Xiaoliang Zhao, Justine N. McCutcheon, Bhaskar Kallakury, Joeffrey J Chahine, Drew Pratt, Mark Raffeld, Yulong Chen, Changli Wang, Giuseppe Giaccone

Small-cell lung carcinoma (SCLC) accounts for 15-20% of all lung cancers, with combined SCLC (CSCLC) comprising 2-5%. Little is known about the clinical characteristics and molecular changes associated with the various histologic components. 205 SCLC cases were resected between 2005-2015. Clinical and pathologic features were analyzed. All CSCLC cases were confirmed by histology and immunohistochemistry. The individual components were microdissected using a novel automated dissection system and DNA was extracted and subjected to targeted exome sequencing. Ten cases of combined CSCLC were identified out of 170 cases with adequate histologic material; squamous cell carcinoma made up the second component in half of these (n=5). There were no significant differences between CSCLC and pure SCLC with respect to clinical features. The median follow-up time was 36 months. Median survival times of pure and CSCLC patients were 58 months and 26 months, respectively (p=0.030). The different components of 3 combined cases were deemed adequate for microdissection and sequencing. Approximately 75% of the identified somatic mutations were present in both components. There were also 15 gene mutations or 6 amplifications unique to only one of the components. We identified no significant clinical or pathologic differences between pure and CSCLC; CSCLC was associated with decreased overall survival compared to pure SCLC. The histologic components of CSCLC had high genetic concordance, but also showed divergent genotypes. These findings may suggest a common precursor with subsequent acquisition of oncogenic changes in CSCLC.