Background: The role of the Human Papillomavirus (HPV) status in patients with hypopharyngeal squamous cell carcinoma (HSCC) remains controversial.
Objective: Our aim was to determine the prognostic and predictive effects of HPV status in patients with locally advanced HSCC (stage III-IVB) receiving primary radiotherapy.
Methods: Patients diagnosed with stage III-IVB HSCC between 2010 and 2016 were identified. HPV status, demographics, clinicopathological characteristics, treatment, and survival data were captured. Kaplan-Meier analysis, multivariable Cox regression analysis, and propensity score matching analysis were performed.
Results: We identified 531 patients in this study and 142 (26.7%) patients with HPV-positive diseases. No significant differences were observed between those with HPV-negative and HPV-positive diseases with regard to demographics, clinicopathological characteristics, and chemotherapy use. HPV-positive HSCC had better head and neck cancer-specific survival (HNCSS; P=.001) and overall survival (OS; P<.001) compared to those with HPV-negative tumors. Similar results were found using the multivariable Cox regression analysis. Sensitivity analyses showed that the receipt of chemotherapy was associated with significantly improving HNCSS (P<.001) and OS (P<.001) compared to not receiving chemotherapy in HPV-negative HSCC, whereas comparable HNCSS (P=.59) and OS (P=.12) were found between both treatment arms in HPV-positive HSCC. Similar results were found after propensity score matching.
Conclusions: Approximately one-quarter of HSCC may be HPV-related, and HPV-positive HSCC is associated with improved survival outcomes. Furthermore, additional chemotherapy appears to be not related to a survival benefit in patients with HPV-positive tumors who received primary radiotherapy.
Head and neck squamous cell carcinoma (HNSCC) accounts for more than 90% of all head and neck malignancies . However, hypopharyngeal squamous cell carcinoma (HSCC) is relatively rare overall, accounting for approximately 3% of all HNSCCs [ ]. Symptoms and signs of HSCC tend to be minimized by patients until severe distress occurs or an obvious mass is found in the neck. Because of this, most patients are diagnosed with locally advanced HNSCC (stage III or IV) [ ], with a 5-year overall survival (OS) of 30%, which has the worst prognosis compared to other sites of HNSCC [ ].
Human papillomavirus (HPV) is an important factor in the carcinogenesis of HNSCC, especially in oropharyngeal squamous cell carcinoma (OSCC) . The existing evidence has shown a better prognosis in patients with HPV-positive OSCC. Moreover, HPV status has also impacted the treatment decision-making of OSCC [ , ]. Several studies with a small sample size suggested that the HPV infection rate in HSCC was relatively low (1.6%-8.5%) [ - ]. However, two recent population-based studies indicated that 17.7%-23.9% of patients with HSCC had HPV-positive diseases [ , ]. This raises our question of whether HPV status has a prognostic effect on HSCC. Currently, contradictory results were observed in several previous studies regarding the prognosis of HPV status in HSCC, with some studies indicating HPV-related HSCC with significantly improved survival outcomes, whereas others have found similar survival rates between HPV-negative and HPV-positive diseases [ , - ]. In addition, there are limited studies assessing the role of HPV status in patients who received primary radiotherapy or chemoradiotherapy regarding the HSCC [ ]. In light of this, we conducted this analysis from the Surveillance, Epidemiology, and End Results (SEER) database to investigate the prognostic and predictive effect of HPV status in stage III-IVB HSCC receiving primary radiotherapy.
Patients Selection Criteria
The data for this study were captured from the SEER database , in which HPV status was categorized as either HPV-negative, HPV-positive, or unknown status. HPV status was determined by p16-immunohistochemistry, in situ hybridization, or polymerase chain reaction methods of pathologic specimens from either the primary hypopharyngeal tumors or metastatic cervical lymph nodes. The HPV data set was reviewed by the SEER data quality team to ensure the accuracy of HPV testing status [ ].
We queried the SEER public database from 2010 to 2016 for patients diagnosed with stage III-IVB HSCC who received primary radiotherapy with or without chemotherapy. We did not include patients diagnosed before 2010 because HPV status was only added as a SEER variable in 2010. Those with unknown HPV status were excluded. In addition, we excluded patients who were treated with non-beam irradiation, including radioactive implants and radioisotopes.
This study was approved by the ethics committee of the Hainan General Hospital (No. ZDYF2022SHFZ130).
The following demographics, clinicopathological characteristics, or treatment data were identified from each patient’s medical record: age, gender, race, grade, tumor location, American Joint Committee on Cancer (AJCC) staging, HPV status, chemotherapy use, insurance status, and marital status. AJCC 7th staging system was used to determine the stage of patients. The primary outcome endpoints were head and neck cancer-specific survival (HNCSS) and OS. HNCSS was defined as the time from the initial diagnosis of HCSS till death due to head and neck cancer. OS was defined as the time from the initial diagnosis of HCSS till death from all causes.
The difference in patients’ characteristics and treatment data were compared using the chi-square test or Fisher exact test. HNCSS and OS curves were estimated using the Kaplan-Meier methods and compared by the log-rank test. A 1:1 propensity score matching (PSM) was conducted to balance the potential confounders. Multivariable Cox regression models were used to investigate whether HPV-positive HSCC was related to better HNCSS and OS. Sensitivity analyses were used to investigate the effect of chemotherapy on survival according to HPV status. Data analyses were conducted using SPSS statistical software (version 22.0; IBM Corp). P<.05 was considered to be statistically significant.
We identified 531 patients in this study (), including 389 (73.3%) patients with HPV-negative diseases and 142 (26.7%) patients who had HPV-positive HSCC. lists the baseline characteristics of the study cohort. A total of 445 (83.8%) patients were male; 404 (76.1%) patients had stage IVA-IVB disease; and 466 (87.8%) patients received chemotherapy. In patients with tumor location available (n=381), 74% (n=282) of the tumor was located in pyriform sinus. No significant difference was found between HPV-negative and HPV-positive diseases with regard to age, gender, race, AJCC staging, tumor grade, tumor location, chemotherapy use, insurance status, and marital status. Patients of younger age (P=.002) and Non-Hispanic White patients (P=.02) were more likely to receive chemotherapy (Table S1 in ).
|Variables||Patients, n||HPV-negative |
(n=389), n (%)
(n=142), n (%)
|Age (years), n (%)||.73|
|<50||40||28 (7.2)||12 (8.5)|
|50-64||242||181 (46.5)||61 (43)|
|>64||249||180 (46.3)||69 (48.6)|
|Gender, n (%)||.79|
|Male||445||325 (83.5)||120 (84.5)|
|Female||86||64 (16.5)||22 (15.5)|
|Race, n (%)||.06|
|Non-Hispanic White||379||267 (68.6)||112 (78.9)|
|Non-Hispanic Black||65||54 (13.9)||11 (7.7)|
|Hispanic (all)||47||34 (8.7)||13 (9.2)|
|Other||40||34 (8.7)||6 (4.2)|
|Grade, n (%)||.19|
|Well differentiated||20||17 (5.7)||3 (2.9)|
|Moderately differentiated||201||155 (52)||46 (45.1)|
|Poorly differentiated or undifferentiated||179||126 (42.3)||53 (52)|
|Tumor location, n (%)||.18|
|Pyriform sinus||282||205 (71.7)||77 (81.1)|
|Aryepiglottic fold||40||30 (10.5)||10 (10.5)|
|Postcricoid region||12||11 (3.8)||1 (1.1)|
|Posterior wall||47||40 (14)||7 (7.4)|
|AJCCb stage, n (%)||.85|
|III||127||95 (24.4)||32 (22.5)|
|IVA||335||245 (63)||90 (63.4)|
|IVB||69||49 (12.6)||20 (14.1)|
|Chemotherapy, n (%)||.91|
|No||65||48 (12.3)||17 (12)|
|Yes||466||341 (87.7)||125 (88)|
|Insurance status, n (%)||.05|
|Insured||22||20 (5.2)||2 (1.4)|
|Uninsured||503||363 (94.8)||140 (98.6)|
|Marital status, n (%)||.32|
|Married||253||180 (48.8)||73 (54.1)|
|Divorced||86||68 (18.4)||18 (13.3)|
|Single||128||91 (24.7)||37 (27.4)|
|Widowed||37||30 (8.1)||7 (5.2)|
bAJCC: American Joint Committee on Cancer.
Survival Outcomes and Prognostic Analyses Stratified by HPV Status
With a median follow-up of 16 (range 0-82) months, a total of 205 deaths were observed, including 152 patients who died of head and neck cancer-related disease. Using Kaplan-Meier survival estimates, HPV-positive patients had better survival outcomes compared to HPV-negative patients. The 3-year HNCSS in HPV-negative and HPV-positive patients was 55.3% and 74.9% (P=.001), respectively (A). The 3-year OS in HPV-negative and HPV-positive patients was 44.5% and 70% (P<.001), respectively ( B).
lists the results of multivariate Cox regression analyses. The results indicated that patients with positive HPV had significantly better HNCSS (hazard ratio [HR]: 0.460; P<.001) and OS (HR: 0.422; P<.001) compared to patients with negative HPV. In addition, patients who received chemotherapy had better HNCSS (HR: 0.405; P<.001) and OS (HR: 0.405; P<.001) than those without chemotherapy. Moreover, age, race, tumor location, AJCC stage, and marital status were also risk factors independently associated with HNCSS or OS.
|Variables||head and neck cancer-specific survival||overall survival|
|HRa||95% CI||P value||HR||95% CI||P value|
|Poorly differentiated or undifferentiated||0.684||0.324-1.448||.32||0.613||0.321-1.170||.14|
aHR: hazard ratio.
cAJCC: American Joint Committee on Cancer.
dHPV: human papillomavirus.
Effect of Chemotherapy After Stratification of HPV Status
Sensitivity analyses were used to investigate the effect of chemotherapy according to HPV status. After adjustment of age, gender, race, grade, tumor location, AJCC stage, insurance status, and marital status, the results of multivariate Cox regression analyses indicated that receipt of chemotherapy was related to better HNCSS (HR: 0.350; P<.001) and OS (HR: 0.342; P<.001) compared to not receiving chemotherapy in patients with HPV-negative HSCC, while similar HNCSS (chemotherapy vs no chemotherapy: HR 0.581; P=.45) and OS (chemotherapy vs no chemotherapy: HR 0.340; P=.07) were observed between both treatment arms in HPV-positive HSCC (). There were 31 (Table S2 in ) and 17 (Table S3 in ) pairs of patients matched using PSM in HPV-negative and HPV-positive groups, respectively. The survival curves by chemotherapy receipt according to HPV status are listed in . Similar results were found after PSM ( and ).
|Variables||Head and neck cancer-specific survival||Overall survival|
|HRa||95% CI||P value||HR||95% CI||P value|
|HPVb- negative (before PSMc)|
|HPV-negative (after PSM)|
aHR: hazard ratio.
bHPV: human papillomavirus.
cPSM: propensity score matching.
In this study, we first investigated the prognostic and predictive effects of HPV status of locally advanced HSCC receiving definitive radiotherapy. Our results showed that 26.7% of patients with locally advanced HSCC had HPV-positive disease. Moreover, patients with positive HPV had a better prognosis than those with negative HPV. The secondary objective of this study was to investigate whether the HPV status could predict the effect of chemotherapy on survival in patients with HSCC receiving radiotherapy. The sensitivity analyses showed that the addition of chemotherapy only improved survival outcomes in HPV-negative HSCC, but not in HPV-positive HSCC.
The etiological relation with cancers developing in the nonoropharynx parts versus the oropharynx remains unestablished. The incidence of HPV infection created a significant difference regarding tumor sites and race. In a large cohort study  from the National Cancer Data Base including 24740 patients with HNSCC, the percentages of HPV-positive disease by tumor location were 17.7% for hypopharynx, 11% for larynx, 10.6% for oral cavity, and 62.9% for oropharynx. A study from Japan [ ] included 493 patients with HNSCC, in whom the prevalence of HPV in oropharyngeal, oral, nasopharyngeal, hypopharyngeal, and laryngeal carcinomas was 34.4%, 0%, 12%, 3.5%, and 3.9%, respectively. Another study from Thailand [ ] showed that the prevalence of HPV in OSCC was only 6%, and no HPV infection was found in laryngeal and hypopharyngeal cancers. However, a case-control study in the Southern Chinese population showed that 29.4% of oropharyngeal cancers, 16.1% of laryngeal cancers, 14.3% of hypopharyngeal cancers, and 2.2% of oral cavity cancers were HPV DNA positive [ ]. In our study, the incidence of HPV-related disease in HSCC was higher than that in the above studies (26.7% vs 3.3%-17.7%), which might be due to the fact that we only included patients in stage III-IVB receiving primary radiotherapy or chemoradiotherapy. Similar results were found in OSCC, which also showed a higher percentage of HPV-related patients receiving primary radiotherapy or chemoradiotherapy [ ]. In addition, the patient selection, the geographical distribution of patients, and the HPV testing methods also played a role in this variability. Moreover, the probability of tobacco use in different cohorts may also lead to a discrepancy in HPV infection rates [ ].
Patients with HPV-positive OSCC were more likely to be male, younger, in an early tumor stage, and in advanced nodal stage . In a recent SEER study including stage I-IV HSCC, they found a higher proportion of HPV-positive patients who were White or Hispanic [ ]. Another SEER study by Abdel-Rahman [ ] indicated that HPV-related HSCC was more likely to involve younger people and higher tumor grades. The Danish Head and Neck Cancer Group trials also found no significant difference regarding age and AJCC stage in laryngeal and hypopharyngeal cancers between p16-negative and p16-positive disease, while the p16-positive disease was more likely to present in female patients (29% vs 17%; P=.02) [ ]. In our study, we also showed that a higher proportion of HPV-related tumors were found in Non-Hispanic White patients; otherwise, no significant differences were found in the demographics, clinicopathological characteristics, or chemotherapy receipt between HPV-negative and HPV-positive diseases.
The role of the HPV status in HSCC remains controversial. Hughes et al  included 94 patients with laryngeal or hypopharyngeal cancers (13% of patients were HPV-related), and HPV did not appear to significantly impact survival or disease control in patients in stage III-IV receiving primary chemoradiotherapy. In addition, a study from Karolinska Institute [ ] included 82 patients with HSCC and found that being HPV DNA positive (n=7) was associated with better OS but not disease-specific survival compared to those being HPV DNA negative, while a similar prognosis was found between p16-negative and p16-positive diseases. Several studies including the Danish Head and Neck Cancer Group trials also showed similar outcomes between p16-negative and p16-positive diseases, suggesting that the prognostic effect may be limited to OSCC only [ - ]. However, a small portion of patients with HPV DNA-positive or p16-positive disease in the above studies limited the study to be applied to the general population. Two larger cohort studies from the National Cancer Data Base (n=1085) and SEER (n=1157) included patients with HSCC, and they found that those with HPV-positive HSCC had better OS and cancer-specific survival compared to those with HPV-negative HSCC [ , ]. To our knowledge, our study was the largest cohort study to investigate the role of HPV status in patients with HSCC receiving primary radiotherapy or chemoradiotherapy. Within this cohort, we suggest that HPV status may be an additional factor for risk stratification of HSCC, and the future revision of the AJCC staging should consider the HPV status.
HPV-positive OSCC is a distinct pathological entity and may deserve a more personalized therapeutic strategy to decrease the severe early and late toxicities, including de-escalation of radiation doses, less toxic chemotherapy treatment, and removal of chemotherapy [- ]. In HPV-positive HNSCC, the data also suggested that intensive chemoradiotherapy approaches did not improve clinical outcomes compared to radiotherapy alone in the definitive radiotherapy setting and postoperative radiotherapy setting [ - ]. In National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology, the optimal treatment options for HSCC are induction chemotherapy, surgery, concurrent chemoradiotherapy, or clinical trials [ ]. Radiotherapy or chemoradiotherapy is not recommended as primary treatment. However, in clinical practice, concurrent chemoradiotherapy remains the main treatment strategy for organ preservation among patients with HSCC. Two previous studies including patients from the SEER and National Cancer Database showed that 81.3% and 72.2% of patients have received radiotherapy or chemoradiotherapy, respectively [ , ]. In this study, we demonstrated a survival benefit of additional chemotherapy in HPV-negative HSCC, whereas radiotherapy outcome did not differ by the receipt of chemotherapy in HPV-positive HSCC. One possible explanation for this finding is that HPV-positive HSCC may be cured by primary radiotherapy. The results of HPV status have been widely used for prognostic assessment and treatment decision-making for OSCC. Our results indicated that the prognosis and treatment response for HSCC could also be individualized according to HPV status.
The reasons for the better prognosis and limited effect from chemotherapy in patients with HPV-related HSCC who received primary radiotherapy remain unsolved. The high response of HPV-associated cancer cells to radiotherapy may be related to cell cycle dysregulation, repopulation signaling, and impaired DNA repair capacity of the tumor cells [- ]. Furthermore, the proximity of the HNSCC to lymphoid tissues may also contribute to the high radiosensitivity of HPV-related tumors, and the interaction between the virus antigens and the immune system may contribute to enhancing the radiosensitivity [ ]. Whether HPV-related HSCC also possesses such enhanced radiosensitivity remains to be clarified. In addition, HPV-negative tumors often carry frequent TP53 mutations, resulting in significant radioresistance [ ]. Moreover, those with HPV-positive HSCC had a better prognosis due to higher immune activity and overexpression of immune proteins compared to those with HPV-negative HSCC, which was similar to the results for OSCC [ - ].
Several limitations should be acknowledged in this study. First, the findings of our study should be viewed with caution because this is a retrospective observational study from a population-based cohort. Second, the rationale for treatment decisions among each patient group cannot be ascertained from the SEER database. Third, the HPV testing results may be heterogeneous with respect to technique, and the results of HPV testing were not centrally reviewed. However, a previous study showed high concordance among the p16-immunohistochemistry, in situ hybridization, or polymerase chain reaction methods for detecting HPV status . Fourth, several confounding factors were not measured in the SEER database, including the chemotherapy regimen, the target volume of radiotherapy, the sequence of chemotherapy and radiotherapy, details regarding patient performance status, and tobacco or alcohol exposure. Moreover, the patterns of locoregional and distant metastasis after primary radiotherapy or chemoradiotherapy were also not routinely captured in the SEER database. Finally, approximately 15% of patients should have undergone salvage surgery for recurrence after radiotherapy or chemoradiotherapy in a previous study [ ]. However, SEER does not record the information regarding salvage surgery, thus it is unable to evaluate the impact of salvage surgery on the prognosis and its distribution in both groups (HPV-positive and HPV-negative). Despite the above limitations, we believe the results from our population-based study are provocative enough to warrant further investigation of the prognostic and predictive effects of the HPV status in HSCC.
In conclusion, our study suggests that approximately one-quarter of HSCC may be HPV-related, and HPV-positive HSCC is associated with improved survival outcomes. Furthermore, additional chemotherapy appears to be not related to a survival benefit in HPV-positive tumors receiving primary radiotherapy. More studies are required to better understand the prognostic and predictive effects of the HPV status in HSCC.
The authors acknowledge the efforts of the Surveillance, Epidemiology, and End Results (SEER) Program tumor registries in the creation of the SEER database.
Conflicts of Interest
Supplementary tables.PDF File (Adobe PDF File), 58 KB
- Concu R, Cordeiro MNDS. Cetuximab and the head and neck squamous cell cancer. Curr Top Med Chem 2018 May 14;18(3):192-198. [CrossRef] [Medline]
- Garneau JC, Bakst RL, Miles BA. Hypopharyngeal cancer: a state of the art review. Oral Oncol 2018 Nov;86:244-250. [CrossRef] [Medline]
- Takes RP, Strojan P, Silver CE, Bradley PJ, Haigentz MJ, Wolf GT, International HeadNeck Scientific Group. Current trends in initial management of hypopharyngeal cancer: the declining use of open surgery. Head Neck 2012 Feb 10;34(2):270-281 [FREE Full text] [CrossRef] [Medline]
- Marur S, Forastiere AA. Head and neck squamous cell carcinoma: update on epidemiology, diagnosis, and treatment. Mayo Clin Proc 2016 Mar;91(3):386-396. [CrossRef] [Medline]
- Wittekindt C, Klussmann J. Tumor staging and HPV-related oropharyngeal cancer. Recent Results Cancer Res 2017:206-133. [CrossRef] [Medline]
- Wagner S, Reder H, Sharma SJ, Würdemann N, Wittekindt C, Klußmann JP. [HPV-associated oropharyngeal cancer-incidence, trends, diagnosis, and treatment]. Urologe A 2018 Dec 12;57(12):1457-1463. [CrossRef] [Medline]
- Dalianis T, Grün N, Koch J, Vlastos A, Tertipis N, Nordfors C, et al. Human papillomavirus DNA and p16(INK4a) expression in hypopharyngeal cancer and in relation to clinical outcome, in Stockholm, Sweden. Oral Oncol 2015 Sep;51(9):857-861. [CrossRef] [Medline]
- Pongsapich W, Eakkasem N, Siritantikorn S, Pithuksurachai P, Bongsabhikul K, Chongkolwatana C. Prevalence of HPV infection in hypopharyngeal and laryngeal squamous cell carcinoma at Thailand's largest tertiary referral center. Infect Agent Cancer 2017 Nov 2;12(1):58 [FREE Full text] [CrossRef] [Medline]
- Rodrigo JP, Hermsen MA, Fresno MF, Brakenhoff RH, García-Velasco F, Snijders PJ, et al. Prevalence of human papillomavirus in laryngeal and hypopharyngeal squamous cell carcinomas in northern Spain. Cancer Epidemiol 2015 Feb;39(1):37-41. [CrossRef] [Medline]
- Tian S, Switchenko JM, Jhaveri J, Cassidy RJ, Ferris MJ, Press RH, et al. Survival outcomes by high-risk human papillomavirus status in nonoropharyngeal head and neck squamous cell carcinomas: A propensity-scored analysis of the National Cancer Data Base. Cancer 2019 Aug 15;125(16):2782-2793 [FREE Full text] [CrossRef] [Medline]
- Abdel-Rahman O. Prognostic value of HPV status among patients with hypopharyngeal carcinoma: a population-based study. Clin Transl Oncol 2020 Sep 14;22(9):1645-1650. [CrossRef] [Medline]
- Hughes RT, Beuerlein WJ, O'Neill SS, Porosnicu M, Lycan TW, Waltonen JD, et al. Human papillomavirus-associated squamous cell carcinoma of the larynx or hypopharynx: Clinical outcomes and implications for laryngeal preservation. Oral Oncol 2019 Nov;98:20-27 [FREE Full text] [CrossRef] [Medline]
- Lassen P, Primdahl H, Johansen J, Kristensen CA, Andersen E, Andersen LJ, Danish HeadNeck Cancer Group (DAHANCA). Impact of HPV-associated p16-expression on radiotherapy outcome in advanced oropharynx and non-oropharynx cancer. Radiother Oncol 2014 Dec;113(3):310-316 [FREE Full text] [CrossRef] [Medline]
- Meshman J, Wang P, Chin R, John MS, Abemayor E, Bhuta S, et al. Prognostic significance of p16 in squamous cell carcinoma of the larynx and hypopharynx. Am J Otolaryngol 2017 Jan;38(1):31-37. [CrossRef] [Medline]
- Ernoux-Neufcoeur P, Arafa M, Decaestecker C, Duray A, Remmelink M, Leroy X, et al. Combined analysis of HPV DNA, p16, p21 and p53 to predict prognosis in patients with stage IV hypopharyngeal carcinoma. J Cancer Res Clin Oncol 2011 Jan 8;137(1):173-181 [FREE Full text] [CrossRef] [Medline]
- SEER*Stat Database: Incidence - SEER 18 Regs Custom Data Head and Neck (select schemas with HPV recode and additional treatment fields), Nov 2018 Sub (2010-2016) - Linked To County Attributes - Total U.S., 1969-2017 Counties, National Cancer Institute, DCCPS, Surveillance Research Program, released April 2019, based on the November 2018 submission. Surveillance, Epidemiology, and End Results (SEER) Program. 1969. URL: http://www.seer.cancer.gov [accessed 2022-05-05]
- Fullerton ZH, Butler SS, Mahal BA, Muralidhar V, Schoenfeld JD, Tishler RB, et al. Short-term mortality risks among patients with oropharynx cancer by human papillomavirus status. Cancer 2020 Apr 01;126(7):1424-1433 [FREE Full text] [CrossRef] [Medline]
- Maruyama H, Yasui T, Ishikawa-Fujiwara T, Morii E, Yamamoto Y, Yoshii T, et al. Human papillomavirus and p53 mutations in head and neck squamous cell carcinoma among Japanese population. Cancer Sci 2014 Apr;105(4):409-417 [FREE Full text] [CrossRef] [Medline]
- Chor JS, Vlantis AC, Chow T, Fung S, Ng FY, Lau C, et al. The role of human papillomavirus in head and neck squamous cell carcinoma: a case control study on a southern Chinese population. J Med Virol 2016 May 03;88(5):877-887. [CrossRef] [Medline]
- Zhan KY, Puram SV, Li MM, Silverman DA, Agrawal AA, Ozer E, et al. National treatment trends in human papillomavirus-positive oropharyngeal squamous cell carcinoma. Cancer 2020 Mar 15;126(6):1295-1305 [FREE Full text] [CrossRef] [Medline]
- Tanaka TI, Alawi F. Human papillomavirus and oropharyngeal cancer. Dent Clin North Am 2018 Jan;62(1):111-120. [CrossRef] [Medline]
- Marshall DC, Kao DD, Bakst R, Sharma S, Ferrandino R, Rosenzweig K, et al. Prognostic role of human papilloma virus status in hypopharyngeal squamous cell carcinoma. Laryngoscope Investig Otolaryngol 2020 Oct 11;5(5):860-867 [FREE Full text] [CrossRef] [Medline]
- De Virgilio A, Costantino A, Mercante G, Petruzzi G, Sebastiani D, Franzese C, et al. Present and future of de-intensification strategies in the treatment of oropharyngeal carcinoma. Curr Oncol Rep 2020 Jul 09;22(9):91. [CrossRef] [Medline]
- Chen AM, Felix C, Wang P, Hsu S, Basehart V, Garst J, et al. Reduced-dose radiotherapy for human papillomavirus-associated squamous-cell carcinoma of the oropharynx: a single-arm, phase 2 study. Lancet Oncol 2017 Jun;18(6):803-811 [FREE Full text] [CrossRef] [Medline]
- Gabani P, Lin AJ, Barnes J, Oppelt P, Adkins DR, Rich JT, et al. Radiation therapy dose de-escalation compared to standard dose radiation therapy in definitive treatment of HPV-positive oropharyngeal squamous cell carcinoma. Radiother Oncol 2019 May;134:81-88. [CrossRef] [Medline]
- O'Sullivan B, Huang SH, Perez-Ordonez B, Massey C, Siu LL, Weinreb I, et al. Outcomes of HPV-related oropharyngeal cancer patients treated by radiotherapy alone using altered fractionation. Radiother Oncol 2012 Apr;103(1):49-56. [CrossRef] [Medline]
- Chen AM, Zahra T, Daly ME, Farwell DG, Luu Q, Gandour-Edwards R, et al. Definitive radiation therapy without chemotherapy for human papillomavirus-positive head and neck cancer. Head Neck 2013 Nov 17;35(11):1652-1656 [FREE Full text] [CrossRef] [Medline]
- Yom S, Torres-Saavedra P, Caudell J, Waldron J, Gillison M, Truong M, et al. NRG-HN002: A Randomized Phase II Trial for Patients With p16-Positive, Non-Smoking-Associated, Locoregionally Advanced Oropharyngeal Cancer. IJROBP 2019 Nov;105(3):684-685 [FREE Full text] [CrossRef]
- Skillington SA, Kallogjeri D, Lewis JS, Piccirillo JF. The role of adjuvant chemotherapy in surgically managed, p16-positive oropharyngeal squamous cell carcinoma. JAMA Otolaryngol Head Neck Surg 2017 Mar 01;143(3):253-259 [FREE Full text] [CrossRef] [Medline]
- Clinical practice guidelines in oncology: head and neck cancers. National Comprehensive Cancer Network. 2021. URL: https://www.nccn.org/professionals/physician_gls/pdf/head-and-neck.pdf [accessed 2021-09-21]
- Hochfelder CG, McGinn AP, Mehta V, Castellucci E, Kabarriti R, Ow TJ. Treatment sequence and survival in locoregionally advanced hypopharyngeal cancer: a surveillance, epidemiology, and end results-based study. Laryngoscope 2020 Nov 10;130(11):2611-2621 [FREE Full text] [CrossRef] [Medline]
- Bates JE, Morris CG, Hitchcock KE, Dziegielewski PT, Mendenhall WM, Amdur RJ. Locally advanced hypopharyngeal and laryngeal cancer: influence of HPV status. Radiother Oncol 2019 Nov;140:6-9. [CrossRef] [Medline]
- Braakhuis BJM, Senft A, de Bree R, de Vries J, Ylstra B, Cloos J, et al. Expression profiling and prediction of distant metastases in head and neck squamous cell carcinoma. J Clin Pathol 2006 Dec 27;59(12):1254-1260 [FREE Full text] [CrossRef] [Medline]
- Sørensen BS, Busk M, Olthof N, Speel E, Horsman MR, Alsner J, et al. Radiosensitivity and effect of hypoxia in HPV positive head and neck cancer cells. Radiother Oncol 2013 Sep;108(3):500-505. [CrossRef] [Medline]
- Rieckmann T, Tribius S, Grob TJ, Meyer F, Busch C, Petersen C, et al. HNSCC cell lines positive for HPV and p16 possess higher cellular radiosensitivity due to an impaired DSB repair capacity. Radiother Oncol 2013 May;107(2):242-246. [CrossRef] [Medline]
- Dok R, Kalev P, Van Limbergen EJ, Asbagh LA, Vázquez I, Hauben E, et al. p16INK4a impairs homologous recombination–mediated DNA repair in human papillomavirus–positive head and neck tumors. Cancer Res 2014 Jan 28;74(6):1739-1751. [CrossRef]
- Perrone F, Suardi S, Pastore E, Casieri P, Orsenigo M, Caramuta S, et al. Molecular and cytogenetic subgroups of oropharyngeal squamous cell carcinoma. Clin Cancer Res 2006 Nov 15;12(22):6643-6651 [FREE Full text] [CrossRef] [Medline]
- Landin D, Ährlund-Richter A, Mirzaie L, Mints M, Näsman A, Kolev A, et al. Immune related proteins and tumor infiltrating CD8+ lymphocytes in hypopharyngeal cancer in relation to human papillomavirus (HPV) and clinical outcome. Head Neck 2020 Nov;42(11):3206-3217. [CrossRef] [Medline]
- Huang SH, Waldron JN, Milosevic M, Shen X, Ringash J, Su J, et al. Prognostic value of pretreatment circulating neutrophils, monocytes, and lymphocytes in oropharyngeal cancer stratified by human papillomavirus status. Cancer 2015 Feb 15;121(4):545-555 [FREE Full text] [CrossRef] [Medline]
- Ward MJ, Thirdborough SM, Mellows T, Riley C, Harris S, Suchak K, et al. Tumour-infiltrating lymphocytes predict for outcome in HPV-positive oropharyngeal cancer. Br J Cancer 2014 Jan 21;110(2):489-500 [FREE Full text] [CrossRef] [Medline]
- Schache A, Liloglou T, Risk J, Filia A, Jones T, Sheard J, et al. Evaluation of human papilloma virus diagnostic testing in oropharyngeal squamous cell carcinoma: sensitivity, specificity, and prognostic discrimination. Clin Cancer Res 2011 Oct 01;17(19):6262-6271 [FREE Full text] [CrossRef] [Medline]
- Putten L, Bree R, Doornaert PA, Buter J, Eerenstein SEJ, Rietveld DHF, et al. Salvage surgery in post-chemoradiation laryngeal and hypopharyngeal carcinoma: outcome and review. Acta Otorhinolaryngol Ital 2015 Jun;35(3):162-172 [FREE Full text] [Medline]
|AJCC: American Joint Committee on Cancer|
|HNCSS: head and neck cancer-specific survival|
|HNSCC: head and neck squamous cell carcinoma|
|HPV: human papillomavirus|
|HR: hazard ratio|
|HSCC: hypopharyngeal squamous cell carcinoma|
|OS: overall survival|
|OSCC: oropharyngeal squamous cell carcinoma|
|PSM: propensity score matching|
|SEER: Surveillance, Epidemiology, and End Results|
Edited by A Mavragani, G Eysenbach; submitted 09.06.22; peer-reviewed by JY Sun, L Liu; comments to author 09.09.22; revised version received 23.09.22; accepted 18.10.22; published 16.12.22Copyright
©Shi-Ping Yang, Xiang-Ying Lin, Min Hu, Cheng-Fu Cai. Originally published in JMIR Public Health and Surveillance (https://publichealth.jmir.org), 16.12.2022.
This is an open-access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work, first published in JMIR Public Health and Surveillance, is properly cited. The complete bibliographic information, a link to the original publication on https://publichealth.jmir.org, as well as this copyright and license information must be included.