Rates of p16 and p53 expression in head and neck cutaneous squamous cell carcinoma vary according to human papillomavirus status

Abstract

The strong association between human papillomavirus (HPV) infection and oropharyngeal squamous cell carcinoma (SCC) is well-documented, with p16 expression serving as a reliable predictor of HPV involvement. HPV-related tumors are characterized by distinct mechanisms affecting p16 and p53 protein pathways. However, the prevalence of HPV and the combined predictive utility of p16 and p53 expression in head and neck cutaneous SCC remain less explored, necessitating further research to understand their role in this subset of SCC. HPV, p16, and p53 statuses were determined using immunohistochemistry staining methods rather than more sensitive techniques such as polymerase chain reaction or HPV genotyping, limiting the ability to assess specific area HPV types potentially associated with prognosis. Further studies assessing multiple molecular markers in head and neck cutaneous patients will better predict the diverse outcomes and potentially the type of treatment targeted to those markers.

Key Words: Squamous cell carcinoma; Oropharyngeal; Non-oropharyngeal; Human papillomavirus; p16; p53

Core Tip: In this editorial, we comment on a retrospective cohort study published in the recent issue of the World Journal of Clinical Cases. The authors of this article aimed to highlight that p16, commonly used as a surrogate marker for human papillomavirus in oropharyngeal squamous cell carcinoma (SCC), is not a reliable indicator in head and neck cutaneous SCC. This finding offers important insights for future research focusing on Asian populations.

INTRODUCTION

Squamous cell carcinoma (SCC) is the second most common skin cancer after basal cell carcinoma, with a tendency to develop from premalignant lesions, particularly in areas that are frequently exposed to sunlight like the head and neck. Major underlying causes for SCC include ultraviolet (UV) radiation, exposure to chemical carcinogens, genetic factors, immune dysfunction, specific medications, and pathogenic viral conditions[1,2]. SCC ranks as the second most prevalent form of non-melanoma skin cancer, comprising around 40.2% of every head and neck malignancies. Several risk factors for the advancement of head and neck SCC (HNSCC) have been recognized, comprising tobacco use, alcohol intake, nutritional influences, and human papillomavirus (HPV) contamination[3].

Like many other oncogenic viruses, HPV integration disrupts cellular immune surveillance and homeostasis by altering gene expression and inducing epigenetic modifications[4]. This process initially enhances cellular proliferation, creating a favorable environment for viral replication and persistence[5]. The key contributors to this mechanism are the HPV oncoproteins E6 and E7, which target and inhibit various cellular proteins. E6 promotes the rapid degradation of p53, disrupting cell cycle checkpoints and driving re-entry into the S-phase[6]. Meanwhile, E7 binds to the retinoblastoma protein (pRb) and triggers its degradation, leading to the upregulation of the cyclin-dependent kinase inhibitor p16[7].

The role of HPV in SCC development is widely recognized, particularly in cases associated with epidermodysplasia verruciformis (EV)[2]. EV is an autosomal recessive inherited skin disorder and significantly increases the risk of SCC development and shows high susceptibility to infection by beta-type HPV, particularly HPV-5 and HPV-8. In EV, SCC often arises in skin with long-term infection with HPV, especially in areas frequently uncovered from sunlight[8].

p53 is a key driver mutation in SCC, functioning as a tumor suppressor to protect against damage caused by UV radiation. Meanwhile, p16 serves as a substitute biomarker for HPV, demonstrating a high accuracy in predicting positive outcomes in oropharyngeal SCC (OPSCC) and being linked to an encouraging clinical outcome[9].

Several studies have investigated the prevalence and role of HPV infections in OPSCC and their correlation with a favorable prognosis[10-12].

This is linked to HPV's ability to upregulate p16 expression, a commonly used surrogate marker for HPV infection that is also associated with better treatment outcomes in these cancers[13].

P16 AND P53 EXPRESSION IN NECK CUTANEOUS SCC

The overexpression of the p16 protein, combined with the loss of function of the p53 tumor suppressor gene, enhance responsiveness to radiotherapy and chemotherapy, leading to improved therapeutic responses and higher overall survival outcomes among patients with HPV-positive OPSCC[9,14].

HPV’s role in oral and oropharyngeal carcinogenesis was first identified by Syrjänen[15] in 1983. Following that, extensive research has explored HPV's role in HNSCC, especially in OPSCC. The prevalence of HPV positivity in OPSCC fluctuates significantly, between 40% and 80%, contingent upon the detection method's sensitivity and specificity[9,16].

OPSCC associated to HPV is more commonly seen in locations like the United States than in Asia or Europe, perhaps as a result of variations in sexual activity and cultural customs, as well as HPV immunization rate[17]. Also, OPSCC associated to HPV is more commonly observed in younger individuals and those having several sexual partners in the past and increased oral-genital contact[18].

Moreover, HPV-positive OPSCC generally displays characteristics of a solitary, confined tumor within the oropharynx, primarily found in the tonsils or at the lingual base, it typically presents with a reduced initial tumor and a decreased incidence of lymphatic spread compared to tumors with no links with HPV[19-21]. Furthermore, OPSCC associated to HPV has a reduced association with smoking and alcohol intake. Subjects often have less comorbid conditions and exhibit greater overall health and physical condition at the time of diagnosis[22,23].

There is evidence suggesting that HPV infection may worsen UV-induced damage and could potentially play a role in the development of SCC. Multiple studies have reported HPV positivity rates in head and neck cutaneous SCC (HNCSCC) ranging from 5% to 20%. However, the role of HPV in the pathogenesis of HNCSCC remains uncertain[24,25].

In the study by Nam et al[1], the HPV detection rate using immunohistochemistry (IHC) for HNCSCC was 8.06%, with 5 out of 62 cases testing positive[1]. This rate was lower than the 21.8% HPV positivity observed in a prior study utilizing the polymerase chain reaction (PCR) technique among North American participants[26]. The difference in testing procedures is believed to be one explanation for this finding. PCR is the most sensitive method for detecting HPV and may yield an increased positivity occurrence compared to the IHC technique applied in this investigation[1,27]. Also, in the study by Nam et al[1], the sample size was relatively modest, consisting of only 62 subjects and featuring a restricted set of HPV-positive cases which may contribute to the observed variation in HPV positivity rates. These constraints underscore the necessity for bigger, multi-site investigations with longer follow-up periods to more thoroughly elucidate the prognostic impact of HPV, p16, and p53 activity in head and HNCSCC.

Moreover, the survey by Nam et al[1] suggests that the expression of p16 and p53, parallel with HPV infection, may serve as poor prognostic indicators in head and HNCSCC, revealing an increased risk of return and metastasis.

P53 is the most frequently mutated gene in SCC, observed in as much as 90% of SCC cases. Once mutated, tumor cells escape programmed cell death and bypass cell cycle arrest, facilitating uncontrolled proliferation and clonal expansion. UV-induced mutations in p53 are implicated in SCC development[28]. The differing functions of p16 and p53 in OPSCC opposed to head and HNCSCC highlight the multifaceted connection between HPV contamination, exposure to UV radiation, and specific molecular shifts associated with head and HNCSCC.

Additionally, the frequency of p53 mutations caused by UV damage in the study by Nam et al[1] was found to be lower than that reported in previous studies involving Caucasian individuals[29]. The same study found no statistically significant relationship between p16 expression and tumor location, suggesting that p16 is not correlated with a favorable prognosis in HNCSCC. These results indicates that the interconnection linking p16 expression and HPV stage can very among OPSCC and HNCSCC. It underscores the requirement for additional studies to clarify the role of p16 in HNCSCC disease mechanism and to evaluate its ability to act as a prognostic tool[1].

On the other hand, Wang et al[30] observed that p16 and p53 serve as important prognostic markers for HNSCC. High levels of p16 and p53 expression are often linked to a more favorable prognosis.

On the whole, the differing positivity rates of p16 in OPSCC and HNCSCC emphasize the multifaceted interaction linking HPV contamination, UV radiation exposure, and other pathogenic influences that contribute to the development of head and neck cancer.

CONCLUSION

HPV-positive OPSCC frequently may be different between geographical regions due to variations in sexual behavior, cultural practices, and HPV vaccination rates. The presence of p16 and p53 expression, in combination with HPV infection, may act as unfavorable forecasts of recovery in head and HNCSCC, suggesting a higher likelihood of reappearance and distant spread.

Further studies evaluating various molecular markers in head and neck cutaneous patients can enhance the prediction of diverse outcomes and help tailor treatments specifically to those markers.