Heterogeneity of large cell carcinoma of the lung: an immunophenotypic and miRNA-based analysis.

Large cell carcinomas (LCCs) of the lung are heterogeneous and may be of different cell lineages. We analyzed 56 surgically resected lung tumors classified as LCC on the basis of pure morphologic grounds, using a panel of immunophenotypic markers (adenocarcinoma [ADC]-specific, thyroid transcription factor-1, cytokeratin 7, and napsin A; squamous cell carcinoma [SQCC]–specific, p63, cytokeratin 5, desmocollin 3, and Δnp63) and the quantitative analysis of microRNA-205 (microRNA sample score [mRSS]). Based on immunoprofiles 19 (34%) of the cases were reclassified as ADC and 14 (25%) as SQCC; 23 (41%) of the cases were unclassifiable. Of these 23 cases, 18 were classified as ADC and 5 as SQCC according to the mRSS. Our data show that an extended panel of immunohistochemical markers can reclassify around 60% of LCCs as ADC or SQCC. However, a relevant percentage of LCCs may escape convincing immunohistochemical classification, and mRSS could be used for further typing, but its clinical relevance needs further confirmation. Large cell carcinoma (LCC) of the lung is 1 of 4 major histopathologic tumor subtypes recognized by current classifications of lung tumors. However, although squamous cell carcinoma (SQCC), adenocarcinoma (ADC), and small cell carcinoma are well-defined entities with typical morphologic, immunophenotypic, and molecular features, LCCs, with the exception of the rare neuroendocrine, rhabdoid, basaloid, and lymphoepithelioma-like subtypes, are defined as poorly differentiated non–small cell tumors lacking features of ADC and SQCC. Therefore, the term LCC has frequently and improperly been used as a synonym of undifferentiated non–small cell lung carcinoma (NSCLC) and has been used as a “wastebasket” for tumors lacking a definite morphologic pattern. Studies show that, by using ancillary techniques, a relevant percentage of LCCs could be reclassified as SQCC or ADC. Gene profiling shows that most LCCs have profiles quite similar to ADC or SQCC. 1-3 Similarly, by using appropriate immunohistochemical stains, almost two thirds of LCCs can be reclassified as poorly differentiated ADC or SQCC. 4,5 These studies have profound clinical relevance because rendering a diagnosis of LCC may represent a challenge for oncologists who need accurate subtyping of lung cancers to provide patients with optimal targeted chemotherapeutic agents, showing different efficacy with specific NSCLC categories (usually effective for ADC and not for others). 6,7