SMARCA4 as a support for the differential diagnosis of poorly differentiated lung carcinomas.

Among non-small cell lung cancers (NSCLCs), sarcomatoid carcinomas account for 3%. They are rare tumours with a poor prognosis, classified into three subgroups, namely pleomorphic carcinoma, pulmonary blastoma and carcinosarcoma. In the 5th edition of WHO Classification of Thoracic Tumours more space is given to SMARC4-deficient lung cancers. Although studies on SMARCA4-deficient lung tumours are limited, a small percentage of SMARCA4 loss is present within NSCLCs. This finding is clinically relevant, as the loss of the SMARCA4 gene is associated with a worse prognosis. In our study, we analysed the presence of the main catalytic subunit of the SMARCA4 gene, the BRG1 protein, in 60 sarcomatoid lung tumours. The results of our study show that 5.3% of sarcomatoid carcinomas have BRG1-loss in tumour cells, proving that a non-negligible amount of lung sarcomatoid carcinomas are SMARCA4-deficient. These data open the debate on the necessity of including the detection of SMARCA4 within a standardised immunohistochemical panel.

Tracing Tumor Heterogeneity of Pleomorphic Carcinoma of the Lung.

INTRODUCTION: Pulmonary pleomorphic carcinoma (PPC) is an aggressive and highly heterogeneous NSCLC whose underlying biology is still poorly understood. METHODS: A total of 42 tumor areas from 20 patients with PPC were microdissected, including 39 primary tumors and three metastases, and the histologically distinct components were subjected to whole exome sequencing separately. We further performed in silico analysis of microdissected bulk RNA sequencing and methylation data of 28 samples from 14 patients with PPC. We validated our findings using immunohistochemistry. RESULTS: The epithelial and the sarcomatoid components of PPCs shared a large number of genomic alterations. Most mutations in cancer driver genes were clonal and truncal between the two components of PPCs suggesting a common ancestor. The high number of alterations in the RTK-RAS pathway suggests that it plays an important role in the evolution of PPC. The metastases morphologically and genetically resembled the epithelial or the sarcomatoid components of the tumor. The transcriptomic and epigenetic profiles of the sarcomatoid components of PPCs with matched squamous-like or adenocarcinoma-like components differed from each other, and they shared more similarities to their matched epithelial components. NCAM1/CD56 was preferentially expressed in the sarcomatoid component of squamous-like PPCs, whereas CDH1/E-Cadherin expression was down-regulated in the sarcomatoid component of most PPCs. CONCLUSION: Lung adenocarcinoma-like PPCs are mainly driven by RTK-RAS signaling, whereas epithelial-mesenchymal transition programs as highlighted by increased NCAM1 and decreased CDH1 expression govern the epithelial-sarcomatoid transition between the clonally related tumor components. Several alterations in PPCs pinpoint therapeutic opportunities.

Perioperative chemotherapy is not associated with improved survival in stage I pleomorphic lung cancer.

OBJECTIVES: Pulmonary pleomorphic carcinoma represents an understudied, rare, and aggressive histologic subtype of non-small cell lung cancer. Better understanding of rare disease subtypes allows for improved individualization of patient care. This study aimed to evaluate current trends in treatment and survival of pleomorphic carcinoma. METHODS: The National Cancer Database was used to identify patients with staged, pleomorphic carcinoma and adenocarcinoma between 2004 and 2015. Patient characteristics and treatments were compared using χ2 tests. Cox proportional hazard models examined survival by stage after controlling for confounders. Propensity score matched Kaplan-Meier curves estimated survivor functions stratified by stage. Differences in survival following treatment for stage I pleomorphic carcinoma with surgery alone versus surgery plus chemotherapy were compared with Cox proportional hazard models and Kaplan-Meier survival curves. RESULTS: One thousand four hundred eight patients with pleomorphic carcinoma and 607,561 patients with adenocarcinoma were identified. Pleomorphic carcinoma accounted for 0.1% of all non-small cell lung cancers. Pleomorphic disease had poorer overall 5-year survival compared with adenocarcinoma for stages I through IV (49.4% vs 59.1%, 34.5% vs 43.8%, 16.9% vs 28.4%, and 5.7% vs 7.8%, respectively; P < .0047 for all). Perioperative chemotherapy was used more frequently for pleomorphic disease (17.5% vs 6.1%; P < .001). For stage I pleomorphic cancer, treatment with surgery alone (n = 253) and surgery with chemotherapy (n = 57) had overall 5-year survival rates of 55.2% and 53.7%, respectively, and were not significantly different (P = .2868). CONCLUSIONS: Pulmonary pleomorphic carcinoma is rare and aggressive, with worse survival when compared with adenocarcinoma. Perioperative chemotherapy has not demonstrated significant survival benefits in stage I pleomorphic cancer.

Local and systemic immunity predict survival in patients with pulmonary sarcomatoid carcinoma.

Pulmonary sarcomatoid cancer (PSC) is a rare, aggressive subtype of non-small cell lung cancer, and measures of local and systemic immunity as biomarkers are incompletely known. We performed this study to characterize the leukocyte composition within the tumor, stroma, and peripheral blood in patients with PSC and correlated our findings with overall survival. Tissue from 30 patients diagnosed with PSC was evaluated by IHC for the presence of CD3+, CD14+, and CD19+ cells and PD-L1 expression. A lymphocyte-to-monocyte ratio (LMR) was calculated for the tumor microenvironment (TME) and peripheral blood. Survival analyses were performed based on IHC scores or groups defined by receiver operating characteristic curve cutoffs. CD3+ and CD14+ cells were found throughout the TME. CD19+ cells were almost exclusive to the stroma and correlated with superior overall survival (HR 0.40, 95% CI 0.21-0.72, p = 0.003). Most patients expressed PD-L1 on the tumor and/or the infiltrating immune cells, but neither the presence nor PD-L1 expression level impacted survival. A more prolific immune infiltration of the TME was associated with improved survival (HR 0.82, 95% CI 0.70-0.98, p = 0.029). PSC patients with a TME LMR ≥1.2 had a median survival of 1598 versus 488 days for a TME LMR <1.2 (p = 0.010). In the peripheral blood, an LMR ≥2.3 was associated with improved median survival (1579 vs. 332 days, p < 0.001). Our data demonstrate multiple measures of the local and systemic immunity are associated with patient survival in PSC.