Human Papillomavirus in Patients With Hypopharyngeal Squamous Cell Carcinoma.

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.

Tumour inflammation signature and expression of S100A12 and HLA class I improve survival in HPV-negative hypopharyngeal cancer.

Hypopharyngeal squamous cell carcinoma (HPSCC) has a very poor prognosis. Local surgery may increase survival, but is often avoided due to significant post-op co-morbidities. Since prognostic markers are lacking, the aim was to find predictive biomarkers that identify patients whose response to oncological treatment is poor and who may benefit from primary surgery to increase survival. Pretreatment biopsies from 23 HPSCC patients, 3 human papillomavirus (HPV) positive and 20 HPV-negative, were analyzed for expression of 750 mRNAs using the Nanostring nCounter IO360 panel in relation to 3-year survival. Validation was performed through immunohistochemistry (IHC) for HLA class I and S100A12 in 74 HPV-negative HPSCC samples. Clustering identified a subset of HPV-negative HPSCC with favorable prognosis and a gene expression signature overexpressing calgranulins and immune genes, distinct from that of HPV-positive HPSCC. Enrichment analysis showed immune signaling, including the tumor inflammation signature, to be enriched in surviving patients. IHC validation confirmed high S100A12 and HLA class I expression to correlate with survival in HPV-negative HPSCC. This shows that immune activity is strongly related to survival in HPV-negative HPSCC. Enrichment of the tumor inflammation signature indicates a potential benefit of immunotherapy. Low expression of both HLA class I and S100A12 could be used to select patients for local surgery.

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.

HPV-positive Squamous Cell Carcinoma of the Larynx, Oral Cavity, and Hypopharynx: Clinicopathologic Characterization With Recognition of a Novel Warty Variant.

Human papillomavirus (HPV) is a principal driver for most oropharyngeal squamous cell carcinomas (OPSCCs), where it is strongly associated with improved survival. HPV is much less frequently detected in squamous cell carcinomas arising in nonoropharyngeal sites (non-OPSCCs), and its pathogenic role and prognostic value in these tumors is unclear. We evaluated the clinicopathologic features of 52 non-OPSCCs considered HPV-positive based upon p16 immunohistochemistry and direct HPV detection using RNA in situ hybridization (ISH), DNA ISH, or real-time DNA polymerase chain reaction. The HPV-positive non-OPSCCs were from the larynx (n=27), oral cavity (n=21), and hypopharynx (n=4). While most cases (n=34, 65%) showed classic histologic features of HPV-positive OPSCC, including endophytic growth, minimal keratinization, and hyperchromatic nuclei without koilocytic changes, a subset (n=13, 25%) were characterized by exophytic growth, exuberant surface hyperkeratosis and parakeratosis, marked nuclear pleomorphism, and prominent koilocytic atypia. These antithetical features were highly reminiscent of the warty variant of HPV-positive squamous cell carcinoma described in anogenital sites. Compared with tumors without warty features, the warty tumors presented at lower stage and were not associated with lymph node metastasis, local recurrence, or distant spread (4 y disease-free survival of 100% vs. 66%, P=0.069). The presence of transcriptionally active HPV as detected by RNA ISH suggests a pathogenic role for HPV in these nonoropharyngeal sites. While most HPV-positive non-OPSCCs are morphologically similar to their tonsillar counterparts, this study highlights a previously unrecognized warty variant that may be associated with a highly favorable clinical outcome.

Locally advanced hypopharyngeal and laryngeal cancer: Influence of HPV status.

BACKGROUND: Larynx preservation with chemoradiotherapy (CRT) is used frequently in the treatment of locally advanced hypopharyngeal/laryngeal squamous cell carcinoma (LSCC). Multiple large retrospective analyses have shown that CRT is associated with worse overall survival (OS) compared to total laryngectomy (TL) in patients with T4a disease. Burgeoning evidence suggests HPV status may play a prognostic role in patients with LSCC. We aimed to determine if HPV status influences OS among patients with T4a LSCC, and, if so, if it may be useful in selecting patients for CRT. METHODS: Using the National Cancer Database (NCDB), we identified 810 patients with T4a N0-3 M0 squamous cell carcinoma of the larynx or hypopharynx with known HPV status who received either definitive CRT (to 66-81.6 Gy with any chemotherapy) or definitive TL (with the addition of 60-70 Gy of adjuvant RT). We evaluated differences in OS using the Kaplan-Meier method and Cox proportional hazards analyses. RESULTS: On multivariate analysis, HPV-negative status (HR = 1.42, p = 0.02) and receipt of CRT (HR = 1.34, p = 0.01) were associated with worse OS when compared to HPV-positive patients and patients receiving TL, respectively. Among patients receiving CRT, 5-year OS was lower among HPV-negative patients (33.4%) when compared to HPV-positive patients (50.6%). CONCLUSIONS: These data suggest that HPV status may be a prognostic factor in patients with T4a LSCC. Further, it supports further investigation into the usefulness of HPV status as a selection factor for larynx preservation with CRT in these patients.

Human papillomavirus in laryngeal and hypopharyngeal lymphoepithelial carcinoma.

The involvement of human papillomavirus (HPV) in laryngeal and hypopharyngeal lymphoepithelial carcinoma was investigated in a series of ten cases (seven laryngeal and three hypopharyngeal), retrieved from the files of three tertiary hospitals in the 2000-2017 period, through polymerase chain reaction with SPF10 primers and INNO-LiPA HPV Genotyping Extra II (Innogenetics). Epstein-Barr virus (EBV) was tested in all cases with in situ hybridization INFORM EBER Probe (Ventana Medical Systems). p16 and p53 expression were immunohistochemically analyzed. Calculated annual incidence was 0.013/100,000, and prevalence was 0.2% of laryngeal and hypopharyngeal carcinomas. All cases were EBV negative. HPV was detected in five cases, three of which also overexpressed p16. HPV16 was detected in four cases, and HPV58 in one case. Five cases were HPV negative, only one of these five overexpressed p16. No recurrence was observed in nine cases during follow-up. The 5-year disease-specific-survival rate was 100%. Mean overall survival was 87 months. Lymphoepithelial carcinoma of the larynx and hypopharynx are not related to EBV. Simultaneous HPV+/p16+ is consistent with HPV causation in a fraction of laryngeal and hypopharyngeal lymphoepithelial carcinomas.

Recombinant adenovirus-p53 enhances the therapeutic effect of surgery and chemoradiotherapy combination in hypopharyngeal squamous cell carcinomas patients.

The purpose of our study was to assess the safety and efficacy of recombinant adenovirus-p53 (rAd-p53) combined with surgery and chemoradiotherapy (CRT) for patients with hypopharyngeal squamous cell carcinomas (HPSCC). This study retrospectively and consecutively collected clinical data of 102 patients with primary HPSCC who were admitted to the Department of Otolaryngology of West China Hospital, Sichuan University in China between March 2010 and December 2015. A retrospective clinical study of 102 patients with HPSCC was carried out from March 2010 to December 2015. All patients were male and were divided into 3 groups based on the treatments they received, including Single Surgery, Surgery + CRT, and Surgery + CRT + rAd-p53. In the Surgery + CRT + rAd-p53 group, rAd-p53 was intratumorally injected on the 1st day preoperatively; peritumorally injected on the 7th day intraoperatively, and on the 21st, 28th, and 35th days postoperatively. Their clinical data were retrospectively collected and analyzed. In our study, for all 102 patients with HPSCC, 16 patients received Single Surgery, 44 patients received Surgery + CRT therapy, and 42 patients received Surgery + CRT + rAd-p53 therapy. In the Surgery + CRT + rAd-p53 group, all patients could tolerate rAd-p53 treatment and no serious side effect was observed. In addition, rAd-p53 application did not increase the side reactions caused by surgery and CRT. Compared with the 3-year overall survival rates of Single Surgery group and Surgery + CRT group, the 3-year overall survival rates of Surgery + CRT + rAd-p53 group was significantly enhanced (P < .05). Similar results were also observed for the 3-year disease-free survival rates. Our results indicate that rAd-p53 therapy may improve the therapeutic effect of patients with HPSCC, and is a safe and effective treatment method for patients with HPSCC. However, further prospective studies with larger sample sizes are needed to validate our findings.

Cancer stage and pack-years, but not p16 or HPV, are relevant for survival in hypopharyngeal and laryngeal squamous cell carcinomas.

PURPOSE: Recently, p16 has been included in the TNM guideline for oropharyngeal carcinomas. The role of HPV and p16 in hypopharyngeal and laryngeal carcinomas has not yet been established sufficiently. METHODS: Hundred and thirty-four patients with hypopharyngeal and laryngeal carcinomas were included in this retrospective analysis. Only patients with known HPV status were eligible for the investigation. Survival probabilities were estimated for different risk factors. RESULTS: Eighty-five patients presented with laryngeal carcinoma and 49 patients with hypopharyngeal carcinoma. 8% were HPV positive (10.6% laryngeal, 4.1% hypopharyngeal carcinoma). Median follow-up time was 58 months. We observed a significantly better overall survival for patients with an early tumor stage compared to advanced carcinoma. One of the hypopharyngeal HPV positive carcinomas was also p16 positive and one was p16 negative. Of the nine HPV positive laryngeal carcinomas, four were p16 positive and five p16 negative. Neither patients who were HPV positive nor patients positive for p16 showed a significantly better outcome than HPV or p16 negative patients. In contrast, nicotine pack-years showed a highly significant correlation with survival in our patient collective. CONCLUSIONS: The data suggest that tumor stage and nicotine exposure seem to have the highest impact on survival in hypopharyngeal and laryngeal squamous cell carcinoma patients. There is no evidence for a better survival for p16 positive or HPV positive patients with hypopharyngeal or laryngeal squamous cell carcinoma. HPV seems to play a minor role in these entities of head and neck carcinoma.

Prognostic significance of p16 in squamous cell carcinoma of the larynx and hypopharynx.

PURPOSE: To evaluate the prognostic significance of p16 expression among patients with squamous cell carcinoma of the larynx (LSCC) and hypopharynx (HSCC). METHODS: The medical records of all patients with locally advanced, non-metastatic LSCC/HSCC were reviewed. p16INK4A (p16) protein expression was evaluated on pathological specimens by immunohistochemistry (IHC), and the Kaplan-Meier method was used to estimate overall survival (OS) and locoregional control (LRC). In select cases, p16 expression was correlated to high-risk and low-risk HPV genotypes using in situ hybridization (ISH). RESULTS: Thirty-one patients (23 LSCC; 8 HSCC) were identified. Seventeen (54.8%) patients were p16 negative; 14 (45.2%) were p16-positive. The primary treatment modality was radiation therapy for 22 (71.0%) patients and surgery for 9 (29.0%). Nineteen (61.3%) patients were evaluated for high-risk HPV and low-risk HPV genotypes by IHC, of whom 2 (10.5%) patients were positive for high-risk HPV and 1 (5.3%) was positive for low-risk HPV. For high-risk HPV, the positive predictive value (PPV), sensitivity, and specificity of p16 was 20.0%, 100%, and 52.9%. There was no significant difference in the 2-year actuarial rates of OS (91% vs. 64%, p=0.34) or LRC (51% vs. 46%, p=0.69) between the p16-positive and p-16 negative patients. CONCLUSION: In this small cohort of 31 LSCC and HSCC patients, p16 was not a significant predictive of either LRC or OS. Furthermore, p16 was poorly correlated with HPV genotyping as identified by ISH.

Copy number gain of 11q13.3 genes associates with pathological stage in hypopharyngeal squamous cell carcinoma.

Squamous cell carcinomas of the hypopharynx (HPSCC) and oropharynx (OPSCC) have markedly different patient outcomes. Differences in HPV prevalence between these two patient groups may account for some of this difference, but other molecular markers of prognosis or pathological phenotype have not been established. Copy number gain of oncogenes is a well-established molecular change contributing to HNSCC development. Quantitative PCR was used to explore copy number gains of specific genes (3q-PIK3CA, TP63; 11q13.3-CCND1, ANO1) in tumor DNA recovered from HPSCC (n = 48) and OPSCC (n = 52) patients. Associations between copy number gain, patient demographics, HPV/p16INK4a status and pathological stage were examined. HPV/p16 prevalence in HPSCC and OPSCC groups was 2.1% and 46.0%, respectively. HPSCCs had frequent gains of CCND1 (56.3%) and ANO1 (56.3%) but few gains of PIK3CA (6.3%). By contrast, OPSCCs had significantly fewer CCND1 (23.1%) and ANO1 (17.3%) gains, and significantly more PIK3CA (26.9%) gains. A mutually exclusive relationship between HPV/p16 and 11q13.3 gains was observed in OPSCCs, while PIK3CA and TP63 gains were similar across HPV-associated and smoking/alcohol-associated patients. ANO1 gain was significantly linked to tumor pathology in HPSCC, associating with nodal metastasis and smaller and less invasive tumors at presentation (P = 0.010). Our results provide a convincing link between a specific molecular change and disease phenotype that appears unique to our HPSCC population, supporting a model of 11q13.3 in promoting metastatic disease progression in HNSCC, and suggest a role for ANO1 as a molecular marker of metastatic disease. © 2016 Wiley Periodicals, Inc.

Impact of cisplatin dose intensity on human papillomavirus-related and -unrelated locally advanced head and neck squamous cell carcinoma.

AIM: The aim is to evaluate the impact of cisplatin dose modification on outcomes of human papillomavirus (HPV)-related (HPV+) and HPV-unrelated (HPV-) locally advanced head and neck cancer (LAHNC) treated with chemoradiotherapy (CRT). PATIENTS AND METHODS: A pooled analysis was conducted of stage III/IV oropharyngeal cancer (OPC), carcinoma of unknown primary (CUP) and laryngo-hypopharyngeal cancer (LHC) patients treated with single-agent cisplatin CRT in 2000-2012 from two tertiary academic cancer centres. HPV status was determined by p16 staining and/or in situ hybridisation. LHC was assumed to be HPV-. Unknown HPV status OPC/CUPs were excluded. Overall survival (OS) was calculated. Multivariable analysis (MVA) evaluated the impact of cisplatin dose intensity on survival for HPV+ and HPV- cohorts separately. RESULTS: A total of 404 HPV+ and 255 HPV- LAHNC (481 OPC, 18 CUP, 160 LHC) patients were included. Median follow-up was 4.3 (0.5-11.9) years. Three-year OS for cisplatin <200, =200, and >200 mg/m2 subgroups were 52%, 60%, and 72% (P = 0.001) for the HPV- and 91%, 90%, and 91% (P = 0.30) for the HPV+ patients. MVA confirmed a survival benefit with cisplatin >200 mg/m2 for the HPV- (hazard ratio [HR] 0.5, 95% confidence interval [CI]: 0.3-0.7, P < 0.001) but not for HPV+ (HR 0.6, 95% CI: 0.4-1.1, P = 0.104). There was a superior OS trend in the HPV+ T4 or N3 high-risk subset (N = 107) with cisplatin >200 mg/m2 (HR 0.5, 95% CI: 0.2-1.1, P = 0.07). CONCLUSIONS: A survival benefit of cisplatin dose >200 mg/m2 is evident for HPV- LAHNC patients, but not for HPV+ cohort overall, although the T4 or N3 subset may benefit from a higher cumulative cisplatin dose.

Effects of HPV-16 infection on hypopharyngeal squamous cell carcinoma and FaDu cells.

Hypopharyngeal squamous cell carcinoma is a common type of malignant tumor among head and neck squamous cell carcinomas (HNSCCs). Heavy smoking and/or drinking is associated with the development of HNSCC. However, HNSCC also occurs in individuals that do not drink or smoke, possibly due to infection with the human papilloma virus (HPV). HPV-16 has been shown to be closely associated with the occurrence of several types of cancers. However, its role in hypopharyngeal squamous cell carcinoma remains unclear. In the present study, we investigated the effects of HPV-16 on hypopharyngeal squamous cell carcinoma and FaDu cells. Lentiviral vectors were used to establish FaDu cells that expressed the E6 and E7 proteins of HPV-16. We used quantitative reverse transcription-polymerase chain reaction (qRT-PCR) assays and western blotting to detect and determine the levels of expression for E6-E7 mRNAs and proteins. Cell Counting Kit-8 (CCK-8) assays, enzyme-linked immunosorbent assays (ELISA), Transwell assays, and flow cytometry were used to assess the effects of HPV-16 E6-E7 on the proliferation, invasion, metastasis and apoptosis of FaDu cells. Expression of microRNAs was analyzed by qRT-PCR. We found that the expression levels of HPV-16 E6-E7 were increased in FaDu cells transfected with the lentiviral vector compared with that observed in the control cells. In addition, the rates of apoptosis were decreased in the transfected cells, while proliferation was increased. The average numbers of cells penetrating the Matrigel were significantly higher than those for the controls. We detected miR-363 and miR-15a, and their expression levels were significantly increased in the HPV-16-positive patients and in FaDu cells expressing HPV-16 E6-E7. We found that HPV-16 E6-E7 appeared to inhibit apoptosis, and to increase cell proliferation, invasion and metastasis. Furthermore, miR-363 and miR-15a were overexpressed in the hypopharyngeal squamous cell carcinoma samples infected with HPV-16, and in FaDu cells stably expressing HPV-16 E6-E7. These findings may provide a new clue of the mechanisms involved in the pathogenesis of HPV-16-positive hypopharyngeal squamous cell carcinoma.

Concurrent Chemoradiotherapy With Cisplatin Versus Cetuximab for Squamous Cell Carcinoma of the Head and Neck.

OBJECTIVES: We previously reported inferior outcomes for locally advanced head and neck cancer treated with cetuximab (C225) versus cisplatin (CDDP). We now examine if this difference persists when accounting for HPV status and update outcomes on the entire cohort. MATERIALS AND METHODS: From 3/106 to 4/1/08, 174 locally advanced head and neck cancer patients received definitive treatment with RT and CDDP (n=125) or RT and C225 (n=49). Of these, 62 patients had tissue available for HPV analysis. RESULTS: The median follow-up was 47 months. The 3-year loco-regional failure, disease-free survival, and overall survival for CDDP versus C225 were 5.7% versus 40.2% (P<0.0001), 85.1% versus 35.4% (P<0.0001), and 90.0% versus 56.6% (P<0.0001), respectively. In the subset with tissue, there was no difference in rates of HPV or p16 positivity between the 2 groups. In this subset, the 3-year loco-regional failure, disease-free survival, and overall survival for CDDP versus C225 were 5.3% versus 32.0% (P=0.01), 86.8% versus 43.2% (P=0.002), and 86.7% versus 76.9% (P=0.09), respectively. Multivariate analysis continued to show a benefit for CDDP. CONCLUSIONS: With longer follow-up and the inclusion of HPV and p16 status for about one third of patients where tissue was available, we continued to find superior outcomes with concurrent CDDP versus C225.

HPV-associated p16 INK4A expression and response to therapy and survival in selected head and neck cancers.

BACKGROUND: Development of squamous cell cancer of head and neck (SCCHN) is associated with human papillomavirus (HPV) infection, which in turn is closely related with expression of p16 INK4A. Loss of p16 INK4A expression by deletion, mutation, or hypermethylation is common in SCCHN. We here evaluated p16 INK4A as a prognostic marker of treatment response and survival in our SCCHN patients with laryngeal, hypopharyngeal or nasopharyngeal cancers. MATERIALS AND METHODS: 131 patients diagnosed with SCCHN between January 2,2006 and July 17, 2010 were examined for p16 INK4A. The median age was 60 years (15-82 years). Fifty one patients were stage I-II and 80 were stage III-IV. Immunohistochemical expression of p16 INK4A was analyzed in pretreatment paraffin-embedded tumor blocks. The influence of p16 INK4A status on disease-free survival, and overall survival after treatment was evaluated. RESULTS: P16 INK4A positivity was found in 58 patients (44%). Tumor-positivity for p16INK4A was correlated with improved disease free survival (70.1 months vs 59 months) and improved overall survival (2, 3 and 5-year values; 77% vs 72%, 70% vs 63% and, 63% vs 55%; respectively). On multivariate analysis, stage was determined as independent prognostic factor for disease-free survival. CONCLUSIONS: Stage was the major prognostic factor on treatment response and survival in our patients. P16 INK4A status predicts better outcome in laryngeal, hypopharyngeal or nasopharyngeal cancer cases treated with surgery plus adjuvant radiochemotherapy as well as with definitive radiation therapy and/or chemotherapy.

Prevalence of human papillomavirus in laryngeal and hypopharyngeal squamous cell carcinomas in northern Spain.

BACKGROUND: Recent studies support a role for human papillomavirus (HPV) in oropharyngeal squamous cell carcinomas (SCCs); however, the significance of HPV in non-oropharyngeal head and neck cancers is uncertain. The aim of this study was to determine the prevalence of HPV in a large cohort of laryngeal and hypopharyngeal SCCs in northern Spain. MATERIALS AND METHODS: Clinical records and paraffin-embedded tumor specimens of 124 consecutive patients surgically treated for laryngeal (62 cases) and hypopharyngeal (62 cases) SCCs between 2002 and 2007 were retrieved. All cases were histologically evaluated, and presence of HPV was assessed by p16-immunohistochemistry followed by GP5+/6+-PCR-based DNA detection. Samples positive in both assays were subjected to HPV genotyping and HPV E6 transcript analysis. RESULTS: Seventeen cases (14%) were positive for p16 immunostaining, of which 2 (1 larynx, 1 hypopharynx, 1.6% of total series) were found positive for HPV DNA by subsequent GP5+6+-PCR. Both SCCs contained HPV type 16 and showed HPV16 E6 mRNA expression. CONCLUSIONS: HPV is only occasionally involved in laryngeal and hypopharyngeal SCC patients in northern Spain.

Association between the standardized uptake value and high-risk HPV in hypopharyngeal squamous cell carcinoma.

CONCLUSION: Median (18)F-FDG PET/CT maximum standardized uptake values (SUV max) cut-off values of 7.9 or greater were associated with high-risk human papillomavirus (HPV) negativity in patients with hypopharyngeal squamous cell carcinoma (HPSCC). Furthermore, median (18)F-FDG PET/CT SUV max cut-off values of 7.9 or greater and high-risk HPV negativity were associated with adverse outcomes. OBJECTIVES: We studied the association and the potential prognostic significance of (18)F-FDG PET/CT and high-risk HPV status in HPSCC. METHODS: The medical records of 45 patients who underwent (18)F-FDG PET/CT for HPSCC before surgery were reviewed. High-risk HPV in situ hybridization was performed to detect HPV infection. RESULTS: The median SUV max was 9.91 ± 4.91 (range 1.9-22.1) and the positive rate of high-risk HPV in situ hybridization was 11% (5 of 45). The SUV max values of negativity for the high-risk HPV subtypes (10.47 ± 4.87) and positivity (5.48 ± 2.45) were found to be significantly different (p = 0.030). The SUV max cut-off value for differentiating negativity for the high-risk HPV subtypes from positivity was 7.9, with a sensitivity of 65% and a specificity of 80%. The 5-year disease-specific survival rate (DSSR) in our cohort was 57%. Patients with an SUV max value higher than 7.9 (p = 0.005) and high-risk HPV negativity (p = 0.047) had decreased 5-year DSSR.

HPV: a factor in organ preservation for locally advanced larynx and hypopharynx cancer?

PURPOSE/OBJECTIVE: To assess the interaction of HPV/p16 status and therapy rendered in patients with locally advanced squamous cell carcinoma of the larynx and hypopharynx. MATERIALS AND METHODS: Forty-seven consecutive patients receiving definitive treatment between 2009 and 2011 for locally advanced larynx or hypopharynx cancer with high-risk HPV and/or p16 testing performed were identified and retrospectively investigated. Overall survival (OS), disease-free survival (DFS), and local recurrence-free survival (LRFS) were assessed. RESULTS: Of 47 evaluable patients, there were 38 (81%) with laryngeal and 9 (19%) with hypopharyngeal tumors, 13 (28%) of which were found to be either HPV or p16 positive. At a median follow-up of 24 months, comparing HPV/p16+ versus HPV/p16- patients, there was no difference in OS, DFS, or LRFS. There was an improvement in 2-year DFS (60% vs 100%, P=.03) and LRFS (80% vs 100%, P=.08), in HPV/p16+ patients treated with chemo/RT versus surgery. There was an improvement in 2-year DFS (100% vs 68%, P=.04) and LRFS (100% vs 72%, P=.05) in HPV/p16+ versus HPV/p16- patients who received chemo/RT. CONCLUSIONS: Patients with HPV/p16+ tumors fared more favorably with chemo/RT than up-front surgery, with improvements in DFS and LRFS. In patients treated with the intent of organ preservation therapy, HPV/p16+ patients had no observed treatment failures. HPV/p16 status should be taken into account when considering organ preservation for locally advanced larynx and hypopharynx cancers.

Presence of human papillomaviruses and p16 expression in hypopharyngeal cancer.

BACKGROUND: Patients with hypopharyngeal cancer have a 5-year survival of only 15% to 30%. Human papillomavirus (HPV) is a risk factor and a favorable prognostic factor for oropharyngeal carcinoma and p16 has been suggested as a surrogate marker for HPV-induced cancer. However, few studies have been performed on HPV and p16 in hypopharyngeal cancer. METHODS: One hundred nine pretreatment hypopharyngeal cancer biopsies were analyzed for presence of HPV and p16 overexpression, and the results were correlated to patient survival. RESULTS: Of 109 tumors, 7 were HPV-positive (4 HPV16) and 18 overexpressed p16. There was some correlation between survival and HPV status, but not with regard to p16 expression. Notably, all patients with HPV16-positive tumors, also overexpressing p16, lived tumor free for more than 3 years. CONCLUSION: Our results indicate that HPV-induced hypopharyngeal cancer is rare and that p16 is not a suitable biomarker for presence of HPV in this tumor type.

Temporal nodal regression and regional control after primary radiation therapy for N2-N3 head-and-neck cancer stratified by HPV status.

PURPOSE: To compare the temporal lymph node (LN) regression and regional control (RC) after primary chemoradiation therapy/radiation therapy in human papillomavirus-related [HPV(+)] versus human papillomavirus-unrelated [HPV(-)] head-and-neck cancer (HNC). METHODS AND MATERIALS: All cases of N2-N3 HNC treated with radiation therapy/chemoradiation therapy between 2003 and 2009 were reviewed. Human papillomavirus status was ascertained by p16 staining on all available oropharyngeal cancers. Larynx/hypopharynx cancers were considered HPV(-). Initial radiologic complete nodal response (CR) (≤1.0 cm 8-12 weeks after treatment), ultimate LN resolution, and RC were compared between HPV(+) and HPV(-) HNC. Multivariate analysis identified outcome predictors. RESULTS: A total of 257 HPV(+) and 236 HPV(-) HNCs were identified. The initial LN size was larger (mean, 2.9 cm vs 2.5 cm; P<.01) with a higher proportion of cystic LNs (38% vs 6%, P<.01) in HPV(+) versus HPV(-) HNC. CR was achieved is 125 HPV(+) HNCs (49%) and 129 HPV(-) HNCs (55%) (P=.18). The mean post treatment largest LN was 36% of the original size in the HPV(+) group and 41% in the HPV(-) group (P<.01). The actuarial LN resolution was similar in the HPV(+) and HPV(-) groups at 12 weeks (42% and 43%, respectively), but it was higher in the HPV(+) group than in the HPV(-) group at 36 weeks (90% vs 77%, P<.01). The median follow-up period was 3.6 years. The 3-year RC rate was higher in the HPV(-) CR cases versus non-CR cases (92% vs 63%, P<.01) but was not different in the HPV(+) CR cases versus non-CR cases (98% vs 92%, P=.14). On multivariate analysis, HPV(+) status predicted ultimate LN resolution (odds ratio, 1.4 [95% confidence interval, 1.1-1.7]; P<.01) and RC (hazard ratio, 0.3 [95% confidence interval 0.2-0.6]; P<.01). CONCLUSIONS: HPV(+) LNs involute more quickly than HPV(-) LNs but undergo a more prolonged process to eventual CR beyond the time of initial assessment at 8 to 12 weeks after treatment. Post radiation neck dissection is advisable for all non-CR HPV(-)/non-CR N3 HPV(+) cases, but it may be avoided for selected non-CR N2 HPV(+) cases with a significant LN involution if they can undergo continued imaging surveillance. The role of positron emission tomography for response assessment should be investigated.

Characteristics and prognostic implications of high-risk HPV-associated hypopharyngeal cancers.

BACKGROUND: High-risk human papillomavirus (HPV) is an oncogenic virus that causes oropharyngeal cancers, and it has a favorable outcome after the treatment. Unlike in oropharyngeal cancer, the prevalence and role of high-risk HPV in the etiology of hypopharyngeal squamous cell carcinoma (HPSCC) is uncertain. OBJECTIVE: The aim of the present study was to evaluate the effect and prognostic significance of high-risk HPV in patients with HPSCC. METHODS: The study included 64 subjects with HPSCC who underwent radical surgery with or without radiation-based adjuvant therapy. Primary tumor sites were the pyriform sinus in 42 patients, posterior pharyngeal wall in 19 patients, and postcricoid area in 3 patients. High-risk HPV in situ hybridization was performed to detect HPV infection. RESULTS: The positive rate of high-risk HPV in situ hybridization was 10.9% (7/64). There was a significant difference in the fraction of positive high-risk HPV among pyriform sinus cancer (16.7%), posterior pharyngeal wall cancer (0%), and postcricoid area cancer (0%) (p = 0.042). The laryngoscopic examination revealed a granulomatous and exophytic appearance in 85.7% (6/7) of patients with high-risk HPV-positive pyriform sinus cancer, but in only 31.4% (11/35) of patients with high-risk HPV-negative pyriform sinus cancer (p = 0.012). Significant correlations were found between positive high-risk HPV and younger age (p = 0.050) and non-smoking status (p = 0.017). HPV-positive patients had a significantly better disease-free survival (p = 0.026) and disease-specific survival (p = 0.047) than HPV-negative patients. CONCLUSIONS: High-risk HPV infection is significantly related to pyriform sinus cancer in patients with HPSCC.