The authors have declared that no competing interests exist.
¶ Membership of the AIRTUM Working Group is provided in the Acknowledgments.
The current study aimed to investigate the incidence and survival patterns of HNSCCs arising from different anatomic sites, potentially related (the oropharynx) or unrelated (the oral cavity, the larynx/hypopharynx) to HPV, to provide clues on possible growing impact of HPV in the epidemiology of HNSCC in Italy. Epidemiological data were retrieved from ten long-term Cancer Registries covering a population of 7.8 million inhabitants. Trends were described by means of the estimated annual percent change (APC) stratified by age and gender, and compared between HPV-related and HPV-unrelated anatomical sites. The data regarding 28,295 HNSCCs diagnosed in Italy between 1988 and 2012 were analyzed. In males, the incidence rate (IR) of cancers arising from sites unrelated to HPV infection significantly decreased in all age groups (APC:-3.31 for larynx/hypopharynx; APC:-1.77 for oral cavity), whereas stable IR were observed for cancers arising from sites related to HPV infection. In females, IR for cancers from HPV-related sites increased significantly over the observed period; the largest increment was noted in those over 60 (APC:2.92%) who also showed a significantly lower number of HNSCCs from the larynx/hypopharynx (APC:- 0.84) and a significantly higher number of oral cavity tumors (APC = 2.15). The five-year relative survival remained largely unchanged in the patients with laryngeal/hypopharyngeal SCC and, conversely, significantly improved in the patients with SCC at HPV-related sites. The trends observed suggest a potential increasing impact of HPV infection on the epidemiology of HNSCC in Italy, but to a lesser extent and with a different pattern from that observed in other Western countries.
In 2020, head and neck cancer (HNC) is expected to affect approximately 833,000 and 151,000 new patients worldwide and in Europe, respectively [
According to recent estimates, worldwide 38,000–45,000 cases of HNC are yearly attributable to HPV [
Interestingly, a significantly increasing prevalence of HPV-driven OPSCC has been observed over recent decades in Europe and North America [
To provide clues on a possible growing impact of HPV infection in the epidemiology of HNC in Italy, the current population-based study set out to investigate the patterns registered over the last quarter century in incidence and survival rates, stratified by age and gender, of HNSCCs arising from different anatomic sites potentially related or unrelated to HPV infection.
Incident cases of HNC registered between 1988 and 2012 were retrieved from the Italian Network of Cancer Registries (AIRTUM) based on a historical pool of 10 population-based Cancer Registries covering a population of 7.8 million of inhabitants (13% of the whole country). All data were fully anonymized before access by the researchers. Only cancer registries that provided data over the entire 1988–2012 period were included in the present analysis (
HNC cases were identified by extracting categories C00-C14 and C30-C32 of the International Classification of Diseases, 10th edition (ICD-10). Information on the cancers’ morphology was codified in accordance with the International Classification of Diseases for Oncology (ICD-O) morphology codes (3rd edition).
Only malignant cases with morphology codes for squamous cell histology or morphologic variants of SCC were included in the analysis (morphology codes 8032, 8033, 8050–8052, 8070–8078, 8082–8084, 8094, 8123) and, depending on the anatomical site of the tumor origin, classified as HPV-related or unrelated.
Anatomic sites that are HPV-related included: the tonsils (C09), the base of the tongue (C01.9, C02.4), other oropharynx sites (C10) and Waldeyer's ring (C14.2). Unrelated HPV sites included: areas of the oral cavity [the tongue (C02 except C02.4), the gum (C03), the floor of the mouth (C04), the palate (C05), other and unspecified parts of the mouth (C06)] and the larynx-hypopharynx [pyriform sinus (C12), the hypopharynx (C13), and the larynx (C32)]. Cancers arising from the lip (C00), the nasopharynx (C11), the nasal cavity (C30), the sinuses (C31), and the salivary glands (C07-08) were not included in the analyses as they are linked to other etiological factors or to ill-defined sites (C14.0, C14.8).
Incidence rates (IR) were reported as European age-standardized and expressed as the number of new cases per 100,000 person-year. Changes in the incidence rates of HPV-related and -unrelated anatomic sites were assessed in relation to the time period, age grouping (classified as 40–49, 50–59 and 60+ years) and gender using the annual percentage change (APC) with the corresponding 95% confidence interval (CI), indicating an increased or decreased trend with a 2-sided
Relative survival was calculated for all the cases included in the cohort analysis (diagnoses formulated between 1988 and 2012) as the ratio of observed to expected survival. National life tables by registry, age, and gender were used for calculating expected survival according to the Ederer II method [
Statistical analyses were performed using the SEER*Stat software, Version 8.3.4 and the Joinpoint Regression Program, Version 4.5.0.1 (Surveillance Research Program, National Cancer Institute).
Site of HNSCC | Total | Males | Females | M/F ratio | ||||||
---|---|---|---|---|---|---|---|---|---|---|
n | % | IR | n | % | IR | n | % | IR | ||
HPV-related | 3984 | 14.1 | 1.8 | 3250 | 13.8 | 3.1 | 734 | 15.3 | 0.6 | 4.4 |
HPV-unrelated | ||||||||||
Oral cavity | 7816 | 27.6 | 3.3 | 5277 | 22.5 | 5.0 | 2539 | 53 | 1.8 | 2.1 |
Larynx/Hypopharynx | 16495 | 58.3 | 6.9 | 14975 | 63.7 | 13.8 | 1520 | 31.7 | 1.2 | 9.9 |
All sites | 28295 | 100 | 13.8 | 23502 | 100 | 25.3 | 4793 | 100 | 4.2 | 4.9 |
HNSCC, head and neck squamous cell carcinoma; IR, incident rate; HPV, human papillomavirus
During the observation period, 3984 cases of potentially HPV-related cancers, 81.6% in males, were diagnosed. The average IR of HNSCCs from HPV-related sites during that period was 3.1 in the males and 0.6 in the females. The incidence remained stable in the males over the observation period (
The average IR of the SCC of the oral cavity was 5.0 and 1.8, respectively, in the males and females. Oral cavity SCC was the most frequent HNSCC in the females (53% of the total). During the last three decades, cancer of the oral cavity significantly fell in the males (APC -1.77%, 95% CI -2.19 to -1.35;
In the males (
In the males (
Age-standardized relative survival (
The figure shows a significantly improved survival in patients with head and neck squamous cell carcinomas arising from human papillomavirus-related sites and from the oral cavity. Expected survival was calculated using the Ederer II method. Age standardized relative survival since diagnosis is the weighted average of age-specific relative survival according to the International Cancer Survival Standard. Bars indicate confidence interval at 95%.
This cancer registry-based study addressed trends in HNSCC incidence at different anatomic sites in Italy in relation to their potential association with HPV infection in Italy over a 25-year period. Overall, the analysis of APC basically identified three different patterns: 1. cancers whose incidence is increasing (SCC at HPV-related and oral cavity sites, both in females); 2. cancers whose incidence is decreasing (SCC of the oral cavity and the larynx/hypopharynx, both in males); 3. cancers whose incidence was substantially constant over the observation period (SCC at HPV-related sites in males and SCC of the larynx/hypopharynx in females). Thus, the analysis confirmed that the incidence rates varied depending on the site and gender.
As has been reported for other tobacco-related cancers, the marked decline in the incidence of laryngeal/hypopharyngeal SCCs across all age groups mirrors the significant reduction characterizing men's smoking habits over the past six decades [
The incidence of other non HPV-related cancers has decreased in all age groups in males. SCCs of the oral cavity have, in particular, declined steadily and significantly over the observation period, even if the decline was lower than that for laryngeal/hypopharyngeal SCCs. The trend in the females moved instead in the opposite direction, namely an overall increase in APC of 2.15% of SCC of the oral cavity, versus stable figures for laryngeal/hypopharyngeal SCC. Similarly to smoking habits, per capita alcohol consumption in Italy has declined in both genders during the last 50 years, a decline that parallels the fall in deaths linked to liver cirrhosis [
Incidence trends for SCCs at HPV-related sites in Italians have remained stable in the males over the entire observation period, while a significant increase in the annual incidence was observed in the females (APC, 2.72%). The stable incidence in OPSCCs in males despite the marked reduction registered in environmental-related HNSCCs suggests that increasing HPV infection rates may be counterbalancing the effects of reduced tobacco and alcohol consumption.
Conversely, in females, the net increase in the incidence of SCCs at HPV-related sites may be due to the increasing role of HPV in these neoplasms in the absence of environmental-related OPSCC reduction. The geographic prevalence of HPV-related OPSCC is quite heterogeneous [
HPV-driven OPSCC is characterized by a highly significant better prognosis compared to the non HPV-driven counterpart[
The study’s strengths include the large sample size and the long study period (25 years) using population-based data in a defined region. Cancer-registry data, characterized by elevated standards of completeness ensure the generalizability of these results. In addition, to our knowledge, this is the first study conducted in Southern Europe aiming to analyze the incidence trends of HNSCC focusing on anatomic sites associated with transforming HPV infection.
The study’s main weakness is the lack of individual patient information on HPV status in tumor tissues and tobacco and alcohol exposure. Indeed, using cancer site as a proxy of HPV-related cancer could leave the door open to misclassification. The results are nevertheless in line with those produced by a prospective study that rigorously defined HPV-driven cases [
In addition, the tendency of registering unspecified sites declined over the observation period. This bias would mean that the IRs for the first study years were underestimated, thus producing an opposite distortion depending on the shape of the trend observed: underestimation of the slope for a decreasing incidence and overestimation for an increasing one. The proportion of cases with unspecified sites was nevertheless low and decreased by less than 1% during the observation period, from 2.7% in 1988–1992 to 2.0% in 2008–2012, meaning that, the effect of this bias was probably quite small.
Finally, incident cases of SCC metastatic to the neck lymph nodes from an unknown primary were not included in the present analysis; as this entity is HPV-driven in a substantial proportion of cases [
Topographically restricted to the oropharynx, HPV-driven HNSCCs, which exhibit a survival benefit compared to HPV-unrelated tumors, have been increasing rapidly in several Western countries. Although to a lesser extent and following different patterns with respect to those observed in other Western countries, the trends in HNSCC incidence and survival rates at the different sites examined here suggest a potential increasing impact of HPV infection on oropharyngeal oncogenesis in Italy. One thousand five hundred sixty-five SCCs are expected to arise from HPV-related sites in Italy in 2017. According to the recent analyses, the fraction of OPSCCs driven by HPV infection in Southern Europe is estimated at between 20 and 30% [
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The authors acknowledge the president L Mangone (Reggio Emilia Cancer Registry; email: