Kristina R. Dahlstrom

Epidemiology of HPV-associated oropharyngeal cancer

Squamous cell carcinoma of the oropharynx is increasing in incidence in epidemic proportion. This site specific increase in incidence is due to an increase in human papillomavirus (HPV)-related squamous cell carcinoma, while the incidence of tobacco related squamous cell carcinoma is decreasing. In particular, the incidence of HPV-related oropharyngeal squamous cell carcinoma (OPSCC) is increased among middle aged white men, and sexual behavior is a risk factor. HPV-related oropharyngeal squamous cell carcinoma represents a growing etiologically distinct subset of head and neck cancers with unique epidemiological, clinical, and molecular characteristics that differ from those of HPV-unassociated cancers. In this review, we discuss the epidemiology of HPV-related OPSCC, the prevalence of oral/oropharyngeal HPV infection, and efforts aimed at reducing the incidence of HPV-related OPSCC.

Squamous cell carcinoma of the head and neck in never smoker–never drinkers: A descriptive epidemiologic study

While the attributed risk factors for the vast majority of patients with squamous cell carcinoma of the head and neck (SCCHN) are smoking and alcohol abuse, there appears to be a rising proportion of SCCHN patients who report no significant smoking or drinking history. This study reports the demographic and potential risk factors of a large series of never smoker–never drinker (NSND) patients.

An evolution in demographics, treatment, and outcomes of oropharyngeal cancer at a major cancer center: A staging system in need of repair

In this retrospective review, the authors examined demographic/clinical characteristics and overall survival in patients with squamous cell carcinoma of the oropharynx at a tertiary cancer center, and they report the characteristics that influenced any observed survival trends over time.

Differences in history of sexual behavior between patients with oropharyngeal squamous cell carcinoma and patients with squamous cell carcinoma at other head and neck sites

An emerging epidemic of human papillomavirus (HPV)‐associated oropharyngeal cancer has been proposed. The purpose of this study was for us to compare the sexual behaviors of patients with squamous cell carcinoma of the oropharynx (SCCOP) and patients with squamous cell carcinoma of non‐oropharyngeal (SCCNOP) head and neck sites to expand our understanding of sexual behavior as a risk factor for HPV‐associated head and neck cancer.

A variant of the DNA repair gene XRCC3 and risk of squamous cell carcinoma of the head and neck: A case‐control analysis

Individuals differ in their ability to repair DNA damage induced by carcinogens. Studies have shown that polymorphisms in DNA repair genes contribute to individual variation in DNA repair capacity and cancer risk. In a hospital‐based case‐control study, we tested the hypothesis that a C to T variant (Thr241Met) of DNA repair gene X‐ray repair cross‐complementing group 3 (XRCC3) is associated with risk of developing squamous cell carcinoma of the head and neck (SCCHN). We genotyped for this variant in 367 non‐Hispanic white patients newly diagnosed with SCCHN and 354 frequency‐matched cancer‐free controls. Compared with the XRCC3 18067CC and 18607CT genotypes, the variant XRCC3 18067TT genotype was associated with a non‐statistically significantly increased risk of SCCHN (adjusted odds ratio [ORadj], 1.36; 95% confidence interval [CI], 0.89–2.08), but this risk was significantly increased among female subjects (ORadj 2.23, 95% CI, 1.00–4.98) and current smokers (ORadj, 2.26; 95% CI, 1.02–4.99). These findings suggest that the variant XRCC3 18067TT genotype may not play a major role in the etiology of SCCHN but may contribute to a subset of SCCHN. Larger studies are needed to verify these findings.

Serum Cotinine Concentration and Wound Complications in Head and Neck Reconstruction

Background: The authors examined whether the preoperative serum concentrations of cotinine accurately predict the risk of complications in patients undergoing flap reconstruction of head and neck cancer defects. Methods: Patients with incident stage III or IV squamous cell carcinoma of the head and neck undergoing resection with pedicled or free flap reconstruction were selected from an existing database of 500 patients with squamous cell carcinoma of the head and neck who participated in a prospective epidemiologic study and were reviewed retrospectively. Preoperative serum cotinine concentrations were determined using a competitive microplate immunoassay. Complications were defined as any adverse postoperative wound outcome at either the donor or recipient site. Results: Eighty-nine patients underwent 101 flap reconstructions. Thirty-seven wound complications occurred in 33 patients. Forty of the 89 patients had a serum cotinine concentration greater than 10 ng/ml; twenty (50 percent) developed postoperative complications, whereas only 13 of 49 patients (27 percent) with a serum cotinine concentration of 10 ng/ml or less developed complications (p = 0.028). The relative risk of wound complications for those with a cotinine concentration greater than 10 ng/ml was approximately double that of patients with a lower cotinine concentration (relative risk, 1.9; 95 percent CI, 1.1 to 3.3). Patients with a cotinine concentration greater than 50 ng/ml had a particularly high risk (relative risk, 2.3; 95 percent CI, 1.1 to 16.7; p = 0.024). The relative risk of wound complications was not significantly associated with self-reported smoking status or history. Conclusion: A serum cotinine concentration greater than 10 ng/ml may predict an increased risk of wound complication in head and neck flap reconstruction and may serve as an objective, easily measured variable with which to identify patients who may benefit from an aggressive smoking cessation program before surgery.

Human Papillomavirus Seropositivity Synergizes with MDM2 Variants to Increase the Risk of Oral Squamous Cell Carcinoma

The increasing incidence of oral squamous cell carcinoma (OSCC) in young adults has been associated with sexually transmitted infections of human papillomavirus (HPV), particularly HPV16. Given the roles of p53 in tumor suppression and of HPV E6 and MDM2 oncoproteins in p53 degradation, we evaluated HPV16 L1 seropositivity and MDM2 promoter variants to examine their possible associations with OSCC risk in a case-control study of 325 patients and 335 cancer-free matched controls. Compared with individuals having MDM2-rs2279744 GT or GG genotypes and HPV16 L1 seronegativity, the TT genotype and HPV16 L1 seronegativity were found to be associated with an odds ratio (OR) of 1.25 [95% confidence interval (CI), 1.06-2.19] for OSCC risk, and GT/GG and HPV16 L1 seropositivity were associated with an OR of 2.81 (95% CI, 1.67-4.74). For those with both the TT genotype and HPV16 L1 seropositivity, the associated OR was 5.57 (95% CI, 2.93-10.6). Similar results were observed for the MDM2-rs937283 polymorphism. Moreover, there was a borderline significant or significant interaction between the individual or combined MDM2 genotypes of the two polymorphisms and HPV16 L1 seropositivity (P(int) = 0.060 for MDM2-rs2279744, P(int) = 0.009 for MDM2-rs937283, and P(int) = 0.005 for the combined MDM2 genotypes) on risk of OSCC. Notably, that effect modification was particularly pronounced in never smokers and never drinkers, and for oropharyngeal as opposed to oral cavity cancer. Taken together, our results indicate that the risk of OSCC associated with HPV16 L1 seropositivity is modified by MDM2 promoter polymorphisms.

Proposed Staging System for Patients With HPV-Related Oropharyngeal Cancer Based on Nasopharyngeal Cancer N Categories

PURPOSE Patients with human papillomavirus (HPV)-related oropharyngeal cancer (OPC) generally present with more advanced disease but have better survival than patients with HPV-unrelated OPC. The current American Joint Commission on Cancer (AJCC)/Union for International Cancer Control (UICC) TNM staging system for OPC was developed for HPV-unrelated OPC. A new staging system is needed to adequately predict outcomes of patients with HPV-related OPC. PATIENTS AND METHODS Patients with newly diagnosed HPV-positive OPC (by p16 immunohistochemistry or in situ hybridization) treated at our institution from January 2003 through December 2012 were included. By using recursive partitioning analysis (RPA), we developed new stage groupings with both traditional OPC regional lymph node (N) categories and nasopharyngeal carcinoma (NPC) N categories. Survival was estimated by the Kaplan-Meier method, and the relationship between stage and survival was examined by using Cox proportional hazards regression analysis. RESULTS A total of 661 patients with HPV-positive OPC met the inclusion criteria. With the traditional TNM staging system, there was no difference in survival between stages (P = .141). RPA with NPC N categories resulted in more balanced stage groups and better separation between groups for 5-year survival than RPA with traditional OPC N categories. With the stage groupings that were based in part on NPC N categories, the risk of death increased with increasing stage (P for trend < .001), and patients with stage III disease had five times the risk of death versus patients with stage IA disease. CONCLUSION New stage groupings that are based on primary tumor (T) categories and NPC N categories better separate patients with HPV-positive OPC with respect to survival than does the current AJCC/UICC TNM staging system. Although confirmation of our findings in other patient populations is needed, we propose consideration of NPC N categories as an alternative to the traditional OPC N categories in the new AJCC/UICC TNM staging system that is currently being developed.

p53 codon 72 polymorphism associated with risk of human papillomavirus-associated squamous cell carcinoma of the oropharynx in never-smokers

The tumor suppressor p53 protein can be bound, degraded and inactivated by the human papillomavirus (HPV) E6 oncoprotein. The p53 proteins susceptibility to this oncoprotein may be influenced by the p53 codon 72 polymorphism, but the role of such a polymorphism in the development of HPV16-associated squamous cell carcinoma of the oropharynx (SCCOP) has not been established. To investigate the role of the p53 codon 72 polymorphism in the risk of HPV16-associated SCCOP, we conducted a hospital-based case-control study of 188 non-Hispanic white patients with newly diagnosed SCCOP and 342 cancer-free control subjects frequency matched by age (+/-5 years), sex, tobacco smoking status and alcohol drinking status. We found that HPV16 seropositivity was associated with an increased risk of SCCOP [adjusted odds ratio (OR), 5.7; 95% confidence interval (CI), 3.7-8.7], especially among never-smokers (adjusted OR, 14.1; 95% CI, 6.0-32.9) and among subjects with the p53 codon 72 variant genotypes [Arginine (Arg)/Proline (Pro) and Pro/Pro] (adjusted OR, 9.2; 95% CI, 4.7-17.7). A significant multiplicative interaction on the risk of SCCOP was also found between the p53 codon 72 polymorphism and HPV16 seropositivity (P = 0.05). Among never-smokers, the risk of SCCOP for those who had both HPV16 seropositivity and p53 codon 72 variant genotypes (Arg/Pro + Pro/Pro) was particularly high (adjusted OR, 22.5; 95% CI, 4.8-106.2). These findings suggest that p53 codon 72 variant genotypes modify the risk of HPV16-associated SCCOP and may be markers of genetic susceptibility to HPV16-associated SCCOP, especially among never-smokers.

A pilot study of Helicobacter pylori infection and risk of laryngopharyngeal cancer

Squamous cell carcinoma of the laryngopharynx has been linked to laryngopharyngeal reflux disease. Helicobacter pylori corpus gastritis decreases gastric acid secretion and provides some protection against complications of gastroesophageal reflux, including adenocarcinoma of the distal esophagus. The aim of this study was to investigate whether H. pylori infection also protects against laryngopharyngeal carcinoma.