In this population-based study of 20-year trends in the incidence and survival of head & neck cancer patients in Estonia, we found that the incidence has significantly increased for hypopharyngeal and oropharyngeal cancers and decreased for lip and laryngeal cancer. More than 60% of head & neck cancers in Estonia are diagnosed at stage IV, except for thyroid, salivary and laryngeal cancers. Survival increased for most sites, but the prognosis remained poor for mouth & pharyngeal cancers with a large disadvantage of male patients. The increase in thyroid cancers was driven by papillary cancers that demonstrated excellent survival.
The slightly declining trend in oral cavity cancer rate, together with the steep decrease in lip and laryngeal cancer incidence is in concordance with previously observed decreasing rates of lung cancer in Estonia . Smoking is one of the strongest risk factors for most head & neck cancers. Daily smoking prevalence among working-age men in Estonia has dropped from 45% in 1996 to 23% in 2018; the respective change among women was from 21–13%; however, the change in women has been too recent to influence cancer occurrence . There have been no particular changes in alcohol consumption as the proportion of men and women who consumed alcohol at least a few times a week fluctuated from 20% in 1996 to 27% in 2008 and to 24% in 2018 . As only 4–6% of oral cancers are known to be HPV-positive, papillomavirus is not expected to play important role in oral cavity cancer pathogenesis . Inconsistent patterns in the incidence of oral cavity cancers has been observed worldwide with trends in some countries contrasting those of lung cancer, suggesting the role of other factors or their interaction . The recent significant increase of tongue cancer incidence in Estonia since 2010 needs further monitoring to confirm. Laryngeal cancer, also mainly caused by smoking and alcohol consumption , demonstrated a significant decline, which correlates with prior research from other European countries [20–22].
The oropharyngeal cancer trend has turned into a steep rise since 2004, which is consistent with similar trends in Europe, US and South-East Asia [2, 3, 20]. These trends have been driven by increasing incidence of HPV-positive cancers, and the role of HPV infection has been confirmed by the increase in the proportion of HPV-positive tumors, shown to reach 70% in the US and Sweden [23, 24]. In the US, the rise in HPV-positive tumors was accompanied by a decrease in HPV-negative tumors . HPV-infections play higher role in economically more-developed countries, whilst in economically less-developed countries, the disease is still mainly caused by tobacco [25–27]. Worldwide, approximately 30% of oropharyngeal cancers are due to HPV infection . Testing for p16 in Estonia started only from 2014 and the expression of p16 in formalin fixed paraffin embedded (FFPE) tissue blocks has been consistently evaluated starting from 2018. Based on unpublished data from the cancer center where most of Estonian head & neck cancer patients are managed, 45% of oropharyngeal cancer cases in 2018–2019 were p16-positive. The trends observed in this study regarding HPV-related cancer sites, together with the continuously increasing risk of cervical cancer in successive birth cohorts  and rising incidence of anal cancer among younger women in Estonia  suggest an important role of HPV infection. Recent studies have also shown an increase in the prevalence of genital warts in Estonia . HPV vaccination, expected to have a protective role against HPV-associated cancers, is available for girls in the national immunization program in Estonia only since 2018. The vaccination coverage reached 61% for the first birth cohort in 2019. Even so, vaccination is unlikely to play a role in incidence rates anytime soon, and unfortunately, boys are not covered by HPV vaccinations in Estonia.
The incidence for hypopharyngeal cancers has shown a significant increase since 2002. Similar trends have been observed in other European countries [2, 20, 21], regardless of decreases in alcohol consumption, the main known risk factor for hypopharyngeal cancer. Alcohol consumption is also not a likely explanation for our findings as the trend resembled that of oropharyngeal cancer rather than that of oral cavity cancer, and therefore partial role of HPV can be suggested. The predominance of men was particularly evident for hypopharyngeal cancer as only 4% of the cases were seen in women, while a fifth of all mouth & pharyngeal cancers were diagnosed in women. The overall proportion of women was similar to that seen in other countries . The excess of men is probably explained by differences in health behavior.
Thyroid cancer was the most common head & neck tumor in females, who constituted 82% of the cases. Recent studies from Europe, USA, Canada, and Australia have reported a steady increase in thyroid cancer incidence over time with a particular increase in papillary thyroid cancer [7, 32]. These trends may be explained by increases in diagnostic activity and changed histological criteria  or linked to changes in risk factors such as iodine supplementation, radiation exposure, Hashimoto thyroiditis, and hormonal or reproductive factors [34–36]. In addition, a link between obesity and thyroid malignancies has been demonstrated . The latter explanations are supported by reports of increasing incidence of advanced-stage thyroid cancers . At the same time, other countries have not reproduced these findings . A recent report suggested a substantial contribution of overdiagnosis to the rising incidence in high-income, but also in less affluent countries . The rise in thyroid cancer incidence in Estonia was significant only in women age 60 years and over (data not shown). A larger increase may have occurred before the start of our study as the availability of new diagnostic procedures increased rapidly in the beginning of the 1990s. According to Cancer in Five Continents, the ASR for women increased from 2.8 to 5.5 from 1983–1987 to 1998–2002 and from 0.6 to 1.2 in men  and stabilized thereafter. Trends in thyroid cancer warrant further monitoring, particularly among younger age groups, as there have been reports of increasing incidence of papillary tumors among young adults .
The survival of mouth & pharyngeal cancer has increased in Estonia, but a large deficit compared to other European countries persists. For these sites, the RS estimates for Estonia in 2010–2016 have not yet reached those observed in Europe in 2000–2007 . The largest survival increase was seen for oral cavity cancers, but the latest estimates for both men and women still remain well below those observed for the Nordic countries . Relative survival of oropharyngeal cancers was 58% in Denmark in 2010–2014  and only 24% in our study. Stage at presentation is the most important prognostic factor for squamous cell head & neck cancers  and patients with advanced tumors show the shortest survival . The majority (62%) of mouth & pharyngeal cancers in Estonia in 2010–2016 presented in stage IV. Roughly, only ¼ of the patients in Estonia presented with an early disease, which is similar to United States, where approximately 29% of head & neck tumors were diagnosed as localized . We observed a huge gender gap in survival for all mouth & pharyngeal cancers, but particularly for oropharyngeal and salivary gland cancers. Significantly later stage at diagnosis for mouth & pharyngeal cancers among men compared to women (proportion of stage IV tumors 65% in men and 52% in women, p < 0.001, data not shown) is one potential explanation. Male sex has been found to be a predictor of late-stage head & neck cancer, together with increased age, black race, absence of health insurance and tumor site . A significant female survival advantage was found in Estonia for five of the nine studied common solid tumors, including mouth & pharyngeal tumors, even after adjusting for age, stage and subsite, suggesting the role of less co-morbidities, higher treatment compliance and better health behavior among women . Smoking status has an impact on survival even in long-term [47, 48], and differences in smoking prevalence and intensity (both before and after diagnosis) might partially explain sex differences. Recent studies elsewhere have shown a change in the profile of oropharyngeal cancer patients towards non-smokers, younger age at diagnosis with better performance status, less co-morbidities and HPV-positivity [49–51]. HPV-positive patients have displayed better overall survival and progression-free survival in comparison to HPV-negative cancer patients indicating separate risk factors, treatment response and prognosis for the disease [48, 50]. The persistently low survival observed in our study, however, suggests the predominance of tobacco- and alcohol-related cancers in Estonia.
Patients with head & neck cancer are known to have a higher comorbidity burden in comparison to general population , which may influence the choice of treatment modality and has a significant negative impact on their survival outcome [53, 54]. Estonian cancer patients have been shown to have more comorbidities than their European counterparts  and this may be particularly true for patients with health behavior-related cancers. Moreover, we also observed a large age difference in mouth & pharyngeal cancer survival, over 20 percentage points in favor of the youngest age group (49% for age < 50, 27% for age ≥ 70 years, data not shown).
Treatment possibilities in terms of timely access to radiotherapy, use of concomitant chemoradiation, adequate palliative care, social support and rehabilitation, utilization of PET-scan for better diagnostics, and centralization of head and neck cancer patients into specialized units are key clinical factors for ensuring the best possible outcomes. Head & neck cancers are mainly treated at one comprehensive cancer center in Estonia. However, the availability of radiotherapy has been severely hindered due to low number of radiotherapy treatment machines up until 2012 . This deficit has caused prolonged waiting times, which have been shown to cause progress of head & neck cancers to next stage . In 2012, less than 60% of patients in Estonia who would have required at least one radiotherapy course were actually treated . The total number of linear accelerators per million inhabitants increased to 4.6 only in 2016, and this recent improvement had no effect on our results.
In EUROCARE-5, the survival deficit of Estonian laryngeal cancer patients compared to those in Central or Northern Europe exceeded 10 percent units . There has been a steady increase and the most recent survival estimates in this study for both men and women are close to those observed in Finland for 2012–2016 . In contrast to Estonia and Finland, men have higher survival for laryngeal cancer than women in other Nordic countries .
Thyroid cancer survival in Estonia is good and higher than in Denmark in 2010–2014, where the five-year RS estimates were 82% in women and 74% in men, and 91% for papillary and 80% for follicular cancer . Our results for both sexes are well comparable with NORDCAN estimates for all Nordic countries . Nevertheless, the gender survival gap of 12 percentage units was larger in Estonia than in the Nordic countries. One possible explanation for women’s survival advantage is that they have higher proportion of papillary tumors than men (67% vs 55%, data not shown), and women have their tumors diagnosed at a significantly earlier stage (stage I proportion 44% for women, 26% for men, data not shown). Also, overdiagnosis may be more common among women, inflating survival estimates .
The main strength of our study was the use of high-quality population-based cancer registry data over a 20-year period. Another strength was the availability of relatively complete TNM-stage information for recent years, as the proportion of unknown stage did not exceed 11% for any site.
The main limitations of the current study were the lack of individual data on major behavioral, socioeconomic and other risk factors, most importantly HPV-status, smoking and alcohol consumption habits, and comorbidities, as well as data on diagnostic and treatment delays and treatment compliance. Small numbers prevented more specific analysis of incidence and survival trends (e.g. by site/morphology and age).