Cancer incidence in the age range 0–34 years: Historical and actual status in Denmark

Authors


Abstract

On the basis of 55 years of continuous cancer registration in Denmark, we present cancer incidence rates, time trends and birth cohort analyses for persons aged 0–34 years. The group of 40,750 cancer patients showed a substantial over-representation of males aged 1–24 years. The cancer pattern among young (15–34 years) men was dominated by testicular cancer (35%), lymphomas (14%) and tumors of the brain (13%), while the pattern among young women was governed by invasive cervical cancer (19%), malignant melanoma (15%) and cancer of the breast (12%). In this age range, a positive time trend was seen after 1970, equivalent to average annual percentage increases of 1.9% for men and 1.8% for women, due mainly to markedly increasing trends for testicular cancer, malignant melanoma, brain tumors, thyroid cancer, skin carcinomas and skin sarcoma among men, and for brain tumors, non-Hodgkin lymphoma, malignant melanoma, skin carcinomas and thyroid cancer among women. We saw no clear time trend for breast cancer among women. The cancer pattern among children (0–14 years) was similar to that reported for other white populations. © 2005 Wiley-Liss, Inc.

Denmark has a population of 5.4 million, 43% of which is below the age of 35 years and 19% below the age of 15 years, in the year 2005. Although less than 5% of all cancers are diagnosed in this age group,1 the consequences of malignant disease early in life may be severe for both the individual and the family. Treatment of cancer at a young age has its own aggregate of late effects in terms of treatment-induced chronic disease, sequelae that affect working life and family function, compromised fertility and fear of transmission of treatment-induced gene mutations to subsequent generations.2 Close surveillance of cancer patterns and of time trends of early-onset cancer is, therefore, of great importance. As stressed by Sir Richard Doll, the study of cancer trends in young adults is important for 2 further reasons: first, because the trends can reflect only relatively recent changes in the prevalence of carcinogenic agents and are not confounded by the effects of changes in the past; and, second, because young people tend to adopt new habits before older persons.3

In Denmark, data of high quality are available on cancer incidence for a consecutive period of 55 years.4 In previous publications, we reviewed the pattern of incidence of cancer in children and adolescents;5, 6, 7 here, we present data for the entire age range 0–34 years, stressing the size of the problem, sex ratios, age-specific incidences, time trends and birth cohort analyses.

Material and methods

Data for our study were extracted from the files of the Danish Cancer Registry.1 All cases of primary cancer (which includes benign tumors of the brain and intracranial meninges, benign tumors of the urinary tract and carcinomas of the skin, the latter including basal cell as well as squamous cell carcinomas) diagnosed during the period 1945–99 in persons aged 0–34 years were included. The Danish Cancer Registry was established in May 1942 to register all cases of cancer in the national population. The Registry receives notifications of all such diseases from hospital departments and practising specialists, at diagnosis and when changes are made to the initial diagnosis. In addition, reports are received from pathology departments and departments of forensic medicine, giving the results of autopsies of cancer patients. Cases first diagnosed at autopsy, i.e. as incidental findings, are also included in the Register. This information is supplemented by an annual review of all death certificates and, since 1987, by an annual search of the Danish National Hospital Patient Registry for unreported cases of cancer. Cases identified in the latter search are traced by sending a letter to the treating hospital, requesting a standard notification. No case is included on the basis of information from the Patient Registry only.

Since 1 January 1978, diagnostic information has been coded according to the International Classification of Diseases for Oncology (ICD-O-1), which permits coding of neoplasms by topography, histology and behavior.8 Before that date (1945–77), tumors were coded according to a modified version of the International Classification of Diseases, Seventh Revision (ICD-7), which is based mainly on tumor topography.9 To present incidence data across the periods, 1945–77 and 1978–99, 2 solutions were chosen. For childhood cancer cases, we applied the ICD-O-1 classification and the Birch and Marsden Childhood Cancer Classification scheme used by the International Agency for Research on Cancer and based on the ICD-O-1,10, 11 for the entire period 1945–99, because the childhood tumors notified during the early period had already been reevaluated and recoded according to the ICD-O-1, as part of a previous study.5 For cancers diagnosed in persons aged 15–34, we applied (whenever appropriate) the ICD-7 classification for the entire period, as the Cancer Registry has developed a computer program that automatically converts ICD-O-1 codes into the modified ICD-7 codes used by the Registry. Because different coding was used for childhood tumors and cancers in young adults, the main diagnostic groups are not identical. Table I lists major similarities and differences between the definitions of the main diagnostic groups of the childhood cancer classification scheme and those of the ICD-7.

Table I. Overview of Major Diagnostic Groups in the Birch and Marsden Childhood Cancer Classification Scheme and the 7th Revision of the International Classification of Diseases (ICD-7)
Birch–Marsden scheme (0–14 years)ICD-7 (15–34 years)
No.Diagnostic groupNo.Diagnostic group
  • 1

    Includes all lymphomas and reticuloendothelial neoplasms other than Hodgkin's disease.

  • 2

    Includes benign and malignant tumors of the CNS as well as malignant tumors of the peripheral nervous system.

ILeukemias204Leukemias
IIaHodgkin's disease201Hodgkin's disease
IIb–fNon-Hodgkin lymphoma1 and  reticuloendothelial neoplasms200, 202Non-Hodgkin lymphoma
IIICNS and miscellaneous intracranial  and intraspinal neoplasms193Brain and nervous  system tumors2
IVSympathetic nervous system tumors,  mainly neuroblastoma  
VRetinoblastoma  
VIRenal tumors180, partlyCancer of kidney  parenchyma
VIIHepatic tumors155.0Liver cancer
VIIIMalignant bone tumors196Malignant bone tumors
IXSoft-tissue sarcomas197Connective tissue tumors
XGerm-cell, trophoblastic and other  gonadal neoplasms175, 178Ovarian and testicular cancer
XIbThyroid carcinoma194Thyroid cancer
XIdMelanomatous neoplasms190Malignant melanoma of skin
XIa, c, eOther carcinomas and other  malignant epithelial neoplasms140–148Cancer of the buccal cavity  and pharynx
151Stomach cancer
153–154Colorectal cancer
160Lung cancer
170Breast cancer
171Cervical cancer
172–173Uterine cancer
181Bladder cancer
191Skin carcinomas and sarcomas
192Cancer of the eye and lachrymal  glands
140–179Other specified sites
XIIOther and unspecified malignant  neoplasms198–199Cancer of secondary and  unspecified sites

To have an overview of the latest patterns of cancer in children and young adults while keeping enough cases for calculating reliable rates, we conducted detailed analyses of the subgroup of cancers diagnosed during the period 1985–99. Age-specific rates were calculated per 100,000 males and females per year, with 4 age groups of children (0, 1–4, 5–9 and 10–14) and 4 of young adults (15–19, 20–24, 25–29 and 30–34) and all Danish citizens in related calendar years and age groups as the denominators. The overall rates of cancer in children and young adults were derived by direct standardization with the “world standard population” to eliminate the effects of changes in the age structure during the study period and to allow comparisons with the incidence statistics of other countries.12 Trends in the incidences of cancers at selected sites and cancers at all sites combined were calculated for the entire study period (1945–99) with the age-standardized incidence rates for 11 consecutive 5-year calendar periods, and were tested by linear regression. Also, the slope of the regression line for the period 1970–99 was used to estimate the average annual percentage changes (AAPCs) for cancers at selected sites and all sites combined in children and in young men and women. As the time trends appeared to change after 1970, AAPCs were calculated for the period 1970–99. Diagnostic groups comprising less than 50 cases were excluded from this analysis.

For the commonest types of cancers in young adults, we also calculated age-specific rates for a set of period-of-birth cohorts, in 8 consecutive 10-year periods (1910–19, 1920–29, 1930–39, 1940–49, 1950–59, 1960–69 and 1970–79). Only cancers of increasing incidence over subsequent birth cohorts were chosen for illustration.

Results

Incidence rates

During the period 1945–1999, cancer was diagnosed in 40,750 persons (48.7% male and 51.3% female) under the age of 35 (Table II). This is equivalent to about 740 new cases of cancer per year in Denmark. Nineteen percent of the cancers were in children (aged 0–14 years) and 81% in young adults (Table II). Death certificates were the only source of information in 1.1% of the cases, the percentage ranging from 4.2% at the beginning of the period to 0.1% at the end. More than 90% of the cases were confirmed histopathologically or cytologically, the percentage ranging from 81% in the 1940s to 96% in the 1980s and 1990s. Figure 1 shows the male:female ratio in cancer incidence in various age groups during the period 1985–1999. Cancer was commonest among male children and adolescents, except during the first year of life, when more malignancies were seen in girls. Among persons aged 25 or older, cancer was again diagnosed more often in women than in men.

Figure 1.

Age-specific male:female ratio of incidence rates for cancers at all sites combined among persons aged 0–34 years, Denmark, 1985–99.

Table II. Numbers and Rates of Early-Onset Cancers in Denmark (1945–99) by Age at Diagnosis and Sex1
Age group (years)MalesFemalesBoth sexesPopulation (Denmark)Percent of all cancer cases
No.Rates2No.Rates2No.Rates2In mio.%
  • 1

    Average population figures for the period were used.

  • 2

    Rates per 100,000 in the age groups; age-standardization (World Standard) was used when 5-year age groups were combined.

All19,85526.220,89527.140,75026.72.47513.7
0–144,37415.13,43212.47,80613.81.06210.7
 0–42,00720.11,64717.33,65418.70.3670.3
 5–91,22712.38699.12,09610.80.3570.2
 10–141,14011.59169.62,05610.60.3570.2
15–3415,48137.417,46341.932,94439.61.41293.0
 15–191,87318.71,29713.63,17016.20.3670.3
 20–243,11131.12,33024.25,44127.70.3680.4
 25–294,51545.94,86851.09,38348.40.3570.9
 30–345,98262.48,96895.714,95078.90.3471.4

The relative frequency of the main diagnostic groups of cancer in childhood (at age 0–14 years) is shown in Figure 2. Leukemias and neoplasms of the central nervous system (CNS) were each the cause of 30% of all malignancies in this age group. Lymphomas represented 8% of all tumors, followed by soft-tissue sarcomas, sympathetic nervous system tumors and renal tumors, with 6% in each group. The relative frequency of each of the other diagnostic groups was 3% or less. The average age-standardized incidence rate of cancers at all sites combined during the period 1985–99 was 17.6 per 100,000 in boys and 14.9 in girls (not shown in figure).

Figure 2.

Relative frequency of cancer in children (annual average, 145 cases) in Denmark during 1985–99.

Figure 3 shows the relative frequency of the main diagnostic groups in young adults (aged 15–34 years). More than one-third of all malignancies were tumors of the breast or the reproductive organs, as testicular cancer accounted for 35% of all cases among men, and cervical cancer accounted for 19% and breast cancer for 12% of tumors in women; ovarian cancer represented 4% of all female cancers. Lymphoma was the second most common group of malignancies in young men, representing 14% of all tumors, while melanomas of the skin were the second most common cancer in young women, comprising 15% of cases. Tumors of the brain and nervous system accounted for 13% of all cases in men and 11% in women.

Figure 3.

Relative frequency of cancer in young adults (annual average, 831 cases) in Denmark during 1985–99.

Figures 4 and 5 show the rapidly changing patterns of cancer during childhood and young adulthood, respectively. CNS neoplasms were the most common subgroup of tumors in children, with the exception of the age group 1–4, for whom leukemia was more common. Leukemias and tumors of the brain and nervous system were commoner among males than females, except during the first year of life. The high incidence of these tumors in female infants explains the low overall male:female ratio during the first year of life (Fig. 1).

Figure 4.

Age-dependent changes in ranking of most frequent cancers in boys and girls aged 0–14 years, 1985–99. Incidence rates are presented per 100,000 of population.

Figure 5.

Age-dependent changes in ranking of most frequent cancers in males and females aged 15–34 years, 1985–99. Incidence rates are presented per 100,000 of population.

Neuroblastomas (principal tumor of sympathetic nervous system tumors), retinoblastoma and renal tumors were common neoplasms among children under 5, but the incidence decreased with age, and these tumors contributed little to the overall pattern of cancer among children from age 10 and more (Fig. 4). In contrast, the rate of malignant bone tumors showed a peak during adolescence, when bone formation is accelerated, and that of Hodgkin's disease showed a peak in the age group 25–29. After an early peak in the incidence of non-Hodgkin lymphoma in boys aged 5–9, the rates of both sexes increased steadily with age in young adults. The transient elevation of rates during the first year of life was due to cases of reticuloendothelial neoplasms included in this diagnostic group (mainly cases of Letterer-Siwe's disease).

Testicular cancer was the commonest cancer in young men, the incidence rate increasing rapidly with age (Fig. 5). Similar patterns were seen for invasive cancer of the cervix and cancer of the breast in young women. Although the age-specific rates of testicular cancer exceeded those of cancers of the cervix and breast combined up to age 30, this pattern was not seen in the age group 30–34. The incidence of tumors of the skin increased rapidly with age, the incidence of melanoma being more than two times higher in young women than in young men.

Time trends

During the period 1945–1999, the overall tumor incidence increased among both children and young adults (Fig. 6), most of the increase occurring after 1970. AAPCs were, therefore, calculated for cancers at specific sites and at all sites combined for the latter period. The results for young men are illustrated in Figure 7 and that for young women in Figure 8. After 1970, the average increase in the incidence of all malignancies in children was about 1% (incidence: 13.3 per 100,000 in 1970–74 and 16.6 in 1995–99), due almost entirely to a substantial increase in the group of CNS neoplasms (AAPC, 2.3%). The increase was seen from the start of registration, but was particularly steep during the most recent 15–20 years. Striking increases were seen in the subgroup benign CNS neoplasms and also in the subgroup astrocytomas, while the incidences of other malignant CNS neoplasms combined remained stable. Thus, benign CNS neoplasms, which formed approximately 15% of the entire CNS group in the 1940s, 1950s and early 1970s, made up 55% of this group in the late 1990s. Similar figures for astrocytomas were 30 versus 50%, and for other malignant CNS neoplasms, 55 versus 45%. The incidences of leukemia—the other major childhood cancer—and of non-Hodgkin lymphomas and Hodgkin's disease rose only slightly during the study period, with AAPCs of 0.2–1.3%. After an increase in the incidence of sympathetic nervous system tumors during the period 1955–80, the rates were stable up to 1995 and appeared to decrease recently.

Figure 6.

Trends in incidence of all neoplasms diagnosed among persons under age 35 in Denmark, by age group.

Figure 7.

Average annual percentage change in cancer incidence by site diagnosed in males aged 15–34 in the period 1970–99 in Denmark. Number of cases in parentheses.

Figure 8.

Average annual percentage change in cancer incidence by site diagnosed in females aged 15–34 in the period 1970–99 in Denmark. Number of cases in parentheses.

Interestingly, the low male:female ratio in cancer of infancy (Fig. 1) seen during the most recent period of investigation (1985–99) seems to differ from an average ratio of 1.26 seen during the entire period 1945–84 (not shown in figures). This development over the last 15 years was primarily due to an increasing number of CNS neoplasms diagnosed in female infants in Denmark. Sex-ratio estimates for this particular age group and calendar period were, however, based on limited number of observations, and the associated trend was of borderline significance only.

Since 1970, the AAPC for all malignancies in young adults was 1.9% for men (Fig. 7) and 1.8% for women (Fig. 8). The AAPC for testicular cancer was 2.5%, but the incidence of this relatively common tumor in young men showed steeply increasing rates over the entire study period, from 4.8 per 100,000 in 1945–49 to 17.7 in 1995; this site accounted for the largest excess in cancer incidence during this period. Figure 9 shows the age-specific incidence curves for testicular cancer in successive birth cohorts. The distance between the curves indicates a particular effect in the post-war generations, although the increase appeared to level-off in the cohorts born between 1970 and 1979. In contrast, little change was observed in the rates of cancers of the breast (AAPC, 0.5%) and cervix (AAPC, 0.6%). Although the rate of cervical cancer increased slightly in the 1970s, after a downward trend in the 1960s, it has actually been decreasing somewhat since 1980. A slight upward trend was observed in the incidence of breast cancer between the late 1950s and the late 1980s, but no increase was observed in the most recent period. No changing patterns were seen for cancers of the breast or cervix, according to birth cohort.

Figure 9.

Age-specific incidence rates of testicular cancer by birth cohort in Denmark, 1945–99.

Skin sarcomas in men showed the highest AAPC during 1970–99 (16.8%), mainly due to a peak in incidence in the early 1990s; the increase was due entirely to an increased number of Kaposi sarcomas, with 100 cases during the period. More recently, a decrease was observed. Only 43 cases of skin sarcoma were observed in females during the last 30 years, 4 being Kaposi sarcomas.

The incidence of melanomas of the skin among young adults has been rising since 1945, whereas the incidence of skin carcinomas began to rise after 1960. The associated AAPCs for the period 1970–1999 were 2.7% and 3.7%, respectively, for young men, and 4.3% and 5.7%, respectively, for young women. Steeper curves were observed for both tumor types in younger birth cohorts, illustrated in Figure 10 for malignant melanoma of the skin among women.

Figure 10.

Age-specific incidence rates of melanoma of the skin in females by birth cohort in Denmark, 1945–99.

As in children, the incidences of tumors of the brain and nervous system in young adults (the latter including tumors of the CNS as well as tumors of the peripheral nervous system) more than doubled during the period 1970–99, with AAPCs of 2.9% for men and 3.0% for women; however, no clear birth cohort effect was seen. The incidence of thyroid cancer also increased during the study period. The AAPC was 3.0% for men and 4.6% for women per year, but the former was based on only 115 cases. Again, the birth cohort pattern among women showed the strongest effects in post-war generations (Fig. 11); the numbers of cases in men were too small for meaningful results.

Figure 11.

Age-specific incidence rates of thyroid cancer in females by birth cohort in Denmark, 1945–99.

The rates of leukemia in young adults decreased slightly in both sexes (AAPC, 0.5% in men and 0.2% in women). Of the lymphomas, the subgroup of non-Hodgkin lymphomas showed the greatest increase (AAPC, 2.4% in men and 3.5% in women). No birth cohort pattern was seen.

Discussion

This work describes the time trends and patterns of incidence of cancer in children, teenagers and young adults, covering the entire age-range of 0–34 years. This age-range displays a very broad range of tumors in regard to histology and possibly etiology. The treatment of cancer among the young has become increasingly successful, and many are able to have children of their own. Consequently, the possible effects of curative treatments on inherited disorders in young cancer survivors are becoming more and more important. Further, young adults diagnosed with cancer at ages 20–34 years are often overlooked in studies of late effects. In spite of the different classification schemes for children and young adults used by the Cancer Registry over time, this study may help to form a general view of the fast but smooth changes of the cancer pattern that occurs over this particular age-range in an European population, and we think that the data may be helpful for researchers in their planning of studies of transgenerational effects of cancer treatments.

Since the late 1970s, the incidence of cancers at all sites combined has increased in children as well as in young adults, due mainly to marked increases in the rates of brain and nervous system tumors in all age groups, in testicular cancer in young men, in malignant melanoma and skin carcinomas in young adults of both sexes, in non-Hodgkin lymphoma in young adults and in thyroid cancer in young women. In addition, we saw a quantitatively less important but large relative increase in the rate of skin sarcoma in young men, with a peak in the early 1990s reflecting the large number of young men with Kaposi sarcoma at that time inadequately treated for AIDS. None of the increases reported were offset by concurrent decreases in the rates of less well-defined or unspecified cancers. We have, however, no good explanation for the rather abrupt increase in the overall rate of cancer, which started in the late 1970s. Although the Registry adopted the ICD-O by 1 January 1978, no changes were introduced neither in the criteria for reporting cases to the Cancer Registry nor in practical procedures followed by the clinics. The proportion of cases known from death certificates only decreased from some 4% in the 1940s to around 0.4% in the late 1970s, where it has remained ever since. Also, the proportion of cancers verified by cytological or histological examination has been close to 100% since the late 1970s. Noteworthy, 4 of the 6 commonest cancers in Denmark—lung cancer, colorectal cancer, prostate cancer and cancer of the bladder—were barely represented in the age group 0–34. Cancer of the female breast and skin carcinomas, both major cancers at older ages, were well represented among young adults.

Our study shows a remarkable change in the male:female ratio of cancer incidence by age, with an excess of cancers in female infants during the first year of life and among women after the age of 25. A predominance of cancer in male children has been reported in many populations,13 whereas a predominance of cancer in female infants has been reported only in the USA,14 mainly due to a predominance of leukemia in girls. The predominance of female infants in our study was a recent development (1985–99) and was due almost entirely to an increasing number of children with CNS neoplasms. The trend, however, was based on limited number of observations in this age group, and the possibility of a chance finding cannot be excluded with reasonable confidence. A predominance of cancer among young adult women was also reported from Canada and the USA; as in Denmark, the rates of female breast cancer and cervical cancer combined exceeded the rates of testicular cancer among persons after the age of 30 in the USA, and malignant melanoma was commoner among young women.15, 16

The incidence of childhood cancer is higher in Denmark than in most other countries in Europe13 and in the USA15 and Australia.17 Most of the difference is due to the high rates of CNS neoplasms, in Denmark, even though upward trends in astrocytomas have also been observed in other parts of Europe,18, 19 the USA (CNS tumors)20 and in Australia (astrocytomas).17 The incidence of leukemia rose only slightly during the study period (AAPC, 0.2%). After an increase in the incidence of sympathetic nervous system tumors in Denmark up to 1984,5 the rates appeared to stabilize or even decrease during the past 20 years.

The overall incidence rate of cancer in young adults is close to that reported from the USA;15 however, the rates of site-specific cancers differ significantly. For instance, the incidence rate of testicular cancer in Denmark is among the highest in the world,21 even in comparison with the other Nordic countries:22 in the age group 15–34, the rate is approximately two times higher in Denmark than in the USA.15 Cryptorchidism is a known risk factor for testicular cancer; however, despite increasing trends worldwide21 and numerous studies, no other causal factors have been identified. Our birth cohort analyses showed an effect on incidence, which was particularly strong in the early post-war generations. This nevertheless now seems to be phasing out.

Invasive cases of cervical cancer were observed twice as frequently in Denmark as in the USA.15 The incidence in young women was in fact even higher, as a marked decrease was observed in the late 1960s in conjunction with the introduction of the Papanicolaou smear technique a few years previously and with the organization of screening programmes.23, 24 The primary cause of cervical cancer is chronic infection with one or more of a subset of types of human papilloma virus, mainly acquired through sexual activity.25

The high incidences of tumors of the brain and nervous system observed in young adults can be explained at least in part by the inclusion in this category of all types of benign intracranial tumors. Thus, during the late 1990s, the subgroup of benign CNS neoplasms made up 55% of the entire category. The only known risk factors for brain tumors are ionizing radiation and some rare heritable conditions,26 and these factors cannot explain the substantial increase in rates over time seen in this study. A more likely explanation for the upward trend is the increasing use of diagnostic imaging,27 although other factors cannot be excluded.

The incidence of malignant melanoma has been rising in most white populations around the world for decades;28 in the USA, it was the most rapidly increasing malignancy during the 1980s.29 Although the rates in young adults have been stabilizing or even falling in some countries,28, 29 the birth cohort pattern observed in this study indicates that the rates in young Danish adults will continue to increase. Melanoma is due mainly to exposure to natural sunlight, as is skin carcinoma.29 The birth cohort pattern was similar for both types of skin cancer, with a particular effect in the generation born in the 1960s when charter flights to southern Europe became common, leading to periodic and intensive whole-body exposure to solar radiation. As skin carcinomas are under-diagnosed and probably underreported in Denmark, at least some of the increase over time may be due to greater awareness of the disease among physicians.

The largest difference in cancer incidence between young adults in the USA and Denmark was seen for thyroid cancer, the rate being approximately 70% lower in Denmark. This relatively low incidence of thyroid cancer in Denmark has been reported previously,30 but no reasonable explanations have been proposed. Ionizing radiation appears to be the most important of the known risk factors for thyroid cancer in children and young adults but probably cannot explain the clear increase seen in women.31

The rates of leukemia and lymphoma in young Danish adults were somewhat lower that those seen among young adults in the USA. The increasing rate of non-Hodgkin lymphoma in young adults in Denmark has been reported in Denmark previously.32 Changing definitions of this tumor and better diagnostic methods may explain the observed increase only partly.

Acknowledgements

We are indebted to Sidsel Helle Boesen from the Institute of Cancer Epidemiology for technical help in statistical analyses and data management.

Ancillary