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Background Merkel cell carcinoma (MCC) is a rare skin cancer that was recently found to be associated with a polyomavirus and with immunosuppression, provoking new interest in its epidemiology. We conducted a nationwide study in Denmark to describe MCC incidence and mortality and the association between MCC and other cancers. Methods We used data from Danish national health and population registers on MCC diagnoses, deaths, and population counts during the study period (1978-2006) to calculate MCC incidence rates, cumulative risks of MCC at age 100 years, and MCC mortality rates by tumor stage. We used Poisson regression to estimate the excess mortality rate ratio attributable to MCC and examined associations between MCC and other cancers diagnosed before and after the MCC diagnosis using standardized incidence rate ratios (SIRs). All statistical tests were two-sided. Results Between January 1, 1978, and December 31, 2006, 185 persons were diagnosed with MCC in Denmark. MCC incidence between 1995 and 2006 was 2.2 cases per million person-years. In the first year after MCC diagnosis, 22% of persons with localized disease died compared with 54% of patients with nonlocalized disease; by 5 years after diagnosis, the proportions of MCC patients who had died increased to 55% and 84%, respectively. MCC incidence was statistically significantly increased more than 1 year after a diagnosis of squamous cell carcinoma of the skin (SIR = 14.6, 95% confidence interval [CI] = 8.4 to 25.6), basal cell carcinoma (SIR = 4.3, 95% CI = 2.7 to 6.6), malignant melanoma (SIR = 3.3, 95% CI = 1.1 to 10.3), chronic lymphocytic leukemia (SIR = 12.0, 95% CI = 3.8 to 37.8), Hodgkin lymphoma (SIR = 17.6, 95% CI = 2.5 to 126), and non-Hodgkin lymphoma (SIR = 5.6, 95% CI = 1.4 to 22.4). Squamous cell carcinoma (SIR = 12.1, 95% CI = 5.1 to 29.1) and chronic lymphocytic leukemia (SIR = 14.7, 95% CI = 3.7 to 58.8) occurred in statistically significant excess more than 1 year after MCC diagnosis. Conclusions These results support the existence of shared risk factors for MCC and other cancers. Heightened awareness of the association between MCC and other cancers, particularly squamous cell carcinoma and chronic lymphocytic leukemia, may facilitate earlier clinical detection and treatment of MCC, thereby improving patient survival. DOI: 10.1093/jnci/djq120

Background Cryptorchidism, hypospadias, and testicular germ cell cancer (TGCC) may be symptoms of a testicular dysgenesis syndrome that manifests during fetal life. To address the inheritability of this syndrome, we examined whether family history of cryptorchidism or hypospadias is associated with an increased risk of TGCC. Methods A total of 2 159883 men born since 1953, identified through Danish health registers, were followed from April 2, 1968, through May 31, 2008. First-, second-, and third-degree relatives were identified in the Danish Family Relations Database; cryptorchidism and hypospadias patients were identified in the Danish Hospital Discharge Register; and TGCC patients were identified in the Danish Cancer Register. Poisson regression was used to calculate the risk ratio for TGCC by family history of cryptorchidism or hypospadias. Results A total of 5441 patients developed TGCC. A personal history of cryptorchidism or hypospadias was associated with an increased relative risk (RR) of developing TGCC (RR = 3.71, 95% confidence interval [CI] = 3.29 to 4.19; and RR = 2.13, 95% CI = 1.26 to 3.61, respectively). For example, in men in their thirties, the overall rate per 100000 is 25.1 in the cohort, but 88.6 and 56.4 in men born with cryptorchidism or hypospadias, respectively. In contrast, relatives of a hypospadias patient did not have a statistically significantly increased risk of TGCC nor did the first- and second-degree relatives of cryptorchidism patients. However, we found a small increased risk of TGCC for third-degree relatives of patients with cryptorchidism. Conclusions Having hypospadias or cryptorchidism was associated with an increased risk of developing TGCC. However, our finding that family history of hypospadias or cryptorchidism generally was not associated with increased risk of developing TGCC does not support the hypothesis of shared inheritability of cryptorchidism, hypospadias, and TGCC. J Natl Cancer Inst 2010;102:187-192

Background Immigrant studies offer insights into the relative importance of environment and genes in disease etiology. There is considerable variation in testicular cancer incidence worldwide. We investigated testicular cancer risk in first- and second-generation immigrants to Denmark, a high-incidence country, to evaluate the relative influence of genes and environment and the potential timing of action of environmental factor(s). Methods A cohort of 2.1 million men who were born since 1930 and lived in Denmark between 1968 and 2003 was established based on information in the Danish Civil Registration System, which included their immigration histories. Cancer histories were obtained from the Danish Cancer Registry. Testicular cancer risk was estimated as rate ratios (RRs) with 95% confidence intervals (CIs) based on log-linear Poisson regression. Results Overall, 4216 testicular cancer cases occurred during 43 million person-years of follow-up in 2.1 million men. These included 166 cases among 344444 direct immigrants to Denmark and 13 cases among 56189 men born in Denmark to immigrant parents. These first- and second-generation immigrants had RRs of testicular cancer of 0.37 (95% CI = 0.31 to 0.43) and 0.88 (95% CI = 0.51 to 1.53), respectively, compared with men bom in Denmark of parents born in Denmark. The rate in first-generation immigrants was not modified by age at immigration or duration of stay and reflected that in the country of origin. Conclusion The testicular cancer risk in first-generation immigrants was lower than that in native-born Danes and reflected that in the countries of origin, whereas the risk in second-generation immigrants was similar to that in natives of Denmark. Together these findings argue for a substantial influence of environmental factors limited to the period early in life, most probably to the period in utero.

Introduction An early first delivery and a large number of childbirths are among the best established factors conferring a low risk of breast cancer.[1] Recent studies have described a dual [...]

Background: The occurrence of acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML) during childhood may be influenced by factors operating in fetal life. Furthermore, childhood ALL has been suggested to be linked to patterns of infection during infancy. Purpose: To explore these hypotheses and other associations, we studied the impact of sibling patterns (e.g., birth order) and birth characteristics (e.g., birth weight) on the risk of childhood ALL and AML. Methods: By linkage of records of population-based registries, a cohort of all children whose mothers were born in Denmark from April 1935 through March 1978 was established. Children who developed ALL or AML during the period from April 1968 through December 1992 were identified by linkage with the Danish Cancer Registry. Birth weights were obtained for children born during the period from January 1973 through December 1992 by linkage with the Medical Birth Registry. Results: The cohort of approximately 2.0 million children was followed for the diagnosis of ALL or AML for 20.9 million person-years. A total of 704 cases of childhood ALL were identified. Among 0-4 year olds, the relative risks (RRs) of ALL for birth order positions 1, 2, 3, and 4+ were 1.00 (reference), 0.85 (95% confidence interval [CI] = 0.68-1.07), 0.91 (95% CI = 0.66-1.25), and 0.57 (95% CI = 0.30-1.06), respectively (P for trend = .09). A decreasing trend was not observed among 5-14 year olds. A significant log-linear association between birth weight and the risk of ALL was observed for both age groups. Overall, the RR of ALL increased by a factor of 1.46 (95% CI = 1.18-1.81) (P = .0005) for each kilogram of increase in birth weight. A total of 114 cases of childhood AML were identified. Children born second or later in the birth order had an increased risk of AML (RR = 1.53; 95% CI = 1.01-2.32) compared with firstborns. A particularly high risk of AML at ages 2 (RR = 2.53; 95% CI = 1.46-4.40) and 3 years was associated with having siblings compared with being an only child at those ages. Similar to the findings for ALL risk, there was a significant association between birth weight and AML risk. The relative increase in AML risk per 1-kg increase in birth weight was 2.14 (95% CI = 1.19-3.85; P = .009). Conclusion and Implications: The association between birth weight and childhood leukemia suggests the importance of intrauterine factors. A plausible explanation may be that increasing birth weight is associated with a higher rate of cell proliferation and/or a larger number of precursor cells being at risk of malignant transformation. The inverse association between birth order and ALL risk among 0-4 year olds was weak, but it was compatible with the hypothesis that delayed exposure to infection may increase the risk of ALL in this age group. The association of childhood AML with birth order and sibship size at young ages deserves further attention in the search for environmental factors that affect childhood AML risk. [J Natl Cancer Inst 1997; 89:939-47]

Introduction The rates of multiple pregnancies have varied considerably during this century. These fluctuations have predominantly been explained by changes in maternal age and parity.[1] New risk factors for multiple [...]

Abstract Objective To estimate the association between maternal age and fetal death (spontaneous abortion, ectopic pregnancy, stillbirth), taking into account a woman's reproductive history. Design Prospective register linkage study. Subjects [...]

Background: A full-term pregnancy is associated with a reduced risk of breast cancer, but the underlying biologic mechanism has not been elucidated. During pregnancy, maternal serum levels of [Alpha]-fetoprotein, an estradiol-binding protein, rise sharply. In culture, [Alpha]-fetoprotein inhibits the growth of estrogen-sensitive cells, including estrogen-sensitive breast cancer cells. Thus, we investigated whether a high level of [Alpha]-fetoprotein in maternal serum during pregnancy is associated with a reduced risk of breast cancer. Methods: From a population-based cohort of 42 057 pregnant women in Denmark, enrolled in an [Alpha]-fetoprotein-screening program from 1978 through 1996, we obtained a complete reproductive history, vital status, and a possible diagnosis of breast cancer (in 117 women) to the end of follow-up on September 1, 1998. Results: During pregnancy, women with an [Alpha]-fetoprotein level greater than or equal to the median value had a 41% lower risk of breast cancer than women with an [Alpha]-fetoprotein level below the median value (relative risk [RR] = 0.59; 95% confidence interval [CI] = 0.41-0.85). RRs for breast cancer by mother's age at childbirth were as follows: 29 years or younger, RR = 0.21 (95% CI = 0.08-0.56); 30-34 years, RR = 0.61 (95% CI = 0.32-1.14); 35-37 years, RR = 0.96 (95% CI = 0.49-1.89); and 38 years or older, RR = 0.71 (95% CI = 0.29-1.75) (P for trend = .02). Further analyses suggested that high levels of [Alpha]-fetoprotein were associated with a reduced incidence of aggressive disease. The most striking finding was that women with high levels of serum [Alpha]-fetoprotein, compared with women with low levels of serum [Alpha]-fetoprotein, showed a particularly reduced incidence of large tumors ([is greater than] 2 cm; RR = 0.24 [95% CI = 0.11-0.50]). Conclusion: A high level of [Alpha]-fetoprotein in maternal serum during any pregnancy is associated with a low overall incidence of breast cancer and, in particular, with a low incidence of advanced breast cancer at diagnosis. This association appears particularly strong for a pregnancy occurring at a young age. [J Natl Cancer Inst 2000;92: 1001-5]

Abstract Objective To investigate whether young age at diagnosis is a negative prognostic factor in primary breast cancer and how stage of disease at diagnosis and treatment influences such an [...]

The aim of the present study was to evaluate whether births occurring at Christmas are different from births taking place on other days of the year. We specifically wanted to [...]

Background: Human papillomavirus-associated anogenital carcinogenesis depends on poorly defined cofactors. Smoking was recently suggested to increase the risk of anal cancer more in premenopausal women than in post-menopausal women. Thus, we used our population-based anal cancer case-control study in Denmark and Sweden to test this hypothesis. Methods: Our study included 417 patients (324 women and 93 men) who were diagnosed with anal cancer (84% invasive cancer) from 1991 through 1994; it also included five patients diagnosed in 1995. Two control groups were used: 1) 554 population control subjects (349 women and 205 men) and 2) 534 patients with rectal adenocarcinoma (343 women and 191 men). Odds ratios (ORs), calculated from logistic regression analyses, were used as measures of relative risk. All P values are two-sided. Results: Compared with the risk for lifelong nonsmokers, the risk of anal cancer was high among premenopausal women who currently smoked tobacco (multivariate OR = 5.6; 95% confidence interval [CI] = 2.4-12.7) and increased linearly by 6.7 % per pack-year smoked (one pack-year is equivalent to one pack of cigarettes smoked per day for 1 year) (P for trend [is less than] .001). Smoking was not statistically significantly associated with anal cancer risk in postmenopausal women or men. Women whose menstrual periods started late were at high risk (multivariate OR = 3.6; 95% CI = 1.8-7.3, for [is greater than or equal to] 17 years of age versus [is less than or equal to] 12 years of age; P for trend [is less than] .001), and body mass index (weight in kg/[[height in m].sup.2]) was inversely associated with risk among women (P [is less than] .001). Conclusions: Because the risk of anal cancer associated with smoking was restricted to premenopausal women and because higher risk was associated with late menarche and lean body composition, female sex hormones may be a factor in anal cancer development in women. Since the anal mucosa is an estrogen-sensitive area, we hypothesize an antiestrogenic mechanism of action for smoking in anal carcinogenesis. [J Natl Cancer Inst 1999;91:708-15]