Quantitative assessment of p16 expression in FNA specimens from head and neck squamous cell carcinoma and correlation with HPV status.

BACKGROUND: This study investigated p16 by immunohistochemistry (IHC) on cellblocks (CBs) and human papillomavirus (HPV) by polymerase chain reaction (PCR) in fine-needle aspiration (FNA) of head and neck squamous cell carcinoma (HNSCC). METHODS: Receiver operating characteristic (ROC) curve analysis was used to assess test performance in CBs compared with p16 IHC in 42 surgical specimens from patients with HNSCC and in correlation with HPV by PCR in cytology specimens. The study assessed HPV by PCR in FNA specimens as a substitute for p16 IHC in surgical specimens. RESULTS: Of 42 cases, 38 CBs showed malignant cells as cohesive clusters of viable cells with or without single tumor cells, whereas 4 specimens were composed exclusively of single tumor cells and degenerated cells. All p16-negative surgical specimens showed an absence of p16 staining in the corresponding CBs (n = 16). In the p16-positive surgical cases (n = 26), corresponding CBs with tumor clusters (n = 23) showed heterogeneous p16 expression ranging from 40% to 100%; however, scoring single cells was challenging and unreliable because of cellular degradation. ROC curve inspection showed the optimal threshold to be at least 40% p16 staining in tumor clusters with 100% sensitivity and specificity. In cases with inadequate CBs, HPV by PCR on needle rinse showed 88% sensitivity and 100% specificity for p16 expression in surgical specimens. CONCLUSIONS: A cutoff of at least 40% p16 expression in tumor clusters may be appropriate for p16 positivity in cytology CB specimens. A positive HPV finding by PCR on needle rinse can be used as a substitute for p16 expression in surgical specimens.

Costs of Definitive Chemoradiation, Surgery, and Adjuvant Radiation Versus De-Escalated Adjuvant Radiation per MC1273 in HPV+ Cancer of the Oropharynx.

PURPOSE: De-escalated treatment for human papillomavirus (HPV)+ oropharynx squamous cell carcinoma (OPSCC) has shown promising initial results. Health-care policy is increasingly focusing on high-value care. This analysis compares the cost of care for HPV+ OPSCC treated with definitive chemoradiation (CRT), surgery and adjuvant radiation (RT), and surgery and de-escalated CRT on MC1273. METHODS AND MATERIALS: MC1273 is a prospective, phase 2 study evaluating adjuvant CRT to 30 to 36 Gy plus docetaxel for HPV+ OPSCC after surgery for high-risk patients. Matched standard-of-care control groups were retrospectively identified for patients treated with definitive CRT or adjuvant RT. Standardized costs were evaluated before radiation, during treatment (during RT), and at short-term (6 month) and long-term (7-24 month) follow-up periods. RESULTS: A total of 56 definitive CRT, 101 adjuvant RT, and 66 MC1273 patients were included. The CRT arm had more T3-4 disease (63% vs 17-21%) and higher N2c-N3 disease (52% vs 20-24%) vs both other groups. The total treatment costs in the CRT, adjuvant RT, and MC1273 groups were $47,763 (standard deviation [SD], $19,060], $57,845 (SD, $17,480), and $46,007 (SD, $9019), respectively, and the chemotherapy and/or RT costs were $39,936 (SD, $18,480), $26,603 (SD, $12,542), and $17,864 (SD, $3288), respectively. The per-patient, per-month, average short-term follow-up costs were $3860 (SD, $10,525), $1072 (SD, $996), and $972 (SD, $833), respectively, and the long-term costs were $978 (SD, $2294), $485 (SD, $1156), and $653 (SD, $1107), respectively. After adjustment for age, T-stage, and N-stage, treatment costs remained lower for CRT and MC1273 versus adjuvant RT ($45,450 and $47,114 vs $58,590, respectively; P < .001), whereas the total per-patient, per-month follow-up costs were lower in the MC1273 study group and adjuvant RT versus CRT ($853 and $866 vs $2030, respectively; P = .03). CONCLUSIONS: MC1273 resulted in 10% and 20% reductions in global costs compared with standard-of-care adjuvant RT and definitive CRT treatments. Substantial cost savings may be an added benefit to the already noted low toxicity and maintained quality of life of treatment per MC1273.

Gender and race interact to influence survival disparities in head and neck cancer.

Gender and race disparities in head and neck squamous cell carcinoma (HSNCC) survival are independently well documented, but no prior studies have examined the joint effect of these factors on HSNCC outcomes. We aim to comprehensively estimate the effect of gender and race on overall survival in HNSCC. We constructed a retrospective cohort from the National Cancer Database for primary HNSCC of the larynx, hypopharynx, oral cavity, and oropharynx from 2010 to 2015. We used Kaplan-Meier curves and Cox proportional hazards regressions to calculate hazard ratios adjusting for treatment type, age, insurance, staging classifications, and comorbidities. Oral cavity cancer was significantly more common among Hispanic and White females compared to other sites. Female non-oropharyngeal HNSCC cases had better five-year overall survival than males (56.3% versus 54.4%, respectively), though Black females (52.8%) had poorer survival than both White (56.2%) and Hispanic (57.9%) males. There were significant differences in oropharyngeal cancer by HPV status. Notably, Black females with HPV-positive oropharyngeal OPSCC had far worse survival than any other race and gender group. These results persisted even when adjusting for potential mediating factors. Clearly gender is a significant prognosticator for HNSCC and has meaningful interactions with race. The distinct site distributions across gender and race reveal important insights into HNSCC among females. Taking into account these gender disparities while considering race is essential to providing appropriate care to head and neck patients and accurately counselling these individuals on prognosis and outcomes.

An Update on Surgical Margins in the Head Neck Squamous Cell Carcinoma: Assessment, Clinical Outcome, and Future Directions.

PURPOSE OF REVIEW: Failure to achieve tumor-free margins is the single largest cause of death for head neck cancer patients. At the same time, it is the only factor that is in complete control of the surgeon. This review summarizes evidence for the definition, clinical implications, and methods to achieve optimal margins. RECENT FINDINGS: The previous universally followed definition of adequate margin (5 mm in final histopathology) has been disputed. Various biological, optical, and imaging adjuncts can aid in achieving optimal margins. Extent of resection and margins in human papilloma virus (HPV)-positive oropharyngeal cancers and following induction chemotherapy remain controversial. Though practiced widely, frozen section-guided margin revision has not conclusively shown improved local control rates. The role of molecular assessment of margins is promising but not established. The definition of adequate margin differs according to the site in the head neck region. Currently, the 5-mm margin at final histopathology is the most commonly accepted definition of an "adequate" margin.

Outcomes of HPV-Associated Squamous Cell Carcinoma of the Head and Neck: Impact of Race and Socioeconomic Status.

BACKGROUND: Socioeconomic factors affecting outcomes of HPV-associated squamous cell carcinoma of the head and neck (SCCHN) are poorly characterized. METHODS: A custom SEER database identified adult patients with primary nonmetastatic SCCHN and known HPV status diagnosed in 2013 through 2014. Multivariable logistic regression defined associations between patient characteristics and HPV status, with adjusted odds ratios (aORs) and 95% confidence intervals reported. Fine-Gray competing risks regression estimated adjusted hazard ratios (aHRs) and 95% confidence intervals for cancer-specific mortality (CSM), including a disease subsite * HPV status * race interaction term. RESULTS: A total of 4,735 patients with nonmetastatic SCCHN and known HPV status were identified. HPV-associated SCCHN was positively associated with an oropharyngeal primary, male sex, and higher education, and negatively associated with uninsured status, single marital status, and nonwhite race (P≤.01 for all). For HPV-positive oropharyngeal SCCHN, white race was associated with lower CSM (aHR, 0.55; 95% CI, 0.34-0.88; P=.01) and uninsured status was associated with higher CSM (aHR, 3.12; 95% CI, 1.19-8.13; P=.02). These associations were not observed in HPV-negative or nonoropharynx SCCHN. Accordingly, there was a statistically significant disease subsite * HPV status * race interaction (Pinteraction<.001). CONCLUSIONS: Nonwhite race and uninsured status were associated with worse CSM in HPV-positive oropharyngeal SCCHN, whereas no such associations were observed in HPV-negative or nonoropharyngeal SCCHN. These results suggest that despite having clinically favorable disease, nonwhite patients with HPV-positive oropharyngeal SCCHN have worse outcomes than their white peers. Further work is needed to understand and reduce socioeconomic disparities in SCCHN.

Two for the price of one: Prevalence, demographics and treatment implications of multiple HPV mediated Head and Neck Cancers.

OBJECTIVES: HPV mediated head and neck squamous cell carcinoma (HPVmHNSCC) is increasing in prevalence in the United States, as are reports of patients with multiple HPVmHNSCCs. The prevalence, demographics, and treatment implications of this emerging clinical entity are poorly understood. MATERIALS AND METHODS: We performed a multitiered assessment of patients with multiple HPVmHNSCC including: 1. systematic review of the literature, 2. query of the 2017 Surveillance, Epidemiology and End Results (SEER) database and 3. institutional level reporting at two high volume academic centers. RESULTS: Systematic literature review: 13 articles met inclusion criteria (48 patients with multiple HPVmHNSCC). Pooled prevalence rate of multiple HPVmHNSCC was 2.64%. SEER database: 60(0.95%) patients with HPVmHNSCC had two tumors. Patients with multiple HPVmHNSCC were more likely to be younger and present with a lower T and N stage (p < 0.025 for all). The second identified tumor was more likely to be contralateral, found synchronously, of smaller size, and to occur in the tonsil (p < 0.05 for all). Institutional reporting: 17(1.69%) patients with HPVmHNSCC had two primary tumors. Similar to the SEER database, patients with multiple HPVmHNSCC were more likely to present with a low T stage and tonsil location (p < 0.007 for both). CONCLUSION: Multiple HPVmHNSCCs occur in a subset of HPVmHNSCC cases with distinct characteristics. Thorough interrogation of all oropharyngeal subsites should be performed as part of the initial workup for HPVmHNSCC, with consideration given to contralateral tonsillectomy at the time of surgical resection for HPV mediated tonsil cancers due to the prevalence of contralateral tonsil primaries.

Concurrent cisplatin or cetuximab with radiotherapy for HPV-positive oropharyngeal cancer: Medical resource use, costs, and quality-adjusted survival from the De-ESCALaTE HPV trial.

BACKGROUND: The De-ESCALaTE HPV trial confirmed the dominance of cisplatin over cetuximab for tumour control in patients with human papillomavirus (HPV)-positive oropharyngeal squamous cell carcinoma (OPSCC). Here, we present the analysis of health-related quality of life (HRQoL), resource use, and health care costs in the trial, as well as complete 2-year survival and recurrence. MATERIALS AND METHODS: Resource use and HRQoL data were collected at intervals from the baseline to 24 months post treatment (PT). Health care costs were estimated using UK-based unit costs. Missing data were imputed. Differences in mean EQ-5D-5L utility index and adjusted cumulative quality-adjusted life years (QALYs) were compared using the Wilcoxon signed-rank test and linear regression, respectively. Mean resource usage and costs were compared through two-sample t-tests. RESULTS: 334 patients were randomised to cisplatin (n = 166) or cetuximab (n = 168). Two-year overall survival (97·5% vs 90·0%, HR: 3.268 [95% CI 1·451 to 7·359], p = 0·0251) and recurrence rates (6·4% vs 16·0%, HR: 2·67 [1·38 to 5·15]; p = 0·0024) favoured cisplatin. No significant differences in EQ-5D-5L utility scores were detected at any time point. At 24 months PT, mean difference was 0·107 QALYs in favour of cisplatin (95% CI: 0·186 to 0·029, p = 0·007) driven by the mortality difference. Health care costs were similar across all categories except the procurement cost and delivery of the systemic agent, with cetuximab significantly more expensive than cisplatin (£7779 [P < 0.001]). Consequently, total costs at 24 months PT averaged £13517 (SE: £345) per patient for cisplatin and £21064 (SE: £400) for cetuximab (mean difference £7547 [95% CI: £6512 to £8582]). CONCLUSIONS: Cisplatin chemoradiotherapy provided more QALYs and was less costly than cetuximab bioradiotherapy, remaining standard of care for nonsurgical treatment of HPV-positive OPSCC.

Incidence and Risk of Second Primary Malignant Neoplasm After a First Head and Neck Squamous Cell Carcinoma.

Importance: Second primary malignant neoplasms (SPMNs) are the leading cause of death in survivors of head and neck squamous cell carcinoma (HNSCC). Recently, human papillomavirus (HPV) has emerged as a risk factor for oropharyngeal squamous cell carcinoma and has different prognosis from classic tobacco/alcohol-associated HNSCC. This suggests that there also may be different risks and burden of SPMNs among patients who's HNSCC were from HPV or tobacco and/or alcohol. Objective: To assess SPMN risks and burden in a large US cohort of patients with a first potentially HPV-associated HNSCC vs non-HPV-associated HNSCC. Design, Setting, and Participants: In this population-based retrospective cohort study, 109 512 adult patients diagnosed with HNSCC between 2000 and 2014 were identified from the Surveillance, Epidemiology, and End Results registry. Exposures: HPV-relatedness based on whether patients' first HNSCC was potentially associated with HPV. Patients were grouped into 2 cohorts: potentially HPV-associated HNSCC, and non-HPV-associated HNSCC. Main Outcomes and Measures: The primary outcome was incidence of SPMN (defined as the first subsequent primary cancer occurring at least 2 months after first cancer diagnosis). Excess SPMN risk was calculated using relative (standardized incidence ratios [SIRs]) and absolute (excess absolute risk [EAR] per 10 000 person-years at risk [PYR]). Results: A total of 109 512 patients with HNSCC (mean [SD] age, 61.9 [12.1] years; 83 305 [76.1%] men) were identified. The overall SIR was 2.18 (95% CI, 2.14-2.22) corresponding to 160 excess cases per 10 000 PYR. The risk among patients with first potentially HPV-associated HNSCC (SIR, 1.98; EAR, 114 excess cases per 10 000 PYR) was lower than those with first non-HPV-associated HNSCC (SIR, 2.28; EAR, 188 excess cases per 10 000 PYR). Overall, the largest SIRs and EARs were observed for cancers of the head and neck, lung, and esophagus. However, the risks of SPMN were lower among potentially HPV-associated HNSCC patients. Conclusions and Relevance: Patients diagnosed with HNSCC experience excess risk of SPMN, which was higher among those with non-HPV-associated HNSCC than from potentially HPV-associated HNSCC. Clinicians should implement strategies that prevent or detect SPMN early in patients with HNSCC.

Evaluation of Diagnostic Utility of a High-Risk Human Papillomavirus PCR Test on Formalin-Fixed, Paraffin-Embedded Head and Neck Tumor Tissues.

The increasing prevalence of high-risk human papillomavirus (HR-HPV)-associated head and neck squamous cell carcinoma (HNSCC) has prompted strong clinical demands for detecting HR-HPV directly in the tumor. Although p16 immunohistochemistry (IHC) has been the standard testing method, it has limitations including false positivity, lack of sensitivity in low tumor cell samples such as fine-needle aspirate (FNA), and its subjectivity. We developed a modified method based on a commercial automated HR-HPV PCR assay and evaluated the performance characteristics and the diagnostic utility of this assay for direct HR-HPV detection in the HNSCC samples. HNSCC formalin-fixed, paraffin-embedded blocks were retrieved from archives including 44 excisions, 63 biopsies, and 16 FNAs. Tissue slices were trimmed from the blocks, deparaffinized, lysed, and loaded on the commercial automated platform for HR-HPV PCR. All specimens had a concurrent p16 IHC performed. The PCR assay showed high concordance with the p16 IHC (96%; 99/103) and excellent positive agreement (91.5%) and negative agreement (100%). In addition, the PCR assay provided more conclusive results in samples with equivocal p16 IHC results. The modified commercial automated HR-HPV PCR test is a labor-efficient, quick, reliable, sensitive, and specific method for detecting HR-HPV in formalin-fixed, paraffin-embedded samples. This assay also showed excellent diagnostic utility in samples with equivocal p16 IHC results, including FNA cell blocks.

Assessment of cellular and serum proteome from tongue squamous cell carcinoma patient lacking addictive proclivities for tobacco, betel nut, and alcohol: Case study.

The intriguing molecular pathways involved in oral carcinogenesis are still ambiguous. The oral squamous cell carcinoma (OSCC) ranks as the most common type constituting more than 90% of the globally diagnosed oral cancers cases. The elevation in the OSCC incidence rate during past 10 years has an alarming impression on human healthcare. The major challenges associated with OSCC include delayed diagnosis, high metastatic rates, and low 5-year survival rates. The present work foundations on reverse genetic strategy and involves the identification of genes showing expressional variability in an OSCC case lacking addictive proclivities for tobacco, betel nut, and/or alcohol, major etiologies. The expression modulations in the identified genes were analyzed in 16 patients comprising oral pre-cancer and cancer histo-pathologies. The genes SCCA1 and KRT1 were found to down regulate while DNAJC13, GIPC2, MRPL17, IG-Vreg, SSFA2, and UPF0415 upregulated in the oral pre-cancer and cancer pathologies, implicating the genes as crucial players in oral carcinogenesis.