Advertisement

International Journal of Clinical Oncology

, Volume 24, Issue 4, pp 375–384 | Cite as

Histologic transformation of non-small-cell lung cancer in brain metastases

  • Meng Jiang
  • Xiaolong Zhu
  • Xiao Han
  • Haiyan Jing
  • Tao Han
  • Qiang Li
  • Xiao DingEmail author
Original Article
  • 110 Downloads

Abstract

Background

Treatment strategies differ substantially for small-cell lung cancer (SCLC), adenocarcinoma and squamous-cell cancer (SCC). Therefore, it is of important significance to identify histologic transformation. There are no reports on histologic transformation in brain metastases (BM) to date. The aim of this study was to analyze the histologic transformation in BM for the first time.

Methods

Medical records were reviewed and patients with both resected BM and primary tumors were examined retrospectively. The histologic diagnosis was confirmed by H&E staining, and additional diagnostic immunohistochemical stains were performed at the discretion of the pathologists. Characteristics of histologic transformation in BM were analyzed.

Results

3 of 24 patients (12.5%) with both resected BM and primary non-small-cell lung cancers (NSCLCs) had evidence of histologic transformation in BM. One case with SCC transformed to adenocarcinoma in brain, one case with adenocarcinoma transformed to SCLC, and another case with adenocarcinoma transformed to SCC. The three cases of histologic transformation were all spontaneous and had not tested gene status.

Conclusions

We disclosed the histologic transformation of NSCLC in BM at a frequency not as low as expected, and speculated it as an evolution promoted by intratumor heterogeneity, though it warrants further prospective multi-institution investigations with comprehensive molecular analysis. Our findings provided further impetus for surgery when the metastatic or recurrent lesion is resectable, and repeated pathologic evaluation to help tailor individualized treatment.

Keywords

Histologic transformation Non-small-cell lung cancer Brain metastases Small-cell lung cancer Surgery 

Notes

Acknowledgements

This work was supported by the Research Award Fund for outstanding Young-Middle aged Scientists of Shandong Province, China [BS2014YY004]; and Shandong Provincial Natural Science Foundation, China [ZR2014HQ064, ZR2014HP042]. The funders had no role in study design; in the collection, analysis and interpretation of data; in the writing of the report; and in the decision to submit the article for publication.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

References

  1. 1.
    Kim TM, Song A, Kim DW, Kim S, Ahn YO, Keam B et al (2015) Mechanisms of acquired resistance to AZD9291: a mutation-selective, irreversible EGFR inhibitor. J Thorac Oncol 10(12):1736–1744.  https://doi.org/10.1097/JTO.0000000000000688 Google Scholar
  2. 2.
    Norkowski E, Ghigna MR, Lacroix L, Le Chevalier T, Fadel E, Dartevelle P et al (2013) Small-cell carcinoma in the setting of pulmonary adenocarcinoma: new insights in the era of molecular pathology. J Thorac Oncol 8(10):1265–1271.  https://doi.org/10.1097/JTO.0b013e3182a407fa Google Scholar
  3. 3.
    Sequist LV, Waltman BA, Dias-Santagata D, Digumarthy S, Turke AB, Fidias P et al (2011) Genotypic and histological evolution of lung cancers acquiring resistance to EGFR inhibitors. Sci Transl Med 3(75):75ra26.  https://doi.org/10.1126/scitranslmed.3002003 Google Scholar
  4. 4.
    Yu HA, Arcila ME, Rekhtman N, Sima CS, Zakowski MF, Pao W et al (2013) Analysis of tumor specimens at the time of acquired resistance to EGFR-TKI therapy in 155 patients with EGFR-mutant lung cancers. Clin Cancer Res 19(8):2240–2247.  https://doi.org/10.1158/1078-0432.CCR-12-2246 Google Scholar
  5. 5.
    Alam N, Gustafson KS, Ladanyi M, Zakowski MF, Kapoor A, Truskinovsky AM et al (2010) Small-cell carcinoma with an epidermal growth factor receptor mutation in a never-smoker with gefitinib-responsive adenocarcinoma of the lung. Clin Lung Cancer 11(5):E1–E4.  https://doi.org/10.3816/CLC.2010.n.046 Google Scholar
  6. 6.
    Popat S, Wotherspoon A, Nutting CM, Gonzalez D, Nicholson AG, O’Brien M (2013) Transformation to “high grade” neuroendocrine carcinoma as an acquired drug resistance mechanism in EGFR-mutant lung adenocarcinoma. Lung Cancer 80(1):1–4.  https://doi.org/10.1016/j.lungcan.2012.12.019 Google Scholar
  7. 7.
    Ma AT, Chan WK, Ma ES, Cheng T, Cheng PN (2012) Small cell lung cancer with an epidermal growth factor receptor mutation in primary gefitinib-resistant adenocarcinoma of the lung. Acta Oncol 51(4):557–559.  https://doi.org/10.3109/0284186X.2011.636757 Google Scholar
  8. 8.
    van Riel S, Thunnissen E, Heideman D, Smit EF, Biesma B (2012) A patient with simultaneously appearing adenocarcinoma and small-cell lung carcinoma harbouring an identical EGFR exon 19 mutation. Ann Oncol 23(12):3188–3189.  https://doi.org/10.1093/annonc/mds525 Google Scholar
  9. 9.
    Morinaga R, Okamoto I, Furuta K, Kawano Y, Sekijima M, Dote K et al (2007) Sequential occurrence of non-small cell and small cell lung cancer with the same EGFR mutation. Lung Cancer 58(3):411–413.  https://doi.org/10.1016/j.lungcan.2007.05.014 Google Scholar
  10. 10.
    Lee JK, Lee J, Kim S, Kim S, Youk J, Park S et al (2017) Clonal history and genetic predictors of transformation into small-cell carcinomas from lung adenocarcinomas. J Clin Oncol 35(26):3065–3074.  https://doi.org/10.1200/JCO.2016.71.9096 Google Scholar
  11. 11.
    Niederst MJ, Sequist LV, Poirier JT, Mermel CH, Lockerman EL, Garcia AR et al (2015) RB loss in resistant EGFR mutant lung adenocarcinomas that transform to small-cell lung cancer. Nat Commun 6:6377.  https://doi.org/10.1038/ncomms7377 Google Scholar
  12. 12.
    Lin Q, Cai GP, Yang KY, Yang L, Chen CS, Li YP (2016) Case report: small cell transformation and metastasis to the breast in a patient with lung adenocarcinoma following maintenance treatment with epidermal growth factor receptor tyrosine kinase inhibitors. BMC Cancer 16:593.  https://doi.org/10.1186/s12885-016-2623-4 Google Scholar
  13. 13.
    Kim WJ, Kim S, Choi H, Chang J, Shin HJ, Park CK et al (2015) Histological transformation from non-small cell to small cell lung carcinoma after treatment with epidermal growth factor receptor-tyrosine kinase inhibitor. Thorac Cancer 6(6):800–804.  https://doi.org/10.1111/1759-7714.12217 Google Scholar
  14. 14.
    Takegawa N, Hayashi H, Iizuka N, Takahama T, Ueda H, Tanaka K et al (2016) Transformation of ALK rearrangement-positive adenocarcinoma to small-cell lung cancer in association with acquired resistance to alectinib. Ann Oncol 27(5):953–955.  https://doi.org/10.1093/annonc/mdw032 Google Scholar
  15. 15.
    Fujita S, Masago K, Katakami N, Yatabe Y (2016) Transformation to SCLC after treatment with the ALK inhibitor alectinib. J Thorac Oncol 11(6):e67–e72.  https://doi.org/10.1016/j.jtho.2015.12.105 Google Scholar
  16. 16.
    Cha YJ, Cho BC, Kim HR, Lee HJ, Shim HS (2016) A Case of ALK-rearranged adenocarcinoma with small cell carcinoma-like transformation and resistance to crizotinib. J Thorac Oncol 11(5):e55–e58.  https://doi.org/10.1016/j.jtho.2015.12.097 Google Scholar
  17. 17.
    Watanabe S, Sone T, Matsui T, Yamamura K, Tani M, Okazaki A et al (2013) Transformation to small-cell lung cancer following treatment with EGFR tyrosine kinase inhibitors in a patient with lung adenocarcinoma. Lung Cancer 82(2):370–372.  https://doi.org/10.1016/j.lungcan.2013.06.003 Google Scholar
  18. 18.
    Hsieh MS, Jhuang JY, Hua SF, Chou YH (2015) Histologic evolution from adenocarcinoma to squamous cell carcinoma after gefitinib treatment. Ann Thorac Surg 99(1):316–319.  https://doi.org/10.1016/j.athoracsur.2014.02.075 Google Scholar
  19. 19.
    Levin PA, Mayer M, Hoskin S, Sailors J, Oliver DH, Gerber DE (2015) Histologic transformation from adenocarcinoma to squamous cell carcinoma as a mechanism of resistance to EGFR inhibition. J Thorac Oncol 10(9):e86–e88.  https://doi.org/10.1097/JTO.0000000000000571 Google Scholar
  20. 20.
    Scher KS, Saldivar JS, Fishbein M, Marchevsky A, Reckamp KL (2013) EGFR-mutated lung cancer with T790M-acquired resistance in the brain and histologic transformation in the lung. J Natl Compr Cancer Netw 11(9):1040–1044Google Scholar
  21. 21.
    Longo L, Mengoli MC, Bertolini F, Bettelli S, Manfredini S, Rossi G (2017) Synchronous occurrence of squamous-cell carcinoma “transformation” and EGFR exon 20 S768I mutation as a novel mechanism of resistance in EGFR-mutated lung adenocarcinoma. Lung Cancer 103:24–26.  https://doi.org/10.1016/j.lungcan.2016.11.012 Google Scholar
  22. 22.
    Kobayashi Y, Sakao Y, Ito S, Park J, Kuroda H, Sakakura N et al (2013) Transformation to sarcomatoid carcinoma in ALK-rearranged adenocarcinoma, which developed acquired resistance to crizotinib and received subsequent chemotherapies. J Thorac Oncol 8(8):e75–e78.  https://doi.org/10.1097/JTO.0b013e318293d96f Google Scholar
  23. 23.
    Le T, Sailors J, Oliver DH, Mayer M, Hoskin S, Gerber DE (2017) Histologic transformation of EGFR mutant lung adenocarcinoma without exposure to EGFR inhibition. Lung Cancer 105:14–16.  https://doi.org/10.1016/j.lungcan.2017.01.005 Google Scholar
  24. 24.
    Peifer M, Fernandez-Cuesta L, Sos ML, George J, Seidel D, Kasper LH et al (2012) Integrative genome analyses identify key somatic driver mutations of small-cell lung cancer. Nat Genet 44(10):1104–1110.  https://doi.org/10.1038/ng.2396 Google Scholar
  25. 25.
    Hsu CL, Chen KY, Kuo SW, Chang YL (2017) Histologic transformation in a patient with lung cancer treated with chemotherapy and pembrolizumab. J Thorac Oncol 12(6):e75–e76.  https://doi.org/10.1016/j.jtho.2017.02.006 Google Scholar
  26. 26.
    Brastianos PK, Carter SL, Santagata S, Cahill DP, Taylor-Weiner A, Jones RT et al (2015) Genomic characterization of brain metastases reveals branched evolution and potential therapeutic targets. Cancer Discov 5(11):1164–1177.  https://doi.org/10.1158/2159-8290.CD-15-0369 Google Scholar
  27. 27.
    Paik PK, Shen R, Won H, Rekhtman N, Wang L, Sima CS et al (2015) Next-generation sequencing of stage IV squamous cell lung cancers reveals an association of PI3K aberrations and evidence of clonal heterogeneity in patients with brain metastases. Cancer Discov 5(6):610–621.  https://doi.org/10.1158/2159-8290.CD-14-1129 Google Scholar
  28. 28.
    Jamal-Hanjani M, Wilson GA, McGranahan N, Birkbak NJ, Watkins TBK, Veeriah S et al (2017) Tracking the evolution of non-small-cell lung cancer. N Engl J Med 376(22):2109–2121.  https://doi.org/10.1056/NEJMoa1616288 Google Scholar
  29. 29.
    de Bruin EC, McGranahan N, Mitter R, Salm M, Wedge DC, Yates L et al (2014) Spatial and temporal diversity in genomic instability processes defines lung cancer evolution. Science 346(6206):251–256.  https://doi.org/10.1126/science.1253462 Google Scholar
  30. 30.
    Zhang J, Fujimoto J, Zhang J, Wedge DC, Song X, Zhang J et al (2014) Intratumor heterogeneity in localized lung adenocarcinomas delineated by multiregion sequencing. Science 346(6206):256–259.  https://doi.org/10.1126/science.1256930 Google Scholar

Copyright information

© Japan Society of Clinical Oncology 2018

Authors and Affiliations

  1. 1.Department of NeurosurgeryShandong Provincial Hospital Affiliated to Shandong UniversityJinanChina
  2. 2.Department of Cardiovascular SurgeryShandong Provincial Hospital Affiliated to Shandong UniversityJinanChina
  3. 3.Experimental DepartmentAffiliated Tumor Hospital of Guangxi Medical UniversityNanningChina
  4. 4.Department of PathologyShandong Provincial Hospital Affiliated to Shandong UniversityJinanChina
  5. 5.Cancer CenterShandong Provincial Hospital Affiliated to Shandong UniversityJinanChina

Personalised recommendations