Sex-specific aspects in patients with oropharyngeal squamous cell carcinoma: a bicentric cohort study

Head and neck squamous cell carcinoma (HNSCC) constitute the seventh leading type of malignancy worldwide with approximately 878.000 new cases and over 444.000 deaths annually [1]. Oropharyngeal squamous cell carcinoma (OPSCC) is the only subgroup of head neck cancer that presents with an increased incidence [2‐4]. Major risk factors are tobacco and alcohol consumption [5, 6]. Over the last two decades, a significant increase in incidence of Human papillomavirus (HPV) related- OPSCC has been observed, in particular in high-income countries [3, 4, 7, 8]. The majority of these OPSCC are associated with high-risk HPV type 16 [9, 10]. Notably, patients with HPV-related OPSCC have a significantly improved prognosis compared to HPV-negative OPSCC, regardless of treatment modality or tumor stage [11‐13].

In general, men are diagnosed with OPSCC much more frequently compared to women (approximately 70% vs. 30%) [14]. Furthermore, in a multicenter study including patients from 29 different countries, Castellsagué and colleagues [15] demonstrated that there is a spatial heterogeneity regarding HPV prevalence and distribution of HPV-related OPSCC according to gender. In the US population the rise in incidence is predominantly attributable to male patients [7, 16], whereas in Germany a higher increase in females was reported [4].

Despite these gender differences in incidence, the patient’s sex is usually not considered in diagnostic procedures, classification or clinical decisions. For many years, gender medicine was a neglected topic in oncology. Meanwhile, further differences in diagnosis, tumor aggressiveness and outcome are known in many cancer entities as papillary thyroid cancer and gastric cancer [17, 18]. Various reasons such as differences in habits (smoking, drinking and sexual behavior), differences according to the immune system, molecular differences or hormonal influences are discussed [2, 17‐20].

Regarding head and neck cancer one explanation for the above described gender disparities is the difference in habits (more smoking and drinking in men) [6, 21]. Regarding HPV related OPSSC one cause might be the cervicovaginal microbiota. It has been reported that females display a higher viral load of the genital mucosa compared to men, despite similar genital HPV prevalence [22, 23]. Consistent with these findings, other studies have reported that HPV may be transmitted more often from female to male, than vice versa [24, 25] and that there are higher rates of HPV transmission via vaginal–oral rather than penile–oral sex [26]. A higher prevalence of oncogenic HPV in the oral cavity of men compared to women was also detected (10.1% vs. 3.6%) [2, 27], which could in part explain the higher prevalence of HPV-related OPSCC in men [2, 28]. Another reason for a higher HPV prevalence of men might be a higher number of sexual partners [2, 3, 29]. This is in line with the finding of a higher diffusion among (non vaccinated) men having sex with men [30‐33].

Independent of HPV infection, another reason for gender disparities in HNSCC might be caused by differences in sexual hormones. Hormones play an important, mostly protective role in different types of cancer in women like hepatocellular carcinoma [34]. A case–control study by Hashim et al. demonstrated that the risk of developing HNSCC was inversely correlated with endogenous and exogenous estrogen exposures [35]. Regarding endogenous hormone exposure, the author specified that women giving birth to a child before 35 years of age had a lower risk of HNSCC than older women or women that have never been pregnant. Furthermore, female hormone pathways can be affected by smoking and alcohol drinking [35, 36]. Smoking is known to increase estrogen catabolism [31], which may be one reason for a different effect of smoking on the risk of developing HNSCC in women than in men.

Here, we performed a bicentric, retrospective analysis of OPSCC patients focused on gender-related overall survival and therapy, with the aim to identify sex-specific differences with potential impact on staging and treatment in the future.

Gender is an important aspect in oncology affecting incidence, treatment and prognosis. Nevertheless, there are still limited data on sex disparities in OPSCC, especially according to HPV-status. In this study, we could gain important insights into sex-related oncologic differences. First of all, we found that almost three times more men than women develop OPSCC, which is in line with data from literature [4, 37]. Various reasons are discussed like hormonal influence, immune response, HPV-status, but also a different lifestyle regarding sexual practices, tobacco and alcohol consumption [6, 14]. In our cohort, age, ECOG status, HPV-status, tumor size, lymph node- and distant metastasis as well as nicotine consumption were equally distributed between males and females. According to the equal distribution of the ECOG status, we can assume that patients were in a comparable state of health.

Furthermore, we could demonstrate that there is a trend for better OS in women compared with men. This is in line with a recently published study of Preissner et al. demonstrating a significantly better 5-year-OS of women in a cohort of almost 150.000 patients with HNSCC [14]. In addition to Preissner et al., we analyzed the OS in different subgroups. Thereby, we could identify that in the subgroup with small tumors and lymphatic metastasis (T1-T2, N +), female patients demonstrated a significantly better OS than men independent of smoking and alcohol consumption. We could also demonstrate that female patients treated with surgery ± adjuvant therapy vs. definitive RCT had a significantly better OS than men. The same results were found in female patients with advanced tumor stage (subgroup AJCC III-IV, M0).

Up-to-date there are no reliable data that adequately explains differences in OS between male and female patients with OPSCC [14]. Looking at other cancer entities, survival advantage of women is often explained with younger age at first diagnosis, less nicotine consumption or with distinct phenotypes of diseases by sex [38, 39].

Nicotine and alcohol consumption are well-known risk factors [13]. Regarding the risk factor smoking, we couldn’t detect gender-specific differences in the overall distribution. Therefore, this does not explain the better OS of women in our OPSCC cohort. One limitation thereby is the lack of granularity with regard to smoking history, which is considered binary because sufficient pack-year data were not available. However, we could demonstrate that smoking seems to have an effect on OS in males and females within certain subgroups: Smoking female presented with a significantly better OS in the subgroup of T1-T2, N + OPSCC compared with males. This can’t be explained by different treatments of males and females as both displayed equal distribution to surgical therapy vs. definitive RCT (Table 1). One explanation might be that smoking affects hormone balance differently in women than in men, as smoking is known to increase estrogen catabolism [36] and thus could confer a survival advantage over men.

Furthermore, we found that significantly more males than females reported alcohol consumption in the total cohort. Alcohol consumption is an important risk factor especially in HPV-negative OPSCC. We therefore analyzed the influence of alcohol consumption also in T1-T2, N + OPSCC and in the subgroup T1-T2, N + , HPV-negative OPSCC (not shown). Again, no significant difference was found between men and women, so the risk factor of alcohol could not explain the better OS of women. These findings are in line with the results of Preissner et al. [14], who could not detect differences in tobacco and alcohol consumption according to sex in their large study population of HNSCC. A limitation of our study is, that we weren’t able to assess the quantity of alcohol consumption due to insufficient data available over the years.

Besides smoking and alcohol, HPV-status is the most important risk- and prognostic factor in OPSCC patients to date. In line with other representative studies such as the RTOG-0129 [13], our study revealed a significantly better 5-year & 10-year OS of patients with HPV-related OPSCC compared to patients with HPV-negative OPSCC (additional Fig. 3A, B). In our study cohort, HPV positivity was defined as a combination of HPV-DNA and p16 positivity. This is important to emphasize, as the definition of HPV positive OPSCC (whether it is defined only by overexpression of p16, independent of HPV-DNA or a combination of HPV-DNA and p16 positivity) is still discussed controversially in literature and not uniform [9, 37, 40‐42]. In addition to the p16 + /HPV + cases we could identify in total 62 patients with p16 overexpression but HPV-DNA negative OPSCC (which is a rate of 4.9% of false positive p16 cases).This rate is comparable with the predicted rate of false positive p16 cases (3.8%) calculated by a recently published formula of Gallus et al. [42]. Recent studies [9, 37, 40‐42] found that patients with p16 + /HPV- OPSCC seem to have the same prognosis or only slightly better than p16-/HPV- cases. Consistent with these findings patients in our cohort with p16 + /HPV- OPSCC (and p16-/HPV + OPSCC) had a significant worse OS than patients with p16 + /HPV + OPSCC (additional Fig. 3C & D).

Interestingly, when OS was analyzed with respect to gender, we could demonstrate better OS of women only in the HPV-negative cohort. This finding contradicts the results of Preissner et al. [14] where better OS of women was found in the HPV-related cohort. Mentioned by the authors themselves, one weakness in their retrospective study cohort was the unclear origin of the HPV test samples. In our study cohort, HPV positivity was defined as a combination of HPV-DNA and p16 positivity, which might in parts explain some discordance of the results. A limitation of our study is the missing investigation on the disease-free survival (DFS), due to the retrospective study design and lacking data on cause of death in most cases. This would have given more accurate information on survival of OPSCC patients based on the disease itself.

Importantly, in our study there were no gender-specific differences in the distribution of HPV-status. Consequently, HPV-status of OPSCC affected the survival probability equally and therefore could not explain the gender-specific differences in OS.

Regarding AJCC8 stages, male patients demonstrated a significant stratification between all stages, whereas women were lacking significance between stage II and III. We could further demonstrate that male patients with p16 negative OPSCC, as well as females with p16 positive and negative OPSCC were lacking significance between different stages. However, this aspect needs to be reviewed within a larger cohort.

In summary, we could demonstrate important sex-specific differences: Females had significantly better OS than males in the subgroup T1-2, N + , independent of risk factors. Men demonstrated significantly better stratification across all AJCC8 stages. In contrast, women did not reveal OS differences between stage II vs. stage III. A comparison of therapy (surgery ± adjuvant therapy vs definitive RCT) demonstrated, that women treated with surgery ± adjuvant therapy had better OS than men in the whole cohort. The same results were detected in the cohort of HPV-negative OPSCC and within high-risk groups (AJCC8 stage III and IV with M0). The cause for these gender disparities cannot be explained adequately by our study and needs to be addressed in the future. Understanding gender differences in OS in OPSCC could impact future treatment strategies, especially in the era of personalized medicine.