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.
Similar content being viewed by others
References
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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):1040–1044
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
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
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
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
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
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
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
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
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
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
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.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of interest
The authors declare that they have no conflict of interest.
About this article
Cite this article
Jiang, M., Zhu, X., Han, X. et al. Histologic transformation of non-small-cell lung cancer in brain metastases. Int J Clin Oncol 24, 375–384 (2019). https://doi.org/10.1007/s10147-018-1369-1
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10147-018-1369-1