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P Kuhdari, S Previato, M Giordani, P Biavati, S Ferretti, G Gabutti, The burden of HPV-related diseases in Italy, 2001–12, Journal of Public Health, Volume 39, Issue 4, December 2017, Pages 730–737, https://doi.org/10.1093/pubmed/fdx025
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Abstract
Human papillomavirus (HPV) infection is the main cause of cervical cancer and plays a relevant role in the development of genital warts and of the cancer of penis and anus, head/neck, oropharynx and genitourinary system. The aim of this study is the evaluation of hospitalizations due to HPV-related pathologies in 2001–12 in Italy.
The national hospital discharge forms were provided by the Ministry of Health. The HPV-related hospitalizations were identified using specific diagnostic codes, accordingly to the ICD-9-CM coding system. The proportion of hospitalizations of potentially HPV-related pathologies, obtained from the literature, was evaluated as well as the hospitalization rates (hr) and their trend over time.
Uterine cervical cancer and CIN III accounted for 40% of hospitalizations (hr: 15.6/100 000 and 17.6/100 000, respectively). Head/neck and oropharynx pathologies accounted for 24.5% of cases (hr: 16/100 000 and 3.9/100 000, in males and females, respectively), followed by genital warts (17.3% of hospitalizations; hr: 7.5/100 000 in males and 8.52/100 000 in females), anal (8.1% of hospitalizations), genitourinary (7.7%) and penis cancers (2.2%).
The study, even if limited to the evaluation of hospitalizations, points out how HPV-related pathologies continue to be a relevant public health issue in Italy with a high impact on population.
Background
Human papillomavirus (HPV) is considered the most common causative agent responsible for sexually transmitted infections in the general population.1 It is estimated that about 80% of sexually active women become infected at least once during their lifetime.2 Even the male population is exposed to this infection, despite the spread of the virus is less known than in the female population.3,4 In recent years several studies have demonstrated the role of HPV in the pathogenesis of cancers in various anatomical sites, in both genders.5
The worldwide prevalence of HPV infection is equal to 11–12%,6 even if a great geographical variability has been described (Sub-Saharian Africa; 24%; East-Europe: 21%; Latin America: 16%). Prevalence is particularly high in Eastern Africa and in Caribbean (>30%).7
When considering women with cytological abnormalities, an Italian study pointed out a prevalence of HPV infection equal to 52.6%.8
Nowadays, more than 140 HPV types have been identified; 40 of these infect the genital tract. Accordingly to the International Agency for research on cancer (IARC), 15 of these types have been classified as high-risk types (HR-HPV)9 and 12 as low-risk types (LR-HPV), being responsible for genital warts and recurrent respiratory papillomatosis.
HR-HPV types, mainly HPV-16 and HPV-18, are the causative agents of about 70% of uterine cervical cancers (UCC).10,11 Worldwide, it is estimated that HPV-16 and HPV-18 are detected in 45% and 16% of cervical cancers, respectively; HPV-31 and HPV-45 are related to about 10% of UCC.12
HR-HPV types are considered as necessary causative agents of high-grade cervical lesions (CIN III) and UCC, being responsible for 100% of these pathologies. A particularly high rate of benign lesions (>90%), such as genital warts, are attributable to LR-HPV types, mainly HPV-6 and HPV-11.13,14 As already published in several papers, 88% of anal cancers, both in males and females, and 50% of penis cancers are attributable to HPV.15,16 HPV prevalence in oropharynx, tonsils and tongue cancers is variable (range: 13–56%) in different geographical areas;15,17 HPV prevalence in larynx cancer is estimated equal to 24%.18
Taking into account the genitourinary tract, 91% of vaginal and 27–100% of vulvar cancers are attributable to HPV.9
Being the assessment of the impact of HR-HPV and LR-HPV in both genders absolutely necessary, this study has been performed in order to evaluate the national HPV-related burden in terms of hospitalizations.
Materials and methods
The hospital discharge form (SDO) has been established in 1991 by the Ministry of Health (Decree of Dec. 28, 1991) in order to have available a systematic summary of information included in the medical record. Accordingly to Italian law, any SDO includes information related to clinical and organizational aspects of each hospitalization and discharge performed in national private and public hospitals. Clinical data included in any SDO are codified accordingly to the ICD-9-CM coding system currently used in Italy. This retrospective study evaluated any SDO related to all HPV-related pathologies occurred in the period 2001–12. In detail, the following ICD-9-CM diagnostic codes have been investigated: 078.11 (Condyloma acuminatum), 141.0–141.9 (malignant cancers of the tongue), 142.0–142.9 (malignant cancers of the major salivary glands), 143.0–143.9 (malignant cancers of the gums), 144.0–144.9 (malignant cancers of the floor of the mouth), 145.0–145.9 (malignant cancers of other or not specified parts of the mouth), 146.0–146.9 (malignant cancers of the oropharynx), 147.0–147.9 (malignant cancers of the nasopharynx), 148.0–148.9 (malignant cancers of hypopharynx), 154.2–154.8 (malignant cancers of the anus), 160.0–160.9 (malignant cancers of the respiratory tract of the intra-thoracic organs and of para-nasal sinuses), 161.0–161.9 (malignant cancers of the larynx), 171.0 (malignant cancers of connective and other soft tissues), 180.0–180.9 (malignant cancers of uterine cervix), 233.1 (CIN III: cervical intraepithelial neoplasia), 184.0–184.9 (malignant cancers of genitourinary organs: vagina, labia, clitoris) and 187.1–187.9 (malignant cancers of the penis). Only hospitalizations due to HPV-related pathology included in the primary diagnosis were taken into account.
Accordingly to international literature, malignant cancers of the tongue, major salivary glands, mouth and oral cavity, oropharinx, hypopharynx, pharynx, larynx, connective and soft tissues and para-nasal sinuses have been included in one category: head and neck cancers. Taking published data into account, the following rates for each cancer/pathology were considered attributable to HPV: 100% for CIN III and cervical cancer5,7 and for genital warts;7 50% for cancer of the penis5,7 and 88% for anal cancer.5,7 Accordingly to Kreimer et al.,18 26% of head and neck cancers were considered HPV-related. Besides, due to high variability reported for the different anatomical sites in several studies,9,15 the rate of cancers of the genitourinary tract attributable by HPV was estimated equal to 77%.
Accordingly to the current regulations, a specific permit by an Ethical Committee was not necessary,19 as no personal data were available and only anonymous unlinked aggregated data were analyzed. This study was performed in compliance to the Helsinki Declaration as well as to the Italian law (Decree n. 196/2003 for the protection of personal data). Statistical analysis was performed by SPSS software (Statistical Package for Social Science). Firstly, data were stratified by gender, year of admission, age class (<14, 15–24, 25–34, 35–44, 45–54, 55–64, 65–74 and >85 years of age), geographical area (Italian regions), type of hospitalization (ordinary hospitalization or day hospital) and of discharge (dead, home discharge, transfer to other hospital or structure). Then, standardized hospitalization rates were calculated and, if possible, compared to data obtained by other studies performed at regional level in Italy. STATA software (Data Analysis and Statistical Software) was used for the direct standardization of rates, using as reference the Italian resident population included in the 2001 census.
The time trends of standardized rates were evaluated by a Joinpoint model (Joinpoint version 4.1.1.5, 2015) that summarise the direction and the intensity of the (linear) trend, estimating an annual percent change (APC). The final model is based on linear segments connected at joinpoints that represent the best fit of observed data. In this study the maximum number of joinpoints was equal to 1. The significance level was set to 0.05 (P < 0.05).
Results
The Ministry of Health provided a national database including 1 297 824 hospitalizations for possibly HPV-related pathologies in the period 2001–12. Taking into account only hospitalizations where possibly HPV-related pathologies were included as primary diagnosis, the number of evaluated records was equal to 523 828 records. On the whole, HPV-related hospitalizations, calculated applying the disease specific-proportion (according to literature data) to the total number of hospitalizations for each disease, were 297 684 (33.2% in males and 66.8%, in females). The general trend of hospitalizations was constant in the considered years. Overall, the 35–44-year-old age classes were the mostly involved one (17.5% of the total studied population), with a difference between genders. The 35–44 and the 55–74-year-old age classes were the most involved for females (26% of all women) and for males (17.3% of males), respectively.
Lombardy (Table 1) was the region with the highest level of hospitalizations (20.1% of all hospitalizations). Analysis of data showed that 37.8 and 62.2% of cases were classified as hospitalization or day-hospital admission, respectively. Most subjects (95%) were discharged at home.
Region . | Number of hospitalization . | Percentage . |
---|---|---|
Lombardia | 59 762 | 20.1% |
Lazio | 31 313 | 10.5% |
Veneto | 25 128 | 8.4% |
Piemonte | 24 519 | 8.2% |
Emilia Romagna | 23 551 | 7.9% |
Campania | 20 151 | 6.8% |
Sicilia | 19 712 | 6.6% |
Toscana | 17 807 | 6.0% |
Puglia | 14 715 | 4.9% |
Liguria | 10 751 | 3.6% |
Friuli Venezia Giulia | 10 533 | 3.5% |
Sardegna | 6614 | 2.2% |
Marche | 6246 | 2.1% |
Abruzzo | 5726 | 1.9% |
Umbria | 5495 | 1.8% |
Calabria | 4959 | 1.7% |
P.A. di Bolzano | 3011 | 1.0% |
P.A. di Trento | 2956 | 1.0% |
Molise | 2283 | 0.8% |
Basilicata | 1760 | 0.6% |
Val d'Aosta | 692 | 0.2% |
Region . | Number of hospitalization . | Percentage . |
---|---|---|
Lombardia | 59 762 | 20.1% |
Lazio | 31 313 | 10.5% |
Veneto | 25 128 | 8.4% |
Piemonte | 24 519 | 8.2% |
Emilia Romagna | 23 551 | 7.9% |
Campania | 20 151 | 6.8% |
Sicilia | 19 712 | 6.6% |
Toscana | 17 807 | 6.0% |
Puglia | 14 715 | 4.9% |
Liguria | 10 751 | 3.6% |
Friuli Venezia Giulia | 10 533 | 3.5% |
Sardegna | 6614 | 2.2% |
Marche | 6246 | 2.1% |
Abruzzo | 5726 | 1.9% |
Umbria | 5495 | 1.8% |
Calabria | 4959 | 1.7% |
P.A. di Bolzano | 3011 | 1.0% |
P.A. di Trento | 2956 | 1.0% |
Molise | 2283 | 0.8% |
Basilicata | 1760 | 0.6% |
Val d'Aosta | 692 | 0.2% |
Region . | Number of hospitalization . | Percentage . |
---|---|---|
Lombardia | 59 762 | 20.1% |
Lazio | 31 313 | 10.5% |
Veneto | 25 128 | 8.4% |
Piemonte | 24 519 | 8.2% |
Emilia Romagna | 23 551 | 7.9% |
Campania | 20 151 | 6.8% |
Sicilia | 19 712 | 6.6% |
Toscana | 17 807 | 6.0% |
Puglia | 14 715 | 4.9% |
Liguria | 10 751 | 3.6% |
Friuli Venezia Giulia | 10 533 | 3.5% |
Sardegna | 6614 | 2.2% |
Marche | 6246 | 2.1% |
Abruzzo | 5726 | 1.9% |
Umbria | 5495 | 1.8% |
Calabria | 4959 | 1.7% |
P.A. di Bolzano | 3011 | 1.0% |
P.A. di Trento | 2956 | 1.0% |
Molise | 2283 | 0.8% |
Basilicata | 1760 | 0.6% |
Val d'Aosta | 692 | 0.2% |
Region . | Number of hospitalization . | Percentage . |
---|---|---|
Lombardia | 59 762 | 20.1% |
Lazio | 31 313 | 10.5% |
Veneto | 25 128 | 8.4% |
Piemonte | 24 519 | 8.2% |
Emilia Romagna | 23 551 | 7.9% |
Campania | 20 151 | 6.8% |
Sicilia | 19 712 | 6.6% |
Toscana | 17 807 | 6.0% |
Puglia | 14 715 | 4.9% |
Liguria | 10 751 | 3.6% |
Friuli Venezia Giulia | 10 533 | 3.5% |
Sardegna | 6614 | 2.2% |
Marche | 6246 | 2.1% |
Abruzzo | 5726 | 1.9% |
Umbria | 5495 | 1.8% |
Calabria | 4959 | 1.7% |
P.A. di Bolzano | 3011 | 1.0% |
P.A. di Trento | 2956 | 1.0% |
Molise | 2283 | 0.8% |
Basilicata | 1760 | 0.6% |
Val d'Aosta | 692 | 0.2% |
Taking into account the rate of each pathology attributable to HPV, CIN III and cervical cancer (nearly 100% HPV-related) accounted for the 40% of all hospitalizations. CIN III were 59 727 (20,1% of total cases, hr: 17.6/100 000), and cervical cancers were 59 718 (20.1% of total cases; hr: 15.6/100 000).
HPV-related head and neck cancers (72 904 hospitalizations equal to 24.5% of total cases) resulted more frequent in males (77.4 and 22.6% of cases in males and in females, respectively). The hospitalization rate was equal to 16/100 000 and to 3.9/100 000 in males and in females, respectively. Genital warts accounted for 17.3% of total hospitalizations (51 596 cases) and were almost equally divided by gender (47.15% in males, hr: 7.48/100 000; 52.85% in females, hr: 8.5/100 000).
The anal cancer represented the 8.1% of HPV-related neoplasms with 24 033 cases (47.5% in males, hr: 3.2/100 000; 52.5% in female, hr: 2.8/100 000). Cancers of the genitourinary tract were exclusively registered in females accounting for the 7.7% of HPV-related pathologies (23 053 hospitalizations; hr: 4.8/100 000). The 2.2% of total HPV-related pathologies were cancers of the penis (6513 cases; hr: 1.8/100 000).
Standardized hospitalization rates are summarized in Table 2.
. | Sex . | % HPV-related diseases (according to literature) . | No. of HPV attributable hospitalizations . | Standardized hospitalization rates (/100 000 inhabitants) . |
---|---|---|---|---|
CIN III | Female | 100% | 59 727 | 176.4 |
Cervical cancer | Female | 100% | 59 718 | 157.6 |
Genitourinary tract (vulva, vagina) | Female | 77% | 23 053 | 50.7 |
Anal cancer | Male | 88% | 11 410 | 33.2 |
Female | 12 623 | 29.3 | ||
Head and neck cancers | Male | 26% | 56 475 | 163.5 |
Female | 16 429 | 40.3 | ||
Genital warts | Male | 100% | 24 326 | 75.2 |
Female | 27 270 | 85.7 | ||
Penile cancer | Male | 50% | 6513 | 19.0 |
. | Sex . | % HPV-related diseases (according to literature) . | No. of HPV attributable hospitalizations . | Standardized hospitalization rates (/100 000 inhabitants) . |
---|---|---|---|---|
CIN III | Female | 100% | 59 727 | 176.4 |
Cervical cancer | Female | 100% | 59 718 | 157.6 |
Genitourinary tract (vulva, vagina) | Female | 77% | 23 053 | 50.7 |
Anal cancer | Male | 88% | 11 410 | 33.2 |
Female | 12 623 | 29.3 | ||
Head and neck cancers | Male | 26% | 56 475 | 163.5 |
Female | 16 429 | 40.3 | ||
Genital warts | Male | 100% | 24 326 | 75.2 |
Female | 27 270 | 85.7 | ||
Penile cancer | Male | 50% | 6513 | 19.0 |
. | Sex . | % HPV-related diseases (according to literature) . | No. of HPV attributable hospitalizations . | Standardized hospitalization rates (/100 000 inhabitants) . |
---|---|---|---|---|
CIN III | Female | 100% | 59 727 | 176.4 |
Cervical cancer | Female | 100% | 59 718 | 157.6 |
Genitourinary tract (vulva, vagina) | Female | 77% | 23 053 | 50.7 |
Anal cancer | Male | 88% | 11 410 | 33.2 |
Female | 12 623 | 29.3 | ||
Head and neck cancers | Male | 26% | 56 475 | 163.5 |
Female | 16 429 | 40.3 | ||
Genital warts | Male | 100% | 24 326 | 75.2 |
Female | 27 270 | 85.7 | ||
Penile cancer | Male | 50% | 6513 | 19.0 |
. | Sex . | % HPV-related diseases (according to literature) . | No. of HPV attributable hospitalizations . | Standardized hospitalization rates (/100 000 inhabitants) . |
---|---|---|---|---|
CIN III | Female | 100% | 59 727 | 176.4 |
Cervical cancer | Female | 100% | 59 718 | 157.6 |
Genitourinary tract (vulva, vagina) | Female | 77% | 23 053 | 50.7 |
Anal cancer | Male | 88% | 11 410 | 33.2 |
Female | 12 623 | 29.3 | ||
Head and neck cancers | Male | 26% | 56 475 | 163.5 |
Female | 16 429 | 40.3 | ||
Genital warts | Male | 100% | 24 326 | 75.2 |
Female | 27 270 | 85.7 | ||
Penile cancer | Male | 50% | 6513 | 19.0 |
The trend of hr of cervical cancer progressively decreased during the studied period; the decrease was statistically significant in the period 2003–12, moving from 17 to 13/100 000 hospitalizations (APC −2.9% [CI 95%: −3.8; −2.1]). Taking CIN III into account, the trend was the opposite; hospitalization rates significantly increased in the period 2001–09, moving from 15.6 to 18.9/100 000 (APC 2.1% [CI 95%:1.4; 3]). A not significant decrease was registered later (Fig. 1a).
The trend of head and neck cancer significantly decreased in females in the period 2006–12 (APC −1.8% [CI 95%: −3.1; −0.6]) as well in males. In males the hospitalization rates changed from 20.1 to 17.7/100 000 (APC −5.4 [CI 95%: −9.5;−1.1]) in the period 2001–03, and then decreased further to 12.8/100 000 (APC −3.4 [CI 95%: −3.9; −3]) in the period 2003–12 (Fig. 1b).
The trend of the cancer of the penis remained almost unchanged in the studied period while the rate of genitourinary cancers showed a statistically significant decrease (APC −1.9% [CI 95%: −2.9; −1.1]).
Genital warts had a statistically significant increase in both genders; the increase was registered in the periods 2001–07 and 2001–08 in females and in males, respectively. APC was 7.2% [CI 95%: 5.6; 8.8] in males and 3.6% [CI 95%: 1.6; 5.6] in females. In the following years a decrease was registered in both genders, being statistically significant only in females (APC −4% [CI 95%: −6.5;−1.4]) (Fig. 2a and b).
The hospitalization rates for anal cancer decreased in the studied period in both genders, but the decline was statistically significant only in males (period 2008–12) (APC −5.6; [CI 95%: −10.3;−0.6]).
Discussion
Main findings
This study describes the national data on HPV-related hospitalizations, their distribution by gender and over time in the period 2001–12.
Accordingly to national studies, performed in cooperation by AIOM (Italian Association of Medical Oncology) and AIRTUM (Italian Association of Cancer Registries), the incidence of cervical cancer, thanks to the ongoing screening program (PAP test for early diagnosis), has continuously decreased;20 on the other hand, CIN III lesions have significantly increased in the last decade.21
Anyway, this study shows that, taking hospital discharge forms into account, CIN III and cervical cancer continue to be the HPV-related pathologies with the highest impact on Italian population, being involved in 40% of HPV-related hospitalizations. The comparison of the results of this study with those of two researches performed at regional level, shows that hospitalization rates for cervical cancer at national level are higher than the one observed in Veneto (15.65/100 000 at national level versus 11.9/100 000 in Veneto Region)16 and lower than in Tuscany (20.2/100 000).22
Contrary to published data that show an increase of HPV-related genitourinary cancers in the last decades,23 this study reveals that, in Italy, hospitalizations due to these specific cancers have progressively and significantly decreased in the period 2003–12.
An increased impact of head and neck cancers in males turns out as well. Published data show that the incidence of these cancers has progressively increased since early 90s in the USA and in Western Europe, mainly in male population, even if the reasons for this fast increase have not been completely understood.24,25 It is unknown why HPV-related head and neck cancers have a higher incidence rate in males; it has been speculated that a high number of sexual partners or a more effective viral transmission occurring during oral sex with infected female partners could play a role.5 The incidence of HPV-related head and neck cancers in males seems related to older age, alcohol consumption and to smoking more than 10 cigarettes/day.26
Our data show a progressive decrease of hospitalizations due to these cancers in males (APC −0,8%). It can be speculated that this trend could be related to the effectiveness of primary prevention (e.g. decrease of smoking as registered in the period 1990–14 by Doxa).27 The decreasing trend of hospitalizations due to head and neck cancers in male Italian populations is consistent with data recently registered in Europe, where hospitalization rates range between 5.6 and 33/100 000.28
Concerning anal cancer, hospitalization rates registered in the present study in both genders are in line with those observed in Veneto and lower than those registered in Tuscany (6.3/100 000 in males and 9.4/100 000 in females). Taking into account data on penile cancer, our results are quite similar to and slightly lower than those registered in Veneto and in Tuscany (2.5/100 000), respectively.
The hospitalization rate for genital warts in males is almost equal to the one observed in Veneto and Tuscany, while in females is lower than in Veneto (11.9/100 000).
What is already known on this topic
Worldwide literature data show that HPV-related pathologies continue to be a relevant public health issue with a high impact in both female and male population. Nevertheless, the epidemiology of HPV-related disease is gradually changing. Countries that have implemented HPV immunization programs have already registered a decrease in the population prevalence of the HPV genotypes responsible for infection and for the different types of related cancers.29
What this study adds
Up to now, in Italy only regional data (Veneto and Tuscany) were available on the burden of HPV-related pathologies in terms of hospitalizations. This is the first study performed at national level addressing this specific topic.
Limitations of this study
The present study has some limitations. The first one is that it was not possible to evaluate the whole impact of HPV-related pathologies, being considered only the most severe cases that have needed hospitalization. Besides, it is not always available an uniform consensus on the rates of different cancers attributable to HPV; for this reason, the rates have been estimated evaluating published data, aware that they show a wide degree of ranging. Finally, inter-regional comparison could be affected by some bias in coding system of different pathologies, already described in other settings;30 this point does not probably severely affect our results, but could potentially imply an over- as well as under-registration of cases.
Conclusions
This study allows to evaluate at national level the impact of HPV-related pathologies, taking into account hospital discharge forms in the last decade.
Even if the study has some limitations, it is confirmed that HPV-related pathologies continue to be a relevant public health issue and have a high impact on Italian population involving both genders.
CIN III and cervical cancer continue to be the most frequent pathologies in females, while head and neck cancers and genital warts are more dominant in males.
A decrease of HPV-related hospitalizations has been registered in the period 2001–12; it should be taken into account that this decrease does not seem to have exclusively involved HPV-related cancers. As a matter of fact, the Ministry of Health has recently published a report showing that in the period 2001–12 hospitalizations and hospital stays have decreased since 2005. As a whole, in Italy a significant decreased use of hospitalization has been registered; this could be related to a better effectiveness of health services and to a lower inappropriateness of hospitalizations.31 Anyway, the registered decrease of hospitalizations could be related to the positive impact of primary (vaccination) and secondary (screening) interventions (at least on CIN III and cervical cancer) already established at national level, that in any case should be reinforced.
Acknowledgements
National Archive of SDO data, Ministry of Health, General Directorate of Healthcare Planning, VI Office.
Funding
None.
References
Personal data protection agency: general authorization for personal data treatment for scientifical purposes, 1th March 2012.
Italian Association of Medical Oncology (Associazione Italiana di Oncologia Medica: AIOM), Italian Association Cancer Registry (Associazione Italiana Registro Tumori: AIRTUM). The Numbers of Cancer in Italy, 2014 [I numeri del cancro in Italia, 2014]. http://www.registri-tumori.it/PDF/AIOM2014/I_numeri_del_cancro_2014.pdf (30 November 2016, date last accessed)
Istituto Superiore di Sanità (National Health Institute).
Health Minister: annual report on hospitalizations. Hospital Discharge Form Data 2012 [Ministero della Salute: Rapporto annuale sull'attività di ricovero ospedaliero. Dati SDO 2012]. http://www.salute.gov.it/imgs/C_17_pubblicazioni_2094_allegato.pdf (30 November 2016, date last accessed).