2010) Primary lung adenocarcinomas in children and adolescents treated for pediatric malignancies. J Thorac Oncol 5:1764–1771

    Article  Google Scholar 

  4. Guddati AK, Marak CP (2012) Pediatric primary lung adenocarcinoma in the absence of congenital pulmonary airway malformation. Med Oncol 29:2661–2663

    Article  Google Scholar 

  5. Bechtel AS, Cheek B, Bradfield S (2018) False lung metastasis: concurrent Ewing sarcoma and minimally invasive adenocarcinoma. J Pediatr Hematol Oncol 40:325–327

    Article  Google Scholar 

  6. De Martino L, Errico ME, Ruotolo S et al (2018) Pediatric lung adenocarcinoma presenting with brain metastasis: a case report. J Med Case Rep 12:243

    Article  Google Scholar 

  7. Yang HB, Namgoong JM, Kim KH, Kim DY, Park J, Shin HB, Youn JK, Lee S, Lee JW, Jung SE, Chung JH, Choe YM, Heo TG, Ho IG, Kim HY (2020) Pediatric adenocarcinoma in Korea: a multicenter study. Cancer Res Treat 52:117–127

    Article  CAS  Google Scholar 

  8. Benjamin DR, Cahill JL (1991) Bronchioloalveolar carcinoma of the lung and congenital cystic adenomatoid malformation. Am J Clin Pathol 95:889–892

    Article  CAS  Google Scholar 

  9. Ohye RG, Cohen DM, Caldwell S, Qualman SJ (1998) Pediatric bronchioloalveolar carcinoma: a favorable pediatric malignancy? J Pediatr Surg 33:730–732

    Article  CAS  Google Scholar 

  10. Lantuejoul S, Ferretti GR, Goldstraw P, Hansell DM, Brambilla E, Nicholson AG (2006) Metastases from bronchioloalveolar carcinomas associated with long-standing type 1 congenital cystic adenomatoid malformations. A report of two cases. Histopathology 48:204–206

    Article  CAS  Google Scholar 

  11. Alwelaie Y, Deyell RJ, Nadel HR, Tucker T, Laskin J, Rassekh SR, Zhou C, English JC, Lee AF (2019) ALK-positive lung adenocarcinoma arising in an adolescent treated for relapsed neuroblastoma. J Thorac Oncol 14:e132–e135

    Article  Google Scholar 

  12. Travis W, Elisabeth B, Burke A et al (2015) WHO classification of tumours of the lung, pleura, thymus and heart, vol 7. IARC Press, Lyon

    Google Scholar 

  13. Longhi A, Bertoni F, Bacchini P (2004) Simultaneous osteosarcoma lung metastasis and second primary lung cancer. J Pediatr Hematol Oncol 26:457–461

    Article  Google Scholar 

  14. Righi L, Vatrano S, Di Nicolantonio F et al (2016) Retrospective multicenter study investigating the role of targeted next-generation sequencing of selected cancer genes in mucinous adenocarcinoma of the lung. J Thorac Oncol 11:504–515

    Article  Google Scholar 

  15. Lo Iacono M, Monica V, Righi L, Grosso F, Libener R, Vatrano S, Bironzo P, Novello S, Musmeci L, Volante M, Papotti M, Scagliotti GV (2015) Targeted next-generation sequencing of cancer genes in advanced stage malignant pleural mesothelioma: a retrospective study. J Thorac Oncol 10:492–499

    Article  CAS  Google Scholar 

  16. Liu X, Wu C, Li C, Boerwinkle E (2016) dbNSFP v3.0: a one-stop database of functional predictions and annotations for human nonsynonymous and splice-site SNVs. Hum Mutat 37:235–241

    Article  Google Scholar 

  17. Bourgon R, Lu S, Yan Y, Lackner MR, Wang W, Weigman V, Wang D, Guan Y, Ryner L, Koeppen H, Patel R, Hampton GM, Amler LC, Wang Y (2014) High-throughput detection of clinically relevant mutations in archived tumor samples by multiplexed PCR and next-generation sequencing. Clin Cancer Res 20:2080–2091

    Article  CAS  Google Scholar 

  18. Choudhary A, Mambo E, Sanford T, Boedigheimer M, Twomey B, Califano J, Hadd A, Oliner KS, Beaudenon S, Latham GJ, Adai AT (2014) Evaluation of an integrated clinical workflow for targeted next-generation sequencing of low-quality tumor DNA using a 51-gene enrichment panel. BMC Med Genet 7:62

    Article  Google Scholar 

  19. Chakravarty D, Gao J, Phillips SM et al (2017) OncoKB: a precision oncology knowledge base. JCO Precis Oncol 2017

  20. Bigay-Gamé L, Bota S, Greillier L, Monnet I, Madroszyk A, Corre R, Mastroianni B, Falchero L, Mazières J, Colineaux H, Lepage B, Chouaid C, GFPC Investigators (2018) Characteristics of lung cancer in patients younger than 40 years: a prospective multicenter analysis in France. Oncology 95:337–343

    Article  Google Scholar 

  21. Crompton BD, Stewart C, Taylor-Weiner A, Alexe G, Kurek KC, Calicchio ML, Kiezun A, Carter SL, Shukla SA, Mehta SS, Thorner AR, de Torres C, Lavarino C, Sunol M, McKenna A, Sivachenko A, Cibulskis K, Lawrence MS, Stojanov P, Rosenberg M, Ambrogio L, Auclair D, Seepo S, Blumenstiel B, DeFelice M, Imaz-Rosshandler I, Schwarz-Cruz y Celis A, Rivera MN, Rodriguez-Galindo C, Fleming MD, Golub TR, Getz G, Mora J, Stegmaier K (2014) The genomic landscape of pediatric Ewing sarcoma. Cancer Discov 4:1326–1341

    Article  CAS  Google Scholar 

  22. Chen X, Bahrami A, Pappo A, Easton J, Dalton J, Hedlund E, Ellison D, Shurtleff S, Wu G, Wei L, Parker M, Rusch M, Nagahawatte P, Wu J, Mao S, Boggs K, Mulder H, Yergeau D, Lu C, Ding L, Edmonson M, Qu C, Wang J, Li Y, Navid F, Daw NC, Mardis ER, Wilson RK, Downing JR, Zhang J, Dyer MA (2014) Recurrent somatic structural variations contribute to tumorigenesis in pediatric osteosarcoma. Cell Rep 7:104–112

    Article  CAS  Google Scholar 

  23. Westra SJ, Brody AS, Mahani MG, Guillerman RP, Hegde SV, Iyer RS, Lee EY, Newman B, Podberesky DJ, Thacker PG (2015) The incidental pulmonary nodule in a child. Part 1: recommendations from the SPR Thoracic Imaging Committee regarding characterization, significance and follow-up. Pediatr Radiol 45:628–633

    Article  Google Scholar 

  24. Murrell Z, Dickie B, Dasgupta R (2011) Lung nodules in pediatric oncology patients: a prediction rule for when to biopsy. J Pediatr Surg 46:833–837

    Article  Google Scholar 

  25. Nonomura A, Mizukami Y, Shimizu J, Watanabe Y, Kamimura R, Takashima T, Tsuchiya H, Tomita K (1994) Simultaneous occurrence of lung adenocarcinoma and fibular osteosarcoma in a 13-year-old girl. Thorac Cardiovasc Surg 42:61–63

    Article  CAS  Google Scholar 

  26. Okui M, Goto T, Hayashi Y, Nakayama R, Kohno M (2013) Bronchioloalveolar carcinoma as a second malignancy in a pediatric osteosarcoma survivor: case report. World J Surg Oncol 11:135

    Article  Google Scholar 

  27. Gazdar AF (2009) Activating and resistance mutations of EGFR in non-small-cell lung cancer: role in clinical response to EGFR tyrosine kinase inhibitors. Oncogene. 28(Suppl 1):S24–S31

    Article  CAS  Google Scholar 

  28. Beau-Faller M, Prim N, Ruppert AM, Nanni-Metéllus I, Lacave R, Lacroix L, Escande F, Lizard S, Pretet JL, Rouquette I, de Crémoux P, Solassol J, de Fraipont F, Bièche I, Cayre A, Favre-Guillevin E, Tomasini P, Wislez M, Besse B, Legrain M, Voegeli AC, Baudrin L, Morin F, Zalcman G, Quoix E, Blons H, Cadranel J (2014) Rare EGFR exon 18 and exon 20 mutations in non-small-cell lung cancer on 10 117 patients: a multicentre observational study by the French ERMETIC-IFCT network. Ann Oncol 25:126–131

    Article  CAS  Google Scholar 

  29. Ruan Z, Kannan N (2018) Altered conformational landscape and dimerization dependency underpins the activation of EGFR by. Proc Natl Acad Sci U S A 115:E8162–E8171

    Article  CAS  Google Scholar 

  30. Gristina V, Malapelle U, Galvano A et al (2020) The significance of epidermal growth factor receptor uncommon mutations in non-small cell lung cancer: a systematic review and critical appraisal. Cancer Treat Rev 85

  31. VanderLaan PA, Rangachari D, Mockus SM et al (2017) Mutations in TP53, PIK3CA, PTEN and other genes in EGFR mutated lung cancers: correlation with clinical outcomes. Lung Cancer 106:17–21

    Article  Google Scholar 

  32. Kurek KC, Luks VL, Ayturk UM, Alomari AI, Fishman SJ, Spencer SA, Mulliken JB, Bowen ME, Yamamoto GL, Kozakewich HPW, Warman ML (2012) Somatic mosaic activating mutations in PIK3CA cause CLOVES syndrome. Am J Hum Genet 90:1108–1115

    Article  CAS  Google Scholar 

  33. Park JY, Cohen C, Lopez D, Ramos E, Wagenfuehr J, Rakheja D (2016) EGFR exon 20 insertion/duplication mutations characterize fibrous hamartoma of infancy. Am J Surg Pathol 40:1713–1718

    Article  Google Scholar 

Download references

Funding

This study was partially supported by a Cassa di Risparmio di Torino grant (RIGL_CRT_19_01) to LR.

Author information

Author notes

  1. Simona Vatrano

    Present address: Department of Pathology, Cannizzaro Hospital, Catania, Italy

Authors and Affiliations

  1. Department of Oncology, University of Turin, Turin, Italy

    Luisella Righi, Simona Vatrano, Ida Rapa, Angela Listì, Jasna Metovic, Fabrizio Tabbò, Marco Volante & Mauro Papotti

  2. Division of Pathology, IRCCS Istituto Ortopedico Rizzoli, Bologna, Italy

    Alberto Righi

  3. Department of Orthopaedic Oncology, IRCCS Istituto Ortopedico Rizzoli, Bologna, Italy

    Michele Rocca & Mariacristina Salone

  4. Divisions of Pathology, Policlinico Hospital and University of Perugia, Perugia, Italy

    Paolo Giovenali & Angelo Sidoni

  5. Department of Medicine, University of Padua School of Medicine, Padua, Italy

    Angelo Paolo Dei Tos

Authors
  1. Luisella Righi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Alberto Righi
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Simona Vatrano
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Ida Rapa
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Angela Listì
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Jasna Metovic
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Michele Rocca
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Mariacristina Salone
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Paolo Giovenali
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Angelo Sidoni
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Fabrizio Tabbò
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Angelo Paolo Dei Tos
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Marco Volante
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Mauro Papotti
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

LR, AR, MV, MP: design of the study; SV, IR, AL: experiments and data analysis; JM, FT, MR, MS, PG, AS, APDT: collection of material.

Corresponding author

Correspondence to Marco Volante.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest. JM is a PhD fellow at the University of Turin.

Informed consent

The informed consents from patients were collected.

Additional information

Publisher’s note

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

This article is part of the Topical Collection on Quality in Pathology

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Righi, L., Righi, A., Vatrano, S. et al. Primary lung adenocarcinoma in three adolescent patients affected by bone sarcomas. Virchows Arch 478, 1125–1134 (2021). https://doi.org/10.1007/s00428-020-02990-7

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00428-020-02990-7

Keywords

Search

Navigation