Clonality Analysis for the Relationship between the Pulmonary Combined Neuroendocrine Carcinoma and "the So-Called Reported Histologic Transformation".

Simple Summary: Histologic transformation has been increasingly common in clinical. However, whether the transformed tumor to be a new component or a combined tumor remains controversial. This study aimed to explore the relationship and focused on 21 combined neuroendocrine carcinoma. The frequency of p53 inactivation as assessed by immunohistochemistry in NEC and non-NEC components was 76.2 and 76.2%, and for Rb, it was 66.7 and 61.9%, respectively. For molecular alterations assessed by whole exome sequencing, the frequency of mutations in TP53, RB1, and EGFR in NEC and non-NEC components was 81.0/81.0%, 28.6/28.6%, and 42.9/42.9%, respectively. Immunohistochemistry was relatively more sensitive in Rb detection. The different components were found to have a common clonal origin based on the clonal evolution analysis of all 21 cases, which was consistent with previous studies on "HT". Our findings highlight the significance of evaluating the protein expression and gene status of TP53, RB1, and EGFR to discover the potential combined component or recognize the potential transformation cases. Therefore, our findings have strong implications in the clinical assessment of combined tumors. Histologic transformation (HT) is common following targeted therapy in adenocarcinoma. However, whether the transformed tumor is a new component or a combined neuroendocrine carcinoma (C-NEC) remains controversial. We aimed to explore the relationship between pulmonary C-NEC and HT. Macro-dissection was performed on different components of surgically resected C-NEC samples. Molecular alterations and clonal evolution were analyzed using whole exome sequencing (WES). The gene statuses for TP53 and RB1 were determined using immunohistochemistry (IHC) and WES to analyze the relationship between C-NEC and reported HT. Sixteen combined small-cell lung cancer patients and five combined large-cell neuroendocrine carcinoma patients were enrolled. The frequency of p53 and Rb inactivation, assessed using IHC in NEC and non-NEC components, was 76.2/76.2% and 66.7/61.9%, respectively. The expression consistency between the components was 81.0 and 85.7% for p53 and Rb, respectively. The frequencies of TP53, RB1, and EGFR mutations, assessed using WES in NEC and non-NEC components, were 81.0/81.0%, 28.6/28.6%, and 42.9/42.9%, respectively. The concordance rates for TP53, RB1, and EGFR were 90.5, 71.4, and 90.5%, respectively. The consistency rate between IHC and WES was 81.0 and 61.9% for TP53 and RB1, respectively. The different components had a common clonal origin for the 21 C-NECs in the clonal analysis, consistent with previous studies on HT. Our study shows that IHC is more sensitive for Rb detection and C-NEC, and the reported HT may be due to differences in evaluations between pathologist and clinicians. Assessing the p53/Rb and EGFR status for such cases would help in recognizing potential transformation cases or uncovering potential combined components. [ABSTRACT FROM AUTHOR]