Hospitalization burden associated with anus and penis neoplasm in Spain (2016-2020)

ABSTRACT

In 2020, there were approximately 50,865 anal cancer cases and 36,068 penile cancer cases worldwide. HPV is considered the main causal agent for the development of anal cancer and one of the causal agents responsible for the development of penile cancer. The aim of this epidemiological, descriptive, retrospective study was to describe the burden of hospitalization associated with anal neoplasms in men and women and with penis neoplasms in men in Spain from 2016 to 2020. The National Hospital Data Surveillance System of the Ministry of Health, Conjunto Mínimo Básico de Datos, provided the discharge information used in this observational retrospective analysis. A total of 3,542 hospitalizations due to anal cancer and 4,270 hospitalizations due to penile cancer were found; For anal cancer, 57.4% of the hospitalizations occurred in men, and these hospitalizations were also associated with significantly younger mean age, longer hospital stays and greater costs than those in women. HIV was diagnosed in 11.19% of the patients with anal cancer and 1.74% of the patients with penile cancer. The hospitalization rate was 2.07 for men and 1.45 for women per 100,000 in anal cancer and of 4.38 per 100,000 men in penile cancer. The mortality rate was 0.21 for men and 0.12 for women per 100,000 in anal cancer and 0.31 per 100.000 men in penile cancer and the case-fatality rate was 10.07% in men and 8,26% in women for anal cancer and 7.04% in penile cancer. HIV diagnosis significantly increased the cost of hospitalization. For all the studied diagnoses, the median length of hospital stays and hospitalization cost increased with age. Our study offers relevant data on the burden of hospitalization for anal and penile cancer in Spain. This information can be useful for future assessment on the impact of preventive measures, such as screening or vaccination in Spain.

KEYWORDS:

• HPV
• anus
• penis
• hospitalizations
• in situ carcinoma
• malignant neoplasia
• HIV

Introduction

According to the last Global Cancer Observatory report, approximately 50,865 anal cancer cases were estimated to occur annually, and the incidence was greater in women (53,33%) than in men. In Europe, a total of 12,776 new cases, 4,027 deaths and a 5-year incidence of 40,826 are estimated to have occurred in 2020 in both sexes.¹ Anal cancer is uncommon in the general population, with a global incidence of just 1 per 100,000 people, although it is reportedly on the rise in more industrialized areas.² In Spain, on the contrary, men present an estimated 320 new cases of anal cancer and 242 new cases in women, an incidence rate of 1.39 per 100,000 men and 1.02 per 100,000 women.^1,2 There are high incidence rates of men who have sex with men (MSM), women with a history of cervical or vulvar cancer, and immunosuppressed people, such as people with HIV and people who have had organ transplants in the past.²

Regarding penile cancer, there was an incidence of 36,068 new cases and 13,211 deaths attributed to this type of neoplasm worldwide in 2020.¹ In Europe, a total of 6,762 new cases, 1,938 deaths and a 5-year incidence of 22,705 cases were estimated. This neoplasm has an incidence of approximately 1.33 cases per 100,000 men.³ In Spain, there were 506 estimated new cases, 119 deaths, a 5-year incidence of 1,716 cases per 100,000 men and an incidence of 1.5 cases per 100,000 men.^1,4 Previous research on the hospitalization rate for malignant neoplasia (MN) of the penis and the anus in Spain showed an increase from 1997 to 2008 in the penile cancer hospitalization rate⁵ and a stable incidence of anus MN from 2009–2013.⁶

Human papillomavirus (HPV) infection is considered the most prevalent sexually transmitted infection and is known to be related to different ano-genital cancers.⁷ Recent research shows that HPV16 was the most frequently detected type, present on 73% of the patients diagnosed with anal cancer; it is followed by the HPV18 genotype, which was responsible for 5% of the anal cancers.^8,9 Regarding penile cancers, HPV DNA was present in 51% of the patients, with HPV16 and HPV18 being the two most common genotypes detected² and with an incidence of penile cancer caused by HPV DNA of 0.54 per 100,000 men.¹⁰

One of the risk factors associated with malignant HPV lesions is immune status. HIV interacts with and contributes to the pathogenesis of HPV infection, and it increases the incidence and prevalence of all HPV-associated diseases.¹¹ HIV infection causes a rapid decrease in CD4 T cells, which is postulated to occur in the anogenital epithelium, and hinders spontaneous resolution of HPV-associated lesions.¹² In the male population, MSM are at a higher risk of contracting HPV at the anal site; however, heterosexual men with HIV are also at risk of acquiring different types of HPV both anal and penile.¹³ In the female population, HIV and HPV coinfection is not as common, as the infection rate is lower in females than in males.¹²

The World Health Organization (WHO) has developed a strategy with the aim of reducing the incidence of cervical cancer to 4 cases per 100,000 people. To achieve this, different goals have been set, among them, the goal of having 90% of girls fully vaccinated against HPV before they reach 15 y of age.¹⁴ All countries in the European Union carry out HPV vaccination in girls. Some countries, such as Spain, have expanded the vaccination strategy to be gender neutral with the nine-valent vaccine, offering more benefits than any other modeled strategy.^15,16

Updating studies in this field is necessary to correctly guide health strategies for disease prevention and health promotion. We have performed an epidemiological, descriptive, retrospective study to describe the burden of hospitalizations associated with anal neoplasms in men and women and with penile neoplasms in men at the national level in Spain during a 5-year period.

Methods

This study was conducted using information from the Conjunto Mínimo Básico de Datos (CMBD), which contains data about admission and discharge dates; age; sex; geographical region; diagnosis; clinical procedures; and discharge status for all hospitalizations in Spain. The clinical codes used were obtained from the Spanish 10th Internal Classification of Diseases (CIE-10).¹⁷ It is estimated that it covers approximately 98% of public hospital admissions, including more than 70% of private hospital admissions, covering 99.5% of the population in Spain.¹⁸ All records between January 1st 2016 and December 31st 2020 were included. We assumed the same epidemiological characteristics for the population and hospitalizations not covered by CMBD and no difference in the age distribution of the population covered by public hospitals compared with the general population.

We excluded pediatric population data from patients up to 14 y of age. The number of hospitalizations for each cancer, the number of those hospitalizations for people living with HIV and the median hospitalization cost were recorded.

The Ministry of Health estimates the cost of these hospitalizations to the health care system. The number of discharges, the overall cost, and the diagnosis cost group were all taken into consideration when calculating the cost. Based on the ICD categorization, age, sex, and resource consumption of the hospitalized patients, the diagnostic cost group was created using diagnosis-related groups (DRGs). Every group may be applied to every linked patient and has a similar weight in terms of hospital expenditures. The DRG calculations were performed by 3 M with Core Grouping System software.¹⁹

Statistical analysis: We assessed the absolute number of hospitalizations, length of hospital stay (ALOS) (days), hospitalization cost (euros), hospitalization and mortality rate (per 100,000 women/men aged >14 y old), and case fatality rate (%). The analyses were gathered per year, age, and sex, when applicable. For hospitalization and mortality rate calculations, we used the data of the female and male population aged >14 y from the municipal registries adjusted by the population targeted by hospitals covered by the CMBD as the denominator. The age-, sex-, and year-specific rates were calculated using the corresponding population as the denominator.

We used the chi-square test to assess significant differences in proportions and ANOVA for multiple comparisons. Poisson models were used to assess differences in hospitalization and mortality rates (per 100,000 women or men aged >14 y old) according to the 5 year period of the study, age group and sex. The hospitalization and mortality rates were used as dependent variables, and year, age and sex were used as independent variables if applicable. All the results are reported with their corresponding 95% confidence intervals (95% CI). For all tests, we considered a p value less than .05 to indicate statistical significance.

All the data included in this study were obtained as part of routine clinical activity and were evaluated retrospectively and anonymously in strict compliance with the current Spanish and European legislation. For this reason, the Research Ethics Committee of Rey Juan Carlos University ruled out the need for formal ethics approval for this study. (Supplementary Material).

Results

Malignant neoplasia and in situ carcinoma in the anus

Between 2016 and 2020, there were 3,542 patients hospitalized for anal cancer of both sexes in Spain, 3,494 of whom were diagnosed with malignant neoplasia (MN) and 48 patients being diagnosed with in situ carcinoma (ISC). (Table 1). The mean age of the hospitalized patients was lower for men than for women (63.31 vs. 64.97 y old, respectively) (p ≤ .001) (Table 1), and in terms of hospital stay and cost of those hospitalizations, the hospitalized men spent more days in the hospital, and their hospitalization had a greater cost than did the hospitalized women. The median stay for men was 11.3 d [IQR 10 d] vs. 10.13 d [IQR 9 d] for women (p ≤ .001), and the median cost was 3,919.22€ [IQR 3,195.54€] for men vs. 3,729.83€ [IQR 2,686.76€] for women (p ≤ .001) (Suppl. Table S1).

Table 1. Sociodemographic variables of the women and men with anal cancer and the men with penile cancer.

		Malignant neoplasia and in situ carcinoma in anus (n = 3494)		Malignant neoplasia and in situ carcinoma in penis (n = 4242)
		n	%	n	%
Sex	Male	2005	57,38%	4245	100,00%
	Female	1489	42,62%
Deceased	No	3169	90,70%	3946	92,96%
	Yes	325	9,30%	299	7,04%
HIV diagnosis	Absent	3103	88,81%	4171	98,26%
	Present	391	11,19%	74	1,74%
		Mean	SD	Mean	SD
Age		64,02	13,56	70,10	13,07
ALOS		10,80	16,71	7,22	9,93
Cost (€)		5.313,85	4.239,24	4.328,44	3.028,80

ALOS: average length of stay.

The hospitalization rate was 2.07 for men and 1.45 for women per 100,000 people (Figures 1 and 2). The mortality rate was 0.21 for men and 0.12 for women per 100,000 people and the case-fatality rate was 10.07% and 8,26%, respectively (Suppl. Table S2, Figures 3 and 4). There were statistically significant differences in hospitalization, mortality, and fatality rates according to sex by age group (p ≤ .001. suppl. Table S2)). There was also a statistically significant difference in the median ALOS score and hospitalization cost between the age groups, and these differences were also observed for both men and women (p ≤ .001, suppl. Table S2). According to the results of the present study, hospitalization rates for both sexes remained stable, without relevant changes (p = .786), although they were greater for men than women, similar to the findings of the Spanish study between 2009 and 2013.¹⁵

Figure 1. Hospitalisation rate (per 100,000 women aged >14 y old) due to MN and ISC in the anus in women per age group and by year of the study period.

Figure 2. Hospitalisation rate (per 100,000 men aged >14 y old) due to MN and ISC in the anus in men per age group and by year of the study period.

Figure 3. Mortality rate and case fatality rate of MN and ISC in the anus in men during the study period (2016 – 2020) per age group.

Figure 4. Mortality rate and case fatality rate of MN and ISC in the anus in women during the study period (2016–2020) per age group.

HIV was diagnosed in 391 of the 3,494 patients hospitalized due to MN of the anus, which represents 11.19% of the total (Table 1). Of them, 283 were male (72.38%) (p ≤ .001). The average length of stay (ALOS) in male patients without an HIV diagnosis was 6 d (IQR 9 d), while that in patients with an HIV diagnosis was 7 d (IQR 14 d). Male patients with HIV incurred a total cost of 5,222.32€ (IQR 4,2229.92€), whereas male patients without HIV only incurred a total of 3,863.93€ (IQR 2,717.77€). Hospitalized HIV males were also markedly younger than hospitalized noninfected patients, with mean ages of 52.92 ± 9.17 vs. 65.02 ± 12.63 y, respectively.

Malignant neoplasia and in situ carcinoma in the penis

During the study period, there were a total of 4,270 hospitalizations due to penile cancer, 4,245 of whom were due to MN of the penis and 25 cases registered as ISC (Table 1). A total of 4.38 patients were hospitalized per 100.00 population, the mortality rate was 0.31 per 100.000 population and the case-fatality rate was 7.04%. (Suppl. Table S2, Figures 5 and 6).

Figure 5. Hospitalisation rate (per 100,000 men >14 y old) due to MN and ISN in the penis per age group and by year of the study period.

Figure 6. Mortality rate and case fatality rate of MN and ISC in the penis during the study period (2016–2020) per age group.

The mean age of the men hospitalized with MN and ISC was 70.1 ± 13.7 y old. Significant changes in the hospitalization rate, mortality rate, and case fatality rate according to age group were observed during the study period (p ≤ .001) (Suppl. Table S2). The median ALOS was 7.22 d (IQR 6 d), and hospitalization had a median cost of 3,578.96€ [IQR 1,476.33€] (Table 1).

Of the 4270 hospitalized individuals, 74 (1.74%) were infected with HIV. Although there was no significant difference in ALOS between patients without an HIV diagnosis (median of 4 d [IQR 6 d] without HIV vs. median of 4 d [IQR 8 d] with HIV), there was a significant difference in the median cost of hospitalization. For patients without HIV, the median cost was 3,578.96€ [IQR 1,488.75€], while for patients with HIV, the median cost was 4,729.05€ [IQR 2578.17€] (p ≤ .001). The HIV-infected patients were also on average much younger than the patients without infection (57.78 ± 9.16 vs. 70.32 ± 13.03 y old) (Table 1).

Figure 5 shows the hospitalization rate per age group from 2016 to 2020., with a significant increase with age (p ≤ .001) (Suppl. Table S2).

Discussion

The results of our study showed an increase in the rate of hospitalization with age both in anal cancer and penile cancer and are in line with those previously published.^10,20

A recent study in Sweden calculated that the annual cost of anal cancer in both sexes was 12.1 million euros, and the annual cost of penile cancer was 2.6 million euros.²¹ In contrast, a recent study in England revealed that hospitalization costs are greater for women than for men.²² As of 2017 in Spain, the estimated annual cost of anal cancer attributed to infection from any type of HPV genotype was 4.42 million €, and the annual cost of penile cancer attributed to any type of HPV increased to 1.58 million euros.²³ Compared with the costs of hospitalization for other cancers, anal cancer in men and women and penile cancer in men represent a slightly lower cost than the estimated cost of cervical cancer in hospitalized women, 4,446€.²⁴ The difference is greater than that of other hospitalization costs, such as the cost of lung cancer, which represents an estimated average cost of 5,366€ and is similar for women and men.²⁵ There is a greater difference from that of other cancers, such as pharyngeal cancer, whose cost was estimated to be 5,955€ in men and 5,541€ in hospitalized women; laryngeal cancer, whose estimated cost is 7,066€ in men and 7,118€ in hospitalized women; or oral cavity cancer, whose estimated cost is 7,486€ in men and 6,984€ in women hospitalized.²⁶

Cost effectiveness of the HPV vaccine can vary depending on a number of factors such as the population being vaccinated, the prevalence of HPV in that population, and the cost of the vaccine itself. In some cases, the HPV vaccine may not be considered cost effective if the population being vaccinated has a low risk of developing HPV-related diseases or if the cost of the vaccine outweighs the potential health benefits. However, in high-risk populations or in settings where HPV prevalence is high, the vaccine can be very cost effective in preventing HPV-related cancers and other health issues. Ultimately, the decision of whether or not to vaccinate against HPV should be based on a careful consideration of these factors.^27,28 Numerous studies have shown that vaccination of men against HPV has reported benefits in terms of reduced HPV prevalence in the groups studied.^29,30 The evidence that HPV vaccination in males has been shown to be effective against infection, together with the clear burden that HPV-related cancers pose to the National Health System, suggests that the implementation of a nationwide vaccination program targeting adolescent males is of utmost importance, not only with the aim of achieving equity between boys and girls, but also as a way to reduce the future economic impact that HPV-related cancers could pose to the Spanish NHS.

Several countries have introduced gender-neutral HPV vaccination in their routine vaccination programs,^23,30–32 with the aim of reducing the incidence of anal cancer and anogenital warts caused by HPV. In Spain, most regions already include adolescent males in the HPV vaccination.³³ Previous studies have shown that the 9vHPV vaccine is cost-effective in individuals aged 9 to 14 y, and that the inclusion of adolescent males is cost-effective.³⁴ However, current vaccination rates remain below the target levels necessary for HPV eradication.³⁵

Our results show that the population over 60 y of age has the highest rate of hospital admissions for anal and penile cancer. This population is outside the vaccination program, so maintaining primary and secondary prevention strategies is highly necessary. Common strategies have been described for the prevention of both cancers, starting with health education interventions to prevent and detect signs and symptoms that allow early action if any warning signs appear. Importantly, promotion of protective factors for anal and penile cancer includes a balanced diet rich in fruits, vegetables, and whole grains, limiting consumption of processed foods and high-fat foods, exercising regularly and maintaining a healthy weight. Also, smoking cessation and promotion of condom use during sex, which in addition to preventing HPV infection, can reduce the risk of other sexually transmitted diseases that can increase the likelihood of developing anal and penile cancer.^36–38

Specifically, secondary prevention of anal cancer focuses on detecting and treating the disease in its early stages, before it causes symptoms or spreads to other parts of the body. Screening tests, such as anal cytology (anal Pap smear) or anal colposcopy, should be performed, especially in individuals with risk factors such as HIV, history of HPV infection, or other risk factors.^39–41 It is recommended that women undergo anal cancer screening if they have a history of precancerous lesions in the cervix, vagina, or vulva.³⁶

Regarding primary prevention of penile cancer, it involves adopting habits and measures to reduce the risk of developing this disease, mainly through good hygiene. Secondary prevention focuses on early detection of the disease through periodic medical examinations.⁴²

It should also be noted that during the COVID-19 pandemic, new cancer cases, as well as prevalent cases, decreased significantly. Measures to reduce mortality and control the pandemic have meant a delay in the care and follow-up of many patients, with significant “collateral damage.” Primary prevention programs (smoking cessation, human papillomavirus vaccine) were postponed, as well as population screening, leading to a decrease in the detection of asymptomatic cancers, and there was a difficulty in the care of patients with signs and symptoms of suspected cancer and poor access to diagnostic tests, as well as a decrease in the number of follow-up and treatment visits and in the diagnostic processes of oncology patients.⁴³

This study has several limitations since it collected data from the CMBD, which provides information only about hospitalized patients and therefore prevents the exact incidence and prevalence of anal and penile cancer in Spain from being calculated. The CMBD also depends on the quality of the clinical history recorded in each Spanish hospital.⁴⁴ The interpretation of the mortality rates should also be analyzed critically because deaths occurring outside the hospitals were not accounted for. Nonetheless, as the focus of our study was hospitalization burden rather than incidence, we are interested in all episodes that necessitate hospitalization, regardless of whether they involved the same patient. Given that deaths outside of hospitals were not considered, we must interpret the mortality rate calculated with CMBD with caution. The observed difference in hospitalizations may be due to a combination of differences in incidence rates in the population and differences in the frequency of hospitalizations per prevalent case in the different subpopulations.

Hospital discharge databases, however, have been shown to be useful resources for cancer monitoring.⁴⁵ The use of hospital medical information systems has also released statistics about the number of hospitalizations due to vulvar and vaginal malignancies.⁴⁶ A strength of this study is that the data were collected nationwide over 5 y. This approach will facilitate the calculation of the real impact of future vaccination on hospitalizations for anal cancer in women and men and for penile cancer in men.

In conclusion, given the burden of hospitalization for these two cancers, it would be beneficial to double down in vaccination efforts against HPV to target younger populations and to insist in primary prevention programs, such as smoking cessation and screening for older populations that are not included in vaccination programs. The information provided in this study could be used in future research to assess the impact of preventive measures in Spain.

Author contributions

Study design: VFA, RGP, AGM.

Data collection: RGP, MA, VHB.

Data analysis: VFA, RGP, VHB.

Study supervision: RGP, AGM.

Manuscript writing: VFA, RGP, MA, VHB and AGM.

Critical revisions for important intellectual content: All of the authors  reviewed the final manuscript before submitting for publication.

Acknowledgments

The authors thank the Subdirección General del Instituto de Información Sanitaria for providing the information on which this study is based.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Supplementary material

Supplemental data for this article can be accessed on the publisher’s website at https://doi.org/10.1080/21645515.2024.2334001.

Additional information

Funding

No public or private body has provided funding for this research.