1 Introduction

Laryngeal cancer ranks as the second most common malignancy of the upper aerodigestive tract, with 210 000 new cases annually [1, 2]. Despite tremendous medical advancements, the mortality rate has remained stable [3]. Traditionally, laryngeal cancer has been associated with a male predominance, attributed to the gender-related difference in the consumption of the two most significant risk factors for laryngeal cancer: tobacco and alcohol [4, 5]. However, the proportion of females with laryngeal cancer has grown to 4:1 male: female ratio [1, 6] partly due to increased smoking and alcohol consumption in females [7, 8]. However, a closer look reveals that additional risk factors might play a role in this particular group [4, 9]. For example, while smoking is considered a significant risk factor for laryngeal cancer, the rate of females among patients with the disease who never smoked is double the rate among patients with a positive smoking history [10]. Such findings lead to the hypothesis that the pathogenesis of laryngeal cancer differs between males and females [9, 11].

Gender-based differences are well recognised in various malignant tumours' pathogeneses, disease courses and prognoses. For instance, among patients over 65 years old with colorectal cancer, women demonstrated a decrease in 5-year survival compared to men [12], while in other cancer types, such as cutaneous melanoma and non-small cell lung cancer, a survival advantage was identified among females [13, 14]. Numerous mechanisms have been suggested to explain these findings, including the possible effect of sex hormones, such as oestrogens, on the process of tumorigenesis [15].

A few studies, including two current Surveillance, Epidemiology and End Results (SEER) investigations, have demonstrated a survival advantage among females with laryngeal cancer compared to males [4, 16, 17]. Nevertheless, there is still a knowledge gap in the medical and scientific literature regarding gender-based differences in laryngeal cancer. Therefore, in this study, we aimed to investigate the relations between gender and tumour characteristics, responses to different treatment regimens and outcomes among laryngeal cancer patients.

2 Materials and Methods

3 Results

3.5 Prognosis

The crude 5-year DSS, OS and DFS rates for the entire cohort were 91.8% (95% CI, 88.5%–95.2%), 71.3% (95% CI, 66.1%–77%) and 74.4% (95% CI, 69%–80.1%), respectively. Despite being diagnosed at more advanced stages and with a higher prevalence of supraglottic SCC, female patients demonstrated prolonged OS compared to males; this gender-based difference in OS is shown in the Kaplan–Meier curve (p = 0.017; Figure 1). However, there were no statistically significant differences between the genders in DSS (log-rank p = 0.12) or DFS (log-rank p = 0.32; Figure 1).

We also performed a subgroup analysis by tumour origin subsite stratified by gender, as visualised in Figure 2; DSS rates by tumour origin subsites did not differ between females (log-rank p = 0.62) and males (log-rank p = 0.46). DFS rates also did not differ significantly by tumour subsites between females (log-rank p = 0.36) and males (log-rank p = 0.18). In contrast, OS rates differed significantly by tumour subsites (log-rank p = 0.0061) for female patients, with a median OS survival time of 111.6 months for supraglottic tumours. Of note, male patients had worse median OS times (116.4 months for glottic tumours vs. 77.3 months for supraglottic tumours), but these differences were not statistically significant (log-rank p = 0.29).

A multivariate Cox proportional hazards regression model including the factors gender, age at diagnosis (years), alcoholism, IVDU status, ≥2 chronic conditions, cardio/cerebrovascular disease, tumour subsite, disease stage (early vs. late), primary surgical treatment status and initial treatment modality, gender remained an independent prognostic factor (HR = 2.08; CI, 1.10–3.96, p = 0.025) for OS, along with older age at diagnosis (HR = 1.06; CI, 1.04–1.09, p < 0.001, per year) and advanced-stage disease (HR = 1.7; CI, 1.08–2.67, p = 0.023).

For DSS and DFS, no independent prognostic factors were found. The factors that affected DSS, OS and DFS are summarised in Table 2. Figure 3 visualises the differences in both DSS and OS by gender using adjusted survival curves calculated using the aforementioned Cox model.

TABLE 2. Disease-specific survival (DSS), disease-free survival (DFS) and overall survival (OS), univariate and multivariate Cox regression model.

		N (%)	DSS		DFS		OS
			HR (univariable)	HR (multivariable)	HR (univariable)	HR (multivariable)	HR (univariable)	HR (multivariable)
Gender	Female	50 (17.2)	—	—	—	—	—	—
	Male	241 (82.8)	2.94 (0.70–12.41)	3.59 (0.77–16.70)	1.39 (0.73–2.63)	1.43 (0.73–2.80)	2.04 (1.12–3.70) a	2.08 (1.10–3.96) a
Age at diagnosis (years)	Mean (SD)	65.2 (11.1)	1.02 (0.99–1.06)	1.02 (0.98–1.06)	1.01 (0.99–1.03)	1.02 (1.00–1.05)	1.05 (1.03–1.07) b	1.06 (1.04–1.09) b
Alcoholism		267 (91.8)	—	—	—	—	—	—
	Yes	24 (8.2)	1.06 (0.25–4.49)	1.18 (0.25–5.59)	0.93 (0.34–2.56)	0.95 (0.30–2.99)	1.85 (1.03–3.33) a	1.89 (0.96–3.73)
IV drug user (IVDU)		281 (96.6)	—	—	—	—	—	—
	Yes	10 (3.4)	0.92 (0.13–6.81)	1.06 (0.13–8.88)	0.83 (0.20–3.38)	0.87 (0.20–3.81)	1.13 (0.46–2.78)	2.19 (0.82–5.88)
≥2 Chronic conditions		136 (46.7)	—	—	—	—	—	—
	Yes	155 (53.3)	1.84 (0.88–3.88)	1.61 (0.66–3.95)	1.05 (0.67–1.65)	0.90 (0.53–1.53)	2.08 (1.43–3.01) b	1.47 (0.96–2.25)
Cardio/cerebrovascular disease		242 (83.2)	—	—	—	—	—	—
	Yes	49 (16.8)	2.96 (1.34–6.55) a	2.40 (0.95–6.08)	1.10 (0.58–2.09)	0.98 (0.47–2.05)	2.13 (1.39–3.26) b	1.25 (0.76–2.04)
Tumour origin site	Supraglottis	65 (22.3)	—	—	—	—	—	—
	Glottis	225 (77.3)	0.91 (0.39–2.13)	1.06 (0.39–2.84)	0.66 (0.40–1.09)	0.53 (0.28–1.00)	0.71 (0.47–1.06)	0.64 (0.40–1.04)
	Subglottis	1 (0.3)	0.00 (0.00–Inf)	0.00 (0.00–Inf)	0.00 (0.00–Inf)	0.00 (0.00–Inf)	0.00 (0.00–Inf)	0.00 (0.00–Inf)
Disease stage	Early (I–II)	167 (57.4)	—	—	—	—	—	—
	Late (III–IV)	124 (42.6)	1.43 (0.70–2.94)	1.59 (0.63–4.00)	1.23 (0.78–1.93)	1.11 (0.59–2.10)	1.37 (0.96–1.96)	1.70 (1.08–2.67) a
Primary surgical treatment		194 (66.7)	—	—	—	—	—	—
	Yes	97 (33.3)	0.98 (0.45–2.11)	0.89 (0.34–2.35)	1.40 (0.89–2.22)	1.65 (0.90–3.04)	0.71 (0.48–1.07)	0.80 (0.47–1.35)
Initial treatment modality	Monotherapy	150 (51.5)	—	—	—	—	—	—
	Dual modality	105 (36.1)	1.55 (0.72–3.35)	2.16 (0.86–5.43)	1.62 (0.99–2.66)	1.77 (1.00–3.16)	1.03 (0.69–1.53)	1.23 (0.77–1.97)
	Triple modality	33 (11.3)	1.14 (0.37–3.54)	1.39 (0.34–5.63)	1.50 (0.76–2.95)	1.16 (0.47–2.81)	0.91 (0.52–1.60)	1.20 (0.57–2.49)
	None	3 (1.0)	0.00 (0.00–Inf)	0.00 (0.00–Inf)	51.24 (6.00–437.36) b	49.19 (4.34–557.87) b	33.56 (9.44–119.36) b	15.50 (3.91–61.36) b

• ^a p < 0.05.
• ^b p < 0.01.

4 Discussion

This study examined the differences between women and men with laryngeal SCC, including disease stage, treatment modality and survival rates. We have acknowledged that laryngeal SCC among women is different: presented at a younger age, predominantly in the supraglottic area, with varying management modalities and, finally, different prognoses.

The female-to-male ratio in our cohort was 1:4.8, which is lower than previously published in a similar study [19]. The high female rate and relatively low alcohol consumption rates (in both sexes, especially men) suggest that perhaps gender-based factors, rather than habitual risk factors, contribute to the different presentations of laryngeal SCC. Over one-third of the female patients in our cohort had supraglottic cancer. In addition, women were likelier to present with supraglottic SCC at a younger age than men, who were likelier to present with glottic cancer at an older age. These findings are similar to those published by Li et al. in their SEER-based investigation of laryngeal cancer [4]. Interestingly, based on our cohort, women were diagnosed at a more advanced disease stage than men, which opposes findings described in the past [4]. This can be explained by the fact that women were most likely diagnosed with supraglottic cancer, as seen in previous studies [19]. However, compared to the sum of Stages III–IV in previous studies, reaching up to 70% [20] in our study, the percentage among women was 58%. This can be attributed to the fact that women are encouraged to perform screening tests at a younger age, including PAP smears for the early detection of cervical cancer and mammography for the early detection of breast cancer. These proactive medical examinations offer an opportunity to address different medical issues and thus diagnose other types of malignancies, such as supraglottic cancer, with fewer clinical manifestations at an early age.

Regarding treatment modality, there was an increased rate of female patients treated with chemotherapy (in most cases as a radiosensitizer as part of CRT) in our cohort, which may correspond with the more advanced stage and patient preference towards laryngeal preservation in this group. Accordingly, Saini, Genden, and Megwalu showed that the female gender negatively correlates with the choice of a surgical treatment option for advanced laryngeal cancer [16]. The higher chemotherapy treatment rates could be explained by the higher percentage of supraglottic cancer among women. As summarised in Table 2, our multivariate Cox model adjusting for treatment modality and tumour location did not identify either factor as associated with poor DSS, OS, or DFS. Therefore, we hypothesise that the higher percentage of CRT among women could be explained by their preferences for a non-surgical solution and their relatively young age at diagnosis, making them fit for this treatment modality.

Our primary endpoint for this study was DSS rates, although we could not demonstrate a statistically significant difference by gender alone (Figure 1), nor by tumour subsite as stratified by gender (Figure 2). Interestingly, we found that OS in women was better despite their advanced-stage disease. This notion was further supported by the multivariate Cox proportional hazards regression model adjusting for possible confounders. Differences between DSS and OS in adjusted survival curves by gender can also be noted in Figure 3. The concept that the female gender is a favourable prognostic factor in laryngeal SCC was described in the past [4], but the exact mechanism for this phenomenon is not entirely understood. There are multiple potential explanations for this phenomenon. First, it has been hypothesised that oestrogen has a protective effect on head and neck cancer and even mitigates the adverse effects of smoking and alcohol use [21, 22]. Second, women present with a different disease phenotype, like the pattern observed in non-small-cell lung cancer [14, 23], and thus have favourable prognoses when addressing laryngeal cancer. Third, health perceptions between women and men: As opposed to men, women are likelier to seek medical care, have better social network support and are likelier to be medically insured [24], all of which offer a favourable prognosis. The discrepancy between DSS and OS rates can also be explained by contributing patient factors such as cardiovascular disease, which was more prevalent significantly in the male group in our cohort.

Our study has several limitations. First, it is limited by its retrospective nature. Additionally, our cohort lacks valuable information regarding other possible risk factors, such as HPV status. Yet, the clinical significance of HPV-related laryngeal cancer, as opposed to oropharyngeal SCC, is yet to be determined. Another limitation is the fact that our sample size was limited and may have suffered from selection bias, as more complex patients were referred to our institution for further treatment, thus possibly altering gender-specific disease characteristics. Finally, our study does not relate to trans-glottic tumours on an individual basis.

5 Conclusions

This study explored gender-based differences in laryngeal SCC. Despite a higher prevalence of advanced-stage disease in female patients, DSS and DFS did not differ significantly between males and females. They demonstrated prolonged OS rates compared to males, and this gender-based difference remained significant even after adjusting for confounders. These findings highlight the need for a tailored approach in the management of laryngeal SCC based on gender-specific differences. Further research is warranted to understand better the underlying mechanisms contributing to the observed gender-based disparities in laryngeal SCC.

6 Author Contributions

Nir Tsur: Investigation, Writing – original draft. Elchanan Zloczower: Review and editing, Michal Tunik: Data curation. Ido Amir: Data curation. Eyal Yosefof: Statistical analysis. Hagit Shoffel Havakuk: Conceptualization, supervisor, review, and editing. Noga Kurman: Conceptualization, Methodology, Writing – review & editing.

Ethics Statement

This study was approved by the Institutional Ethics Committee of Rabin Medical Center (IRB-RMC 0731-2020). The research was conducted ethically, with all study procedures being performed according to the requirements of the World Medical Association's Declaration of Helsinki. Written informed consent was waived due to the retrospective nature of this study.

Conflicts of Interest

The authors declare no conflicts of interest.