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Introduction: Xenograft models of epithelial malignancies potentially have greater correlation with clinical end points. We implanted 153 primary non–small cell lung carcinomas into non-obese diabetic-severe combined immunodeficient mice to develop primary lung cancer xenografts. Sixty-three xenografts formed. However, in 19 implantations, tumors consisted of a lymphocyte proliferation without a carcinoma component. We further characterized these lymphomas to determine clinicopathological features associated with their formation. Methods: Lymphomas were investigated morphologically and by silver in situ hybridization to determine their species of origin. Characterization both of the xenograft lymphomas and the primary NSCLCs from which they were derived included immunohistochemistry for lymphoma markers and Epstein Barr virus Early RNA (EBER) by in situ hybridization. DNA was profiled using the MassARRAY platform; EML4-ALK translocations and lymphocyte infiltration were assessed in the primary tumor. Lymphoma formation was correlated with patient and primary tumor characteristics and survival. Results: The lymphocytic tumors were EBER positive, human diffuse large B-cell lymphomas (DLBCLs). Significantly more DLBCLs that formed in mice arose in primary lung adenocarcinomas and in epithelial growth factor receptor mutant never smokers. DLBCL formation was not associated with the degree of tumor-infiltrating lymphocytes or EBER-positive lymphocytes in the primary NSCLCs. Patients whose tumors developed DLBCL had longer disease-free survival compared with patients whose tumors formed epithelial xenografts (hazard ratio: 0.44; 95% confidence interval: 0.18 -1.06, Wald p = 0.07), regardless of genotype. Conclusion: We hypothesize that mechanisms involved in the active suppression of viral antigens may also be involved in the suppression of tumor antigens, and may have resulted in the observed favorable clinical outcome.

Introduction: Phosphatase and tensin homolog (PTEN) has been established as a tumor suppressor gene with an important role in regulating the phosphatidylinositol-3-kinase/AKT antiapoptotic and survival pathway. The prognostic role of PTEN in non–small-cell lung carcinoma has not been evaluated completely in the context of other molecular information. Methods: Tissue microarrays containing 152 resected non–small-cell lung cancer specimens were used to investigate PTEN and p53 by immunohistochemistry and PTEN by fluorescence in situ hybridization. DNA was isolated and subjected to mutational profiling using the Sequenom Oncocarta v1.0 panel. Clinicopathological features were correlated with PTEN expression, gene copy number, and mutation status. Results: PTEN staining was absent in 63 (41.4%) of the cases. Significantly more squamous cell carcinomas compared with adeno carcinomas demonstrated loss of (negative) PTEN staining (26 of 44 [59%] versus 32 of 94 [34%]; p = 0.009). PTEN gene copy deletion was present in only seven of 124 evaluable cases (5.6%); all deleted cases were immunohistochemistry negative. In univariate and multivariate (MV) analyses adjusted for sex, age, histology, and stage, loss of PTEN protein expression was associated with significantly shorter disease-free survival (MV hazard ratio: 1.78, 95% confidence interval: 1.01–3.14, p = 0.048), whereas no significant associations were seen with p53 or KRAS and epidermal growth factor receptor (EGFR) mutation status. Importantly, the prognostic value of absent PTEN staining was limited to adenocarcinomas, with MV diseasefree survival hazard ratio of 2.68 (95% confidence interval: 1.35– 5.32, p = 0.005), whereas no such association was seen in squamous cell carcinomas. Conclusion: Absence of PTEN protein expression is an independent prognostic marker in early-stage resected lung adenocarcinoma.

The reported prevalence for presence of human papillomavirus (HPV) genome in lung cancer varies across the world, and limited data are available for North America. P16 immunostaining is used as a surrogate marker for the presence of HPV in cervical and head and neck cancers. In non-small cell lung carcinoma (NSCLC), the association between P16 protein overexpression and HPV remains unclear. We investigated the presence of HPV genome by in situ hybridization (ISH) and polymerase chain reaction (PCR) and P16 or Rb protein expression by immunohistochemistry (IHC) in 336 surgically resected primary NSCLC: 204 adenocarcinoma (AdC) and 132 squamous cell carcinoma (SqCC). HPV genome was detected in 5 (1.5%) of 336 tumors studied by both ISH and PCR; all of them were typed as HPV16 and found in SqCC (3.8%). Despite being solitary tumors and clinically considered as primary lung cancers, all 5 patients had past history of HPV associated squamous cell carcinomas of other organ sites, thus highly suggestive of being metastases. P16 immunostaining was found in 137 (40.8%) tumors, with 109 (32.4%) showing high level expression. All HPV positive (+) cases showed P16 high expression. P16 and Rb protein expressions were inversely correlated (P