International Journal of Clinical Oncology

, Volume 23, Issue 2, pp 235–242 | Cite as

Histological transformation after acquired resistance to epidermal growth factor tyrosine kinase inhibitors

  • Yi Shao
  • Dian-Sheng ZhongEmail author
Review Article


Non-small-cell lung cancer patients with sensitive epidermal growth factor receptor mutations generally respond well to tyrosine kinase inhibitors (TKIs). However, acquired resistance will eventually develop place after 8–16 months. Several mechanisms contribute to the resistance including T790M mutation, c-Met amplification, epithelial mesenchymal transformation and PIK3CA mutation; however, histological transformation is a rare mechanism. The patterns and mechanisms underlying histological transformation need to be explored. We searched PubMed, EMBASE and search engines Google Scholar, Medical Matrix for literature related to histological transformation. Case reports, cases series, and clinical and basic medical research articles were reviewed. Sixty-one articles were included in this review. Cases of transformation to small-cell lung cancer, squamous cell carcinoma, large-cell neuroendocrine carcinoma and sarcoma after TKI resistance have all been reported. As the clinical course differed dramatically between cases, a new treatment scheme needs to be recruited. The mechanisms underlying histological transformation have not been fully elucidated and probably relate to cancer stem cells, driver genetic alterations under selective pressure or the heterogeneity of the tumor. When TKI resistance develops, we recommend that patients undergo a second biopsy to determine the reason, guide the next treatment and predict the prognosis.


Lung carcinoma Epidermal growth factor receptor Tyrosine kinase inhibitor Acquired resistance Histological transformation 



This work was supported by WU JIEPING Medical Foundation (320.6750.16136). No other specific funding, financial disclosures or assistance declared.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.


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Copyright information

© Japan Society of Clinical Oncology 2017

Authors and Affiliations

  1. 1.Department of Medical OncologyTianjin Medical University General HospitalTianjinChina

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