Risk of Pathologic Extranodal Extension and Other Adverse Features After Transoral Robotic Surgery in Patients With HPV-Positive Oropharynx Cancer.

Importance: Understanding patient-specific risk of adverse histopathologic findings after primary surgery for human papillomavirus (HPV)-positive oropharynx squamous cell carcinoma (OPSCC) may help guide patient consultations. Objective: To determine the likelihood of adverse histopathologic features that may indicate adjuvant radiotherapy or chemoradiotherapy after primary surgery for HPV-positive OPSCC according to 2021 National Comprehensive Cancer Network guidelines. Design, Setting, and Participants: This retrospective cohort study was performed at a single academic tertiary care center. Of 258 patients who underwent transoral robotic surgery (TORS) from March 1, 2012, to March 1, 2021, 136 consecutive, treatment-naive patients with HPV-positive OPSCC without obvious clinical extranodal extension (ENE) who underwent definitive TORS and neck dissection were included in the analysis. Indications for surgical treatment included non-deeply infiltrative oropharynx tumors, minimal soft palate involvement, and low suspicion for pathologic ENE. Exposures: Primary site TORS with neck dissection. Main Outcomes and Measures: The primary outcomes were the adverse histopathologic features of pathologic ENE and positive surgical margins (PSM) that are indications for possible adjuvant chemoradiotherapy. Outcomes were compared among varying American Joint Committee on Cancer 7th edition (AJCC-7) T and N categories and patient clinical characteristics. Results: Of the 136 patients included in the analysis (113 men [83.1%]; median age, 63 [interquartile range, 55-70] years), 109 (80.1%) had at least 1 indication for possible adjuvant radiotherapy. Twenty-seven patients (19.9%) had pathologic ENE and 10 (7.3%) had PSM. Thirty-four patients (25.0%) had pathologic ENE and/or PSM, whereas 3 (2.2%) had both. Age, smoking history, history of alcohol consumption, and clinical T category were not associated with pathologic ENE, PSM, lymphovascular invasion, perineural invasion, or pN2 category or greater. The proportion of pathologic ENE varied by clinical N category: 0 of 16 for cN0, 8 of 48 (16.7%) for cN1, 3 of 23 (13.0%) for cN2a, and 16 of 45 (35.6%) for cN2b. Compared with patients with cN1-cN2a disease, patients with cN2b disease had higher odds of pathologic ENE (odds ratio, 3.01; 95% CI, 1.14-8.10). Clinical and pathologic N category were concordant in 77 patients (56.6%), whereas 42 (30.9%) were upstaged and 17 (12.5%) were downstaged. Conclusions and Relevance: In this cohort study, approximately one-quarter of carefully selected patients with HPV-positive OPSCC without obvious clinical ENE undergoing primary surgery had pathologic ENE and/or PSM. Patients with AJCC-7 cT0-cT2 cN0-cN2b disease, especially cN0-cN2a, without signs of clinical ENE may represent appropriate candidates for primary surgery when avoidance of adjuvant chemotherapy and/or reduction of adjuvant radiotherapy dose/extent are the goals.

Increasing prevalence of human papillomavirus-positive oropharyngeal cancers among older adults.

BACKGROUND: The incidence of oropharyngeal squamous cell carcinoma (OPSCC) is increasing among older adults. It is unknown whether these trends can be explained by human papillomavirus (HPV) and whether HPV-related tumors remain associated with an improved prognosis among older patients. METHODS: In a retrospective study of OPSCCs diagnosed from 1995 to 2013 at 2 National Comprehensive Cancer Network-designated cancer centers, p16 immunohistochemistry and in situ hybridization (ISH) for HPV-16, high-risk DNA, and/or E6/E7 RNA were performed. The median age at diagnosis was compared by p16 and ISH tumor status. Trends in age were analyzed with nonparametric trends. Survival was analyzed with the Kaplan-Meier method and Cox proportional hazards models. RESULTS: Among 239 patients, 144 (60%) were p16-positive. During 1998-2013, the median age increased among p16-positive patients (Ptrend = .01) but not among p16-negative patients (Ptrend = .71). The median age of p16-positive patients increased from 53 years (interquartile range [IQR] in 1995-2000, 45-65 years) to 58 years (IQR for 2001-2013, 53-64 years). Among patients ≥ 65 years old, the proportion of OPSCCs that were p16-positive increased from 41% during 1995-2000 to 75% during 2007-2013 (Ptrend = .04). Among all age groups, including older patients, a p16-positive tumor status conferred improved overall survival in comparison with a p16-negative status. CONCLUSIONS: The median age at diagnosis for HPV-related OPSCC is increasing as the proportion of OPSCCs caused by HPV rises among older adults. The favorable survival conferred by an HPV-positive tumor status persists in older adults. Cancer 2018;124:2993-9. © 2018 American Cancer Society.

Genome-wide methylation profiling and the PI3K-AKT pathway analysis associated with smoking in urothelial cell carcinoma.

Urothelial cell carcinoma (UCC) is the second most common genitourinary malignant disease in the USA, and tobacco smoking is the major known risk factor for UCC development. Exposure to carcinogens, such as those contained in tobacco smoke, is known to directly or indirectly damage DNA, causing mutations, chromosomal deletion events and epigenetic alterations in UCC. Molecular studies have shown that chromosome 9 alterations and P53, RAS, RB and PTEN mutations are among the most frequent events in UCC. Recent studies suggested that continuous tobacco carcinogen exposure drives and enhances the selection of epigenetically altered cells in UCC, predominantly in the invasive form of the disease. However, the sequence of molecular events that leads to UCC after exposure to tobacco smoke is not well understood. To elucidate molecular events that lead to UCC oncogenesis and progression after tobacco exposure, we developed an in vitro cellular model for smoking-induced UCC. SV-40 immortalized normal HUC1 human bladder epithelial cells were continuously exposed to 0.1% cigarette smoke extract (CSE) until transformation occurred. Morphological alterations and increased cell proliferation of non-malignant urothelial cells were observed after 4 months (mo) of treatment with CSE. Anchorage-independent growth assessed by soft agar assay and increase in the migratory and invasive potential was observed in urothelial cells after 6 mo of CSE treatment. By performing a PCR mRNA expression array specific to the PI3K-AKT pathway, we found that 26 genes were upregulated and 22 genes were downregulated after 6 mo of CSE exposure of HUC1 cells. Among the altered genes, PTEN, FOXO1, MAPK1 and PDK1 were downregulated in the transformed cells, while AKT1, AKT2, HRAS, RAC1 were upregulated. Validation by RT-PCR and western blot analysis was then performed. Furthermore, genome-wide methylation analysis revealed MCAM, DCC and HIC1 are hypermethylated in CSE-treated urothelial cells when compared with non-CSE exposed cells. The methylation status of these genes was validated using quantitative methylation-specific PCR (QMSP), confirming an increase in methylation of CSE-treated urothelial cells compared to untreated controls. Therefore, our findings suggest that a tobacco signature could emerge from distinctive patterns of genetic and epigenetic alterations and can be identified using an in vitro cellular model for the development of smoking-induced cancer.

Multidisciplinary service utilization pattern by advanced head and neck cancer patients: a single institution study.

Purpose. To analyze the patterns and associations of adjunctive service visits by head and neck cancer patients receiving primary, concurrent chemoradiation therapy. Methods. Retrospective chart review of patients receiving adjunctive support during a uniform chemoradiation regimen for stages III-IV head and neck squamous cell carcinoma. Univariate and multivariate models for each outcome were obtained from simple and multivariate linear regression analyses. Results. Fifty-two consecutive patients were assessed. Female gender, single marital status, and nonprivate insurance were factors associated with an increased number of social work visits. In a multivariate analysis, female gender and marital status were related to increased social work services. Female gender and stage IV disease were significant for increased nursing visits. In a multivariate analysis for nursing visits, living greater than 20 miles between home and hospital was a negative predictive factor. Conclusion. Treatment of advanced stage head and neck cancer with concurrent chemoradiation warrants a multidisciplinary approach. Female gender, single marital status, and stage IV disease were correlated with increased utilization of social work and nursing services. Distance over 20 miles from the center was a negative factor. This information may help guide the treatment team to allocate resources for the comprehensive care of patients.

The molecular biology of laryngeal cancer.

Novel techniques have led to the discovery of many genes and gene products important in the development of HNSC and laryngeal cancer. Tumor suppressive genes and oncogenes have been identified, and many of their roles have been elucidated in a genetic progression model. As these molecular pathways become better understood, the information obtained will increasingly be used to guide patient therapy. Specifically, advances will probably be made in (1) molecular characterization of steps leading to laryngeal cancer; (2) molecular screening, staging, and surveillance; (3) molecularly based therapy, including gene transfer and small molecule therapy directed at specific molecular pathways involved in neoplasia; and (4) characterization of patients who are at high risk for laryngeal cancer. In the final analysis, however, smoking cessation for those at risk for head and neck cancer would have greater effect than all these efforts combined.