Utility of Genomic Analysis in Differentiating Synchronous and Metachronous Lung Adenocarcinomas from Primary Adenocarcinomas with Intrapulmonary Metastasis

Abstract

Distinguishing synchronous and metachronous primary lung adenocarcinomas from adenocarcinomas with intrapulmonary metastasis is essential for optimal patient management. In this study, multiple lung adenocarcinomas occurring in the same patient were evaluated using comprehensive histopathologic evaluation supplemented with molecular analysis. The cohort included 18 patients with a total of 52 lung adenocarcinomas. Eleven patients had a new diagnosis of multiple adenocarcinomas in the same lobe (n = 5) or different lobe (n = 6). Seven patients had a history of lung cancer and developed multiple new tumors. The final diagnosis was made in resection specimens (n = 49), fine needle aspiration (n = 2), and biopsy (n = 1). Adenocarcinomas were non‐mucinous, and histopathologic comparison of tumors was performed. All tumors save for one were subjected to ALK gene rearrangement testing and targeted Next Generation Sequencing (NGS). Using clinical, radiologic, and morphologic features, a confident conclusion favoring synchronous/metachronous or metastatic disease was made in 65% of patients. Cases that proved challenging included ones with more than three tumors showing overlapping growth patterns and lacking a predominant lepidic component. Genomic signatures unique to each tumor were helpful in determining the relationship of multiple carcinomas in 72% of patients. Collectively, morphologic and genomic data proved to be of greater value and achieved a conclusive diagnosis in 94% of patients. Assessment of the genomic profiles of multiple lung adenocarcinomas complements the histological findings, enabling a more comprehensive assessment of synchronous, metachronous, and metastatic lesions in most patients, thereby improving staging accuracy. Targeted NGS can identify genetic alterations with therapeutic implications.

Comparative mutational evaluation of multiple lung cancers by multiplex oncogene mutation analysis

“…Finally, the number of targeted genes in our NGS panel may be relatively small. Recent studies on mutational analysis using NGS have included a larger number of targeted genes than we did . Begg et al indicated that at least 20 markers are required from a statistical perspective to distinguish between clonal and independent tumors with high accuracy .…”

“…With the advances in high‐throughput sequencing technologies, mutational analysis for specific driver and suppressor genes has been shown to be useful for distinguishing between multiple primary tumors and pulmonary metastases . In recent years, in patients with MLC, several reports have been published of mutational analyses by NGS, which allows analysis for multiple gene mutations at once . In this study, we investigated the mutational profiles by NGS of 20 lung cancer‐related genes in surgically resected paired tumors obtained from the same patients and compared the clinicopathological diagnoses with the diagnoses based on mutational evaluation.…”

“…[11][12][13] In recent years, in patients with MLC, several reports have been published of mutational analyses by NGS, which allows analysis for multiple gene mutations at once. 14,15 In this study, we investigated the mutational profiles by NGS of 20 lung cancer-related genes in surgically resected paired tumors obtained from the same patients and compared the clinicopathological diagnoses with the diagnoses based on mutational evaluation. In histopathologically IM cases, we found a good concordance rate (86%) with the diagnosis based on the mutational evaluation.…”

“…Recent studies on mutational analysis using NGS have included a larger number of targeted genes than we did. 14,15 Begg et al indicated that at least 20 markers are required from a statistical perspective to distinguish between clonal and independent tumors with high accuracy. 25 In the present study, although we analyzed 20 lung cancerrelated genes, paired tumors from five patients (cases 10, 11, 14, 23, and 31) failed to show any mutations.…”

Different EGFR gene mutations in two patients with synchronous multiple lung cancers: A case report

“…Most recently, next‐generation sequencing assays for the detection of genomic alterations with therapeutic, diagnostic, and prognostic significance in lung cancer have been routinely utilized in major medical centers. Saab et al reviewed 18 patients with a total of 52 lung adenocarcinomas to evaluate the efficacy of comprehensive histopathological evaluation supplemented with molecular analysis using next‐generation sequencing . The combined morphological and genomic data approach proved to be of significant value and achieved a conclusive diagnosis in 94% of the patients tested.…”