Background: Incidence of human papillomavirus (HPV)-associated oral and oropharyngeal squamous cell carcinomas (OSCC and OPSCC) is on a rising trend globally and has specific therapeutic implications. HPV-related tumors have a distinct pathogenetic mechanism targeting p16 and p53 both. However, there are limited studies evaluating p16 and p53 expression in combination. Aim: The aim of the study is to evaluate p16 and p53 immunohistochemical expression pattern in OSCC and OPSCC, with special reference to HPV association. Study Design: This was a hospital-based prospective study done over 22 months (September 2018 to June 2020), including a total of 54 cases of OSCC and OPSCC. They were subjected to clinicopathological evaluation, p16 and p53 immunohistochemistry, and DNA polymerase chain reaction testing for testing of HPV association, followed by analysis of data by statistical methods. Results: Out of 54, 43 cases were OSCC and 11 cases were OPSCC. A total of nine cases were HPV positive. HPV association was found to be significant with tonsil as primary site, age range between 40 and 60 years, and absence of tobacco or alcohol habit. Presence of HPV infection was also significantly associated with p16 overexpression, in combination with p53 negativity. The findings indicate that p16 overexpression combined with a negative p53 expression can be used for HPV detection and the former alone may be used as diagnostic marker in OPSCC only. Conclusion: HPV-associated OSCC and OPSCC are a unique subset of cancers, and using combination of molecular biomarkers could help in diagnosis and prognosis.
Keywords: DNA polymerase chain reaction, human papillomavirus, p16, p53, squamous cell carcinoma
|How to cite this URL:|
Ghosh U, Tripathy R, Lenka A, Turuk J, Mohapatra D. Immunohistochemical evaluation of p16 and p53 in oral and oropharyngeal squamous cell carcinoma with special regard to human papillomavirus status. J Microsc Ultrastruct [Epub ahead of print] [cited 2022 Dec 1]. Available from: https://www.jmau.org/preprintarticle.asp?id=361128
| Introduction|| |
Carcinoma of head and neck is the sixth most common type of cancer in the world today. oropharyngeal squamous cell carcinoma (OPSCC) constitute an important part of head and neck tumors, and globally 300,000 men and 130,000 women get diagnosed with these diseases annually. Most common etiologies established for the aforementioned types of cancer are tobacco smoking, betel quid chewing, and alcohol consumption. However, another etiological factor whose significance came to light through different studies is the oncogenic human papillomavirus (HPV).
Human papilloma viral infection in cervical and anal cancer has been studied in detail. Studies suggest that there are more than 100 known genotypes of HPV, out of which 13 can cause cancers of the cervix and anorectal region. The most common subtypes are 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, and 68, with high-risk (HR) type 16 and 18 taking the prize for being responsible for 70% of the cases., However, the same cannot be said with regard to its role in cancers of the oral and oropharyngeal region as its association with the latter has only been hinted at in a few studies. Global incidence rate of HPV-associated oral and oropharyngeal cancers ranges from 14% to 85% depending on the region, with oropharyngeal cancers being more common in the Western World.,
The primary players in the pathogenesis and malignant transformation of HPV virus are the E6 and E7 proteins, which target p16 and p53 tumor-suppressor genes. Very few studies, especially in the Indian subcontinent, have evaluated the role of both these genes' expression in combination, in relation to HPV association.
The present study intervenes in this context. It is being conducted in a tertiary care hospital and aims to evaluate p16 and p53 expression in OSCC and oropharyngeal squamous cell cancers (OPSCC) in association with HPV status and clinicopathological findings. It will thus attempt to fill in the spaces which have hitherto remained blank with regard to the effects of this elusive virus and its biomarkers on the disease.
| Materials and Methods|| |
Hospital-based prospective study conducted at the department of pathology.
22 months (September 2018 to June 2020).
Patients with diagnosed OSCC and OPSCC, including all histological subtypes, as well as those with regional lymph node metastases with clinical findings consistent with an oral or oropharyngeal primary. Metastatic squamous cell carcinoma (SCC) of unknown primary in a cervical (level IA, IB), upper, or mid-jugular chain lymph node were also considered.
Patients in whom fresh tissue could not be obtained for DNA polymerase chain reaction (PCR).
54 cases of OSCC and OPSCC after considering the inclusion and exclusion criteria.
All relevant information was collected directly from the patients and the data register in the department of ear, nose, and throat (ENT), oncosurgery, and dental surgery.
Approval for the study was taken from the institutional ethical committee on January 4, 2019. Informed consent was taken from all participants in this study during the time period of the study, on a case-by-case basis.
Diagnosis and molecular detection
Two samples were collected for each patient, one fixed in formalin and the other collected in normal saline. All formalin-fixed samples underwent histopathological evaluation and diagnosis. All fresh tissue samples were sent for DNA PCR to Regional Medical Research Centre. The sequence of the forward and reverse primers used in this case are 5'GAA GAG CCA AGG ACA GGTAC 3' and 5'CAA CTT CAT CCA CGT TCA CC 3' (beta globin) and 5'ATG CAT GCA GAT ACA CCT ACA TTG3' and 5'TGG TAG ATT ATG GTT TCT GAG AA 3' (HPV viral DNA). Appearance of the band in the same range as the positive control was considered positive for presence of HR HPV.
Immunohistochemistry was done in all cases using p16 and p53 biomarkers. They were interpreted as follows:
Data collected on 54 cases were analyzed using Microsoft Excel. For test of significance, “P” < 0.05 has been taken (95% confidence interval) as statistically significant.
| Results|| |
A total of 54 patients who had visited the oncosurgery, ENT, and dental departments and subsequently diagnosed as OSCC and OPSCC have been included. Out of them, 43 were male and 11 were female, resulting in a male: female ratio of 4:1. Out of a total of 11 women, nine had OSCC and two had OPSCC, and out of 43 men, 34 were having OSCC and nine were having OPSCC. Each of the cases was subjected to conventional PCR, for the detection of HPV.
Based on PCR studies, a total of nine were HPV positive, out of which three were OSCC (33.33%) and the remaining six were OPSCC (66.67%), including the two who presented with cervical metastases [Figure 1]. Hence, the HPV-negative tumors (83.33%) are much more, compared to those thar are associated with HPV infection (16.67%). In cases which demonstrate HPV positivity, it is observed that the viral association is more common in OPSCC, which is seen to be statistically significant [Table 1].
|Figure 1: Human papillomavirus DNA polymerase chain reaction of 6 positive cases and 1 inconclusive case (taken as negative), along with positive control β-globin (the first band marked red)|
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In case of OPSCC, the most common site was found to be tonsil as the two cases of cervical metastases also had tonsil as their primary. In OSCC, all three positive cases originated from the tongue (posterior aspect) [Table 2].
|Table 2: Distribution of cases by human papilloma virus status with location, demography, and risk factors|
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The relationship of the demographical profile with HPV status was also done and appeared to be independent of the sex of the patient. In contrast, the association of HPV infection with younger and middle-aged groups, with a greater number of the cases in the range of 40–60 years (66.66%), was found to be statistically significant. Considering etiology, HPV status was found to be associated with the absence of tobacco and alcohol habit [Table 2].
All cases underwent thorough histopathological evaluation and diagnosis [Figure 2] before being subjected to immunohistochemical evaluation with p16 and p53 marker. In case of p16, percentage, staining intensity, and confluence was considered. The confluence was categorized by intensity (moderate and intense) and percentage (<25%, 25%–50%, 51%–75%, >75%). In case of p53, only percentage and staining intensity were considered [Figure 3]. Their expression was tabulated by comparing with the HPV status.
|Figure 2: (a) Human papillomavirus-positive oropharyngeal squamous cell carcinomas (tongue) with tumor component (black arrow) (H and E, ×400), (b): Human papillomavirus-positive oropharyngeal squamous cell carcinomas (supraglottic region) demonstrating mitosis (yellow arrow) and large anaplastic cells (black arrow) (H and E, ×400), (c) Human papillomavirus-negative oropharyngeal squamous cell carcinomas (supraglottic region) showing extensive areas of necrosis (black arrow) (H and E, ×400)|
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|Figure 3: (a) Immunostaining of p16 of the tumor cells (strong, diffuse nuclear and cytoplasmic, with more than 90% confluence) (IHC, ×100), (b) Positive immunostaining of p16 (strong, diffuse nuclear and cytoplasmic staining) (IHC, ×400), (c) Positive immunostaining of p53 at the tumor invasive front (intense nuclear staining) (IHC, ×400), (d) Immunostaining of p16 (cytoplasmic only, considered negative) (IHC, ×400), (e) p16-positive control (cervical cancer) (×400), (f) p53-positive control (breast cancer) (×400)|
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Out of 54 cases, a total of 11 demonstrated p16 overexpression; four were HPV positive and the remaining negative for HPV. Ten cases showed intense staining with confluence in more than 75% of the tumor cells. One case was placed under moderate staining as the cytoplasm had taken up more stain, with confluence about 70%. Negative p53 expression was found to be associated with HPV positivity. Seven (77.77%) HPV-positive cases were p53 negative while the rest (22.22%) were positive [Table 3]a.
Out of the 11 cases demonstrating p16 over-expression, four (44.44%) were OPSCC and the remaining seven were OSCC. Out of the four OPSCC cases, three were HPV positive and one was negative. Conversely, out of the seven OSCC cases, only one was HPV positive and the remaining were negative for the virus. Hence, 75% of OPSCC cases were also HPV positive. These negative cases could be showing p16 overexpression because of some underlying mechanism independent of HPV status [Table 3]b.
All the cases have been divided into four distinct categories according to immunohistochemical expression: p16 (+)/p53 (−), p16 (−)/p53 (+), p16 (+)/p53 (+), and p16 (−)/p53 (−). The columns have been divided on the basis of HPV status. Presence and absence of HPV infection were found to be significant in p16 (+)/p53 (−) and p16 (−)/p53 (+) categories, respectively [Table 3]a.
All patients were followed up to a period ranging from 6 months to 1 year, depending on the time of diagnosis. Three out of 45 HPV-negative cases died during the follow-up period. The remaining 42 HPV-negative and nine HPV-positive cases were all subjected to a combined approach of surgery and chemoradiation and are responding well. There was significant association of HPV infection with improved survival, independent of stage, and grade of disease [Table 4].
|Table 4: Distribution of cases based on patient survival with human papillomavirus status|
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| Discussion|| |
According to the Global Cancer Observatory (GLOBOCAN project), which is under the International Agency for Research on Cancer, 2018, there were 354,864 new cases of lip and oral cavity and 92,887 new cases of oropharynx in that year. Oral cancers are much more frequently encountered in South Asia, while oropharyngeal cancers are more prevalent in the Western World. given by the WHO.
The HPV is a small nonenveloped double-stranded circular DNA virus belonging to the family Papillomaviridae, which commonly affects epithelial cells. With regard to its role in cancers, it is the HR HPV type 16 and 18 which is important.
HPV-associated head and neck squamous cell carcinomas (HNSCCs) have been identified as a unique subcategory, with their own particular epidemiology and pathogenesis.
There appears to be a geographical difference in HPV rates of oropharyngeal cancers with persistently lower rates in Asian countries when compared to Western Europe and the US, as evidenced by a study by Toman et al., which observed 59 oropharyngeal specimens from two university hospitals in Japan.
The present study showed HPV positivity in a total of nine out of 54 (16.66%) cases, which indicates a low incidence of HPV-associated SCCs in this region. HPV infection was significantly correlated with site (P = 0.0001) in both OSCC and OPSCC, with tonsil as the primary site in OPSCC (50% of OPSCC-positive cases) and posterior aspect of tongue as the most common site in OSCC (66.66% of OSCC-positive cases). These findings were comparable in case of OPSCC, where Singh et al. also encountered that HPV-positive cases were in the oropharynx, especially tonsil and base of tongue in their 2017 study. In case of OSCC, there was contradicting information available. Mishra et al.'s 2006 study reported HPV prevalence in the oral cavity, albeit low, while Lingen et al. reported none., Our study thus indicates further large-scale research.
Male patients outnumbered the females, considering overall cases. However, HPV status was found to be independent of the sex of the patient. There was a significant association of HPV-related SCC in people below 60, with greater number of the cases in the range of 40–60 years (66.66%). This was in contrast to Singh et al. who found no such association with age or sex. However, Meng et al., 2018 found HPV infection to be significantly associated with male sex and middle age. In terms of etiological factors, negative history of tobacco and alcohol exposure was found to be statistically significant (P = 0.0001). The combination of HPV positivity alongside the absence of tobacco exposure history appeared to have the best outcome in OPSCC, as evidenced by Schwartz et al. in 1998. Hafkamp et al. and Kumar et al. in 2008 also conducted studies in this aspect and found a similar association. In contrast, Smith et al. in 2004 and D'Souza et al. in 2007 observed that HPV status appeared to be independent of tobacco and or alcohol habit.
p16 and p53 are tumor-suppressor genes and key targets in the loss of cell cycle controlling case of HR HPV infection. p16 overexpression along with decreased expression of p53 (wild type) has been highly correlated with the presence of HPV in both HNSCC and cervical SCC, according to Koyamatsu et al. in their 2003 study. Stephen et al.'s 2013 study observed that p16 expression was significantly associated with oropharynx as site, a finding that could be attributed to the lack of a substantial amount of non OPSCC cases.
The molecular aspect of HPV-associated OSCC is still untouched, especially in Indian population. On analyzing the relationship of these two markers with HPV status in both oral and oropharyngeal cancers, it was observed that there was significant association of p16 expression and p53 nonexpression with HPV positivity (P = 0.0001). This was comparable to Shinohara et al., who, in their 2013 Japanese study comprising 53 patients, used p16 to quantify HPV load and took p53 into consideration, as it is commonly expressed in cancers where smoking is the etiological factor, observing an inverse relationship between the two markers with regard to HPV status. Singh et al. however found overexpression of p16 to be independent of HPV status. Yang et al.'s 2019 study also indicated that concordance between p16 overexpression and HPV positivity is weak in OSCC. Further, high percentage staining of p16 (50%–70%) in HPV-negative cases confirmed that p16 overexpression in OSCC cases is not solely due to the HPV infection. Similarly, Heinzel et al. and Rushatamukayanunt et al. in 2014 also did not find association of p16 expression with HPV infection in OSCC. In 2016, Zafereo et al. reported that p16 overexpression in OSCC cases is rarely driven by HPV and OSCC cases that overexpresses p16 may be a unique subset deserving further study. Further, worth noting is a recent study by Benzerdjeb et al., which observed that a subset of p16-positive OPSCC was unrelated to HPV and showed mutant-type staining of p53 expression, a finding which helped to reclassify a subset of p16-positive OPSCC as OPSCC-unrelated HPV.
Immunohistochemical expression of the markers in the present study was divided into four categories. Presence of HPV infection is statistically significant in case of p16+/p53 − cases (P = 0.0001), while HPV negativity is significant in p53+/p16− (P = 0.0012).
Double-positive and double-negative cases were observed by Shinohara et al. and Perri et al. in their 2014 and 2020 studies, respectively, in which both categories were found to have poorer prognoses than those who were only p16 positive. The reason for such cases is not known, and the reason why they are poorer prognostically is also unclear. It has been suggested that it could be because of other carcinogenic factors stronger than HPV or mutated p53.
Based on the findings of our study, detection of p16 overexpression, along with negative expression of p53, can be considered to be effective in determining the presence of HR HPV-associated SCC. In addition, p16 alone may be considered as a surrogate marker for HPV-associated OPSCC, a finding that was in agreement with Shinohara et al. However, Sabu et al.'s study on HPV and its molecular detection strongly suggested that detection of p16 provides a suboptimal prognostic information if not combined with detection of HPV DNA and neither of the tests alone is the optimal method for detection. Hence, extensive studies must be done on a larger study population for proper evaluation.
In the present study, the three patients who died during the period of follow-up were HPV-negative OSCC; two were p16 (−)/p53 (−) and one, p16 (−)/p53 (+). The remaining underwent surgery and/or chemotherapy and radiotherapy and were doing well. There was significant association of HPV infection with improved survival (P = 0.0076), comparable to Smith et al.'s 2010 study, where they have followed their study population for almost a decade and observed that HNSCC patients with the combination of p16 (+), p53 (−), and HR HPV (+) also have the best clinical outcomes whereas those with the opposite status markers, p16 (−), p53 (+), and HR HPV (−), have the worst outcome. These results also echoed with El Azeem et al., who explored p16 and p53 expression in OSCC and oropharyngeal SCC in Egyptian patients and observed HPV is related to favorable prognostic factors, whereas p53 is related to adverse prognosis. It appears that two major pathways are operable for OSCC and oropharyngeal SCC genesis, and one of them is HPV related.
| Conclusion|| |
HPV-associated HNSCCs have been recognized as a unique subtype with their own pathogenetic mechanism. Using multiple molecular markers together in HNSCCs will help in diagnosing this particular group, prediction of prognosis, and also implementation of potentially targeted treatment. This study combined DNA detection, along with immunohistochemistry detection, and observed that disease-specific recurrence free survival was highest in case of p16 (+)/p53 (−)/HR HPV (+), as compared to p16 (−)/p53 (+)/HR HPV (−) tumors.
Vaccination against HPV in female genital tract and anal cancer and warts has been widely used. However, cancers of the head and neck have been left off the list until now. Food and Drug Administration has approved the use of gardacil 9 as vaccination against HPV associated HNSCC as of June 2020. Hence, detection of HPV in OPSCCs and OSCCs has utmost importance in population screening, as well as future vaccination programs.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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Department of Pathology, Institute of Medical Sciences and SUM Hospital, Bhubaneswar, Odisha
Source of Support: None, Conflict of Interest: None
[Figure 1], [Figure 2], [Figure 3]
[Table 1], [Table 2], [Table 3], [Table 4]