|Year : 2020 | Volume
| Issue : 1 | Page : 10-16
Clinicopathological association of p16 and its impact on outcome of chemoradiation in head-and-neck squamous cell cancer patients in North-East India
Srigopal Mohanty1, Yumkhaibam Sobita Devi2, Nithin Raj Daniel3, Dulasi Raman Ponna4, Madhubala Devi5, Laishram Jaichand Singh2
1 Department of Medical Oncology, Kilpauk Medical College, Chennai, Tamil Nadu, India
2 Department of Radiation Oncology, RIMS, Imphal, Manipur, India
3 Department of Medical Oncology, BBCI, Guwahati, Assam, India
4 Tiruvarur Medical Centre, Tiruvarur, Tamil Nadu, India
5 Department of Pathology, RIMS, Imphal, Manipur, India
|Date of Submission||15-Dec-2019|
|Date of Acceptance||05-Mar-2020|
|Date of Web Publication||25-Mar-2020|
Dr. Yumkhaibam Sobita Devi
Department of Radiation Oncology, RIMS, Imphal, Manipur
Source of Support: None, Conflict of Interest: None
Purpose: Human papillomavirus-associated head–and-neck squamous cell cancer (HNSCC) is following an increasing trend in Western countries, which has unique biology and confers better prognosis, whereas there are limited data from Indian studies in this context.
Methods: We conducted a prospective cohort study to evaluate the clinicopathological association of p16 in locally advanced HNSCC and its impact on outcome of chemoradiation. The study population was divided into two arms; p16-positive and p16-negative arms. All patients were treated with concurrent chemoradiation using weekly cisplatin.
Statistical Analysis Used: SPSS version 21 for Windows was used for statistical analysis. Chi-square test and multivariate analysis were performed to evaluate different association and impact of p16. P <0.05 was considered statistically significant.
Results: The present study found p16-positive HNSCC patients to be associated with better performance status (P = 0.010), oropharyngeal primary location (P = 0.034), advanced nodal stage at presentation (P = 0.000), and higher histopathologic grade of tumor (P = 0.021) and was associated with better response (P = 0.005) to concurrent chemoradiation. Subsite analysis revealed p16-positive oropharyngeal squamous cell cancer (OPSCC) to have significantly better response (P = 0.036) to chemoradiation, whereas a trend toward better response to chemoradiation (P = 0.066) was found among p16-positive non-OPSCC. Higher p16 expression score was associated with better (P = 0.000) response to chemoradiation. Multivariate analysis revealed p16 to have an independent positive impact on tumor response to chemoradiation in HNSCC irrespective of tumor subsite.
Conclusion: p16 overexpression is a good prognostic factor in both OPSCC and non-OPSCC. Treatment response have a positive correlation with intensity of p16 staining in the tissue biopsy material.
Keywords: Clinicopathology, head-and-neck squamous cell cancer, p16, response to chemoradiation
|How to cite this article:|
Mohanty S, Devi YS, Daniel NR, Ponna DR, Devi M, Singh LJ. Clinicopathological association of p16 and its impact on outcome of chemoradiation in head-and-neck squamous cell cancer patients in North-East India. Cancer Transl Med 2020;6:10-6
|How to cite this URL:|
Mohanty S, Devi YS, Daniel NR, Ponna DR, Devi M, Singh LJ. Clinicopathological association of p16 and its impact on outcome of chemoradiation in head-and-neck squamous cell cancer patients in North-East India. Cancer Transl Med [serial online] 2020 [cited 2020 May 28];6:10-6. Available from: http://www.cancertm.com/text.asp?2020/6/1/10/281365
| Introduction|| |
Head-and-neck squamous cell cancer (HNSCC) is the eighth most common type of cancer, with an estimated annual incidence of approximately 835,000 cases. Nearly 57.5% of global head-and-neck cancers occur in Asia, especially in India, for both the sexes. Tobacco, alcohol use, and human papillomavirus (HPV) infection are the three most common risk factors associated with HNSCC. HPV prevalence in HNSCC varies from 10% to 90%, depending on the anatomic location and geographic distribution of the population. The majority of cases include HPV-16 subtype, with other reported subtypes being HPV-18, 31, 33, 35, and 45. HPV-16 subtype accounts for 87% of the oropharyngeal, 68% of oral, and 69% of laryngeal HPV-positive carcinomas. The HPV oncogene E7 inactivate retinoblastoma protein (pRB), results in overexpression of p16 gene. p16 is a tumor suppressor gene, located on chromosome 9p21. The p16 protein binds to and inactivates cyclin-dependent kinase 4 and 6, thereby inhibiting the phosphorylation of pRB. This results in cell cycle arrest at G1-S checkpoint and allows DNA repair and apoptosis. High-risk HPV infections are frequently associated with the overexpression of p16 gene, for which it is used as a surrogate marker for HPV infection.
HPV testing methods are divided into two categories. The direct method detects the presence of virus using in situ hybridization (ISH) or polymerase chain reaction (PCR), and the indirect method uses p16 as biomarker for HPV infection. The ISH for detecting HPV DNA has high specificity and acceptable sensitivity, but its major disadvantage is its high cost and availability at limited number of centers., PCR is highly sensitive at detecting HPV DNA or RNA within small amounts of tumor samples, which may result in false-positive results due to its high sensitivity to HPV genomes, which may be present in nonmalignant HPV infections. Immunohistochemical analysis of p16, which detects transcriptionally active HPV, has become the standard for clinical assessment of HPV status because of its quick, inexpensive, and readily available nature.
The p16 expression profile and its predictive and prognostic impact on tumor response to chemoradiation in HNSCC (both oropharyngeal and nonoropharyngeal) in the Indian population is still not clear. Most of the Western studies till now have shown its positive prognostic impact in the case of oropharyngeal squamous cell carcinoma (OPSCC) only.,,, Whereas one study has shown its positive prognostic impact in both oropharyngeal and non-OPSCC (NOPSCC).
The better treatment response in HPV positive HNSCC could be due to; (i) high sensitivity to radiotherapy, because of impaired double stranded break repair capacity of the tumor cells, combined with a better general health status in this group of patients, (ii) Hypoxic HPV positive tumor cells can be more easily induced to apoptosis because of overexpression of p16 and wild type TP53, (iii)Improved local immunity after the treatment helps in the eradication of HPV and regression of the tumor.,,,
Based on the paucity of Indian literature available on the expression profile of p16 and its impact on treatment outcome in the Indian population of HNSCC patients, the present prospective study was conducted to assess the clinicopathological association of p16 and its impact on tumor response to chemoradiation in locally advanced HNSCC (both OPSCC and NOPSCC).
| Methods|| |
A prospective cohort study was carried out at a regional cancer center in North-East India, after obtaining ethical approval from the institution's research ethic board. The total study period was 2 years from August 2016 to July 2018. The study population included patients who were newly diagnosed and histopathologically confirmed cases of locoregionally advanced head-and-neck squamous cell carcinoma. Patients were staged prior to the initiation of treatment according to the American Joint Committee on Cancer staging 2010 criteria. The study population was divided into two arms. Patients with tumor block positive for p16 were placed in one arm, whereas patients with p16-negative tumor blocks were placed in another arm.
Based on the study design, the sample size was calculated using the following formula:
where N is the size per group
u = 0.84 at 80% power, v = 1.645 at 90% level of significance
p1= Proportion in one group = 96.6%
p2= Proportion in another group = 76.9%.
A minimum of 66 cases, 33 in each arm (arm A and arm B), were planned to recruit for the study.
All patients in the study received external beam radiotherapy using cobalt-60 teletherapy machine (Theratron 780-C, model number A112109-101 [M/s AECL, Ontario, Canada, (1988)]) with a source to skin distance (SSD) of 80 cm to a total dose of 70 Gy over 35 fractions (200 cgy per fraction, 5 days in a week). Every patient received concurrent chemotherapy, i.e., injection cisplatin 35 mg/m IV, every weekly till the completion of radiotherapy. Co-medications and supportive care were given whenever required.
During the treatment, patients were evaluated weekly for regression of tumor, subjective symptoms, and any radiation reaction in skin and mucous membrane. Complete hemogram and biochemical parameters were checked before the start of treatment and weekly during treatment. The early tumor response was assessed by clinical evaluation and imaging studies, as per the Response Evaluation Criteria in Solid Tumors criteria at 6 weeks following completion of the chemoradiation.
Quantitative evaluation of p16 immunostaining
The immunohistochemistry (IHC) expression of p16 was quantified by a double-blind protocol and classified according to nuclear and cytoplasmic positivity. The biopsies were scored as positive when more than 5% cells (cutoff) stained positively, diffuse (30%–85% of labeled cells with strong positivity) [Picture 1], focal (10%–30% of labeled nuclei and cytoplasm strongly positive) [Picture 2], sporadic (5%–10% of nuclei and cytoplasm with weak and scattered positivity) [Picture 3], negative (0%–5% of nuclei and cytoplasm positive) [Picture 4]. Sporadic positivity for p16 was considered as low expression, focal positivity as moderate expression, and diffuse positivity as high IHC expression. Data were analyzed using IBM SPSS Statistics software for Windows, Version 21.0 (Armonk, NY: IBM Corp). The frequency distribution of different categorical variables such as age, sex, performance status, stage, grade, site, p16 status, and tumor response was analyzed by using Chi-square analysis, and the dependence of tumor response on different variables was evaluated by multivariate analysis (P < 0.05 and confidence interval of 95%).
| Results|| |
Out of the total 83 patients, 40.9% of the patients were found p16 positive, with the median age of 63 years at diagnosis. Greater frequency of younger age patients (48.7%) was found in p16-positive arm as compared to the older age group (34.1%), though the difference in distribution was not found to be statistically significant (P = 0.176). p16-positive arm was found to have significantly greater proportions of patients having better Karnofsky Performance Status ≥80%, as compared to the p16-negative arm (70.6% vs. 34.7%, respectively, with P = 0.024) [Table 1].
In the present study, the prevalence of smokers, alcoholics, and oral tobacco users was 80.7%, 56.6%, and 60.2%, respectively. Both the arms were found to have greater frequency of smokers (82.3% vs. 79.6% with P = 0.754), greater frequency of alcoholics (50% vs. 61.2% with P = 0.316), and greater frequency of oral tobacco users (52.9% and 65.3% with P = 0.263) in the p16-positive and p16-negative groups, respectively [Table 1].
Disease was diagnosed most commonly in T3 stage irrespective of p16 status (47.1% vs. 40.8% in p16-positive and p16-negative arms, respectively) followed by T2 stage (44.1% vs. 34.7% in p16-positive and p16-negative arms, respectively). The frequency of T4 disease was relatively more in p16-negative arm (18.4%), as compared to p16-positive arm (5.9%), but the difference between the two arms was not statistically significant (P = 0.401) [Table 1].
Greater proportions of patients in the p16-positive arm were diagnosed with advanced nodal stage, i.e., N2 or N3 disease (64.7%) as compared to p16-negative arm (28.6%). The difference in nodal stage at presentation between the two arms was found statistically significant (P = 0.005) [Table 1].
When pathological grades of tumor were compared between the two arms, it was found that the frequency of high-grade tumor (Grade 2 or 3) was more frequent (64.7%) in p16-positive arm as compared to p16-negative (46.9%) arm, and the difference was statistically significant (P = 0.021) [Table 1].
In the present study, the prevalence of p16 positivity was found in 64.3% of oropharyngeal, 45.8% of laryngeal, 31.3% of hypopharyngeal, and 31% of oral cavity primary tumors [Table 1].
The prevalence of high p16 expression score was found greater among OPSCC (28.6%) as compared to NOPSCC (7.2%), and the difference was found close to statistical significance (P = 0.062) [Figure 1].
|Figure 1: Bar diagram, showing the frequency distribution of p16 expression scores with respect to different primary sites|
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Higher p16 expression score was found to be associated with better tumor response to chemoradiation, irrespective of primary tumor site [Figure 2].
|Figure 2: Bar diagram, showing tumor response to chemoradiation with different p16 expression score|
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Multivariate analysis (P < 0.05 and confidence interval of 95%) revealed the better performance status of patient, oropharyngeal primary tumor, p16 positivity, and higher p16 expression score to be associated with better tumor response, whereas smoking and advanced T stage were found to have poorer tumor response to chemoradiation [Table 2].
|Table 2: Multivariate analysis, showing the dependence of tumor response on different variables in the present study|
Click here to view
| Discussion|| |
In the present study, the prevalence of p16-positive HNSCC was 40.9%, which was much higher compared to published data from North India (20% to 23%)., This difference in p16 positivity could be attributed to the different ethnicity, distinct genome pool, and different cancer incidence pattern of Northeast Indian population compared to mainland India. Out of the total 83 patients, there was no difference in the distribution of p16 in the two age groups, which contradicts previous study findings of HPV-positive HNSCC to be diagnosed more commonly in the younger age group., p16-positive HNSCC patients are commonly diagnosed with good performance status as compared to p16-negative patients., Better performance status during diagnosis among p16-positive HNSCC patients was also observed in the present study, which was in concordance with the above studies. Smoking is an independent risk factor and negatively affects survival in HNSCC. The accumulated lifetime number of pack-years of smoking independently affects prognosis for both HPV-positive and negative HNSCC patients. Patients with HPV-positive HNSCC were reported less likely to be tobacco user, alcohol user, or chronic smoker;,, whereas, in the present study, the prevalence of chronic smokers, chronic alcoholics, and oral tobacco users was found higher in the whole study population irrespective of p16 status (equally in both arm A and arm B). The present study contradicts the above study findings, whereas it supports the previous study report of overall higher prevalence of smokers, alcohol, and oral tobacco users in Northeast Indian cohort of HNSCC patients.
The complete tumor response rate in the present study in both the arms (61.8% in p16-positive arm and 24.5% in p16-negative arm) was found relatively lesser than that found in a similar study (96.6% in p16-positive arm and 76.9% in p16-negative arm), probably because of simultaneous higher prevalence of chronic smokers, chronic alcoholics, and oral tobacco users in northeastern states of India.
The present study did not find any significant association of p16 positivity with tumor stage during diagnosis, which contradicts the findings of a previous study, which reported p16-positive HNSCC to be commonly diagnosed with an early tumor stage. In the present study, p16 positivity in HNSCC was found to be associated with advanced nodal stage (N2/N3) at presentation, which was in concordance with previous study findings., Greater proportions of patients in p16-positive HNSCC in the present study were diagnosed with high-grade tumor. This finding was in concordance with that of previous study reports.,
In the present study, the prevalence of p16 positivity was found statistically significantly higher (P = 0.034) in OPSCC (64.3%) as compared to NOPSCC (36.2%). Similar result was found in a previous study, where the frequency of p16 positivity in OPSCC was 52% and in NOPSCC was 14%. In p16-positive HNSCC patients, complete response rate (58.8%) was found statistically significantly higher (P = 0.005) as compared to p16-negative patients (24.5%) in the present study. This result supports the previous reports of improved outcome associated with p16 overexpressing HNSCC tumor treated by chemoradiation.,
p16-positive OPSCC has been reported to be associated with better treatment outcome and survival.,,, In the present study, the complete tumor response rate in p16-positive OPSCC was 77.8%, which was statistically significantly greater (P = 0.036) than p16-negative OPSCC (20%). Among NOPSCC, p16-positive tumor had complete response rate (52%) greater than p16-negative tumor (25%); the difference was close to statistical significance (P = 0.066).
When the tumor response was compared in relation to p16 expression score in different subsites, it was found that higher p16 expression score was associated with greater response to chemoradiation (P = 0.000). p16 is not a perfect surrogate marker for HPV infection with a 30% false-positive rate, which could be due to difference in the HPV study techniques or due to the non-HPV-related overexpression of p16 gene. However, HPV-negative/p16-positive HNSCC patients were found to have improved prognosis over HPV-negative/p16-negative cohorts. The present study revealed p16 overexpression to be associated with improved prognosis in HNSCC (both OPSCC and NOPSCC), and the tumor response was found to have a positive correlation with high p16 expression score.
| Conclusion|| |
p16 positive HNSCC patients are diagnosed with better performance status, advanced nodal stage, and high grade tumor. p16 may not be a perfect surrogate marker of HPV infection, but it has independent positive prognostic impact in both OPSCC and non OPSCC. Further prospective studies on non OPSCC with longer follow up is warranted to confirm the prognostic role of p16 in this cohort.
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Conflicts of interest
There are no conflicts of interest.
| References|| |
Bray F, Ferley J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA: Cancer J Clin
2018; 68: 394–424.
Chaturvedi P. Head and neck surgery. J Can Res Ther
2005; 1: 240–8.
Gillison ML, D'souza G, Westra W, Sugar E, Xiao W, Begum S, Viscidi R. Distinct risk factor profiles for human papilloma virus type 16 positive and human papilloma virus type 16 negative head and neck cancers. J Natl Cancer Inst
2008; 100(6): 407–20.
Shapiro GI, Edwards CD, Kobzik L, Godleski J, Richards W, Sugarbaker DJ, Rollins BJ. Reciprocal Rb inactivation and p16 expression in primary lung cancers and cell lines. Cancer Res
1995; 55(3): 505–9.
Gillison ML, Koch WM, Capone RB, Spafford M, Wu L, Zahurak ML, Daniel RW, Viglione M, Symer DE, Shah KV, Sidransky D. Evidence for causal relation between human papilloma virus and head and neck cancers. J Natl Cancer Inst
2000; 92(9): 709–20.
Dayyani F, Etzel CJ, Liu M, Ho CH, Lippma SM, Tsao AS. Meta-analysis of the impact of human papilloma virus on cancer risk and overall survival in head and neck squamous cell carcinomas. Head Neck Oncol
2010; 2: 15–21.
Fregonesi PA, Teresa DB, Duarte RA, Neto CB, Oliveira MR, Soares CP. p16INK4a
immunohistochemical expression in premalignant and malignant oral lesions infected with human papilloma virus. J Histochem Cytochem
2003; 51(10): 1291–7.
Fakhry C, Gillison ML. Clinical implications of human papillomavirus in head and neck cancers. J Clin Oncol
2006; 24(17): 2606–11.
Lizard G, Demares-Poulet MJ, Roignot P, Gambert P. In situ
hybridization detection of single-copy human papillomavirus on isolated cells, using a catalyzed signal amplification system: GenPoint. Diagn Cytopathol
2001; 24(2): 112–6.
Blitzer GC, Smith MA, Harris SL, Kimple RJ. Review of clinical and biologic aspects of human papilloma virus positive squamous cell carcinoma of head and neck. Int J Radiat Oncol Biol Phys
2014; 88(4): 761–70.
Lassen P, Primdahl H, Johansen J, Kristensen CA, Andersen E, Andersen LJ, Evensen JF, Eriksen JG, Overgaard J; Danish Head and Neck Cancer Group (DAHANCA). Impact of HPV associated p16 expression on radiotherapy outcome in advanced oropharynx and non oropharynx cancer. Radiother Oncol
2014; 113: 310–6.
Lohaus F, Linge A, Tinhofer I, Budach V, Gkika E, Stuschke M, Balermpas P, Rödel C, Avlar M, Grosu AL, Abdollahi A, Debus J, Bayer C, Belka C, Pigorsch S, Combs SE, Mönnich D, Zips D, Neubeck CV, Baretton GB, Löck S, Thames HD, Krause M, Baumann M; DKTK-ROG. HPV DNA status is a strong prognosticator of loco regional control after postoperative radio chemotherapy of locally advanced oropharyngeal carcinoma: results from a multicenter explorative study of the German Cancer Consortium Radiation Oncology Group (DKTK-ROG). Radiother Oncol
2014; 113: 317–23.
Fischer CA, Zlobec I, Green E, Probst S, Storck C, Lugli A, Tornillo L, Wolfensberger M, Terracciano LM. Is the improved prognosis of p16 positive oropharyngeal squamous cell carcinoma dependent on the treatment modality? Int J Cancer
2010; 126: 1256–62.
Chung CH, Zhang Q, Kong CS, Harris J, Fertig EJ, Harari PM, Wang D, Redmond KP, Shenouda G, Trotti A, Raben D, Gillison ML, Jordan RC, Le QT. p16 protein expression and human papilloma virus status as prognostic biomarkers of non oropharyngeal head and neck squamous cell carcinoma. J Clin Oncol
2014; 32(35): 3930–8.
Rieckmann T, Tribius S, Grob TJ, Meyer M, Busch CJ, Petersen C, Dikomey E, Kriegs M. Head and neck squamous cell carcinoma cell lines positive for human papilloma virus and p16 possess higher cellular radio sensitivity due to an impaired DSB repair capacity. Radiother Oncol
2013; 107: 242–6.
Lajer CB, von Buchwald C. The role of human papillomavirus in head and neck cancer. APMIS
2010; 118(6-7): 510–9.
Ragin CC, Taioli E. Survival of squamous cell carcinoma of the head and neck in relation to human papillomavirus infection: review and meta-analysis. Int J Cancer
2007; 121(8): 1813–20.
Lau HY, Brar S, Klimowicz AC, Petrillo SK, Hao D, Brockton NT, Kong CS, Lees-Miller SP, Magliocco AM. Prognostic significance of p16 in locally advanced squamous cell carcinoma of the head and neck treated with concurrent cisplatin and radiotherapy. Head Neck
2011; 33(2): 251–6.
Eisenhauer EA, Therasse P, Bogaerts, Schwartz LH, Sargent D, Ford R, Dancey J, Arbuck S, Gwyther S, Mooney M, Rubinstein L, Shankar L, Dodd L, Kaplan R, Lacombe D, Verweij J. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer
2009; 45: 228–47.
Klaes R, Friedrich T, Spitkovsky D, Ridder R, Rudy W, Petry U, Dallenbach-Hellweg G, Schmidt D, Von Knebel Doeberitz M. Overexpression of p16 (INK4a) as a specific marker for dysplastic and neoplastic epithelial cells of the cervix uteri. Int J Cancer
2001; 92(2): 276–84.
Bahl A, Kumar P, Dar L, Mohanti BK, Sharma A, Thakar A, Karthikeyan V, Sikka K, Singh C, Poo K, Lodha J. Prevalence and trends of human papilloma virus in oropharyngeal cancer in a predominantly north Indian population. Head Neck
2014; 36(4): 505–10.
Murthy V, Swain M, Teni T, Pawar S, Kalkar P, Patil A, Chande A, Ghonge S, Laskar SG, Gupta T, Budrukkar A, Agrawal J. Human papillomavirus/p16 positive head and neck cancer in India: prevalence, clinical impact, and influence of tobacco use. Indian J Cancer
2016; 53(3): 387–93.
Sharma JD, Kalita M, Nirmolia T, Saikia SP, Sharma A, Barman D. Cancer: scenario and relationship of different geographical areas of the globe with special reference to northeast India. Asian Pac J Cancer Prev
2014; 15(8): 3721–79.
Smith EM, Ritchie JM, Summersgill KF, Klussmann JP, Lee JH, Wang D, Haugen TH, TurekLP. Age, sexual behavior and human papilloma virus infection in oral cavity and oropharyngeal cancers. Int J Cancer
2004; 108(5): 766–72.
Ralli M, Singh S, Yadav S, Sharma N, Verma R, Sen R. Assessment and Clinicopathological correlation of p16 expression in head and neck squamous cell carcinoma. J Can Res Ther
2016; 12(1): 232–7.
Sharma JD, Baishya N, Kataki AC, Kalita CR, Das AK, Rahman T. Head and neck squamous cell carcinoma in young adults: a hospital based study. Indian J Med Paediatr Oncol
2019; 40 Suppl S1: 18–22.
O'Sullivan B, Huang SH, Su J, Garden AS, Sturgis EM, Dahlstrom K, Lee N, Riaz N, Pei X, Koyfman SA, Adelstein D, Burkey BB, Friborg J, Kristensen CA, Gothelf AB, Hoebers F, Kremer B, Speel EJ, Bowles DW, Raben D, Karam SD, Yu E, Xu W. Development and validation of a staging system for HPV related oropharyngeal cancer by the international collaboration on oropharyngeal cancer network for staging (ICON-S): a multicentre cohort study. Lancet Oncol
2016; 17(4): 403–4.
Murthy V, Calcuttawala A, Kirti Chadha, d'Cruz A, Krishnamurthy A, Mallick I. Human papillomavirus in head and neck cancer in India: current status and consensus recommendations. South Asian J Cancer
2017; 6(3): 93–8.
Fakhry C, Westra WH, Li S, Cmelak A, Ridge JA, Pinto H, Forastiere A, Gillison ML. Improved survival of patients with human papilloma virus positive head and neck squamous cell carcinoma in a prospective clinical trial. J Natl Caner Inst
2008; 100(4): 261–9.
Kong CS, Narasimham B, Cao H, Kwok S, Erickson JP, Koong A, Pourmand N, Le QT. The relationship between human papillomavirus status other molecular prognostic markers in head and neck squamous cell carcinomas. Int J Radiat Oncol Biol Phys
2009; 74(2): 553–61.
[Figure 1], [Figure 2]
[Table 1], [Table 2]