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Background: Oral cavity squamous cell carcinomas (OCSCCs) are relatively common in multiple non-human primate species but are poorly documented in Goeldi's monkeys., Methods: Four Goeldi's monkeys with OCSCC, from three zoological collections, underwent necropsy with cytology, histopathology, immunohistochemistry, and pan-herpesvirus PCR analysis., Results: All animals were euthanised and exhibited poor-to-emaciated body condition. Three OCSCCs arose from the maxillary oral mucosa and a single OCSCC was primarily mandibular, with bone invasion evident in three cases. Histologically, one OCSCC in situ was diagnosed, whilst the rest were typically invasive OCSCCs. Neoplastic cells were immunopositive for pancytokeratin and E-cadherin. All examined cases were negative for regional lymph node (RLN) and/or distant metastases, cyclooxygenase-2 (COX-2) immunoexpression, and panherpesvirus PCR expression., Conclusions: OCSCCs in Goeldi's monkeys may be deeply invasive, but not readily metastatic. No herpesvirus-association or COX-2 expression was evident; the latter suggesting that NSAIDs are unlikely to be a viable chemotherapeutic treatment., (© 2024 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Objective: Assess the testing rates and prognostic significance of human papilloma virus (HPV) status in hypopharynx malignancies., Study Design: Historical cohort study., Setting: National Cancer Database., Methods: Review of the National Cancer Database was conducted between 2010 and 2017 for squamous cell carcinomas (SCCs) of the hypopharynx. We investigated how often the tumors were tested for HPV and whether it was associated with survival outcomes., Results: A total of 13,269 patients with hypopharynx malignancies were identified. Most cases were not tested for HPV status (n = 8702, 65.6%). Of those tested, 872 (19.1%) were positive for HPV and 3695 (80.9%) were negative. The proportion of nonoropharyngeal SCCs tested for HPV increased nearly every year during the study, with roughly one-third of cases (31.9%) being tested in 2017. In the facilities classified as high-testing centers of nonoropharyngeal SCCs of the head and neck, 18.7% of hypopharyngeal tumors were HPV positive. HPV-negative status was associated with worse survival on multivariable analysis. In propensity score-matched analysis controlling for all factors significant in multivariable regression, 2-year survival remained higher in the HPV-positive cohort (77.7% vs 63.1%, P < .001)., Conclusions: HPV-positive tumors constitute a sizable minority of hypopharynx tumors and are associated with improved survival. Expansion of HPV testing to hypopharynx malignancies may be warranted.

Introduction: Human papillomavirus (HPV), p16, and p53 have been investigated as prognostic markers in various HPV-related cancers. Within the field of vaginal cancer, however, the evidence remains sparse. In this systematic review, we have compiled the presently published studies on the prognostic significance of HPV and immunohistochemical expression of p16 and p53 among women with vaginal cancer., Material and Methods: We conducted a systematic search of PubMed, Embase, and Cochrane Library to identify relevant studies published until April 2021. We included studies reporting survival after histologically verified vaginal cancers tested for HPV, p16, and/or p53. Survival outcomes included overall survival, disease-free survival, disease-specific survival, and progression-free survival., Results: We included a total of 12 studies. The vast majority of vaginal cancer cases included in each study were squamous cell carcinomas (84%-100%). Seven studies reported survival after vaginal cancer according to HPV status, and the majority of these studies found a tendency towards improved survival for women with HPV-positive vaginal cancer. Three out of four studies reporting survival according to p16 status found an improved survival among women with p16-positive vaginal cancer. For p53, only one of six studies reported an association between p53 expression and survival., Conclusions: This systematic review suggests that women with HPV- and p16-positive vaginal cancer have an improved prognosis compared with those with HPV- or p16-negative vaginal cancer. Results for p53 were varied, and no conclusion could be reached. Only 12 studies could be included in the review, of which most were based on small populations. Hence, further and larger studies on the prognostic impact of HPV, p16, and p53 in vaginal cancer are warranted., (© 2021 The Authors. Acta Obstetricia et Gynecologica Scandinavica published by John Wiley & Sons Ltd on behalf of Nordic Federation of Societies of Obstetrics and Gynecology (NFOG).)

Objective: For human papillomavirus-associated oropharynx carcinoma treated with definitive surgery, we aimed to find predictors of adverse histopathology indicating the possible need for adjuvant therapy., Study Design: Retrospective review., Setting: National Cancer Database., Methods: We analyzed 2347 eligible patients from 2010 to 2015. We evaluated (1) the ability of clinical nodal staging and extranodal extension designation per the AJCC, seventh edition (American Joint Committee on Cancer), to predict histopathology and (2) the likelihoods for adverse postsurgery histopathology by common clinical stages., Results: Clinical nodal staging predicted pathologic nodal staging 65% of the time, with 24% (569/2347) being upstaged and 11% (251/2347) being downstaged. In patients with cN+ disease, clinical extranodal extension distinction had the following accuracy for pathologic extranodal extension: positive predictive value, 81% (88/109); negative predictive value, 73.1% (505/691); sensitivity, 32.1% (88/274); and specificity, 96.0% (505/526). Patients with cT1-2, N0-N2c, without clinical extranodal extension had the following proportions of pN2+ without pathologic extranodal extension (indicating consideration for adjuvant radiation): cN0, 11%; cN1, 31%; cN2a, 67% (8% downstaged); cN2b, 66% (6% downstaged); and cN2c, 35% (17% downstaged). From this group, patients had the following proportions of pathologic extranodal extension (indicating consideration for adjuvant chemoradiation): cN0, 6%; cN1, 20%; cN2a, 27%; cN2b, 28%; and cN2c, 48%., Conclusion: For human papillomavirus-associated oropharynx carcinoma, nodal clinical staging per the American Joint Committee on Cancer, seventh edition, predicts pathologic stage about two-thirds of the time, leading to up- and downstaging. Clinical extranodal extension assessment has low sensitivity and moderate predictive capability. With careful selection, definitive surgery can allow patients to often avoid adjuvant chemotherapy and sometimes avoid adjuvant radiation.

Objective: To explore the survival implications of human papillomavirus (HPV) positivity and subtype in larynx cancer through a national cancer database. To investigate staging discrepancies in larynx cancer associated with HPV status., Study Design: Retrospective observational cohort study., Setting: National Cancer Database., Methods: Data were extracted concerning adults with known HPV status who were treated between 2010 and 2016 for laryngeal squamous cell carcinoma. Patients without known HPV subtype were excluded. Cox multivariable regression models were fit to evaluate the survival impact of HPV status, characterized as a binary variable (HPV+ vs HPV-) and by subtype. Two- and 5-year survival rates were calculated via the Kaplan-Meier method and compared by stage between the HPV+ and HPV- cohorts per the log-rank test., Results: Patients with HPV+ larynx cancer were younger (60.5 vs 64.3 years, P < .001), more likely to have private insurance (37.2% vs 31.2%, P < .001), more commonly White (84.6% vs 82.4%, P = .013), and more likely to present with nodal disease (42.6% vs 33.0%, P < .001). HPV positivity and HPV subtype 16 were associated with improved overall survival. One-stage discrepancies in 5-year survival were observed between the HPV+ and HPV- cohorts: stage II HPV+ (69.45%) vs stage I HPV- (65.77%); stage IV HPV+ (47.67%) vs stage III HPV- (46.80%)., Conclusions: HPV positivity and infection with HPV subtype 16 are correlated with improved overall survival in patients with laryngeal squamous cell carcinoma, manifesting with a 1-stage incremental survival advantage. Future prospective studies are indicated to corroborate the findings from this large-population database retrospective study.

Objective: To estimate the prevalence of oral high-risk human papillomavirus (hr-HPV) infection and the proportion of hr-HPV-related oropharyngeal squamous cell carcinoma (OPSCC) among Indigenous and non-Indigenous populations., Data Source: Electronic database searches of PubMed, PubMed Central, Embase, MEDLINE, Scope, and Google Scholar were conducted for articles published from January 2000 until November 2019., Review Methods: Studies were included with a minimum of 100 cases assessing hr-HPV infection in either population samples or oropharyngeal cancer tumor series. The objective was to conduct meta-analyses to calculate the pooled prevalence of oral hr-HPV infection by adjusting for age group or sex in primary studies, the incidence of OPSCC, and the proportion of hr-HPV-related OPSCC in Indigenous people and non-Indigenous/general populations., Results: We identified 47 eligible studies from 157 articles for meta-analyses. The pooled prevalence of oral hr-HPV infection was 7.494% (95% CI, 5.699%-9.289%) in a general population, with a higher prevalence among men (10.651%) than women (5.176%). The pooled incidence rate was 13.395 (95% CI, 9.315-17.475) and 7.206 (95% CI, 4.961-9.450) per 100,000 person-years in Indigenous and non-Indigenous populations, respectively. The overall pooled proportion of hr-HPV-related OPSCC was 50.812% (95 CI, 41.656%-59.969%). The highest proportion was in North America (60.221%), while the lowest proportion was in the Asia-Pacific (34.246%)., Conclusion: Our findings suggest that in the general population, the prevalence of oral hr-HPV infection is lower among females and those in younger age groups. The incidence of OPSCC was higher among Indigenous than non-Indigenous populations, with the proportion being highest in North America.

Objective: To investigate the patterns of care and outcomes of treatment of early stage tonsil cancers, controlling for human papillomavirus (HPV) status., Study Design: Historical cohort study., Setting: National Cancer Database (NCDB)., Methods: Review of the NCDB between 2010 and 2017 for all T1-2N0M0 tonsillar squamous cell carcinoma (SCC). Demographics, clinical characteristics, HPV status, treatment regimens, and survival were analyzed., Results: A total of 4720 patients were identified with early stage SCC of the tonsil. Most were tested for HPV (2759 [58.5%]). Among tested patients, 1758 (63.7%) were positive for HPV and 1001 (36.3%) were negative for HPV. HPV-positive patients had higher 3-year survival compared to HPV-negative patients (93.2% vs 77.8%, P < .001). Among HPV-positive patients, there was no significant difference in survival between treatment cohorts. However, in the HPV-negative cohort, 3-year survival was higher in both bimodality surgical-based settings (tonsillectomy + neck dissection + radiotherapy, 86.0% vs chemoradiotherapy, 69.6%, P = .01) and for all surgical-based treatments when compared to nonsurgical management (84.6% vs 69.3%, P < .001). This difference was maintained in multivariable regression controlling for age, sex, comorbidities, clinical T stage, and treatments. In a subpopulation of HPV-negative patients propensity score matched by all factors significant in multivariable analysis, 3-year survival remained higher in the surgically treated group compared to the nonsurgically treated cohort (84.9% vs 67.1%, P < .001)., Conclusions: Surgical- or radiation-based treatment resulted in similar survival in early stage HPV-positive tonsil cancer. Surgical-based treatments were associated with longer survival in HPV-negative cancers. These findings should be further investigated in a randomized prospective trial.

Objective: Despite epidemiologic evidence that second primaries occur infrequently in HPV (human papillomavirus)-associated oropharyngeal squamous cell carcinoma, recent recommendations advocate for elective contralateral palatine tonsillectomy. We aimed to study this discordance and define the necessary extent of up-front surgery in a large contemporary cohort with long-term follow-up treated with unilateral transoral robotic surgery. We hypothesized that second primaries are discovered exceedingly rarely during follow-up and that survival outcomes are not compromised with a unilateral surgical approach., Study Design: Retrospective cohort analysis., Setting: Tertiary care academic center between 2007 and 2017., Methods: Records for patients with p16-positive oropharyngeal squamous cell carcinoma of the tonsil and workup suggestive of unilateral disease who underwent ipsilateral transoral robotic surgery were analyzed for timing and distribution of locoregional recurrence, distant metastases, and second primary occurrence as well as survival characteristics., Results: Among 295 included patients, 21 (7.1%) had a locoregional recurrence; 17 (5.8%) had a distant recurrence; and 3 (1.0%) had a second primary during a median follow-up of 48.0 months (interquartile range, 29.5-62.0). Only 1 (0.3%) had a second primary found in the contralateral tonsil. The 2- and 5-year estimates of overall survival were 95.5% (SE, 1.2%) and 90.1% (SE, 2.2%), respectively, while the 2- and 5-year estimates of disease-free survival were 90.0% (SE, 1.8%) and 84.7% (SE, 2.3%)., Conclusion: Second primary occurrence in the contralateral tonsil was infrequent, and survival outcomes were encouraging with unilateral surgery. This provides a rationale for not routinely performing elective contralateral tonsillectomy in patients whose workup suggests unilateral disease.

Objective: For human papilloma virus-associated oropharynx squamous cell carcinoma (HPV+ OPSCC), we evaluated the distribution of neck-level lymph node (LN) metastasis, based on postsurgical histopathology, and the incidence of and risk factors for occult LN metastases, as these patterns need clarification for this newer cancer subset., Study Design: Retrospective cohort study., Setting: National Cancer Database (NCDB)., Methods: We analyzed 2358 patients in the NCDB with HPV+ OPSCC who underwent neck dissection (ND) from 2010 to 2015. Incidence and distribution of LN metastases were calculated for neck levels I to V. Variables associated with occult LN metastasis were assessed by multivariate logistic regression., Results: In therapeutic NDs (n = 1935), the following proportions of positive LNs were found: level I, 9.0% (n = 175); level II, 81.0% (n = 1568); level III, 29.6% (n = 573); level IV, 11.9% (n = 230); and level V, 4.9% (n = 95). In elective NDs (n = 423), occult-positive LNs were found in 35.8% (n = 152), with the following proportions by level: level I, 3.3% (n = 14); level II, 26.9% (n = 114); level III, 8.7% (n = 37); level IV, 4.0% (n = 17); and level V, 0.2% (n = 1). The presence of occult LNs was independently associated with a Charlson-Deyo score of 1 (odds ratio, 2.26; 95% CI, 1.18-4.31; P = .014) and lymphovascular invasion (odds ratio, 5.91; 95% CI, 3.21-11.18; P < .001). Occult LN metastases were not significantly associated with pT classification, primary site, or number of LNs resected., Conclusion: For HPV+ OPSCC, occult nodal disease is common. Therapeutic NDs should encompass at least levels II, III, and IV and possibly I, whereas elective NDs could possibly encompass levels II and III., Level of Evidence: 4.

Objective: To investigate differences in epidemiology of oropharyngeal squamous cell carcinoma (OPSCC) with regards to human papillomavirus (HPV), race, and socioeconomic status (SES) using the National Cancer Database (NCDB)., Study Design: Population-based cohort study., Setting: Racial and socioeconomic disparities in survival of OPSCC have been previously acknowledged. However, the distribution of HPV-related cancers and its influence on survival in conjunction with race and SES remain unclear., Subjects and Methods: All patients with OPSCC in the NCDB with known HPV status from 2010 to 2016 were included. Differences in presentation, HPV status, treatment, and outcomes were compared along racial and socioeconomic lines. Univariable and multivariable Cox regression survival analyses were performed., Results: In total, 45,940 patients met criteria. Most were male (38,038, 82.8%), older than 60 years (23,456, 51.5%), and white (40,156, 87.4%), and lived in higher median income areas (>$48,000, 28,587, 62.2%). Two-thirds were HPV positive (31,007, 67.5%). HPV-negative disease was significantly more common in lower SES (<$38,000, 2937, 41.5%, P < .001) and among blacks (1784, 55.3%, P < .001). Median follow-up was 33 months. Five-year overall survival was 81.3% (95% CI, 80.5%-82.1%) and 59.6% (95% CI, 58.2%-61.0%) in HPV-positive and HPV-negative groups, respectively. In univariable and multivariable analyses controlling for HPV status, age, stage, and treatment, black race (hazard ratio [HR], 1.22; 95% CI, 1.11-1.34; P < .001) and low SES (HR, 1.58; 95% CI, 1.45-1.72; P < .001) were associated with worse survival., Conclusion: Significant differences in HPV status exist between socioeconomic and racial groups, with HPV-negative disease more common among blacks and lower SES. When controlling for HPV status, race and SES still influence outcomes in oropharyngeal cancers.

Objectives: (1) To estimate the association between neck dissection lymph node yield (LNY) and survival among patients with surgically treated human papilloma virus (HPV)-associated oropharyngeal squamous cell carcinoma (OPSCC). (2) To identify a clinically relevant quality metric for surgical treatment of HPV-related OPSCC., Study Design: Retrospective cohort study., Setting: National Cancer Database., Subjects and Methods: From the National Cancer Database, 4130 patients were identified with HPV-associated OPSCC treated with primary surgery from 2010 to 2016. Based on prior literature, an adequate neck dissection LNY was defined as ≥18 lymph nodes. To determine whether LNY is associated with survival, univariable and multivariable Cox proportional hazards regression was performed. Analysis was stratified by adjuvant therapy regimen., Results: A total of 2113 patients (51.2%) underwent surgery with or without adjuvant radiation (S ± RT), and 2017 patients (48.8%) underwent surgery with adjuvant chemoradiation. LNY ≥18 was associated with a 5-year survival benefit of 7.15% (91.7% for LNY ≥18, 84.5% for LNY <18, P = .004) for the S ± RT cohort on unadjusted survival analysis. For the S ± RT group, LNY ≥18 was associated with decreased hazard of death (hazard ratio, 0.45; 95% CI, 0.29-0.70; P < .001) after adjustment for patient characteristics, TNM staging, surgical margins, extranodal extension, and treating facility characteristics. For surgery with adjuvant chemoradiation, the adjusted hazard ratio estimate for LNY ≥18 was 0.64 (95% CI, 0.41-1.00), but the result was not statistically significant ( P = .052)., Conclusion: An adequate LNY from a neck dissection may affect survival when HPV-related OPSCC is treated with up-front surgery.

The incidence of oral tongue cancer, the majority subsite of oral cavity cancer, is rising among young people with less exposure to tobacco and alcohol. Viral causes have been proposed, including Merkel cell polyomavirus (MCPyV). We evaluated patient and tumor characteristics among 126 incident oral cavity cancers (OCCs). Consistent with generational norms, younger patients had less exposure to tobacco and a greater number of oral sexual partners than older OCCs. In addition, younger patients were more likely to present at an earlier stage and with cancer arising from the oral tongue (each P < .05). A subset of 44 cases was centrally tested for MCPyV large T antigen expression by immunohistochemistry. In the presence of controls, none of the tumors expressed MCPyV. These findings exclude consideration of MCPyV as an etiologic factor in OCC and may generate hypotheses for future examinations of the factors underlying the rise in oral tongue cancers.

Objective: Characterize the survival impact of smoking on HPV-related (human papillomavirus) oropharyngeal squamous cell carcinoma., Data Sources: Articles from 2000 to 2019 in the PubMed, Embase, and Cochrane Library databases were systematically reviewed for content and inclusion/exclusion criteria., Review Methods: Two reviewers independently analyzed the databases for eligibility and quality of the articles. Demographic data, smoking history, and survival outcomes were recorded. Hazard ratios and 95% CIs were collectively analyzed through a random effects meta-analysis model., Results: Fifteen articles were included in the meta-analysis for overall survival, disease-specific survival, disease-free survival, progression-free survival, and locoregional recurrence outcomes. The overall survival hazard ratio was 2.4 for ever having smoked (95% CI, 1.4-4.0; P = .0006, I 2 = .384) and 3.2 for current smoking (95% CI, 2.2-4.6; P < .0001, I 2 = 0). The hazard ratio for disease-specific survival in current smokers was 6.3 (95% CI, 1.3-29.3; P = .0194, I 2 = 0). Ever smoking had a larger impact on overall survival and disease-specific survival than the 10-pack year smoking threshold., Conclusion: Smoking negatively affects survival in patients with HPV-related oropharyngeal carcinoma across all outcomes. Current smoking during treatment is associated with the greatest reduction in survival, possibly secondary to diminished radiation therapy efficacy.

Objective: Extranodal extension (ENE) is known to be associated with poor outcomes in head and neck squamous cell carcinoma. The objective of this study is to examine the impact of extent of ENE on survival in oropharyngeal carcinoma in the human papillomavirus (HPV) era., Study Design: Retrospective database review., Setting: Review of the National Cancer Database., Subjects and Methods: The National Cancer Database was used to examine surgically treated head and neck squamous cell carcinoma of the tonsil and base of tongue from 2010 to 2015. Nodes available for pathologic examination were classified as ENE negative (-), ENE clinically (+), or ENE (+) on pathology only. The primary outcome was overall survival. Cox regression modeling was used to examine the effect of ENE on survival while controlling for patient demographics, HPV status, stage, adjuvant radiation, and chemotherapy., Results: Of the 66,106 patients identified, 16,845 were treated with surgery ± adjuvant therapy, 8780 of whom were known HPV+. Overall 5-year survival for this group was 86%. Documented ENE was associated with over a 60% decrease in survival for clinical (hazard ratio [HR], 1.63) and pathologic (HR, 1.62) ENE compared to negative ENE, after adjustment for stage, adjuvant radiation ± chemotherapy, HPV, and other variables. No significant differences were found between clinical and pathologic ENE (HR, 1.001)., Conclusion: While both surgically resected clinical and pathologic ENE are associated with decreased survival, no significant differences are observed between the two. The impact of these observations on potential de-escalation therapeutic strategies requires further study.

Background: Human papillomavirus (HPV)-mediated oropharyngeal cancer (OPC) is associated with dramatically improved survival in comparison with HPV-negative OPC and can be successfully treated with surgical and nonsurgical approaches. National treatment trends for OPC were investigated with the National Cancer Data Base (NCDB)., Methods: The NCDB was reviewed for primary HPV-mediated OPC in 2010-2014. Multivariable regression was used to identify predictors of both nonsurgical therapy and receipt of adjuvant chemoradiation (CRT)., Results: There were 13,363 patients identified with a median age at diagnosis of 58 years. The incidence of triple-modality treatment (surgery with adjuvant chemotherapy) decreased from 23.7% in 2010 to 16.9% in 2014 (R 2  = 0.96), whereas the incidence of nonsurgical treatment increased from 63.9% to 68.7% (R 2  = 0.89). Hospitals in the top treatment volume quartile (quartile 1 [Q1]; n = 29) had a lower rate of positive margins (16.3%) than bottom-quartile centers (n = 741; rate of positive margins, 36.4%; P < .001); Q1 hospitals used surgical therapy significantly more. Independent predictors of nonsurgical therapy included older age, advanced disease, lower hospital volume, and living closer to the hospital or outside the Pacific United States. In surgically treated patients, younger age, lower hospital volume, nodal disease, positive surgical margins, and extranodal extension (ENE) also predicted more adjuvant CRT use., Conclusions: The use of upfront surgical treatment decreased from 2010 to 2014. Hospital volume shows a strong, inverse correlation with the rate of positive surgical margins. The upfront treatment strategy is predicted not only by staging but also by patient-, geographic-, and hospital-specific factors. Lower hospital volume remains independently associated with increased triple-modality therapy after adjustments for positive margins, ENE, and pathologic staging., (© 2019 American Cancer Society.)

The improved survival in patients with HPV-positive (human papilloma virus) oropharyngeal squamous cell carcinoma as compared with HPV-negative disease calls for treatment that preserves quality of life, particularly a functional swallow. There are several trials currently assessing treatment de-escalation in terms of less invasive transoral robotic surgery, reduced-dose radiotherapy, and omission of chemotherapy in this disease cohort. It is important for head and neck oncology surgeons to stay abreast of developments in this area to offer their patients the most up-to-date treatment and consider recruiting patients to trials at their institutions. For this purpose, we provide a summary of current trials and associated challenges in managing a disease with fast-evolving treatment algorithms.

Purpose: Current state-of-the-art models for estimating the pharmacokinetic parameters do not account for intervoxel movement of the contrast agent (CA). We introduce an optimal mass transport (OMT) formulation that naturally handles intervoxel CA movement and distinguishes between advective and diffusive flows., Method: Ten patients with head and neck squamous cell carcinoma (HNSCC) were enrolled in the study between June 2014 and October 2015 and underwent DCE MRI imaging prior to beginning treatment. The CA tissue concentration information was taken as the input in the data-driven OMT model. The OMT approach was tested on HNSCC DCE data that provides quantitative information for forward flux ( Φ F ) and backward flux ( Φ B ). OMT-derived Φ F was compared with the volume transfer constant for CA, K trans , derived from the Extended Tofts Model (ETM)., Results: The OMT-derived flows showed a consistent jump in the CA diffusive behavior across the images in accordance with the known CA dynamics. The mean forward flux was 0.0082 ± 0.0091 ( min - 1 ) whereas the mean advective component was 0.0052 ± 0.0086 ( min - 1 ) in the HNSCC patients. The diffusive percentages in forward and backward flux ranged from 8.67% to 18.76% and 12.76% to 30.36%, respectively. The OMT model accounts for intervoxel CA movement and results show that the forward flux ( Φ F ) is comparable with the ETM-derived K trans ., Conclusions: This is a novel data-driven study based on optimal mass transport principles applied to patient DCE imaging to analyze CA flow in HNSCC., (© 2019 International Society for Magnetic Resonance in Medicine.)

Objective: Optimal timing of postoperative radiotherapy (PORT) remains understudied in human papillomavirus (HPV)-related oropharyngeal squamous cell carcinoma. Objectives are to determine if delays between surgery and radiotherapy, breaks during radiotherapy, disease, or patient factors are associated with recurrence or survival decrements in HPV-related disease., Design: Retrospective review., Setting: Academic medical center., Subjects: A total of 240 cases of HPV-positive oropharyngeal squamous cell carcinoma from 2000 to 2016., Methods: Patient and tumor characteristics (American Joint Committee on Cancer, eighth edition), delays to radiation initiation, and breaks during radiation were recorded. Overall survival (OS) and recurrence-free survival (RFS) were analyzed., Results: RFS and OS were not significantly affected by delays to PORT >6 weeks or by treatment intervals >100 days (surgery to PORT completion). Breaks during PORT significantly imparted an OS detriment (hazard ratio [HR], 2.4; 95% CI, 1.2-4.8). Advanced-stage disease was significantly associated with reduced RFS and OS. Subgroup analysis of stage I versus stage II/III disease found that >6 weeks to PORT initiation and treatment intervals >100 days did not significantly decrease RFS or OS in either stage group. Advanced-stage disease was significantly associated with worsened OS (HR, 6.6; 95% CI, 2.3-19.1) and RFS (HR, 5.3; 95% CI, 1.5-18.4). Breaks during PORT significantly reduced RFS (HR, 3.6; 95% CI, 1.2-10.8) and OS (HR, 3.2; 95% CI, 1.2-9.0) in the stage II/III subset., Conclusion: Delays to radiotherapy initiation and prolonged treatment time did not affect recurrence or survival in HPV-related oropharyngeal disease. Locoregionally advanced disease was consistently associated with worse outcomes. Breaks during PORT may affect recurrence and survival, although larger studies are needed to confirm this finding.

Background: Equus caballus papillomavirus 8, a recently discovered virus, has been reported to cause generalised papillomavirus in horses., Objectives: To describe a case in which multiple viral plaques, viral papillomas, squamous cell carcinoma (SCC) in situ and invasive squamous cell carcinoma (ISCC) were associated with EcPV8 in a horse., Study Design: Case report., Methods: A 16-year-old mixed breed horse presented with dozens of raised crusted papular to nodular lesions over a course of 4 years. Masses had been surgically excised four times and cisplatin beads and emulsion were implanted on three different occasions; however new masses continue to develop in sites of previous masses as well as new sites., Results: Multiple viral plaques, viral papillomas, SCC in situ and ISCC, localised to the inguinal region, were diagnosed via histopathology. EcPV8 DNA was detected via PCR., Main Limitations: Since only a few cases have been reported, we do not know the incidence of EcPV8 nor how often it may be associated with SCC in situ or ISCC without further study., Conclusions: This is the fourth reported case of viral papillomatosis in the context of an EcPV8 infection in a horse. This is the first case in which SCC has been associated with EcPV8., (© 2018 EVJ Ltd.)

Objectives: To determine the oncologic outcomes of patients undergoing salvage surgery for recurrent oral cavity squamous cell carcinoma (OCSCC) and oropharyngeal squamous cell carcinoma (OPSCC) after initial treatment with surgery and adjuvant therapy., Study Design: Retrospective case series with chart review., Setting: Five academic tertiary care centers., Subjects and Methods: Patients included those with OCSCC and OPSCC who were initially treated with surgery and adjuvant therapy between 2000 and 2015 and underwent salvage surgery for local and/or regional recurrence., Results: A total of 102 patients were included (76% OCSCC, 24% OPSCC). Five-year overall survival was 31% (95% CI, 21%-41%) and was significantly improved among patients with human papillomavirus-associated oropharyngeal tumors (hazard ratio [HR], 0.34; 95% CI, 0.11-0.98) and significantly worse for those with postoperative positive margins (HR, 2.65; 95% CI, 1.43-4.93). Adjuvant (chemo)reirradiation was not associated with disease control or survival regardless of margin status. Combined locoregional recurrence was significantly correlated with a positive margin resection (HR, 5.75; 95% CI, 1.94-17.01). Twenty-five patients (25%) underwent a second salvage surgical procedure, of whom 8 achieved long-term disease control., Conclusion: Patients presenting with resectable recurrence after initial therapy with surgery and adjuvant therapy have a reasonable salvage rate when a negative margin resection can be attained. Patients with postoperative positive margins have poor survival outcomes that are not significantly improved with adjuvant (chemo)reirradiation. Those with combined locoregional recurrence are at particularly high risk for postoperative positive margins. The functional consequences of salvage surgery and its effect on quality of life are critical in decision making and require further investigation.

Background: Radiation Therapy Oncology Group (RTOG)-0129 recursive partitioning analysis was the basis for risk-based therapeutic intensification trials for oropharyngeal cancer (OPC). To the authors' knowledge, the question of whether RTOG-0129 overall survival (OS) estimates for low-risk, intermediate-risk, and high-risk groups are similar in other data sets or applicable to progression-free survival (PFS) is unknown. Therefore, the authors evaluated whether survival differences between RTOG-0129 risk groups persist at 5 years, are reproducible in an independent clinical trial, and are applicable to PFS, and whether toxicities differ across risk groups., Methods: Prospective randomized clinical trials were analyzed retrospectively. RTOG-0129 evaluated standard versus accelerated fractionation radiotherapy concurrent with cisplatin. RTOG-0522 compared the combination of cisplatin and accelerated fractionation with or without cetuximab. Patients with OPC with available p16 status and tobacco history were eligible., Results: There was a total of 260 patients and 287 patients, respectively, from RTOG-0129 and RTOG-0522, with median follow-ups for surviving patients of 7.9 years (range, 1.7-9.9 years) and 4.7 years (range, 0.1-7.0 years), respectively. Previous OS differences in RTOG-0129 persisted at 5 years. In RTOG-0522, the 5-year OS rates for the low-risk, intermediate-risk, and high-risk groups were 88.1%, 69.9%, and 45.1%, respectively (P for trend, <.001). The 5-year PFS rates for the same 3 groups were 72.9%, 56.1%, and 42.2%, respectively. In RTOG-0522 among a subgroup of patients considered to be at very good risk (p16-positive disease, smoking history of ≤10 pack-years, and classified with T1-T2 disease with ipsilateral lymph nodes measuring ≤6 cm or T3 disease without contralateral or >6 cm lymph nodes), the 5-year OS and PFS rates were 93.8% and 82.2%, respectively. Overall rates of acute and late toxicities were similar by risk group., Conclusions: RTOG-0129 risk groups persisted at 5 years and were reproducible in RTOG-0522. However, there was variability in the estimates. These data underscore the importance of long-term follow-up and appropriate patient selection in therapeutic deintensification trials., (© 2019 American Cancer Society.)

Objective: (1) To identify p16 protein in laryngeal squamous cell carcinoma (LSCC) specimens and to correlate it with the presence of human papillomavirus (HPV) found in these specimens from a previous study. (2) To analyze p16 impact on 10-year overall and disease-free survival., Study Design: Retrospective case series with oncologic database chart review., Setting: Academic tertiary care hospital., Subjects: A total of 123 samples of LSCC (taken from the glottis only) from patients treated with primary surgical resection between 1977 and 2005., Methods: p16 protein expression was analyzed through immunohistochemistry and compared with the presence of HPV established in our previous studies. Results were compared with histologic, clinicopathologic, and survival parameters, with a 10-year follow-up., Results: Of the samples, 39.02% were positive for p16, but only 11.38% were positive for both p16 and HPV. The p16+ cohort showed a significant improvement in disease-free survival ( P = .0022); statistical significance was not achieved for overall survival. p16+ cases had fewer relapses over time, with no relapses after a 2-year follow-up. Age at the time of diagnosis and tobacco consumption were the only epidemiologic factors that influenced overall survival., Conclusion: The expression of p16 protein was a beneficial prognostic factor for disease-free survival among patients with LSCC of the glottis, with no relapses after a 2-year follow-up.

Objectives: To assess the impact of pathologic features and chronic tobacco use on human papillomavirus (HPV)-related oropharyngeal squamous cell carcinoma (OPSCC)., Study Design: Case series with chart review., Setting: Single tertiary care referral center., Subject and Methods: A total of 301 patients were treated for OPSCC from 2008 to 2016. Clinical and pathologic T and N stage, American Joint Committee on Cancer (AJCC) stage (seventh and eighth edition staging manuals), cigarette pack years, alcohol use, and presence of extranodal extension (ENE), perineural invasion (PNI), or lymphovascular invasion (LVI) were assessed. Patients were stratified into HPV negative, HPV-positive heavy smokers (≥20 pack years), and HPV-positive nonsmokers. Five-year survival by Kaplan-Meier method was assessed., Results: Of the HPV-positive patients, 97 were nonsmokers and 73 were heavy smokers. HPV-positive heavy smokers had significantly decreased survival compared to their nonsmoking counterparts ( P = .02). The presence of ENE was associated with a significantly decreased 5-year survival ( P = .02) in heavy smokers relative to nonsmokers in HPV-positive patients. Furthermore, for the AJCC eighth edition, clinically stage 1 HPV-positive heavy smokers had significantly decreased survival relative to nonsmokers ( P = .01)., Conclusions: This series highlights the potential need for more aggressive therapy for HPV-positive patients with extensive tobacco use under the new staging system.

Background: The objective of the current study was to characterize the incidence, pattern, and impact on oncologic outcomes of retropharyngeal lymph node (RPLN) involvement in HPV-associated oropharyngeal cancer (OPC)., Methods: Data regarding patients with HPV-associated OPC who were treated at The University of Texas MD Anderson Cancer Center with intensity-modulated radiotherapy from 2004 through 2013 were analyzed retrospectively. RPLN status was determined by reviewing pretreatment imaging and/or reports. Outcomes analysis was restricted to patients with lymph node-positive (+) disease. Kaplan-Meier survival estimates were generated and survival curves were compared using the log-rank test. Bayesian information criterion assessed model performance changes with the addition of RPLN status to current American Joint Committee on Cancer staging. Competing risk analysis compared modes of disease recurrence., Results: The incidence of radiographic RPLN involvement was 9% (73 of 796 patients) and was found to vary by primary tumor site. The 5-year rates of freedom from distant metastases (FDM) and overall survival were lower in patients with RPLN(+) status compared with those with RPLN-negative (-) status (84% vs 93% [P = .0327] and 74% vs 87% [P = .0078], respectively). RPLN(+) status was not found to be associated with outcomes on multivariate analysis. Bayesian information criterion analysis demonstrated that current American Joint Committee on Cancer staging was not improved with the inclusion of RPLN. Locoregional and distant disease recurrence probabilities for those patients with RPLN(+) status were 8% and 13%, respectively, compared with 10% and 6%, respectively, for those with RPLN(-) status. RPLN(+) status portended worse 5-year FDM in the low-risk subgroup (smoking history of <10 pack-years) and among patients who received concurrent chemotherapy but not induction chemotherapy., Conclusions: RPLN(+) status was associated with worse overall survival and FDM on univariate but not multivariate analysis. In subgroup analyses, RPLN(+) status was associated with poorer FDM in both patients with a smoking history of <10 pack-years and those who received concurrent chemotherapy, suggesting that RPLN(+) status could be considered an exclusion criteria in treatment deintensification efforts seeking to omit chemotherapy., (© 2019 American Cancer Society.)

Background: With an expectation of excellent locoregional control, ongoing efforts to de-intensify therapy for patients with human papillomavirus-associated squamous cell oropharyngeal cancer necessitate a better understanding of the metastatic risk for patients with this disease. The objective of this study was to determine what factors affect the risk of metastases in patients with squamous cell cancers of the oropharynx., Methods: Under a shared use agreement, 547 patients from Radiation Therapy Oncology Group 0129 and 0522 with nonmetastatic oropharyngeal squamous cell cancers who had a known p16 status and smoking status were analyzed to assess the association of clinical features with the development of distant metastases. The analyzed factors included the p16 status, sex, T stage, N stage, age, and smoking history., Results: A multivariate analysis of 547 patients with a median follow-up of 4.8 years revealed that an age ≥ 50 years (hazard ratio [HR], 3.28; P = .003), smoking for more than 0 pack-years (HR, 3.09; P < .001), N3 disease (HR, 2.64; P < .001), T4 disease (HR, 1.63; P = .030), and a negative p16 status (HR, 1.60; P = .044) were all factors associated with an increased risk of distant disease., Conclusions: Age, smoking, N3 disease, T4 disease, and a negative p16 status were associated with the development of distant metastases in patients with squamous cell cancers of the oropharynx treated definitively with concurrent chemoradiation., (© 2018 American Cancer Society.)

Objective: To characterize patterns of neck lymph node (LN) metastases in human papillomavirus (HPV)-associated oropharyngeal squamous cell carcinoma, represented by p16 positivity (p16+OPSCC)., Study Design: Case series with chart review., Setting: Tertiary care center., Subjects and Methods: Neck dissection (ND) specimens of nonirradiated p16+OPSCC patients were analyzed for frequencies of clinically evident and occult LNs by neck level. Local, regional, and distant recurrences were reviewed., Results: Seventy p16+OPSCC patients underwent primary site transoral robotic surgery and 82 NDs of varying levels. Metastatic pathologic LNs were found at the following frequencies: 0% (0/28) in level I, 75.6% (62/82) in level II with 57.4% (35/61) in level IIA and 13.1% (8/61) in level IIB, 22.0% (18/82) in level III, 7.0% (5/71) in level IV, and 6.3% (1/16) in level V. The level V LN was clinically evident preoperatively. Five of 21 (23.8%) elective NDs contained occult LNs, all of which were in level II and without extranodal extension. Twenty-seven (38.6%) patients underwent adjuvant radiation; 19 (27.1%) patients underwent adjuvant chemoradiation. With a mean follow-up of 29 months, 3 patients had developed recurrences, with all but 1 patient still alive. All patients who recurred had refused at least a component of indicated adjuvant treatment., Conclusions: For p16+OPSCC, therapeutic NDs should encompass any levels bearing suspicious LNs and levels IIA-B, III, and IV, while elective NDs should be performed and encompass at least levels IIA-B and III. These selective ND plans, followed by indicated adjuvant treatment, are associated with a low nodal recurrence rate.

This study aimed to examine the possible association of human papillomavirus (HPV) with oral cavity squamous cell carcinomas (OCSCCs) in Saudi Arabia. Forty-five paraffin-embedded tumor blocks that represent different subsets of OCSCCs between 2010 and 2014 were retrieved and histologically evaluated. The presence of high-risk HPV (16, 18, 31, and 33) was assessed by p16-immunohistochemistry followed by DNA detection using in situ hybridization technique. Twenty-four patients were male with the mean age of 59.3 years, and 21 patients were female with the mean age of 61.2 years. Forty-one cases were positive for p16 immunostaining, and the remaining four cases were negative. However, none of the 45 cases showed DNA-expression for any HPV subtypes (16, 18, 31, and 33). High-risk HPV appears not to be involved in the etiology of OCSCCs in older Saudi patients, but further studies with cross section of a younger age group are still required., Competing Interests: The authors declare no conflicts of interests.

Background: Accurate, individualized prognostication in patients with oropharyngeal squamous cell carcinoma (OPSCC) is vital for patient counseling and treatment decision making. With the emergence of human papillomavirus (HPV) as an important biomarker in OPSCC, calculators incorporating this variable have been developed. However, it is critical to characterize their accuracy prior to implementation., Methods: Four OPSCC calculators were identified that integrate HPV into their estimation of 5-year overall survival. Treatment outcomes for 856 patients with OPSCC who were evaluated at a single institution from 2003 through 2016 were analyzed. Predicted survival probabilities were generated for each patient using each calculator. Calculator performance was assessed and compared using Kaplan-Meier plots, receiver operating characteristic curves, concordance statistics, and calibration plots., Results: Correlation between pairs of calculators varied, with coefficients ranging from 0.63 to 0.90. Only 3 of 6 pairs of calculators yielded predictions within 10% of each other for at least 50% of patients. Kaplan-Meier curves of calculator-defined risk groups demonstrated reasonable stratification. Areas under the receiver operating characteristic curve ranged from 0.74 to 0.80, and concordance statistics ranged from 0.71 to 0.78. Each calculator demonstrated superior discriminatory ability compared with clinical staging according to the seventh and eighth editions of the American Joint Committee on Cancer staging manual. Among models, the Denmark calculator was found to be best calibrated to observed outcomes., Conclusions: Existing calculators exhibited reasonable estimation of survival in patients with OPSCC, but there was considerable variability in predictions for individual patients, which limits the clinical usefulness of these calculators. Given the increasing role of personalized treatment in patients with OPSCC, further work is needed to improve accuracy and precision, possibly through the identification and incorporation of additional biomarkers., (© 2018 American Cancer Society.)

Background: More than 400,000 cases of oropharyngeal squamous cell cancer (OPSCC) are diagnosed every year worldwide and this is rising. Much of the increase has been attributed to human papillomavirus (HPV). HPV-positive OPSCC patients are often younger and have significantly improved survival relative to HPV-negative patients. Traditional management of OPSCC has been with radiotherapy with or without chemotherapy, as this was shown to have similar survival to open surgery but with significantly lower morbidity. Techniques have evolved, however, with the development of computerised planning and intensity-modulated radiotherapy, and of minimally invasive surgical techniques. Acute and late toxicities associated with chemoradiotherapy are a significant burden for OPSCC patients and with an ever-younger cohort, any strategies that could decrease treatment-associated morbidity should be investigated., Objectives: To assess the effects of de-intensified adjuvant (chemo)radiotherapy in comparison to standard adjuvant (chemo)radiotherapy in patients treated with minimally invasive transoral surgery (transoral robotic surgery or transoral laser microsurgery) for resectable HPV-positive oropharyngeal squamous cell carcinoma., Search Methods: The Cochrane ENT Information Specialist searched the Cochrane ENT Trials Register; Central Register of Controlled Trials (CENTRAL); Ovid MEDLINE; Ovid Embase; CINAHL; Web of Science; ClinicalTrials.gov; ICTRP and additional sources for published and unpublished trials. The date of the search was 26 April 2018., Selection Criteria: Randomised controlled trials (RCTs) in patients with carcinoma of the oropharynx (as defined by the World Health Organization classification C09, C10). Cancers included were primary HPV-positive squamous cell tumours originating from the oropharyngeal mucosa. Tumours were classified as T1-4a with or without nodal spread and with no evidence of distant metastatic spread. The intervention was minimally invasive transoral surgery followed by de-intensified adjuvant therapy (either omission of chemotherapy or reduced-dose radiotherapy). The comparator was minimally invasive transoral surgery followed by standard concurrent chemoradiotherapy or standard-dose radiotherapy. The treatments received were of curative intent and patients had not undergone any prior intervention, other than diagnostic biopsy., Data Collection and Analysis: We used the standard methodological procedures expected by Cochrane. Our primary outcomes were overall survival (disease-related survival was to be studied where possible) and disease-free survival, measured at one, two, three and five years. Our secondary outcomes included assessment of swallowing ability and voice, measured at one, six, 12 and 24 months. We planned to use GRADE to assess the quality of evidence for each outcome., Main Results: We did not identify any completed RCTs that met our inclusion criteria. However, three eligible studies are in progress:ADEPT is a phase III trial comparing postoperative radiotherapy with or without cisplatin in HPV-positive T1-4a OPSCC patients. Included patients must have received minimally invasive surgery and demonstrated extra-capsular spread from disease in the neck.ECOG-E3311 is a phase II trial of treatment for HPV-positive locally advanced OPSCC (stages III-IVa + IVb without distant metastasis). Patients are stratified after minimally invasive surgery. Medium-risk patients are randomised to either standard or reduced-dose radiotherapy.PATHOS is a phase III trial of treatment for HPV-positive OPSCC (T1-3, N0-2b). Patients are stratified after minimally invasive surgery. Medium-risk patients are randomised to either standard or reduced-dose radiotherapy. High-risk patients are randomised to radiotherapy with or without concurrent cisplatin., Authors' Conclusions: This review highlights the current lack of high-quality randomised controlled trials studying treatment de-escalation after minimally invasive surgery in patients with HPV-positive OPSCC. However, trials that will meet the inclusion criteria for this review are in progress with results expected between 2021 and 2023.

Objective We evaluated the ability of the American Joint Committee on Cancer (AJCC) seventh edition staging system to prognosticate the overall survival of patients with human papillomavirus (HPV)-positive laryngeal squamous cell carcinoma. Study Design Retrospective analysis. Setting National Cancer Database. Subjects and Methods Patients diagnosed with laryngeal squamous cell carcinoma who were treated with curative intent were identified in the National Cancer Database. Multivariate analysis was utilized to determine factors correlated with overall survival in the HPV-negative and HPV-positive cohorts. Unadjusted and propensity score-weighted Kaplan-Meier estimation was used to determine overall survival of HPV-negative and HPV-positive patients across AJCC stage groupings. Results We identified 3238 patients with laryngeal squamous cell carcinoma, of which 2812 were HPV negative and 426 were HPV positive. Overall survival adjusted for age, sex, and comorbidity status confirmed significant differences among all consecutive stage groupings (I vs II, P < .001; II vs III, P < .05; III vs IVA, P < .001; IVA vs IVB, P < .05) in the HPV-negative cohort, whereas only stages IVAs and IVB ( P < .01) exhibited a significant difference in overall survival for HPV-positive patients. Conclusion The current AJCC staging system does not accurately distinguish risk of mortality for patients with HPV-positive disease. These data support the consideration of HPV status in estimating prognosis as well as clinical trial design and clinical decision making for patients with laryngeal squamous cell carcinoma.

Background: Human papillomavirus (HPV) vaccines can potentially prevent greater than 90% of cervical and anal cancers as well as a substantial proportion of vulvar, vaginal, penile, and oropharyngeal cancers caused by certain HPV types. Because more than 38,000 HPV-associated cancers are diagnosed annually in the United States, current studies are needed to understand how relative survival varies for each of these cancers by certain demographic characteristics, such as race and age., Methods: The authors examined high-quality data from 27 population-based cancer registries covering approximately 59% of the US population. The analyses were limited to invasive cancers that were diagnosed during 2001 through 2011 and followed through 2011 and met specified histologic criteria for HPV-associated cancers. Five-year relative survival was calculated from diagnosis until death for these cancers by age, race, and sex., Results: The 5-year age-standardized relative survival rate was 64.2% for cervical carcinomas, 52.8% for vaginal squamous cell carcinomas (SCCs), 66% for vulvar SCCs, 47.4% for penile SCCs, 65.9% for anal SCCs, 56.2% for rectal SCCs, and 51.2% for oropharyngeal SCCs. Five-year relative survival was consistently higher among white patients compared with black patients for all HPV-associated cancers across all age groups; the greatest differences by race were observed for oropharyngeal SCCs among those aged <60 years and for penile SCCs among those ages 40 to 49 years compared with other age groups., Conclusions: There are large disparities in relative survival among patients with HPV-associated cancers by sex, race, and age. HPV vaccination and improved access to screening (of cancers for which screening tests are available) and treatment, especially among groups that experience higher incidence and lower survival, may reduce disparities in survival from HPV-associated cancers. Cancer 2018;124:203-211. Published 2017. This article is a U.S. Government work and is in the public domain in the USA., (© 2017 American Cancer Society.)

Background: Over the last decade, the causal link between human papillomavirus (HPV) infection and squamous cell carcinoma of the anus (SCCA) has been well described. Because HPV infection in one site is often associated with other sites of infection, it then follows that patients with SCCA may have an increased risk of additional HPV-related cancers. Identifying and targeting at-risk sites through cancer screening and surveillance may help to guide best practices. The current study sought to ascertain sites and risk of HPV-related second primary malignancies (SPMs) in survivors of SCCA., Methods: Using population-based data from 1992 through 2012, the authors identified patients with SCCA and determined their risk of HPV-related SPMs, including anal, oral, and genital cancers. Standardized incidence ratios (SIRs), defined as observed to expected cases, were calculated to determine excess risk., Results: Of 10,537 patients with SCCA, 416 developed HPV-related SPMs, which corresponded to an overall SIR of 21.5 (99% confidence interval [99% CI], 19.0-24.2). Men were found to have a higher SIR (35.8; 99% CI, 30.7-41.6) compared with women (12.8; 99% CI, 10.4-15.5). SIRs for a second SCCA were markedly higher in men (127.5; 99% CI, 108.1-149.2) compared with women (47.0; 99% CI, 34.7-62.1), whereas SIRs for oral cavity and pharyngeal cancers were elevated in men (3.1; 99% CI, 1.5-5.7) and women (4.4; 99% CI, 1.5-9.7). SIRs for sex-specific sites also were elevated, with male genital cancers having an SIR of 19.6 (99% CI, 8.7-37.6) and female genital cancers an SIR of 8.3 (99% CI, 6.1-11.0)., Conclusions: Patients with index SCCA are at an increased risk of subsequent HPV-related SPMs. The elevated risk is most striking in patients with second primary SCCAs; however, the risk of second cancers also appears to be increased in other HPV-related sites. Cancer 2017;123:4013-21. © 2017 American Cancer Society., (© 2017 American Cancer Society.)

Background: Extranodal (or extracapsular) extension (ENE) is an adverse prognostic factor in patients with head and neck cancers who undergo primary surgery. However, the significance of ENE in human papillomavirus (HPV)-positive oropharyngeal squamous cell carcinoma (OPSCC) is not well established, and single-institution studies have not established that ENE predicts inferior outcome. The authors investigated the prognostic value of ENE in HPV-positive patients who underwent primary surgery and whether adjuvant chemoradiation improved overall survival (OS) compared with radiation alone in ENE-positive patients., Methods: Patients who underwent primary surgery for pathologic T1 (pT1) through pT4 tumors, pathologic N1 (pN1) through pN3 lymph node status, HPV-positive OPSCC were identified in the National Cancer Data Base from 2010 through 2012. Features associated with ENE were analyzed. Univariable and multivariable Cox regression analyses identified predictors of OS. The effect of adjuvant treatment on OS in ENE-positive cohort was also evaluated., Results: In total, 1043 patients met inclusion criteria, among whom 43.5% were ENE-positive. Of the ENE-positive patients who had treatment details available, 72% received concurrent chemoradiotherapy, 16% received radiotherapy, and 12% received no adjuvant treatment. After a median follow-up of 28.4 months, ENE was associated with worse 3-year OS (89.3% vs 93.6%; P = .01). On multivariable analysis that included involved lymph nodes, only ENE, lymphovascular invasion, pT3/pT4 tumors, and Charlson-Deyo score were associated with worse OS. Among ENE-positive patients, there was no difference in 3-year OS between those who received adjuvant concurrent chemoradiotherapy versus radiotherapy alone (89.6% vs 89.3%, respectively; P = .55). Propensity score-matched comparison revealed similar results., Conclusions: ENE is associated with inferior OS in patients with HPV-positive OPSCC. However, OS was not better with adjuvant chemoradiotherapy compared with radiotherapy alone in ENE-positive patients. The current findings support the need for prospective studies of adjuvant chemoradiation in HPV-positive patients with ENE. Cancer 2017;123:2762-72. © 2017 American Cancer Society., (© 2017 American Cancer Society.)

Cervical cancer is the fourth most common malignancy diagnosed in women worldwide. Nearly all cases of cervical cancer result from infection with the human papillomavirus, and the prevention of cervical cancer includes screening and vaccination. Primary treatment options for patients with cervical cancer may include surgery or a concurrent chemoradiotherapy regimen consisting of cisplatin-based chemotherapy with external beam radiotherapy and brachytherapy. Cervical cancer causes more than one quarter of a million deaths per year as a result of grossly deficient treatments in many developing countries. This warrants a concerted global effort to counter the shocking loss of life and suffering that largely goes unreported. This article provides a review of the biology, prevention, and treatment of cervical cancer, and discusses the global cervical cancer crisis and efforts to improve the prevention and treatment of the disease in underdeveloped countries. Cancer 2017;123:2404-12. © 2017 American Cancer Society., (© 2017 American Cancer Society.)

Objective To describe management and oncologic outcomes for patients who develop locoregional recurrence (LRR) or distant metastasis (DM) following transoral robotic surgery for human papilloma virus (HPV)-positive oropharyngeal squamous cell carcinoma (OPSCC). Study Design Case series with chart review. Setting Tertiary care referral center. Subjects and Methods A total of 286 patients with HPV-positive OPSCC who underwent transoral robotic surgery-based treatment from May 2007 to May 2015. Results Of 286 patients (12.2%), 35 met inclusion criteria. Of these, 19 experienced an LRR and 16 developed a DM; 2 patients with LRR subsequently developed DM. In those patients with an LRR, 79% had T1/T2 tumors, and 47% had N0/N1 nodal disease, compared with 75% and 6% in the DM group, respectively. The median time to LRR or DM was 0.6 years (interquartile range [IQR], 0.4-1.0) and 1.8 years (IQR, 1.0-2.1), respectively. Salvage treatment with intent to cure was attempted in 23 patients (16 LRR, 7 DM). The median time from LRR or DM to last follow-up for the 18 patients who were still alive after salvage was 1.9 years (IQR, 0.4-3.8; range, 7 days-6.2 years). Estimated cancer-specific survival rates at 3 years following intent-to-cure treatment were 63% (95% CI, 39-100; number still at risk, 5) in the LRR group and 100% (95% CI, 100-100; number still at risk, 2) in the DM group. Conclusion Overall, LRR and DM for HPV-positive OPSCC following transoral robotic surgery-based therapy are infrequent. In our subset of patients who underwent intent-to-cure treatment, cancer-specific survival rates were favorable. Therefore, aggressive salvage treatment for LRR and DM for HPV-positive OPSCC should be recommended for appropriate candidates.

Background: Cervical cancer is a predominantly human papillomavirus (HPV)-driven disease worldwide. However, its incidence is unexplainably low in western Asia, including Saudi Arabia. Using this paradigm, we investigated the role of HPV infection rate and host genetic predisposition in TP53 G72C single nucleotide polymorphism (SNP) presumed to affect cancer incidence., Methods: Patients treated between 1990 and 2012 were reviewed, and a series of 232 invasive cervical cancer cases were studied and compared with 313 matched controls without cancer. SNP was genotyped by way of direct sequencing. HPV linear array analysis was used to detect and genotype HPV in tumor samples., Results: The incidence of cervical cancer revealed bimodal peaks at 42.5 years, with a slighter rebound at 60.8 years. Among all cases, 77% were HPV-positive and 16 HPV genotypes were detected-mostly genotypes 16 (75%) and 18 (9%)-with no difference by age, histology, or geographical region. Although the TP53 G72C genotype was not associated with overall cervical cancer risk, it was significantly associated with HPV positivity (odds ratio, 0.57; 95% confidence interval, 0.36-0.90; P = .016). Furthermore, the variant C allele was significantly overtransmitted in the population (P < .0003)., Conclusion: Cervical cancer incidence displays bimodal curve peaking at a young age with secondary rebound at older age. The combination of relative low HPV infection and variant TP53 72C allele overtransmission provide a plausible explanation for the low incidence of cervical cancer in our population. Therefore, HPV screening and host SNP genotyping may provide more relevant biomarkers to gauge the risk of developing cervical cancer. Cancer 2017;123:2459-66. © 2017 American Cancer Society., (© 2017 The Authors. Cancer published by Wiley Periodicals, Inc. on behalf of American Cancer Society.)

Human papillomavirus (HPV) causes greater than 5% of cancers worldwide, including all cervical cancers and an alarmingly increasing proportion of oropharyngeal cancers (OPCs). Despite markedly reduced cervical cancer incidence in industrialized nations with organized screening programs, cervical cancer remains the second most common cause of death from cancer in women worldwide, as developing countries lack resources for universal, high-quality screening. In the United States, HPV-related OPC is only 1 of 5 cancers with a rising incidence since 1975 and now has taken over the cervix as the most common site of HPV-related cancer. Similar trends follow throughout North America and Europe. The need for early detection and prevention is paramount. Despite the common etiologic role of HPV in the development of cervical cancer and HPV-associated OPC, great disparity exists between incidence, screening modalities (or lack thereof), treatment, and prevention in these 2 very distinct cohorts. These differences in cervical cancer and HPV-associated OPC and their impact are discussed here. Cancer 2017;123:2219-2229. © 2017 American Cancer Society., (Published 2017. This article is a U.S. Government work and is in the public domain in the USA.)

Background: Patients with human papillomavirus (HPV)-related oropharyngeal cancer (OPC) have improved survival when compared with those with HPV-negative OPC. Unfortunately, the American Joint Committee on Cancer seventh edition (AJCC-7ed) staging system does not account for the prognostic advantage observed with HPV-positive OPC. The purpose of the current study was to validate and compare 2 recently proposed staging systems for HPV-positive OPC., Methods: Patients treated for HPV-positive OPC from 2005 to 2015 at Johns Hopkins Hospital (JHH) were included for analysis. The International Collaboration on Oropharyngeal cancer Network for Staging (ICON-S) and The University of Texas MD Anderson Cancer Center (MDACC) staging systems were applied and survival was calculated using Kaplan-Meier methods. Cox proportional hazard regression was used to determine the relationship between stage of disease and survival. Models were compared using the Akaike information criterion (AIC)., Results: A total of 435 patients were eligible for analysis. There was a dramatic shift in lymph node category and overall stage of disease when ICON-S and MDACC stage were applied to the JHH cohort. There was superior stratification of overall survival and progression-free survival by ICON-S stage. Both proposed models had an improved fit based on AIC scores (P<.001 for both) over the AJCC-7ed. The ICON-S staging system had the lowest AIC score, and thus a better fit within the JHH population., Conclusions: The current analysis provides external validation for both staging systems in an independent and heterogeneously treated patient population. Although the MDACC staging system is an improvement over the AJCC-7ed, the ICON-S stage provides superior stratification of overall and progression-free survival, thereby supporting its use as the updated AJCC staging system for OPC. Cancer 2017;123:1768-1777. © 2017 American Cancer Society., (© 2017 American Cancer Society.)

Background: The incidence of human papillomavirus (HPV)-associated (HPV-positive) head and neck squamous cell carcinoma (HNSCC) of the oropharynx has dramatically increased over the last decade and continues to rise. Newly diagnosed HPV-positive HNSCCs in the United States currently outnumber any other HPV-associated cancers, including cervical cancer. Despite introduction of the HPV vaccine, the epidemic of HPV-positive HNSCC is expected to continue for approximately 60 years. Compared with patients who have tobacco-associated HNSCC, those who have HPV-positive HNSCC have better overall survival and response to treatment. Current treatment, including chemotherapy and radiation therapy, is associated with lifelong morbidity, and there are limited treatments and no curative options for patients who develop recurrent metastatic disease. Therapeutic de-escalation (decreased radiation dose) is being tested through clinical trials; however, those studies select patients based solely on tumor and patient smoking characteristics. Mechanisms of HPV-driven carcinogenesis in HNSCC are not well understood, which limits new therapeutic strategies and hinders the appropriate selection of patients for de-escalation therapy., Methods: The authors analyzed HNSCC data from The Cancer Genome Atlas to identify molecular characteristics that correlate with outcomes and integration status of the HPV genome., Results: The current investigations identified a subset of HPV-positive HNSCCs with mutations in the genes TRAF3 (tumor necrosis factor receptor-associated factor 3) and CYLD (cylindromatosis lysine 63 deubiquitinase). Defects in TRAF3 and CYLD correlated with the activation of transcriptional factor nuclear factor κB, episomal HPV status of tumors, and improved patient survival., Conclusions: Defects in TRAF3/CYLD were accompanied with the activation of nuclear factor κB signaling and maintenance of episomal HPV in tumors, suggesting that these mutations may support an alternative mechanism of HPV tumorigenesis in head and neck tumors. Cancer 2017;123:1778-1790. © 2017 The Authors. Cancer published by Wiley Periodicals, Inc. on behalf of American Cancer Society. This is an open access article under the terms of the Creative Commons Attribution NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes., (© 2017 The Authors. Cancer published by Wiley Periodicals, Inc. on behalf of American Cancer Society.)

Background: Human papillomavirus (HPV) is a well-established prognostic marker for oropharyngeal squamous cell cancer (OPSCC). Because of the limited numbers of women and nonwhites in studies to date, sex and racial/ethnic differences in prognosis have not been well explored. In this study, survival differences were explored by the tumor HPV status among 1) patients with OPSCCs by sex and race and 2) patients with nonoropharyngeal (non-OP) head and neck squamous cell cancers (HNSCCs)., Methods: This retrospective, multi-institution study included OPSCCs and non-OP HNSCCs of the oral cavity, larynx, and nasopharynx diagnosed from 1995 to 2012. Race/ethnicity was categorized as white non-Hispanic, black non-Hispanic, Asian non-Hispanic, and Hispanic of any race. Tumors were centrally tested for p16 overexpression and the presence of HPV by HPV16 DNA and high-risk HPV E6/E7 messenger RNA in situ hybridization. Kaplan-Meier and Cox proportional hazards models were used to evaluate overall survival (OS)., Results: The study population included 239 patients with OPSCC and 621 patients with non-OP HNSCC with a median follow-up time of 3.5 years. After adjustments for the tumor HPV status, age, current tobacco use, and stage, the risk of death was lower for women versus men with OPSCC (adjusted hazard ratio, 0.55; P = .04). The results were similar with p16. In contrast, for non-OP HNSCCs, HPV positivity, p16 positivity, and sex were not associated with OS., Conclusions: For OPSCC, there are differences in survival by sex, even after the tumor HPV status has been taken into account. For non-OP HNSCC, the HPV status and the p16 status are not of prognostic significance. Cancer 2017;123:1566-1575. © 2017 American Cancer Society., (© 2017 American Cancer Society.)

Objective To determine the presence of human papillomavirus (HPV) in head and neck squamous cell carcinoma, specifically in the larynx without the bias of other sublocations, and to describe the different serotypes of HPV and their impact on overall and disease-free survival after 10-year follow-up. Study Design Retrospective case series with chart review of ear, nose, and throat oncologic database. Setting Academic tertiary care hospital. Subjects A total of 123 samples of larynx squamous cell carcinoma were included, only from the glottis and treated only with surgery between 1977 and 2005. Methods DNA extraction was carried out by polymerase chain reaction, and subsequent visualization was performed in low-density arrays. Results were compared with histologic, clinicopathologic, and survival parameters, with a 10-year follow-up. Results HPV DNA was detected in 22.76% (n = 28) of the samples. Eleven genotypes were detected, 2 of which had never been described in the larynx (HPV43 and HPV62). No increasing trend of HPV was observed over time. HPV presence did not correlate with better survival during the follow-up. Smoking was proven as an independent factor in relation to the presence of HPV. Conclusion HPV may represent a notable factor in the development of a subset of laryngeal squamous cell carcinoma without significant influence on overall and disease-free survival. More studies, including oncogene transcription proteins, would be necessary to draw more relevant conclusions about the relevance of HPV infection in the larynx.

Background: Indicators of poor oral health, including smoking, have been associated with increased risk of head and neck squamous cell carcinoma, especially oropharyngeal squamous cell carcinoma (OPSCC), yet few studies have examined whether this association is modified by human papillomavirus (HPV) status., Methods: Data from interviews and tumor HPV status from a large population-based case-control study, the Carolina Head and Neck Cancer Study (CHANCE), were used to estimate the association between oral health indicators and smoking among 102 HPV-positive patients and 145 HPV-negative patients with OPSCC and 1396 controls. HPV status was determined by p16INK4a (p16) immunohistochemistry. Unconditional, multinomial logistic regression was used to estimate odds ratios (ORs) for all oral health indictors adjusting for important covariates., Results: Routine dental examinations were associated with a decreased risk of both HPV-negative OPSCC (OR, 0.52; 95% confidence interval [CI], 0.35-0.76) and HPV-positive OPSCC (OR, 0.55; 95% CI, 0.36-.86). Tooth mobility (a proxy for periodontal disease) increased the risk of HPV-negative disease (OR, 1.70; 95% CI, 1.18-2.43) slightly more than the risk for HPV-positive disease (OR, 1.45; 95% CI, 0.95-2.20). Ten or more pack-years of cigarette smoking were strongly associated with an increased risk of HPV-negative OPSCC (OR, 4.26; 95% CI, 2.85-6.37) and were associated less with an increased risk of HPV-positive OPSCC (OR, 1.62; 95% CI, 1.10-2.38)., Conclusions: Although HPV-positive and HPV-negative HNSCC differ significantly with respect to etiology and tumorigenesis, the current findings suggest a similar pattern of association between poor oral health, frequency of dental examinations, and both HPV-positive and HPV-negative OPSCC. Future research is required to elucidate interactions between poor oral health, tobacco use, and HPV in the development of OPSCC. Cancer 2017;71-80. © 2016 American Cancer Society., Competing Interests: There are no conflicts of interest to disclose., (© 2016 American Cancer Society.)

Objective: The incidence of oropharyngeal squamous cell carcinoma (SCCa) has increased in the United States despite a decrease in tobacco usage, and it may be driven by an increase in oral human papilloma virus (HPV) infection. We studied the incidence of tongue base and tonsillar SCCa over time to understand the changing epidemiology of oropharyngeal SCCa., Setting: Large national tumor registry., Subjects and Methods: We studied patients diagnosed with oropharyngeal SCCa in SEER data (Surveillance, Epidemiology, and End Results) from 1973 to 2009. Age-adjusted incidence rates standardized to the 2000 US population were computed, with stratifications for age, sex, race, and stage., Results: The sample included 10,061 tongue base and 11,515 tonsillar oropharyngeal cancers. When stratified by age, the incidence of oropharyngeal SCCa in patients ≤55 years of age more than doubled over 30 years. While the incidence rate in females remained stable, the rate in males more than doubled, from 2 per 100,000 persons in 1973 to >4 per 100,000 persons in 2009. The age-adjusted incidence of oropharyngeal SCCa in patients of black race/ethnicity remained consistently elevated, but the incidence in patients of white race/ethnicity rose from 1.3 per 100,000 persons to >2.5 per 100,000 persons, surpassing the incidence in black patients starting in 2002., Conclusion: The observation that the incidence of oropharyngeal SCCa is increasing among younger white males, despite a reduction in tobacco usage in the United States, is consistent with HPV as the source. Primary and secondary prevention strategies may be warranted in this population., (© American Academy of Otolaryngology—Head and Neck Surgery Foundation 2016.)

Background: The incidence of oropharyngeal squamous cell carcinoma caused by oncogenic HPV (HPV-OPSCC) is rising worldwide. HPV-OPSCC is commonly diagnosed by RT-qPCR of HPV-16 E6 and E7 oncoproteins or by cyclin-dependent kinase inhibitor 2A, multiple tumor suppressor 1 (p16) immunohistochemistry (IHC). Droplet digital PCR (ddPCR) has been recently reported as ultra-sensitive and highly precise method of nucleic acid quantification for biomarker analysis. We aimed to validate this method for the detection of HPV-16 E6 and E7 in HPV-OPSCC., Methods: Participants were recruited from January 2015-November 2015 at initial presentation to the University of Alberta Head and Neck Oncology Clinic. RNA was extracted, purified and quantified from prospectively collected participant tissues, and ddPCR was performed with fluorescent probes detecting HPV-16 E6 and E7. Results from ddPCR were compared with p16 IHC performed by clinical pathology as standard of care., Results: Head and neck tissues were prospectively obtained from 68 participants including 29 patients with OPSCC, 29 patients with non-OPSCC and 10 patients without carcinoma. 79.2% of patients with OPSCC were p16 positive. The sensitivity and specificity of ddPCR HPV E6/E7 compared with p16 IHC in OPSCC was 91.3 and 100%, respectively. The amount of target RNA used was ≤1 ng, 20-50 times lower than reported by other for RT-qPCR HPV E6/E7., Conclusions: The ddPCR of HPV E6/E7 is a novel and highly specific method of detecting HPV-16 in OPSCC. Cancer 2016;122:1544-51. © 2016 American Cancer Society., (© 2016 American Cancer Society.)