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Updated: Oct 18, 2025
Author Spotlight: Advancements in Molecular Biomarker Testing for Non-Squamous Non-Small Cell Lung Cancer
Published on: September 8, 2023
Histologic Changes in Non-Small Cell Lung Cancer under Various Treatments: A Comparison of Histology and Mutation
Chang Gok Woo1,2, Seung-Myoung Son1,2, Ho-Chang Lee1,2
1Department of Pathology, Chungbuk National University Hospital, Cheongju, Korea.
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 inhibitors (TKI). 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 (epidermal growth factor receptor)-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 (NSCC). Three patients experienced two histologic changes, which the changed tumors returned to its original subtype or changed to a combined tumor after treatments. Four cases showed combined histology in the first or second change.
Conclusion:
The histology of NSCC 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 occur 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.
Insights
Histologic changes in non-small cell lung cancer (NSCC) can occur with various treatments, leading to different subtypes. These phenotypic changes are not fixed, suggesting repeated biopsies are crucial for refining treatment strategies.
Area of Science:
- Oncology
- Cancer Biology
- Translational Research
Background:
- Histologic change is a known resistance mechanism in lung cancer.
- The most common change is adenocarcinoma (AdenoCa) to small cell carcinoma (SCC) under tyrosine kinase inhibitors (TKI).
- The role of other treatment modalities in driving histologic changes remains unclear.
Purpose of the Study:
- To investigate histologic changes in non-small cell lung cancer (NSCC) following various treatments.
- To compare molecular profiles of primary tumors with treatment-induced histologic changes.
- To understand the plasticity of NSCC histology under different therapeutic pressures.
Main Methods:
- Analysis of eight NSCC cases with documented histologic changes post-treatment.
- Exome sequencing to compare molecular profiles between primary and changed tumors.
- Review of treatment modalities including tyrosine kinase inhibitors (TKI), immunotherapy, and surgery.
Main Results:
- Adenocarcinoma (AdenoCa) transformed into small cell carcinoma (SCC) retained initial mutations after TKI and/or surgery.
- EGFR-mutant AdenoCa shifted to squamous cell carcinoma (SqCa) after TKI and immunotherapy.
- Squamous cell carcinoma (SqCa) transformed into combined AdenoCa and SqCa after surgery, showing conserved genetic variations.
- Three patients experienced dual histologic changes, with tumors reverting to original subtypes or becoming combined.
- Four cases exhibited combined histology at the first or second change.
Conclusions:
- Non-small cell lung cancer (NSCC) histology can dynamically change to single or combined subtypes in response to diverse treatments.
- These phenotypic shifts appear unfixed and can occur independently of genetic status or treatment type.
- Consecutive biopsies during progressive disease or recurrence are essential for adapting treatment strategies.
