Morphological and molecular approach to synchronous non-small cell lung carcinomas: impact on staging

Abstract

Distinction between multiple primary cancers and intrapulmonary metastases in patients with synchronous multifocal lung cancer can be challenging. Histological and genotypic assessment of multifocal lung tumors have been suggested to influence the staging. The aim of this study was to determine the role of morphology and genotype in staging of surgically treated multifocal non-small cell lung carcinoma. Synchronous lung cancers from 60 patients (42 with adenocarcinoma and 18 with squamous cell carcinoma), clinically considered to represent intrapulmonary metastases, were histologically subtyped according to the 2015 World Health Organization classification of lung tumors and subjected to genotypic analysis (KRAS, EGFR, BRAF, PIK3CA, ALK, MET and ROS1 in adenocarcinoma and PIK3CA and p16 in squamous cell carcinoma). Concordance between clinical criteria and histological subtyping was identified in about 50% of cases (Po 0.0001). Genotypically, 44% of adenocarcinomas and 60% of squamous cell carcinomas with identified molecular alterations were considered to be intrapulmonary metastases. Concordance between histological and molecular staging was observed in 89% of adenocarcinomas and 56% of squamous cell carcinomas. Univariate survival analyses failed to demonstrate significant differences in overall or cancer-specific survival in patients with adenocarcinoma and squamous cell carcinomas restaged according to histology and/or molecular profile. Lymph node metastases (N1/N2 vs N0) (P = 0.03) and age 465 years (P = 0.05) were associated with shorter overall survival. In addition, squamous cell carcinomas with p16 deletion showed shorter overall survival when compared with squamous cell carcinomas without p16 deletion (P = 0.05). No correlation between other molecular alterations, clinico-pathological characteristics and prognosis was found. Our study demonstrates that a comprehensive genotypic and morphological assessment of surgically treated multifocal lung cancers is feasible but not sufficient to establish their clonal relationship and prognosis. Modern Pathology (2016) 29, 735-742; doi:10.1038/modpathol.2016 published online 15 April 2016 The reported incidence of multiple synchronous tumors of the lung in recent series is up to 20%. 1,2 Staging of such tumors as independent primary tumors or intrapulmonary metastases is often challenging. Morphological criteria, especially those proposed by Martini and Melamed, 3 have been used as the main tool with the idea that morphology of metastases should match the primary tumor, while different morphology supports classification of tumors as unrelated separate primaries. However, clinico-pathological distinction between the two possibilities is not always possible and may not be prognostic.Over the past decade, multiple studies using different molecular approaches to analysis of synchronous lung tumor nodules have emerged, including DNA microsatellite analysis, CGH/aCHG and most recently next-generation sequencing. 2,[4][5][6][7][8][9][10] The data from published rep...

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

“…These findings along with studies utilizing DNA microsatellite analysis [25], [26], loss of heterozygosity [47], comparative genomic hybridization [28], and immunohistochemistry [24] highlight the importance of using genomic profiling in conjunction with clinicopathological criteria in order to better differentiate independent primary tumors from intrapulmonary metastasis [25], [26], [27], [28], [29], [36], [48], [49]. Recent investigations stress the significance of a multidisciplinary approach for studying the clonal relationship of multifocal lung tumors [50].…”

Targeted sequencing may facilitate differential diagnostics of pulmonary tumours: a case series

“…A recent study by Schneider and co-workers showed a concordance between histological (Martini and Melamed criteria [19]) and molecular classification of synchronous primary lung cancers vs. intrapulmonary metastasis in 24 of 27 adenocarcinomas (89%) using a panel of seven genes (analysis with Sanger sequencing and FISH) [47]. In that study, two cases with different morphological features exhibited the same KRAS mutation (similar to our case 5) while one case with morphologically similar tumours had discordant KRAS mutation status suggesting separate synchronous primary tumours (like our case 4).…”

Lung Carcinoma Staging Update

“…19,20 In molecularly inconclusive cases, morphologic subtyping may be more informative. 17,21 It is interesting that the results of comparative genomic hybridization have been proposed as criteria for distinguishing second primary tumors from intrapulmonary metastases. Although there are research studies supporting that recommendation, solid tumors are not routinely subjected to comparative genomic hybridization assays in the clinical practice.…”

“…9 Several studies have demonstrated concordance between gene mutation and rearrangement profiles and tumor morphology, although discordant results with Martini and Melamed criteria 8 were reported in up to 50% of the cases. [10][11][12][13][14][15][16][17] The assumption is that the matched-driver mutations or gene rearrangements define the tumors as clonally related, whereas discordant molecular abnormalities suggest independent primary tumors. Earlier studies using a few genes indicated a broad range of discordance (25%-49%) in driver mutations between primary and metastatic lung tumors, but most recent studies using a next-generation sequencing approach have demonstrated much greater concordance (94%).…”