Cancer Res Treat.  2022 Jul;54(3):737-743. 10.4143/crt.2021.773.

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

• Woo CG
• Son SM
• Lee HC
• Han HS
• Lee KH
• Kim D
• Kim EG
• Lee OJ

• KMID: 2531320
• DOI: http://doi.org/10.4143/crt.2021.773

Abstract

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.

Keyword

Lung neoplasms; Transformation; Adenocarcinoma; Small cell carcinoma; Squamous cell carcinoma

Figure

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  Fig. 1 (A) Lung adenocarcinoma (AdenoCa; case 4) exhibiting a combined histology (small cell carcinoma [SCC] and AdenoCa) at histologic change under epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) treatment. Squamous cell carcinoma (SqCa; case 5) in advanced stage exhibited histologic change into SCC after cisplatin plus radiotherapy. AdenoCa (case 7) harboring an EGFR exon19 deletion was changed into SqCC after EGFR-TKI plus programmed death-1 inhibitor treatment. Under another EGFR-TKI, the AdenoCa then histologically switched in the lymph node to a combined SCC and SqCC. After a surgical resection, the AdenoCa (case 8) histologically changed into SqCC in another lobe, and adenosquamous carcinoma was identified after a second resection. (B) Clinicopathological characteristics of the patients with histologically changed lung cancer. CCRT, concurrent chemoradiotherapy; CTx, chemotherapy; RTx, radiation therapy; TKI, tyrosine kinase inhibitor.

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  Fig. 2 Whole exome sequencing analysis identified the same driver mutations between primary adenocarcinoma and changed small cell carcinoma (cases 1, 2, and 3). In case 5, the primary squamous cell carcinoma and changed small cell carcinoma had different mutations. Case 7 showed the same variants between primary adenocarcinoma and the third mixed small cell carcinoma and squamous cell carcinoma. In the molecular analysis of case 8, the molecular profile of the initial cell carcinoma and the third adenosquamous carcinoma. The same variants existed in the second and third tumors.

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  Fig. 3 Non–small cell carcinoma subjected to various selective pressures can undergo histologic change to small cell carcinoma or another non-small cell carcinoma, independent of treatment modalities. AdenoCa, adenocarcinoma; CCRT, concurrent chemoradiotherapy; CTx, chemotherapy; immunoTx, immunotherapy; SCLC, small cell lung cancer; SqCa, squamous cell carcinoma; TKI, tyrosine kinase inhibitor.

Reference

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