Incidence and survival of vulvar and vaginal cancers in a province of Northern Italy: a population-based study

Highlights

• •Vulvar cancer incidence is statistically decreasing (APC −2.3), mortality is stable.
• •Vaginal cancer incidence is decreasing (APC −3.3), mortality is stable.
• •5-years survival is 63 % and 61 %, respectively for vulva and vagina.
• •30 s tumors were observed: 27 for vulva and 3 for vagina.

Abstract

Background

This study aims to describe the incidence, mortality, and survival trends of vulvar and vaginal cancers in a population-based cohort from Northern Italy, with a particular focus on the development of second primary malignancies.

Methods

Data were retrieved from the Cancer Registry of Reggio Emilia, covering the period 1996–2021. Vulvar and vaginal cancers were classified according to ICD-O-3 topography codes C51 and C52, respectively. Age-standardized incidence and mortality rates were calculated using the European Standard Population. Relative survival estimates were computed using the Pohar Perme method. Time trends were analyzed using Joinpoint Regression, and the occurrence of second primary malignancies was assessed based on medical records.

Results

A total of 328 cases were identified: 264 vulvar (80.5 %) and 64 vaginal cancers (19.5 %). The median age at diagnosis was 76.1 years for vulvar cancer and 70.2 years for vaginal cancer. Squamous cell carcinoma was the predominant histological subtype (78 % vulvar, 57.8 % vaginal). The incidence of vulvar cancer showed a significant annual decrease (APC −2.3 %, 95 %CI −3.5; −1.0), while mortality remained stable. Vaginal cancer also exhibited a decreasing incidence trend (APC −3.3 %, 95 %CI −9.1; 2.9), though not statistically significant. The five-year survival rate was 63 % for vulvar cancer and 44 % for vaginal cancer, with a significant improvement for vaginal cancer in the years (1996–2006: 33 %; 2007–2018: 61 %). Second primary malignancies were observed in 30 patients (27 with vulvar and 3 with vaginal cancer).

Conclusion

Although vulvar and vaginal cancers remain rare, their burden is significant, particularly in older women. The declining incidence may be attributed to the effects of HPV vaccination and improved screening practices. However, the stable mortality rates underscore the need for optimized treatment strategies. Given the association with second malignancies, long-term surveillance is essential to improving patient outcomes.

Policy Summary

Vulvar and vaginal cancers are rare but require careful and continuous monitoring. Knowledge of the incidence curves and survival of these tumors should encourage stakeholders to invest both in terms of primary prevention (smoking cessation and sex education) but also secondary prevention by implementing screening campaigns without neglecting the importance of HPV vaccination and access to care for all, without regional disparities.

1. Introduction

Gynecological tumors are among the most prevalent neoplasms and are of considerable clinical interest, particularly due to the potential for cervical cancer early detection through organized screening programs (Loud and Murphy, 2017, Teixeira et al., 2021) and the widespread availability of prophylactic HPV vaccination (Schuind et al., 2024, Dattani and Samborska, 2024). Vulva and vagina cancers present a global incidence rates of 0.83 and 0.36 per 100,000 women, respectively (International Agency for Research on Cancer, 2025). These malignancies share some risk factors, including multiple sexual partners, early sexual activity, advanced age, alcohol consumption, HIV infection, and previous gynecological tumors (Huang et al., 2023, Li et al., 2023). Poor hygiene has also been implicated (Huang et al., 2024), while rare and aggressive subtypes may arise from mesonephric residues or endometriotic foci (Palicelli et al., 2025, Cozzolino et al., 2017).

Vulvar cancer accounts for 5.8 % of all gynaecological malignancies and is frequently diagnosed at an early stage (Abu-Rustum et al., 2024). The predominant histological subtype is squamous cell carcinoma (Merlo, 2020), which generally carries a favorable prognosis (Moberg et al., 2024); however rarer histotypes require multimodal treatment and have a worse prognosis (Barcellini et al., 2024). One-third of squamous cell carcinomas are HPV-related and exhibit a less aggressive course than HPV- independent counterparts (Darwish et al., 2024). Precancerous vulvar progresses slowly typically transforming over 8 years (Stroup et al., 2008), though immune dysregulation can accelerate malignant progression.

Vaginal tumors constitute 3 % of gynecological malignancies (Rajaram et al., 2015) and a very small portion of cancers overall (American Cancer Society, 2025). This malignancy predominantly affects elderly women, though incidence is rising in younger populations due to increasing HPV prevalence (Bray et al., 2020). Five-year survival rates range from 45 % (Trétarre et al., 2023) to 58.7 % (Forner, 2023). Primary vaginal cancer is diagnosed in the absence of concurrent or prior cervical or vulvar malignancy within 5 years (Adams et al., 2021). Due to its rarity, treatment strategies remain heterogeneous and non-standardized, relying on retrospective studies and small cohorts (Hiniker et al., 2013). Early symptoms, such as persistent pruritus, can facilitate timely diagnosis and enable curative surgery (Merlo, 2020).

Vulvar and vaginal tumors may also develop synchronously or metachronously after primary cervical cancer (Matsuo et al., 2018), underscoring the importance of careful surveillance for secondary neoplasms and reinforcing HPV vaccination’s critical role in prevention (Bray et al., 2020, Matsuo et al., 2018).

In the Emilia-Romagna Region (North Italy), HPV vaccination has been actively and free of charge for twelve-year-olds, starting with the 1997 birth cohort. For adolescents born in 1996, vaccination was provided free of charge, at their parents' request. For birth cohorts starting with 1996, subsequently extended to those born in 1994 and 1995, the right to free vaccination is guaranteed up to age 26 (Salute Regione Emilia-Romagna, 2025).

This study analyzes the incidence, survival, and data of secondary tumors in patients with vulvar and vaginal malignancies in a northern Italian province.

2. Materials and methods

2.1. Study setting and data source

This research uses data from the Cancer Registry (CR) of Reggio Emilia, a province in Northern Italy, which has a population of 532,000 people. Since this is a population-based cancer registry, we have included all registered cases of malignant tumors of the vulva and vagina. The CR, as per international standards, uses three priority information sources: pathology reports, which contribute 90 % of the data, hospital discharge records, which contribute 18 %, and death certificates, which contribute less than 2 % (these are national standards, valid for all surgeries in general). To these, specialist reports, medical records, or the GP can be added. Therefore, we consider that this study included 100 % of women with vulvar and vaginal cancer occurring in the province of Reggio Emilia in the years 1996–2021. The study included 328 cases of vulvar and vaginal cancer, which were microscopically confirmed in 97.6 % of cases.

In general, the Reggio Emilia CR is considered a good quality registry because it presents, for all tumors, high percentages of microscopic confirmations and low percentages of DCO (Death Certificate Only) cases (Mangone et al., 2015). Moreover, the CR includes up-to-date information, with data available through 2021. The CR’s activities are authorized by the provincial Ethics Committee of Reggio Emilia (Protocol no. 2014/0019740, dated 04/08/2014).

This study covers all cases of vulvar and vaginal cancer recorded in the CR between 1 January 1996 and 31 December 2021. These cancer cases were classified according to the International Classification of Diseases for Oncology, Third Edition (ICD-O-3), with topography codes C51 and C52 for vulvar and vaginal cancers, respectively (Fritz et al., 2013).

The data were reported overall and separately for the vulva and vagina by age group (<50, 50–69, 70+), period of diagnosis (1996–2000, 2001–2005, 2006–2010, 2011–2015, 2016–2021) and morphology (Squamous cell carcinomas, Basal cell carcinomas, Adenocarcinomas, Ductal and lobular carcinomas, Nevi and melanomas, Other). Furthermore, the data were reported according to the nationality of the patients (Italians and non-Italians).

2.2. Statistical analysis

Relative survival estimates net survival without other causes of death. It is defined as the ratio observed in a cohort of cancer patients to the proportion of expected survivors in a comparable set of cancer-free individuals. For the vulva and vagina, 5-year relative survival was estimated with the Pohar Perme method for all periods and divided into two different periods (1996–2006 and 2007–2018); with this estimator, net survival for a cohort is estimated by weighting by the inverse of the individual-specific expected survival probabilities. We've divided the total number of years into two periods that appear to be consistent: 1996–2006 (11 years) and 2007–2018 (12 years) of incidence. Furthermore, in Emilia-Romagna, the HPV vaccination was introduced in 2008 for girls in their twelfth year. The weights inflate the observed person-time and number of deaths to account for person-time and deaths not observed because of mortality due to competing causes.

For both cancer sites and separately for the vulva and vagina data, age-standardized incidence and mortality rates were calculated using the Province of Reggio Emilia population (recorded on 1 January of each year) as denominators. The reported age is the mean +/− standard deviation, and we've also added the minimum and maximum ranges. The direct method of standardization was applied to adjust rates for age using the 2013 European Standard Population as a reference. “Trends over time were analyzed by calculating the annual percent change (APC) in age-standardized rates using Joinpoint Regression for both cases and for the vulva and vagina groups. The APC is one way to characterize the trends in cancer rates over time: the output includes the estimated annual percentage rate change. With this approach, the cancer rates are assumed to change at a constant percentage of the rate of the previ- ous year. The joinpoint model uses statistical criteria to determine when and how often the APC changes. The maximum number of joinpoints predicted for these analyses was fixed to four (Institute and Regression, 2021).

The incidence of second cancers occurring after the diagnosis of vulvar or vaginal cancer was also calculated. We defined Synchronous as second tumors appearing within 6 months of diagnosis of the first tumor, and Metachronous as tumors diagnosed more than 6 months after the first diagnosis. Furthermore, for metachronous tumors, the time from onset to the first tumor was calculated (<1 year, 1–5 years, 6–10 and >10 years).

2.3. Ethics

According to Italian legislation, Cancer Registries are authorized to collect personal data for surveillance purposes without explicit individual consent. Given that this study is a descriptive analysis based on Registry data without any direct patient intervention, approval from a research ethics committee was not required.

3. Results

Between 1996 and 2021, a total of 328 malignant tumors were recorded (Table 1): comprising 264 cases (80.5 %) of vulvar cancer and 64 cases (19.5 %) of vaginal cancer. Both tumor sites predominantly affected women over the age of 70, with 192 cases (72.7 %) of vulvar cancers and 39 cases (61 %) of vaginal cancers occurring in this age group. The mean age at diagnosis was 76.1 years (SD 11.9; range 31–99) for women with vulvar cancer, and 70.2 years (SD 15.1; range 34–97) for vaginal cancer. Histopathological analysis revealed that squamous cell carcinoma was the most frequent morphology (206 cases, 78 %) of vulvar cancers, followed by basal cell carcinoma (19 cases, 7.2 %). Similarly, squamous cell carcinoma was the predominant subtype among vaginal cancers (37 cases, 57.8 %), followed by adenocarcinoma (10 cases, 15.6 %). Microscopic confirmation was achieved in 98.1 % of 259 vulva tumors and 95.3 % of 61 vaginal tumors, while the remaining cases were diagnosed through imaging and other instrumental examinations. Regarding patient nationality, 2.7 % (9 cases) occurred in foreign-born women, with a higher proportion observed in vaginal (5 cases, 7.8 %) compared to vulvar cancer (4 cases, 1.5 %).

Table 1.

Reggio Emilia Cancer Registry. Vulvar and vaginal cancer, years 1996–2021. Number of cases by age, period of diagnosis, morphology, method of diagnosis, and nationality.

	All		Vulva		Vagina
	n	%	n	%	n	%
Overall	328		264	80.5	64	19.5
Age at diagnosis
<50	13	4.0	6	2.3	7	10.9
50–69	84	25.6	66	25.0	18	28.1
70+	231	70.4	192	72.7	39	61.0
	mean	sd	mean	sd	mean	sd
	74.9	12.8	76.1	11.9	70.2	15.1
Period of diagnosis
1996–2000	74	22.6	54	20.5	20	31.2
2001–2005	59	18.0	51	19.3	8	12.5
2006–2010	62	18.9	50	18.9	12	18.8
2011–2015	63	19.2	53	20.1	10	15.6
2016–2021	70	21.3*	56	21.2	14	21.9
Morphology
Squamous cell carcinomas	243	74.1	206	78.0	37	57.8
Basal cell carcinomas	19	5.8	19	7.2	0	0.0
Adenocarcinomas	11	3.4	1	0.4	10	15.6
Ductal and lobular carcinomas	13	4.0	13	4.9	0	0.0
Nevi and melanomas	18	5.5	14	5.3	4	6.3
Other	24	7.3	11	4.2	13	20.3
Method of diagnosis
Clinical/instrumental	8	2.4	5	1.9	3	4.7
Histological	320	97.6	259	98.1	61	95.3
Population
Italians	319	97.3	260	98.5	59	92.2
Non-Italians	9	2.7	4	1.5	5	7.8

Among patients with vulvar cancer, 4 synchronous tumors were diagnosed within 6 months of the primary tumor, including 2 rectal carcinomas, 1 breast carcinoma, and 1 non-Hodgkin lymphoma (Table 2). Additionally, 23 metachronous tumors were identified more than 6 months after the initial diagnosis, with skin, breast, digestive, and dermatological cancers being the most frequent secondary neoplasms. In patients with vaginal cancer, 1 case of bladder tumor was recorded within 6 months, while 2 tumors (1 melanoma and 1 leukemia) were recorded beyond the 6-month threshold. The 25 metachronous tumors were diagnosed in the following periods: 2 cases < 1 year (6–12 months), 8 cases in the range 1–5 years, 8 in the range 6–10 years and 7 cases more than 10 years from diagnosis. The 5-year survival rate was 62 % for vulvar cancer and 44 % for vaginal cancer. When stratified by diagnostic period, the 5-year survival for vulvar cancer remained relatively constant, 64 % in 1996–2006 and 63 % in 2007–2018. In contrast, vaginal cancer showed a significant improvement in 5-year survival over time, increasing from 33 % in 1996–2006 to 61 % in 2007–2018 (see Table 3).

Table 2.

Reggio Emilia Cancer Registry. Vulvar and vaginal cancer, years 1996–2021. Number of synchronous and metachronous tumors.

	Vulva	Vagina	Total
Synchronous	4	1	5
Rectum	2
Breast	1
Non Hodgkin’s Lymphoma	1
Bladder		1
Metachronous	23	2	25
Skin, no melanoma	7
Breast	5
Mouth	1
Colon	1
Brain	1
Esophagus	1
Larynx	1
Non Hodgkin’s Lymphoma	1
Stomach	1
Bladder	1
Myeloma	1
Undefined	1
Leukemia		1
Melanoma		1
Total	27	3	30

Table 3.

Reggio Emilia Cancer Registry. Vulvar and vaginal cancer, years 1996–2018. 5-year relative survival of vulvar and vaginal cancer, by period.

		1996–2006				2007–2018
Vulva	Years	n	Relative survival	95 % CI		n	Relative survival	95 % CI
	1	117	88 %	78 %	93 %	124	85 %	76 %	91 %
	3	80	69 %	57 %	79 %	80	65 %	53 %	74 %
	5	69	64 %	51 %	75 %	66	63 %	47 %	72 %
Vagina		n
	1	37	62 %	43 %	76 %	23	84 %	60 %	94 %
	3	16	43 %	25 %	60 %	15	59 %	35 %	76 %
	5	11	33 %	17 %	51 %	13	61 %	36 %	79 %

Longitudinal analysis of incidence and mortality trends over the 25-year study period (Fig. 1) demonstrated a significant decline in the incidence of vulvar cancer (APC-2.3 %, 95 %CI −3.5; −1.0), while mortality rates remained stable (APC 0.1 %, 95 %CI −2.5; 2.9) (Fig. 1A). A similar but non-significant decreasing trend was observed for vaginal cancer, with a decrease in incidence (APC −3.3, 95 %CI −9.1; 2.9) and mortality (APC −1.8 %, 95 %CI −5.8; 1.4) (Fig. 1B).

4. Discussion

This study aimed to describe the incidence, and survival of vulvar and vaginal cancers in a population-based study in Northern Italy and to report the association with second malignancies.

The study examined a population of 328 patients (264 vulvae and 64 vagina) recorded by the Reggio Emilia Cancer Registry from 1996 to 2021. The mean age at diagnosis was 76.1 years for vulvar cancer and 70.2 years for the vagina. Squamous cell carcinoma was the most prevalent histological subtype in both vulvar and vaginal cancers, with a high proportion of cases confirmed microscopically. Notably, the incidence among foreign women differed between the two tumors, representing 1.5 % of vulvar and 7.8 % for vaginal cancer. This variation may reflect distinct etiological mechanisms: vulvar cancer, especially in elderly patients, frequently develops in the context of chronic dermatoses such as lichen sclerosus, and is largely HPV-independent, whereas vaginal cancer is probably linked to HPV infection, potentially accounting for its higher prevalence among foreign women (Tornesello et al., 2014).

In our region, HPV vaccination has been actively and freely offered to twelve-year-olds since 1997. Those born in 1996 had free access upon parental request, with the offer later extended to individuals born in 1994 and 1995, all entitled to free vaccination up to age 26. Above this age, the vaccine is available at a reduced cost. Since 2006, the free offer has also included males up to age 26. The PNPV sets a 95 % coverage target for females born from 2003 and males from 2006. To date, the cohorts that have achieved the best results are those born in 2006, 2007, and 2008, with coverage above 80 %. The youngest cohort examined, that of 2012, has a full-cycle coverage of 60.9 %, but this is expected to increase over the years, as HPV vaccination is also administered in the years following the active call. In the 1997–2011 cohorts, complete coverage was 75.3 % and 75.1 % in females and 71.8 % and 66.8 % in males, respectively in the Emilia Romagna region and in the province of Reggio Emilia (Salute Regione Emilia-Romagna, 2025).

Furthermore, from July 2019 to November 2022, 4025 women have started HPV-vaccination cycle in RER and 55.5 % of them have already completed it. It was also documented an increase of vaccination coverage for 1995–1996-1997 cohort of 7.7 %, 7.6 % and 4.6 % for 1st dose, respectively, and 5.8 %, 4.1 % and 1.1 % for completed cycle. The mean current coverage is 35.8 %, 60.0 %, 72.9 % for 1st dose and 26.4 %, 52.4 %, 67.7 % for a full course, for 1995–1996-1997 cohort respectively (Giampà et al., 2023). In Italy, a region-based survey conducted in 2022 involved 10,000 Italian women over the age of 18. Among the 3,160 respondents, national HPV vaccination coverage for women over 26 was 26 %, with significant regional differences (Montalti et al., 2024).

Within six months’ post-diagnosis, 5 patients developed second tumors (4 with the vulvar and 1 with vaginal cancers), while metachronous tumors were observed in 25 patients (23 vulvar and 2 vaginal cancer cases). The most recent period analyzed demonstrated a comparable 5-year survival rate of 65 for vulvar and 63 % for vaginal cancers. Incidence trends showed a significant decline for vulvar tumors and a non-significant decline for vaginal cancer, whereas mortality rates remained stable for vulvar cancer and exhibited a slight decrease for vaginal cancer. Although the stage is not present at diagnosis, the information collected on the size reports a decreasing trend for vaginal tumors which went from an average size of 4.3 cm in the years 1996–2000 to 3.5 cm in the years 2016–2021, while no change was observed in the size of vulvar tumors (1.5 cm in the years 1996–2000 vs 3.1 cm in the years 2016–2021).

4.1. Vulvar cancers

Globally, there are approximately 7,500 new cases of vulvar cancer per year (equal to 0.5 % of tumors) and 1,800 deaths (0.3 % of mortality) (National Cancer Institute, 2025). The highest incidence rate is recorded in Western Europe (2.4), followed by North America (1.9) and Northern Europe (1.9) (Huang et al., 2023). The incidence trend increases with age (Bray et al., 2020, Berenson et al., 2022), and reaches a peak in the over 85 s (Mousavi et al., 2024). Although the trend appears to be increasing, it seems that the increase is mainly small tumors < 2 cm, except in the elderly where even the most advanced tumors continue to be diagnosed (Holleczek et al., 2017).

The incidence trend in our cohort showed a significant annual decline of 2.3 %, potentially reflecting the impact of adherence to cervical screening programs (Loud and Murphy, 2017) and, more recently, a first slight positive impact of HPV vaccination (Dattani and Samborska, 2024) cannot be excluded. Regarding 5-year survival, data from the Swedish Cancer Registry indicate an increase in five-year survival from 53 % in the 1960 s to 72 % in 2019 (Moberg et al., 2024), while SEER data reports an excellent 5-year survival at 71 % (Mousavi et al., 2024).

4.2. Vaginal cancers

In 2020, 18,000 new cases were estimated globally with an ASR (Adjusted Standardized Rate) of 0.36 per 100,000 (Ferlay et al., 2024), while approximately 8,200 deaths were estimated with a rate of 0.15 per 100,000, with higher rates in South Central Asia and South Africa. The trend appears to be increasing especially in Iceland, Chile, Burman, and UK (Huang et al., 2024). In France, an incidence rate of 0.2 per 100,000 was recorded (Trétarre et al., 2023), closely resembling the incidence observed in our study in 2021 (0.5 per 100,000). This tumor predominantly affects older women, with a reported average age of 75 years (Trétarre et al., 2023), slightly higher than the 70.2 years observed in our study. Squamous cell carcinoma remains the most frequent histological subtype, followed by adenocarcinoma: HPV infections represent the main risk factor for vaginal cancer (Huang et al., 2024). The incidence trend in our cohort appears to be decreasing, consistent with findings from France (Trétarre et al., 2023), largely linked to the effectiveness of vaccinations (Bray et al., 2020). The 5-year survival rate for vaginal cancer varies across studies, with estimates ranging from 45 % (Trétarre et al., 2023) to 58.7 % (Forner, 2023), aligning with the survival rate reported in our study (63 %). Survival is strongly conditioned by the stage as it goes from 69 % in localized forms to 26 % in advanced forms, especially more frequent in older women (American Cancer Society, 2025).

Women with a history of cervical cancer are at increased risk of developing secondary tumors, with reported mean intervals of 6.5 years and 5.4 years, respectively (Matsuo et al., 2018). Our study identified 30 cases of second tumors in women with primary vulvar and vaginal cancer, underscoring the critical role of surveillance in these patients (Matsuo et al., 2018) and highlighting the importance of HPV vaccination (Bray et al., 2020). Given the anatomical proximity of the vagina to vital organs such as the bladder, urethra, and rectum, surgical treatment is strictly limited for early-stage disease or selected cases. Most vaginal cancer patients undergo radiotherapy, chemotherapy, or a combination of both modalities (Adams et al., 2021). Very important in the management of these patients is having the possibility of a targeted path with an MDT (Multisciplinary Team) (Abu-Rustum et al., 2024, Olawaiye et al., 2021) because it allows management of the patient that takes into account not only the disease but also the aspects related to the person.

4.3. Strengths and weaknesses

This study's strengths include its population-based design spanning 25 years, minimizing selection bias, and providing robust epidemiological insights. The use of a well-established Cancer Registry ensures reliable data on incidence, survival, and second malignancies. The high rate of microscopic confirmation enhances diagnostic accuracy, while findings emphasize the need for specialized management and multidisciplinary care. However, some limitations should be considered when interpreting the results. A first limitation is linked to the lack of information on stage and treatment but this is a population study: the data collected by the CRs includes topography, morphology, date of diagnosis, and follow-up. The possibility of including data on stage and treatment requires a new protocol approved by the ethics committee, allowing us to access the medical records and collect the requested information. It would be particularly important to have information on therapies because the treatment itself could influence the diagnosis of a second tumor. As the study is restricted to a single province in Northern Italy, its findings may not be fully generalizable to other populations with different healthcare infrastructures, risk factor distributions, and screening practices. Another potential limitation is the underestimation of second malignancies, as variations in follow-up duration and reporting practices may have influenced the identification of synchronous and metachronous tumors.

5. Conclusion

This study highlights the significance of registering vulvar and vaginal cancers, which, despite their rarity, present considerable therapeutic challenges, particularly in younger women. Early symptoms enable timely diagnosis, yet increased awareness among healthcare professionals and the public remains essential for improving primary prevention through HPV vaccination and hygiene measures, as well as secondary prevention via cervical screening programs. Additionally, the high incidence of second malignancies underscores the need for long-term oncologic surveillance. Ultimately, this study reinforces the necessity of centralized care, continued research, and targeted awareness efforts to optimize the management and prognosis of these rare but clinically significant malignancies.

Ethics Statement

According to Italian legislation*, population-based cancer registries collect pseudonymised personal data for surveillance purposes that do not need the collection of explicit individual consent, without any direct or indirect intervention on patients, therefore the approval of a research ethics committee was not required.

*Presidente del Consiglio dei Ministri. Decreto del Presidente del Consiglio dei Ministri, 3/3/2017,41 Identificazione dei sistemi di sorveglianza e dei registri di mortalità, di tumori e di altre patologie. 17A03142, GU Serie Generale n.109 del (12-05-2017). Available at: https://www.gazzettaufficiale.it/eli/id/2017/05/12/17A03142/sg last access: February 4, 2025.

CRediT authorship contribution statement

Isabella Bisceglia: Writing – original draft, Investigation, Data curation, Conceptualization. Francesco Marinelli: Formal analysis. Vincenzo Dario Mandato: Writing – original draft, Validation, Supervision. Debora Pirillo: Visualization. Fortunato Morabito: Writing – review & editing. Antonino Neri: Validation, Supervision. Lucia Mangone: Writing – review & editing, Validation, Supervision.

Funding

This study was partially supported by the Italian Ministry of Health – Ricerca Corrente Annual Program 2025.

Data availability

The data presented in this study are available on request from the corresponding author. The data are not publicly available due to ethical and privacy issues; requests for data must be approved by the Ethics Committee after the presentation of a study protocol.