Applying recommended definition of aggressive prostate cancer: a validation study using high-quality data from the Cancer Registry of Norway.

BACKGROUND: The Prostate Cancer Cohort Consortium (PC3) Working Group proposed a definition for aggressive prostate cancer (PC) for aetiologic epidemiologic research. We aimed to validate this definition as well as a second approach utilising only information on stage at diagnosis. METHODS: First primary PCs diagnosed 2004 - 2009 in the population-based Janus Serum Bank (JSB) cohort were identified by linkage to the population-based Cancer Registry of Norway (CRN) (n = 3568). The CRN and Norwegian Prostate Cancer Registry provided clinicopathological data for these cases. Approach 1 classified PC as aggressive if it was clinically T4, or N1, or M1, or had a Gleason score ≥8 at diagnosis (as proposed). Approach 2 classified PC as aggressive if CRN stage at diagnosis was 'regional spread' or 'distant metastases'. Both approaches were validated by calculating the sensitivity and positive predictive value (PPV) against PC-death within 10 years of diagnosis. RESULTS: Overall, 555 died from PC within 10 years. Approach 1 classified 24.7% of cases as aggressive and 13.6% were unclassified due to missing information. Approach 2 classified 19.6% as aggressive and 29% were unclassified. Sensitivity was highest for Approach 1 (0.76, 95% CI: 0.72 - 0.80 vs 0.69, 95% CI: 0.64 - 0.73), while PPVs were similar for both approaches (0.43, 95% CI: 0.40 - 0.46 and 0.40, 95% CI: 0.36 - 0.44). We observed similarly high sensitivity and higher PPVs than those reported by the PC3 Working Group. CONCLUSIONS: The proposed definition of aggressive PC was applicable and valid in the JSB cohort. Stage at diagnosis can be useful if data on cTNM or Gleason score is unavailable.

Anthropometric factors and Breslow thickness: prospective data on 2570 cases of cutaneous melanoma in the population-based Janus Cohort.

BACKGROUND: Breslow thickness is the most important prognostic factor of localized cutaneous melanoma (CM), but associations with anthropometric factors have been sparsely and incompletely investigated. OBJECTIVES: To examine prediagnostic body mass index (BMI), body surface area (BSA), and height, weight and weight change in relation to Breslow thickness, overall and by anatomical site and histological subtype; and to assess possible nonlinear associations between these anthropometric factors and Breslow thickness. METHODS: CMs in the Janus Cohort were identified between 1972 and 2014. Linear regression was used to estimate geometric mean ratios (GMRs) of Breslow thickness with 95% confidence intervals (CIs) according to anthropometric factors. Restricted cubic splines in generalized linear models predicted adjusted mean Breslow thickness, and were used to assess possible nonlinear relationships. RESULTS: Of 2570 cases of CM, obese patients had a GMR of 1·16 (95% CI 1·04-1·30) of Breslow thickness vs. normal-weight patients. For BSA and weight, quintile 5 showed GMRs of 1·13 (95% CI 1·00-1·27) and 1·17 (95% CI 1·03-1·33) of Breslow thickness vs. quintile 1, respectively. Associations seemed restricted to superficial spreading melanomas and CMs on the trunk and lower limbs. The associations plateaued at an adjusted mean Breslow thickness of about 2·5 mm (BMI 29 kg m-2 , BSA 2·05 m2 and weight 90 kg), before declining for the highest values. No associations were found for height and weight change. CONCLUSIONS: This large case-series of incident CM demonstrated positive associations between BMI, BSA, weight and Breslow thickness, and suggested that behavioural or other mechanisms apply at high values.

Trends in incidence of thick, thin and in situ melanoma in Europe.

BACKGROUND: We analysed trends in incidence for in situ and invasive melanoma in some European countries during the period 1995-2012, stratifying for lesion thickness. MATERIAL AND METHODS: Individual anonymised data from population-based European cancer registries (CRs) were collected and combined in a common database, including information on age, sex, year of diagnosis, histological type, tumour location, behaviour (invasive, in situ) and lesion thickness. Mortality data were retrieved from the publicly available World Health Organization database. RESULTS: Our database covered a population of over 117 million inhabitants and included about 415,000 skin lesions, recorded by 18 European CRs (7 of them with national coverage). During the 1995-2012 period, we observed a statistically significant increase in incidence for both invasive (average annual percent change (AAPC) 4.0% men; 3.0% women) and in situ (AAPC 7.7% men; 6.2% women) cases. DISCUSSION: The increase in invasive lesions seemed mainly driven by thin melanomas (AAPC 10% men; 8.3% women). The incidence of thick melanomas also increased, although more slowly in recent years. Correction for lesions of unknown thickness enhanced the differences between thin and thick cases and flattened the trends. Incidence trends varied considerably across registries, but only Netherlands presented a marked increase above the boundaries of a funnel plot that weighted estimates by their precision. Mortality from invasive melanoma has continued to increase in Norway, Iceland (but only for elder people), the Netherlands and Slovenia.

Ultraviolet radiation and skin cancer risk in offshore workers.

BACKGROUND: Excess skin cancer mortality and incidence have been reported among both land-based and offshore petroleum workers. The association between skin cancer and ultraviolet radiation (UVR) exposure has not been examined in these workers, although they have long off-duty periods and high average income that may allow travelling to sunny destinations. In addition, they have access to solariums free of charge on many accommodation platforms. AIMS: To prospectively examine risk of incident cutaneous melanoma (CM) and non-melanoma skin cancer (NMSC), according to sun-tanning habits with adjustment for aromatic hydrocarbon exposure. METHODS: A cohort of men employed offshore from 1965 to 1999 was linked through the Cancer Registry of Norway 1999-2012. Cox regression adapted to a stratified case-cohort design was used to estimate hazard ratios with 95% confidence intervals. RESULTS: The cohort included 24917 men. During 13.5 years of follow-up, 112 CMs and 70 NMSCs occurred. A positive dose-response relationship was seen between sunburn frequency and risk of CM (Ptrend < 0.05) and NMSC (Ptrend < 0.01). Solarium use both before and after age 20 was related to increased risk of NMSC. Sunscreen use was associated with increased risk of NMSC (Ptrend < 0.001). CONCLUSIONS: UVR exposure seems to be a significant contributor to the elevated risk of skin cancer observed in North Sea offshore workers. The positive association between solarium use and NMSC risk adds to the growing body of literature on artificial UV devices as carcinogenic.

Cancer risk among parous women following assisted reproductive technology.

STUDY QUESTION: Do women who give birth after assisted reproductive technology (ART) have an increased risk of cancer compared with women who give birth without ART? SUMMARY ANSWER: Without correction, the results indicate an increase in overall cancer risk, as well as a 50% increase in risk of CNS cancer for women giving birth after ART, however the results were not significant after correcting for multiple analyses. WHAT IS KNOWN ALREADY: Studies regarding the effects of hormonal treatments involved with ART on subsequent cancer risk have provided inconsistent results, and it has also been suggested that infertility itself could be a contributory factor. STUDY DESIGN, SIZE, DURATION: A population-based cohort consisting of all women registered in the Medical Birth Registry of Norway as having given birth between 1 January 1984 and 31 December 2010 was assembled (n = 812 986). Cancers were identified by linkage to the Cancer Registry of Norway. Study subjects were followed from start of first pregnancy during the observational period until the first cancer, death, emigration, or 31 December 2010. PARTICIPANTS/MATERIALS, SETTING, METHODS: Of the total study population (n = 806 248), 16 525 gave birth to a child following ART. Cox regression analysis computed hazard ratios (HR) and 95% confidence intervals (CI) comparing cancer risk between ART women and non-ART women; for overall cancer, and for cervical, ovarian, uterine, central nervous system (CNS), colorectal and thyroid cancers, and for malignant melanoma. MAIN RESULTS AND THE ROLE OF CHANCE: A total of 22 282 cohort members were diagnosed with cancer, of which 338 were ART women and 21 944 non-ART women. The results showed an elevated risk in one out of seven sites for ART women. The HR for cancer of the CNS was 1.50 (95% CI 1.03- 2.18), and among those specifically subjected to IVF (without ICSI) the HR was 1.83 (95% CI 1.22-2.73). Analysis of risk of overall cancer gave an HR of 1.16 (95% CI 1.04-1.29). Among those who had delivered only one child by the end of follow-up, the HR for ovarian cancer was 2.00 (95% CI 1.08-3.65), and for those nulliparous at entry the HR was 1.80 (95% CI 1.04-3.11). However, all findings became non-significant after correcting for multiple analyses. LIMITATIONS, REASONS FOR CAUTION: The results of elevated risk of overall cancer and CNS cancer lost significance when adjusting for multiple analyses, implying an important limitation of the study. The follow-up time was relatively short, especially for ART women. In addition, as the cohort was relatively young, there were few incident cancers, especially for some rarer cancer forms, such as uterine cancer. Risk assessments according to different causes of infertility could not be done. WIDER IMPLICATIONS OF THE FINDINGS: In light of the findings in the present study, further studies should be made on risk of CNS and ovarian cancer, and continued monitoring of all those treated with ART is encouraged. Our findings may only be generalizable to women who give birth after ART, and the risk for women who remain nulliparous after ART remains to be assessed. STUDY FUNDING/COMPETING INTEREST: The study was funded by the Norwegian National Advisory Unit on Women's Health. All authors claim no competing interests.

Incidence trends of melanoma of the skin compared with other localisations, in the Norwegian population, 1956-2005.

BACKGROUND: Increasing incidence rates (IRs) of cutaneous malignant melanoma (CMM) have been associated with increased exposure to ultraviolet radiation (UVR). The aim of this study was to compare the changes over time in IRs of malignant melanoma in anatomical localisations exposed to different levels of UVR in the same population. PATIENTS AND METHODS: All incident cases of melanoma (invasive) diagnosed 1956-2005 were extracted from the database of the Cancer Registry of Norway. The average percentage change of the age-standardised IRs per 5-year period of diagnosis was calculated (loglinear regression) by anatomical localisation (skin, eye, internal organs and external genitalia). RESULTS: CMM represented 91.7% of the total number of melanomas, while ocular melanoma and melanoma in the internal organs represented 6.2% and 1.2%, respectively. The average quinquennal percentage increase in IRs for CMM and melanoma in internal organs was 23.3% [95% confidence interval (CI) 20.9-25.8] and 14.0% (95% CI 8.2-19.7), respectively. The corresponding analysis for ocular melanoma showed an increase of 1.3% (95% CI -1.5 to 4.2) and a decrease (not significant) for melanoma on male (-8.8%) and female (-2.1%) external genitalia. CONCLUSION: A wide variation in IRs and trends between the four anatomical localisations with unlike levels of UVR exposure suggests different causal pathways for melanoma.

Association between serum 25(OH)D and death from prostate cancer.

Based on observations that for certain cancers, mortality varies according to sun exposure, vitamin D has been proposed to influence on disease progression. This study aims to investigate whether serum levels of 25(OH)D are associated with prognosis in patients with prostate cancer. In total, 160 patients with a serum sample in the JANUS serum bank were included. For 123 patients a pre-treatment serum sample was taken, whereas 37 of the patients had received hormone therapy prior to the blood collection. The serum level of 25(OH)D was classified as low (<50 nmol l(-1)), medium (50-80 nmol l(-1)) or high (>80 nmol l(-1)). A Cox proportional hazard regression model was used to assess the association between serum 25(OH)D and cancer mortality. During follow-up, 61 deaths occurred, of whom 52 died of prostate cancer. The median time of follow-up was 44.0 months (range, 1.2-154.6). Serum 25(OH)D at medium or high levels were significantly related to better prognosis (RR 0.33; 95% CI 0.14-0.77, RR 0.16; 95% CI 0.05-0.43) compared with the low level. Analysis restricted to patients receiving hormone therapy gave a stronger association. The serum level of 25(OH)D may be involved in disease progression and is a potential marker of prognosis in patients with prostate cancer.

Birth weight and melanoma risk: a population-based case-control study.

We investigated whether lower birth weight was associated with lower risk of melanoma later in life. This population-based case-control study included all incident cases of histologically verified invasive melanoma diagnosed until 31 December 2003 in the Norwegian population born between 1967 and 1986 (n=709). The control group without malignant disease was established by random sampling from the same source population as the cases (n=108 209). Data on birth weight, gender, mother's residence and parental age at the time of birth were collected from the Medical Birth Registry of Norway and data on cancer from the Cancer Registry of Norway. The Mantel-Haenszel test of linear trend showed no trend in risk across the birth weight categories: individuals in the highest quartile of birth weight (>or=3860 g) had an odds ratio (OR) of 1.19 (95% confidence interval, CI: 0.77-1.84) compared to individuals with birth weight <2500 g. The adjusted OR was 0.81 (95% CI: 0.52-1.26) for birth weight below 2500 g (exposed). Though not statistically significant, the results suggest that low birth weight might influence the risk of melanoma later in life.

Season of diagnosis is a prognostic factor in Hodgkin's lymphoma: a possible role of sun-induced vitamin D.

Experimental studies show that vitamin D derivatives are potent anticarcinogenic factors. Epidemiological observations support this, and vitamin D sufficiency has been hypothesised to be an important risk-reducing factor in several forms of cancer. Vitamin D level exhibits seasonal variations. In the present work, we have investigated the effect of the season of diagnosis on the risk of death among Hodgkin's lymphoma patients diagnosed in Norway between 1964 and 2000. Risk estimates were calculated as relative risk (RR), with 95% confidence intervals (95% CI), using Cox regression model. Epidemiological data for this period indicate that season of diagnosis is a strong prognostic factor for Hodgkin's lymphoma, with approximately 20% lower case fatality for patients diagnosed during autumn vs winter diagnosis (RR = 0.783, 95% CI,-0.62 to 0.99; P = 0.041). Notably, the improved autumnal survival rate was higher than 60% (RR = 0.364, 95% CI, -0.15 to 0.87; P = 0.025) for patients younger than 30 years. This finding may be related to higher endogenous levels of vitamin D in autumn, with a favourable influence on the conventional therapy.

Breast and other cancers in 1445 blood relatives of 75 Nordic patients with ataxia telangiectasia.

Epidemiological studies have consistently shown elevated rates of breast cancer among female blood relatives of patients with ataxia telangiectasia (AT), a rare autosomal recessive disease. A large proportion of the members of AT families are carriers of AT-causing gene mutations in ATM (Ataxia Telangiectasia Mutated), and it has been hypothesised that these otherwise healthy carriers are predisposed to breast cancer. This is an extended and enlarged follow-up study of cancer incidence in blood relatives of 75 patients with verified AT in 66 Nordic families. Blood relatives were identified through population registry linkages, and the occurrence of cancer was determined from cancer registry files in each country and compared with national incidence rates. The ATM mutation carrier probabilities of relatives were assigned from the combined information on location in family, consanguinity, if any, and supplementary carrier screening in some families. Among the 1445 blood relatives of AT patients, 225 cancers were observed, with 170.4 expected, yielding a standardised incidence ratio (SIR) of 1.3 (95% confidence interval (CI), 1.1-1.4). Invasive breast cancer occurred in 34 female relatives (SIR, 1.7; 95% CI, 1.2-2.4) and was diagnosed in 21 women before the age of 55 years (SIR, 2.9; 95% CI, 1.8-4.5), including seven mothers of probands (SIR, 8.1; 95% CI, 3.3-17). When the group of mothers was excluded, no clear relationship was observed between the allocated mutation carrier probability of each family member and the extent of breast cancer risk. We concluded that the increased risk for female breast cancer seen in 66 Nordic AT families appeared to be restricted to women under the age of 55 years and was due mainly to a very high risk in the group of mothers. The findings of breast cancer risk in mothers, but not other likely mutation carriers, in this and other studies raises questions about the hypothesis of a simple causal relationship with ATM heterozygosity.

Weak associations between sociodemographic factors and breast cancer: possible effects of early detection.

Differences in incidence and survival of breast cancer have been observed to vary with regard to sociodemographic factors. This might be related to variation in frequency of doctor consultation and in time of diagnosis, since sociodemographic factors appear to influence the individual's attention to cancer symptoms and susceptibility to participate in screening programmes. This study aimed to examine the variation in breast cancer incidence and case fatality in sociodemographic groups in Norway, and to discuss whether any variation can result from temporal variation in detection time. The study included 589 521 women with information on residential history, childbearing pattern, educational level and occupational physical activity. Analyses were conducted using Poisson and Cox regression models. Although all the associations were weak, breast cancer incidence was associated with residence in urban areas, high age at first childbirth and high level of education. The urban women also tended to have better survival compared with the rural women. Childlessness was associated with high incidence and high case fatality. A high educational level was associated with the lowest case fatality. This study may emphasize the importance of discussing potential effects of early cancer detection. This is particularly important in epidemiological studies revealing weak associations between sociodemographic factors and breast cancer. Mortality rates may be less influenced by problems associated with early detection and, thus, analyses of breast cancer-specific mortality could give additional information.

Cutaneous malignant melanoma in Norway: variation by region of residence before and after the age 17.

OBJECTIVE: The aim of this study was to examine indirectly the importance of sun exposure during childhood and adolescence for the development of cutaneous malignant melanoma (CMM) by using a migration approach. METHODS: A nested case-control study was carried out based on all inhabitants living in Norway at any time between 1960 and 1980. The cases were all diagnosed between 1960 and 1992 (n = 13,934) and 10 controls were added for each case (n = 130,507). Analyses were conducted on residence history in the southeast, mid-west and northern part of Norway, before and after age 17, also including working condition and educational level. RESULTS: Birthplace in southeast was found to be twice as hazardous for the risk of CMM compared with birthplace in the north. The region of residence before as well as after age 17 was shown to influence the risk of CMM; the risk pattern in migrants tended to change direction toward the risk in the region to which they move. Associations was found between indoor working condition and CMM, and between high level of education and CMM, which support the hypothesis that pattern of sun exposure in adulthood affects the risk of CMM. CONCLUSION: The results indicate sun exposure at any age to be of importance for the lifetime risk of CMM.

Height, weight and gastrointestinal cancer: a follow-up study in Norway.

It has been suggested that components of our diet play an essential role in carcinogenesis. Anthropometric indices, such as body weight and height, have often been considered as measurements of prevailing diet and nutrition in childhood respectively. To investigate to what extent height and body weight are associated with the risk of gastrointestinal cancer, data from a Norwegian screening programme for tuberculosis were analysed. More than 1,100,000 individuals, aged 30-69 years at the time of examination, were included in the study. Body weight, expressed as Quetelet's index (QI), and height records were linked with vital status data from Statistics Norway and the Cancer Registry of Norway. The analysis shows that individuals in the first quintile of height had a lower relative risk than later quintiles for colon cancer, independent of sex and stage of disease at completion of follow-up. The association between height and rectal cancer is similar, but weaker. Men in the fifth quintile of QI have a relative risk of 1.39 for colon cancer, compared with the first quintile, and they also have a slightly elevated risk for rectal cancer. Among women, the pattern is unclear, but we observed a significant relationship between high QI and cancer of the gallbladder. Our results indicate that prevailing diet and living conditions in early life do play a role, and seem to support the hypothesis that anthropometric indices could be of importance as indirect markers for the risk of colon cancer and, to some extent, for cancer of the rectum and gallbladder.

Height, weight and cancer of the oesophagus and stomach: a follow-up study in Norway.

Epidemiological studies have suggested that socioeconomic conditions, including dietary factors, can affect the risk of several gastric cancers. Anthropometric indices, such as body weight and adult height, have been considered as measurements of prevailing diet and nutrition, respectively, in early life. The objective of this study was to evaluate the association between body mass and height and the risk of cancer of the oesophagus and stomach. The analysis was based on data from a national Norwegian screening programme for tuberculosis, which ran from 1963 to 1975, screening more than 1,100,000 individuals, aged 30-69 years at the time of examination. The participants were followed until December 1989. Body weight (expressed as Quetelet's index (QI) and height records were linked with vital status data from Statistics Norway and the Cancer Registry of Norway. Individuals in the first quintile of height appear to have an increased risk of oesophageal cancer in both sexes. Low QI was found to increase the risk for oesophageal squamous cell carcinoma, whereas high QI was linked to an elevated risk of oesophageal adenocarcinoma. The analysis reveals a relationship between low QI and the risk of stomach cancer. There were no associations between stomach cancer and height. These associations indicate that prevailing and early life conditions could play a role in later cancer development; they support the hypothesis that anthropometric indices are important as markers for the risk of oesophageal cancer and, to some extent, for cancer of the stomach.

Is prostatic intraepithelial neoplasia in the transition/central zone a true precursor of cancer? A long-term retrospective study in Norway.

Prostatic intraepithelial neoplasia (PIN) has been considered as a precursor of prostatic cancer. Few reports have dealt with the long-term follow-up of PIN lesions, and there is still a lack of proof that PIN is a true premalignant lesion. The objective of this study was to evaluate PIN in the transition/central zone as a marker for subsequent development of prostatic cancer. The PIN status of tissue specimens from 789 men without prostate cancer was determined in 508 transurethral resections and 281 transvesical prostatic enucleations. All slides were reviewed blind and independently by two pathologists. The patients were followed for an average of 11 years, and the incidence of subsequent cancer and cause-specific survival were analysed. Thirty-six cases of clinical prostatic cancer occurred among the cohort of 789 men through follow-up. No association between the presence of PIN in the transition/central zone and subsequent cancer development was found. There was also no difference in survival related to PIN status among the subsequent cancer patients.

Prediagnostic level of fatty acids in serum phospholipids: omega-3 and omega-6 fatty acids and the risk of prostate cancer.

Ecological and case-control studies have demonstrated a positive correlation between consumption of fat and the risk of prostate cancer. Two recent human studies have focused on alpha-linolenic acid as a risk factor for prostate cancer. Animal experiments have shown that dietary omega-6 polyunsaturated fatty acids have generally stimulated tumour development, whereas omega-3 polyunsaturated fatty acids have diminished it. The aim of our study was to investigate the association between these fatty acids and the subsequent risk of prostate cancer. Blood donors to the Janus serum data bank in Norway, who later developed prostate cancer, were matched to blood donors without prostate cancer (141 matched sets); the proportional level of fatty acids measured before diagnosis in the donors' serum was examined. The risk of later prostate cancer was analysed by conditional logistic regression. Increasing risk for prostate cancer was found with increasing quartiles of palmitoleic, palmitic and alpha-linolenic acid. An inverse risk association was found with increasing levels of tetracosanoic acid, for the ratios of linoleic to alpha-linolenic acid and arachidonic to eicosapentaenoic acid. There was no clear association between the risk effect of total omega-3 and total omega-6 fatty acids. There were no indications of a relationship between fatty acids and more aggressive cancers. Our results verify recent findings of a positive association between alpha-linolenic acid and a negative association between the ratio of linoleic to alpha-linolenic acid and the risk of prostate cancer.

Prostatic intraepithelial neoplasia in surgical resections: relationship to coexistent adenocarcinoma and atypical adenomatous hyperplasia of the prostate.

BACKGROUND: High grade prostatic intraepithelial neoplasia (PIN) is associated with coincident prostate carcinoma, and has been considered to be a precursor of prostate carcinoma. Most studies on PIN have been performed on total prostatectomy or core needle biopsy specimens. Few reports deal with the occurrence of PIN in consecutive surgical resections, which is the objective of the current study. METHODS: A total of 1135 nonselected surgical specimens from the prostate, examined during 1974 and 1975, underwent blind review by 2 experienced pathologists. There were 79 core needle biopsies, 731 transurethral resections of the prostate and 325 transvesical prostatic enucleations. The kappa coefficient for interobserver reproducibility was 0.66 for PIN and 0.86 for carcinoma. RESULTS: Grade 1 PIN was found in 9%, Grade 2 PIN in 32%, and Grade 3 PIN in 20% of the total cases. Atypical adenomatous hyperplasia (AAH) was found in 11% and adenocarcinoma in 27% of the cases. Grade 3 PIN was associated with coincident adenocarcinoma in 39% of the cases. The prevalence of carcinoma for cases with Grade 1 and 2 PIN did not exceed that of those with Grade 0 PIN. PIN was most commonly found in association with small carcinomas. The mean age of the entire group of patients was 70.0 years, and was 69.4 years for patients with PIN without coincident carcinoma. Patients with PIN and coincident carcinoma had a mean age of 71.7 years, similar to all PIN grades, but patients with carcinoma without PIN had the highest mean age, 73.3 years. CONCLUSIONS: PIN is a common histologic finding in tissues from prostatic resections. In this study, Grade 3 PIN was strongly associated with coincident carcinoma, but lower grade PIN was not. There was no association between PIN and AAH. Patients with PIN did not appear to have a higher mean age than corresponding patients without PIN.