Clinicopathological and molecular features of non-small cell lung cancer that transform to small-cell lung cancer: Case reports and literature review

The purpose of this study is to explore the clinical and pathological characteristics as well as the molecular pathogenesis of patients with non-small cell lung cancer (NSCLC) transforming into small cell lung cancer (SCLC).

We investigated 14 patients with advanced NSCLC that transformed into SCLC. Whole genome sequencing (WES) was applied to analyse 14 tumour specimens (including NSCLC and SCLC specimens from each patient) from 7 patients to detect genetic predictive factors for small-cell transformation. The clinicopatho­logical characteristics of these 14 patients were collected and analysed. In addition, a detailed literature review was conducted to identify similar cases of transforma­tion from NSCLC to SCLC.

Fourteen cases were included. The basic condition of patients who had undergone the transformation was found to be similar to those individuals without any trans­formation. After SCLC transformation, the mutation spectrum changed: C>T de­creased and C>A increased. In comparison to the initial NSCLC, the copy number variants (CNV) burden in the transformed SCLC increased considerably in a subset of patients. Clonal evolution analysis revealed intriguing connections and notable differences between the genetic clones of the initial NSCLC and the transformed SCLC. It was found that the process of transformation took a longer time in fe­males compared to males. Furthermore, it was observed that the transformation time for LADC was longer compared to squamous cell carcinoma (SCC). Addition­ally, the analysis revealed that after completion of the transformation, the OS time for males was found to be longer than that for females.

Secondary biopsy is a crucial step in assessing the genetic and histological alter­ations that occur after a patient develops resistance to their initial treatment. This procedure is vital not only for individuals who have been treated with tyrosine kinase inhibitors but also for those who have undergone chemotherapy or immuno­therapy. One interesting finding is that the mutation rate of p53 and RB1 in trans­formed SCLC is lower compared to de novo SCLC. Specifically, there is a decrease in the C > T mutation and an increase in the C > A mutation following transforma­tion. Moreover, the transformed SCLC appears to originate from the major clones of the initial NSCLC.