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 Table of Contents  
Year : 2020  |  Volume : 6  |  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

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 Submission15-Dec-2019
Date of Acceptance05-Mar-2020
Date of Web Publication25-Mar-2020

Correspondence Address:
Dr. Yumkhaibam Sobita Devi
Department of Radiation Oncology, RIMS, Imphal, Manipur
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/ctm.ctm_34_19

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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 2021 Aug 5];6:10-6. Available from: http://www.cancertm.com/text.asp?2020/6/1/10/281365

  Introduction Top

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.[1] Nearly 57.5% of global head-and-neck cancers occur in Asia, especially in India, for both the sexes.[2] Tobacco, alcohol use, and human papillomavirus (HPV) infection are the three most common risk factors associated with HNSCC.[3] HPV prevalence in HNSCC varies from 10% to 90%, depending on the anatomic location and geographic distribution of the population.[4] The majority of cases include HPV-16 subtype, with other reported subtypes being HPV-18, 31, 33, 35, and 45.[5] HPV-16 subtype accounts for 87% of the oropharyngeal, 68% of oral, and 69% of laryngeal HPV-positive carcinomas.[6] 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.[7]

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.[8],[9] 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.[10]

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.[8],[11],[12],[13] Whereas one study has shown its positive prognostic impact in both oropharyngeal and non-OPSCC (NOPSCC).[14]

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.[6],[15],[16],[17]

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 Top

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%[18]

p2= Proportion in another group = 76.9%.[18]

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[2] 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.[19]

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.[20] 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 Top

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].
Table 1: Distribution of different variables in the two arms

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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

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  Discussion Top

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%).[21],[22] 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.[23] 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.[3],[5] p16-positive HNSCC patients are commonly diagnosed with good performance status as compared to p16-negative patients.[3],[24] 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;[3],[5],[25] 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.[26]

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),[19] 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.[27] 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.[8],[27] 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.[6],[28]

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%.[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.[13],[19]

p16-positive OPSCC has been reported to be associated with better treatment outcome and survival.[13],[14],[15],[16] 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,[29] 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.[30] 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 Top

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.

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  [Figure 1], [Figure 2]

  [Table 1], [Table 2]


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