Is the incidence of early-onset cancers increasing in the northeast of Italy? A 30-year analysis of the regional cancer registration data by age, 1987-2019.

Abbreviations

annual percent change

International Classification of Diseases

Veneto Tumour Registry

INTRODUCTION

Cancer is a leading cause of death worldwide. The International Agency for Research on Cancer estimated 20 million new cancer cases in 2022 (19.6 million were recorded in 2020), with approximately one in five men or women developing cancer in a lifetime. 1 Surveillance, Epidemiology, and End Results data estimate that 4.2% of all new cases diagnosed in 2024 in the United States will occur among Adolescents and Young Adults ages 15–39. 2 After decades of increased incidence, they found that the incidence of cancer in children has finally leveled off. However, rates continue to increase among adolescents (ages 15–19 years), including a 4% increase per year in thyroid cancer, which is likely associated with overdiagnosis. 3 In addition, the average age of cancer patients is decreasing. The proportion of cancer diagnoses among middle‐aged people (50–64 years) has increased from 25% in 1995 to 30% in 2019–2020. Meanwhile, the proportion of patients aged 65 and older has decreased from 61% to 58%. This occurred despite an increase in the general population of both middle‐aged and older people (from 13% to 19% for ages 50–64 years and from 13% to 17% for ages 65 and older). 3 , 4 Different types of cancers, including gastrointestinal cancers and multiple myeloma, showed a significant increase among young adults aged 20–50 years, suggesting a possible global epidemic. 5 , 6 In Italy, a 15% increase in the incidence rate was observed between 1990 and 2021 in the 15–49 years group, with 133.6 new cases per 100,000 people in 1990 to 153.1 in 2021. 7

Exploring the cancer burden by age groups may help elucidate risk factors that differ among younger populations in comparison with adults and older populations and can provide information for the implementation of more appropriate, age‐based preventive strategies and control measures. Although incidence of cancer is lower under 50 years of age than above age 50 years, its personal and societal costs are high since it has a significant impact on mortality and morbidity. 8

In the present population‐based study, we aimed to assess the incidence trends of malignancy by site, stratified by age group and sex, during a period of just over 30 years (1987–2019) in a large northern Italian population.

MATERIALS AND METHODS

The context

The Veneto region, which includes the city of Venice, is located in northeastern Italy and has a resident population of more than 4.8 million people. The national healthcare system is based on the fundamental values of universality, free access, freedom of choice, pluralism of supply, and equity. 9 The national benefits package to be guaranteed throughout the country is established by the central government, which also oversees and allocates funding for regional health systems. The regions, through local health authorities, are responsible for financing, planning, and delivering health care at the local level.

Data sources

This retrospective population‐based cohort study draws on epidemiological data of cancer incidence recorded by the Regional Veneto Tumour Registry (VTR). Population coverage increased from 1,154,000 inhabitants in 1987 to nearly 5 million (encompassing the entire regional population) in 2014 (see Table S1 ). The fraction of the population covered by the Registry has risen from 53% in 2008–2013 to 100% (approximately 5 million residents) from 2014 onwards. Table S2 shows that the older registration area gave cancer incidence estimates comparable with the more recent data available for the whole population.

Data are originally recorded according to ICD‐O‐3 classification and transcoded in the International Classification of Diseases, 10th Revision (ICD‐10). 10 , 11 The temporal trends in cancer incidence (standardized for the European population in 2013) were calculated based on the tumor type and sex of the patient.

VTR records all malignancies (ICD‐10 C00–C43, C45–C96), focusing only on invasive cutaneous malignant melanoma (C43) among skin malignancies, as well as non‐malignant tumors of the urinary bladder (D09.0, D41.4), identified according to ICD‐10. 12

Statistics

A joinpoint regression analysis was performed to identify any significant changes in the annual trends (using the European standard population in 2013) of age‐standardized incidence rates for the most frequent cancer sites, stratified by sex and three age classes (0–49, 50–64, and 65 and more years). 13 For each identified trend, the annual percent change (APC) was calculated by fitting a regression line to the natural logarithm of the rates, using the calendar year as a regression variable in the Joinpoint Regression Program 4.6. 13 The number of joinpoints was determined automatically by the software: the program selects the smallest number of joinpoints such that adding one more joinpoint would not yield a statistically significant improvement. Therefore, in the final model, each of the joinpoints and its corresponding changes in trend can be interpreted as significant. The Joinpoint program selects the final model using the Permutation Test method. The graph for each tumor model depicts statistically significant changes in trend.

RESULTS

Current epidemiological profile

In 2019, the VTR recorded 32,782 incident malignancies. Three thousand three hundred sixty‐nine were young (0–49 years old), 8141 were adults (50–64 years old), and 21,272 were old adults (≥ 65 years old) (Table 1 ).

In young adults, the five most frequent cancer sites (breast, invasive cutaneous melanoma, thyroid, non‐Hodgkin lymphoma, and testis) accounted for 59.8% of all malignancies. Melanoma was the most frequent cancer in men, followed by testis cancer (14.7% and 12.5%, respectively). In women, breast malignancies accounted for 43.1% of all incident cancers, followed by thyroid cancer (29.8%).

Cancer incidence rates for women and men stratified in the three age groups are presented in Table 2 and Figure 1 .

In some cancer sites, the model cannot be estimated due to a lack of observed cases; therefore, only the observed values are shown in the graphs: gallbladder in both sexes under 50; esophagus, larynx, pancreas, and multiple myeloma and immunoproliferative diseases in young females; prostate in young males; testis in old adult males.

All cancers combined

Incident rates varied over time across the different cancer sites and age groups. Overall, the incidence of cancer among men has been significantly decreasing in all three age groups even if with different slopes (young: APC −0.3, 95% CI −0.4 to −0.1 [1987–2019]; adults: APC −2.4, 95% CI −2.7 to −2 [2007–2019]; old adults: APC −1.6, 95% CI −1.7 to −1.4 [1998–2019]). On the other hand, cancer incidence among women has shown improvement in the last decade, following a previously rising trend. In fact, the incidence rates for the young group have remained mostly stable since 2014 (APC −0.6, 95% CI −2.0 to 0.7), while rates for the adults have been stable since 2004 (APC −0.3, 95% CI −0.6 to 0). Notably, cancer incidence among older women has been decreasing since 1996 (APC −0.3, 95% CI −0.4 to −0.2).

Mostly increasing trends in the young

Significant increasing incidence trends were observed for invasive cutaneous melanoma in the young population as well as among other age groups in both sexes. The slope was similar in different age and sex groups: APC 2.9 (95% CI 2.3 to 3.5) among young men, and 3.1 (95% CI 2.6 to 3.6) among young women. The trend was significantly higher in old adult men (APC 4.6, 95% CI 4.1 to 5).

Breast cancer has been rising significantly among young women until 2003; it remained steady afterward (APC 1.7, 95% CI 0.9 to 2.6 [1987–2002]; APC 0, 95% CI −0.4 to 0.5 [2002–2019]). Comparable trends were also observed in the other age groups.

Since 1987, testis cancer has been consistently increasing in young men (APC 2.9, 95% CI 2.3 to 3.4); by contrast, incidence rates in adults aged have been mostly stable in the same period.

A significant increase in incidence rates of Hodgkin disease has been observed in young women since 1987 (APC 1.3, 95% CI 0.7 to 1.9); but not in men. At the other end of the age spectrum, in the same period, the incidence rates decreased significantly in old adult women (APC −1.7, 95% CI −2.8 to −0.5 [1987–2019]).

The incidence of multiple myeloma and immunoproliferative disorders among young men fluctuated since 1987, but the overall trend has been upward (APC 1.7, 95% CI 0.5 to 2.8). By contrast, older populations have shown no significant changes in incidence trends since at least 1997.

Mostly decreasing trends in young adults

Between 1987 and 2019, a significant decline in oral cavity cancer incidence was observed among young women (APC −1.2, 95% CI −2.2 to −0.3). Among young men, a marked decline occurred from 2000 to 2012 (APC −8.6, 95% CI −10.9 to −6.3), followed by a period with no significant changes in incidence rates (APC 2.5, 95% CI −1.9 to 7.1).

Regarding the esophagus, we observed significantly declining incidence trends in all ages and sex populations, with the sharpest trend among young men (APC −6.0, 95% CI −7.3 to −4.8). Data on women also showed declining trends, although to a lesser extent, which could not be verified for the young population.

Stomach cancer incidence decreased significantly in all age groups, in both men and women, except in young men in the years 2009 to 2019 (APC 0.5, 95% CI −3.7 to 4.9). Among young women, the decline was less pronounced compared to other age groups (APC −2.0, 95% CI −2.8 to −1.1).

A remarkable decline in incidence rates of rectum cancer has emerged since 2008 in young males (APC −7.6, 95% CI −12.1 to −2.8), following years of overall stability. By contrast, the trend observed in young females was not significant. A significant increase followed by a sharp decline was observed in the other age groups, in both males and females.

A decline in larynx cancer trend was registered in young men (APC −6.7, 95% CI −7.8 to −5.7). This trend was confirmed in older adult women.

In young adults, we observed a decline in incidence rates of lung cancer (males: APC −5.6, 95% CI −6.2 to −5.1; females: APC −1.2, 95% CI −2.0 to −0.3). A decreasing trend in lung cancer was observed in other age classes in men, but not in women.

A slight decreasing incidence trend was also observed in bladder cancer. The decline was significant among males of all ages (young: APC −0.8, 95% CI −1.5 to −0.2; adults: APC −1.6, 95% CI −1.9 to −1.3; old adults: APC −1, 95% CI −1.2 to −0.8 [1994–2019]) and among young women (APC −1.8, 95% CI −3.1 to −0.4 [1992–2019]).

The incidence of non‐Hodgkin lymphoma decreased among young men since 1995 (APC −1.9, 95% CI −2.7 to −1.1) but not in young women. Incidence rates also decreased since 1987 in adult men and in older adult women.

Mixed trends in the young

A sharp increase in corpus uteri cancer was observed in young women between 1987 and 1997, followed by a sharp decline between 1998 and 2010 and a new significant rise after 2010 (APC 3.9, 95% CI 0.1 to 7.8 [1987–1998]; APC −4, 95% CI −7.1 to −0.8 [1998–2010]; APC 4.4, 95% CI 0.9 to 7.9 [2010–2019]). The rise was also detected in other age groups (adults: APC 0.7, 95% CI 0.3 to 1.2 [1987–2019]), and for older adults after 1996.

Thyroid cancer showed increasing trends in women across all age groups until 2013/2014, after which the trends stabilized or even declined. The most significant APC was observed in young women (APC −4.2, 95% CI −7.5 to −0.7 [2013–2019]). In contrast, during the same period, thyroid cancer incidence continued to rise among young (APC 2.4, 95% CI 0.6 to 4.2 [2007–2019]) and old adult (APC 3.4, 95% CI 2.4 to 4.5 [1987–2019]) men, while adult men have not experienced any significant change since 2014.

No significant trends in the young

We observed substantially stable, or with no significant values, incidence trends among young individuals in both sexes with colon, liver, pancreas, cervix uteri, ovary, kidney and urinary tract, brain and central nervous system cancers, and leukemia.

DISCUSSION

In the present study, we have analyzed the incident trends of malignancies in a population under 50 years old (conventionally referred to as early‐onset cancers) in North East Italy, comparing it with the population over 50. Overall, in the analyzed population aged 0–49 years (“the young”), the incident rates of cancers declined in men but increased in women until 2014. During the study period, the incidence rates showed an overall ascending trend in invasive cutaneous melanoma and thyroid cancer in both sexes, cancer of corpus uteri and Hodgkin disease among females, testis cancer and multiple myeloma (and immunoproliferative diseases) among males. Trends were decreasing in oral cavity, stomach, lung, and bladder cancers in both sexes and in esophageal, rectal, laryngeal cancers, and non‐Hodgkin lymphoma only in males. Finally, a series of cancers (i.e., colon, liver, pancreas, breast, cervix uteri, ovary, kidney, and brain cancers and leukemia) had a stable incidence in the young population.

The steepest increase in young cancer incidence concerns cutaneous malignant melanoma. International and national literature has consistently reported an increase in melanoma incidence across all thickness classifications and age groups since the 1990s. 14 , 15 , 16 , 17 , 18 While a recent European study predicts continued growth in melanoma incidence in Southern Europe into the 2030s, 16 Bucchi et al. have noted a stabilization or even a decline in melanoma incidence among Italians under 35 over the last 5 years. 19 This positive trend was attributed by the authors to improved sun exposure and protection behaviors, with benefits expected to extend to a larger portion of the population in the coming years. However, such improvement is not confirmed in our population.

Female breast cancer is the most common cancer both in Europe and globally. 20 , 21 According to the American Cancer Society, it is also the most commonly diagnosed cancer among young women aged 30–39 years. 22 Its significance as a public health concern is supported by the fact that breast cancer is the leading cause of female cancer mortality in many countries, including Italy, both overall and among young adults. 20 , 22 Temporal trends from the VTR reveal that breast cancer incidence among young adults in the Veneto region remained stable between 2002 and 2019, following 15 years of linear growth. These findings align with data from previous Italian and European studies, 23 , 24 which found an increasing trend in 1990–2005 and a plateau since 2010 in most European countries, including Italy. Also, in California, the incidence rates of invasive breast cancer increased by 0.8% per year from 1988 to 2001 and decreased by 4.4% per year from 2001 to 2004 among women aged 40 years and older, as well as in women with all histologic subtypes, tumor sizes, hormone receptor‐defined types, and all stages except distant disease. The author noted that the most significant change in risk factors observed since 2001 was the relative decrease in the percentage of women reporting the use of combined estrogen and progestin hormone therapy. Other risk factors, such as low Body Mass Index, nulliparity, late age at first birth, contraceptive use, and alcohol consumption, did not decrease during this period. Nevertheless, our results show that, since 2007, incidence rates among older adults have begun to rise again, with an annual percentage change of 1.1%, compared to sustained stability in the young population. The current trends in our analyses and consistent patterns by age group prompt an exploration of non‐biological factors that may be involved in stabilizing the incidence profile, such as the design of prevention strategies or changes in diagnostic criteria, as already documented for thyroid or prostate malignancies. The increase in breast cancer rates before the 2000s could result from increased voluntary access to diagnostic imaging prior to the launch of regional screening programs. Such “diagnostic anticipation” could partially explain the flattening cancer incidence documented in the following years. 25

Testicular cancer is the most common malignancy among young adult males, with incidence peaking in the 25‐ to 34‐year age range. 26 , 27 Over the past few decades, incidence rates for this cancer have been reported to rise among young adults in most developed countries, 28 including Italy. 24 However, the underlying cause of this international upward trend remains unclear. 28 Data from the VTR align with previous findings, showing a consistent upward trend since 1987, with an APC of 2.9.

Aggregated data on incidence rates of Hodgkin lymphoma in young populations show stable incidence rates since the 2000s in most countries. 28 , 29 Data from the VTR, on the other hand, reveal a long‐lasting upward trend in Hodgkin disease incidence among females. A similar gender difference was previously reported in an American study by Zhu et al., 30 which observed that while female incidence rates were initially lower than male rates in 1973, they increased over subsequent years, eventually aligning with the mostly stable rates seen in males. In the Veneto region, incidence rates of Hodgkin's disease among young females keep increasing, exceeding those observed in males, a trend that should be investigated and validated in future studies.

The incidence of multiple myeloma varies widely across the globe, with European countries, along with North America and Australasia, reporting some of the highest rates. 31 Data from Cancer Incidence in Five Continents suggest a slight, although not statistically significant, decline in incidence for both younger and older age groups in Italy. 32 However, data from the VTR align more closely with the results of a study of 25 US cancer registries, 33 with a significant upward trend in young men, compared to a more stable trend in the older population. Further studies should provide more insights into the risk factors for this disease in young adulthood to explain this worrying upward trend.

Although mortality from corpus uteri cancer is declining in most European countries, including Italy, 34 its incidence has increased in many countries worldwide over the past decade. 35 According to data from Cancer Incidence in Five Continents, this upward trend does not extend to Italy, regardless of age group. 36 However, data from the VTR indicate a fluctuating pattern of incidence for corpus uteri cancer among young women in Veneto, with a significant increase observed in the last decade. Factors that might play a role in the increase in uterine body cancer include obesity, changes in reproductive behavior—such as increased use of oral contraceptives, delayed delivery, nulliparity—and the use of estrogen hormone therapy. 37 , 38

Thyroid cancer exhibits sex‐specific trends, largely attributed to overdiagnosis. Both global 39 and Italian 40 , 41 studies have reported similar patterns, linking the rise in cases to the increased detection of indolent papillary thyroid cancers made possible by advancements in imaging technology. Consistent with data from the VTR, this phenomenon appears to affect females disproportionately. However, prevalence from US autopsy data shows no significant gender differences in the occurrence of subclinical thyroid cancer. 42 Proposed explanations for the higher rate of overdiagnosis in females include greater engagement with healthcare services, driven by reproductive health monitoring and behavioral factors, as well as increased clinical attention from physicians as a consequence of a broader scientific focus on hormonal factors in females and autoimmune thyroid diseases. 42 Therefore, the increased incidence of thyroid cancer observed in 2019 compared to 1987 is unlikely to result in higher morbidity or mortality within the population. 43 On the other hand, overtreatment and lifelong medical care caused by overdiagnosis can significantly affect patients' quality of life. 44 In line with the reason outlined by previous literature, the temporal trends drawn from the VTR are similar in shape for young adults and older people. Up to 2019, thyroid cancer incidence rates among men continued to rise, whereas rates among women peaked in 2013 and subsequently declined significantly.

Our analysis reveals a decline in the incidence of cancers of the oral cavity, esophagus, stomach, rectum, larynx, lung, bladder, and non‐Hodgkin lymphoma. These trends align with findings from other studies focusing on European countries 24 , 45 , 46 ; however, according to VTR data, the incidence of esophageal cancer, rectal cancer, laryngeal cancer, and non‐Hodgkin lymphoma has decreased among men but not among women. Except for non‐Hodgkin lymphoma, all cancers showing a declining trend are associated with smoking or drinking behavior, underscoring the positive impact of behavioral and cultural changes in recent years, also supported by the success of awareness campaigns. 33 , 47 , 48

According to VTR data, leukemia and cancers of the colon, liver, cervix uteri, ovary, and kidney have decreased among older populations but not among younger individuals. These findings largely align with an earlier Italian study by Stracci et al., who reported no decrease in the incidence of these malignancies among the population under age 50. 24 The main exceptions are represented by liver cancer in men, which showed a decreasing trend, and kidney and urinary tract cancer in men (increasing trend). According to previous literature, the incidence of liver cancer and particularly hepatocellular carcinoma is decreasing in many countries, including Italy, mainly due to reduced exposure to risk factors such as HBV, HVC, and aflatoxin. 1 , 41 , 49 Although VTR data show downward trends among adults aged 50–64 and those over 65, the slope among younger adults does not reach statistical significance for either men or women. Conversely, trends in kidney cancer incidence among young adults remain a subject of debate, as most European studies focusing on all‐age populations have reported declining rates in many countries. 50 Finally, international data on colon cancer incidence rates among young people are heterogeneous, 51 likely due to a combination of environmental and lifestyle factors that are not yet fully understood. 52 The VTR figures are consistent with previous literature showing that, in Italy, colon cancer incidence rates have not changed significantly among young adults. 51 , 53

This study has some limitations. It did not allow the calculation of the trend for all age groups since for gallbladder and prostate cancer and for tumors of the esophagus, pancreas, larynx, and multiple myeloma in women it was not possible to calculate the APC in the young group, since incident cases were missing in one or more years. Secondly, the significance level was set at 0.05 for each test; so we cannot exclude that some results may be statistically significant due to chance. Finally, the results of the present study may have low representativeness on a global scale since it focused on data in the northern Italian region. However, the risk of selection bias is minimized by its population‐based design, and the measurement variability is reduced by using standardized algorithms following international guidelines, 54 hence increasing the reliability of the values.

CONCLUSION

Understanding age‐specific cancer incidence trends is a crucial aspect of health research. In particular, investigating cancer incidence in young populations provides valuable insights into the expected evolution of cancer epidemiology in the coming years. Such knowledge can inform the future allocation of healthcare resources and guide research efforts to identify and address risk factors associated with cancer development.

AUTHOR CONTRIBUTIONS

Alessandra Buja: Conceptualization; methodology; project administration; writing – review and editing. Chiara Trevisiol: Methodology; visualization; writing – original draft; writing – review and editing. Andrea Miatton: Methodology; visualization; writing – original draft; writing – review and editing. Stefano Guzzinati: Data curation; writing – review and editing. Emanuela Bovo: Formal analysis; visualization; writing – review and editing. Simone Mocellin: Conceptualization; funding acquisition; writing – review and editing. Alberto Fantin: Conceptualization; writing – review and editing. Massimo Rugge: Conceptualization; writing – review and editing; supervision. Vincenzo Bronte: Conceptualization; supervision; writing – review and editing. Manuel Zorzi: Data curation; resources; writing – review and editing.

FUNDING INFORMATION

This research has received “Current Research” funds from the Italian Ministry of Health to cover publication costs.

CONFLICT OF INTEREST STATEMENT

The authors declare no conflicts of interest.

ETHICS STATEMENT

This retrospective study involving human participants was in accordance with the ethical standards of the institutional research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. The data used for this study was procured by the Veneto Regional Health System, which provided de‐identified data. Any possibility of individual identification was removed. Personal data were used in anonymous aggregate form. Since the data used for the study were deidentified and anonymous, the pertaining ethics committee ensured a waiver of consent as per the Italian and European laws on privacy and data protection.

Supporting information

Table S1. Average population covered by the Veneto Cancer Registry (RTV).

Table S2. Age‐standardized incidence rates (ASR) per 100,000 residents for the historical area (HA) and whole region for cancer sites and sex. Period 2014–2019 (European 2013 Standard Population).

ACKNOWLEDGMENT

Open access funding provided by BIBLIOSAN.

DATA AVAILABILITY STATEMENT

The data supporting this study's findings are held by the Veneto Epidemiological Registry and were used under license for this work. The anonymized minimal data set necessary to replicate our findings has been made publicly available at the following link: https://doi.org/10.6084/m9.figshare.28254605 . Further information is available from the corresponding author upon reasonable request.

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