This article is a continuation of the "Do You Know Your Guidelines" series. This was launched as an initiative of the American Head and Neck Society to increase the awareness of current best practices pertaining to head and neck cancer. The National Comprehensive Cancer Network (NCCN) guidelines for managing cancer of the paranasal sinuses are reviewed in a systematic fashion. These guidelines outline the workup, treatment, and surveillance of patients with cancer of the maxillary and ethmoid sinuses.

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The human papillomavirus (HPV) expresses the viral oncogene E7 that inhibits the retinoblastoma protein (RB1). RB1 mediates contradictory cell growth and cell death pathways via E2F family members. Here, we assessed the extent to which HPV oncogenes caused toxicity as measured by mouse survival and tumor growth. Materials/Methods: iHPV mice contained a LoxP-Stop-LoxP (LSL)-iE6E7 transgene in which conditional E6E7 expression is regulated by Cre recombinase. We constitutively expressed HPV oncogenes by breeding iHPV transgenic mice to CMV-Cre transgenic mice expressing Cre recombinase under a CMV promoter (CMV-HPV mice). We induced HPV oncogene expression in adult mice using RosaHPV mice containing the iHPV transgene and a Rosa-CreER tam transgene expressing a tamoxifenregulated (TAM) regulated Cre recombinase in all tissues. We studied primary oral tumors using triple transgenic KHR mice containing a K14-CreER tam transgene, a LSL-iE6E7 transgene and a LSL-Kras G12D transgene that formed HPV-positive oral tumors after TAM treatment. We assessed the role of E2f1 on survival and oral tumor formation using RosaHPV-E2f1-/mice and KHR-E2f1-/mice, respectively, that contained a homozygous E2f1deletion. HPV oncogene expression and E2f target gene expression was assessed by quantitative RT-PCR. Results: Induction of HPV oncogenes caused embryonic lethality as CMV-HPV double transgenic mice were born at significantly lower frequencies compared to mice carrying single transgenes (P<.0001). Tamoxifen treatment of adult RosaHPV (RosaHPV+TAM) mice caused recombination of the LSL-E6E7 transgenes and HPV oncogene expression in all organs tested. Furthermore, RosaHPV+TAM mice had decreased survival compared to vehicle treated RosaHPV mice (median survival: 50d for RosaHPV+TAM vs not reached for RosaHPV-TAM; P<.0001). Decreased survival in RosaHPV+TAM mice was associated with focal necrosis in hepatocytes and pancreatic tissues and the activation of the E2f target genes. Deletion of E2f1 increased survival of RosaHPV+TAM mice indicating that E2f1 mediated HPV oncogene toxicity (median survival: not reached for RosaHPV-E2f1-/mice vs 49 days for RosaHPV-E2f1 +/mice vs 30 days for RosaHPV-E2f1 +/+ ; P<.0001). Compared to tumors with heterozygous loss of E2f1, KHR tumors with homozygous loss of E2f1 grew faster and had more proliferating tumor cells as measured by Pcna immunohistochemistry (tumor volume at d18: 453.7 mm 3 for KHR-E2f1-/vs 139.7 mm 3 for KHR-E2f1 +/-; PZ.0004). Conclusion: Our results indicate that HPV oncogenes activated the E2f1 pathway to cause toxicity in normal mice and to suppress oral tumor growth. These results suggest that selective modulation of the E2f1 pathway, which is activated in HPV tumors, may facilitate tumor regression.

Background: The aim of this study is to address the paucity of data on the potentially unique patterns of neck nodal metastases in HPV-positive oropharyngeal squamous cell carcinoma (HPV+OPSCC). Methods: The neck dissection (ND) specimens of varying levels of HPV+OPSCC patients at University of California-San Francisco from 2010-2016 were reviewed for the numbers and frequencies of clinically evident and occult nodes by neck level, and for those with extra-capsular spread (ECS). Smoking history (&gt;10 pack-years), T status, and local, regional and distal recurrences were also assessed for possible associations with nodal metastatic behavior. Results: Sixty HPV+OPSCC patients underwent primary site trans-oral robotic surgery and 65 NDs, of which 21 (32%) were elective. Forty-three (65%) NDs were in non-smokers. Overall, the mean number of positive nodes per ND was 2.5 (range 1-9). The frequencies of at least one pathologically positive node for neck levels 1b, 2, 2a, 2b, 3, 4, and 5 were 0% (0/41), 67.7% (44/65), 43% (23/53), 13% (7/53), 27.7% (18/65), 7% (4/54), and 8% (2/23), respectively. All positive level 5 positive nodes were clinically evident preoperatively. Five of 21 (24%) elective NDs had occult disease only in levels 2A, 2B, and 3, with a mean number of positive nodes of 1.8 (range 1-3). Three of 21 (14%) elective NDs had nodes with ECS. Six of 44 (13%) therapeutic NDs had occult nodes outside the known preoperative distribution in levels 2b, 3 and 4. There were no occult 2a nodes. Smoking history, primary site, and T status were not statistically significantly associated with a differing metastatic nodal behavior. Twenty-three of 60 and 18 of 60 patients underwent adjuvant radiation and adjuvant chemoradiation, respectively. Thirteen of the 19 patients who only underwent surgery had positive lymph nodes, of which five had N1 disease and four had N2b disease. All four of N2b disease patients refused adjuvant therapy and none have had a recurrence as of follow-up (mean 28 months, range 3-51). The overall mean follow-up was 29.1 months (range 2-76 months), with 72% of patients having at least 12 months. One of 65 (1.5%) NDs developed a neck recurrence in the skin overlying level 2 in a patient in the therapeutic ND cohort who had undergone chemoradiation for ECS. No undissected neck levels developed metastatic nodal disease. Two of 60 (3%) patients developed local recurrence. No patients developed distant metastases. One patient in the cohort died of an unrelated cause. There have been no cancer-related deaths. Conclusions: For HPV+OPSCC, therapeutic NDs should encompass any levels bearing suspicious nodes and levels 2a, 2b, 3, and 4, while elective NDs should be performed and encompass at least levels 2a, 2b, and 3. ECS may be present in occult nodes. For HPV+OPSCC, these selective ND plans, followed by the indicated adjuvant treatment, is associated with a low neck recurrence rate. Citation Format: Madeleine P. Strohl, Steven J. Wang, Patrick K. Ha, Jonathan R. George, Chase M. Heaton, Ivan H. El-Sayed, Jon Mallen St Clair, William R. Ryan. Patterns of neck nodal metastases and recurrence in human papilloma virus-associated oropharyngeal squamous cell carcinoma after neck dissection [abstract]. In: Proceedings of the AACR-AHNS Head and Neck Cancer Conference: Optimizing Survival and Quality of Life through Basic, Clinical, and Translational Research; April 23-25, 2017; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(23_Suppl):Abstract nr 17.