Histologic Changes in Non–Small Cell Lung Cancer under Various Treatments: A Comparison of Histology and Mutation Status in Serial Samples

Purpose Histologic change is a resistant mechanism in lung cancer. The most common histological change is the switch from adenocarcinoma (AdenoCa) to small cell carcinoma (SCC) against to tyrosine kinase inhibitor (TKI) inhibitors. However, it is not clear whether other treatment modalities are involved in the histologic changes. Materials and methods We investigated histological changes in eight cases, after various treatments, and compared the molecular profiles between primary tumors and changed tumors using exome sequencing where tissue was available. Results Three cases of AdenoCa that were changed into SCC retained the initial mutations after TKI and/or surgical treatment. After treatment with TKI and immunotherapy, an EGFR-mutant AdenoCa changed to squamous cell carcinoma (SqCa). SqCa in a patient treated with surgery was changed into combined adenoCa and SqCa. These two cases showed the same genetic variations between the two distinct non-small cell carcinomas. Only surgical treatment might induce histologic change. Three patients experienced two histologic changes, which the changed tumors returned to its original state or changed to a combined tumor after treatments. Four cases showed combined histology in first or second change. Two SqCas were changed to SCC. Conclusion The histology of non-small cell carcinoma can be changed to a single pattern or combined subtypes after various treatment modalities, and the phenotypic changes seem not fixed. Therefore, additional morphologic changes may occurred regardless of their genetic status and types of treatments. To refine the new treatment strategy, consecutive repeated biopsies in progressive disease or recurrent tumor are necessary.