Gallstones, cholecystectomy and risk of cancers of the liver, biliary tract and pancreas

To examine the association between gallstones and cholecystectomy, we conducted a nationwide population-based cohort study in Denmark. Patients with a discharge diagnosis of gallstones from 1977 to 1989 were identified from the Danish National Registry of Patients and followed up for cancer occurrence until death or the end of 1993 by record linkage to the Danish Cancer Registry. Included in the cohort were 60 176 patients, with 471 450 person-years of follow-up. Cancer risks were estimated by standardized incidence ratios (SIRs) and 95% confidence intervals (CIs) stratified by years of follow-up and by cholecystectomy status. Among patients without cholecystectomy, the risks at 5 or more years of follow-up were significantly elevated for cancers of liver (SIR = 2.0, CI = 1.2-3.1) and gallbladder (SIR = 2.7, CI = 1.5-4.4) and near unity for cancers of extrahepatic bile duct (SIR = 1.1), ampulla of Vater (SIR = 1.0) and pancreas (SIR = 1.1). The excess risk of liver cancer was seen only among patients with a history of hepatic disease. Among cholecystectomy patients, the risks at 5 or more years of follow-up declined for cancers of liver (SIR = 1.1) and extrahepatic bile duct (SIR = 0.7), but were elevated for cancers of ampulla of Vater (SIR = 2.0, CI = 1.0-3.7) and pancreas (SIR = 1.3, CI = 1.1-1.6). These findings confirm that gallstone disease increases the risk of gallbladder cancer, whereas cholecystectomy appears to increase the risk of cancers of ampulla of Vater and pancreas. Further research is needed to clarify the carcinogenic risks associated with gallstones and cholecystectomy and to define the mechanisms involved.     

Alcoholism and liver cirrhosis in the etiology of primary liver cancer.

The aim of this study was to determine the risk of developing primary liver cancer in patients with a diagnosis of alcoholism, liver cirrhosis, or both. Three population-based, mutually exclusive cohorts were defined on the basis of hospital discharge diagnosis between 1965 and 1983. Complete follow-up through 1984--excluding the first year of follow-up--showed that among 8,517 patients with a diagnosis of alcoholism, 13 cancers occurred, vs. 4.2 expected (standardized incidence ratio (SIR) = 3.1; 95% confidence interval (CI) = 1.6 to 5.3); among 3,589 patients with liver cirrhosis, 59 cancers occurred, vs. 1.7 expected (SIR = 35.1; 95% CI = 26.7 to 45.3), and among 836 patients with both diagnoses, 11 cancers occurred, vs. 0.3 expected (SIR = 34.3; 95% CI = 17.1 to 61.3). Thus, alcoholism alone entailed a moderately increased risk and alcoholism with liver cirrhosis did not increase the high relative risk for liver cancer more than cirrhosis alone. We conclude that alcohol intake may be a liver carcinogen only by being causally involved in the development of cirrhosis; and further, that the risk of developing liver cancer following cirrhosis in this population is similar to or higher than that after chronic hepatitis-B-virus infection in other Western countries.     

Merkel cell carcinoma and multiple primary cancers.

Merkel cell carcinoma (MCC) is an aggressive neuroendocrine tumor of the skin for which causative factors remain largely unknown. The site-specific risks of multiple primary cancers associated with MCC, which may provide insight into etiologic influences, have not been quantified in large population-based studies. We estimated the long-term risk of subsequent primary tumors after a first primary MCC (1,306 patients) and the risk of second primary MCC following other first primary cancers (2,048,739 patients) within 11 population-based cancer registries which report to the National Cancer Institute's Surveillance, Epidemiology, and End Results Program (1986-2002). Patients with first primary MCC were at significantly increased risk of developing a subsequent cancer [standardized incidence ratio (SIR), 1.22; 95% confidence intervals (95% CI), 1.01-1.45; observed (O = 122)], with significant excesses restricted to the first year after diagnosis (SIR, 1.71; 95% CI, 1.21-2.33; O = 39). Significantly elevated site-specific risks were observed for cancers of salivary gland (SIR, 11.55; 95% CI, 2.32-33.76; O = 3), biliary sites other than liver and gallbladder (SIR, 7.24; 95% CI, 1.46-21.16; O = 3), and non-Hodgkin lymphoma (SIR, 2.56; 95% CI, 1.23-4.71; O = 10). Nonsignificantly increased risks of 2-fold or higher were seen for chronic lymphocytic leukemia, and cancers of the small intestine and brain. A significantly increased 1.36-fold risk (95% CI, 1.19-1.55; O = 221) of MCC as a second primary malignancy was observed among patients with all other first primary cancers taken together. In particular, significant 3- to 7-fold excesses of MCC followed multiple myeloma (SIR, 3.70; 95% CI, 1.01-9.47; O = 4), chronic lymphocytic leukemia (SIR, 6.89; 95% CI, 3.77-11.57; O = 14), non-Hodgkin lymphoma (SIR, 3.37; 95% CI, 1.93-5.47; O = 16), and malignant melanoma (SIR, 3.05; 95% CI, 1.74-4.95; O = 16). Although enhanced medical surveillance may play a role, increased reciprocal risks suggest that MCC may share etiologic influences with other malignancies. Heightened awareness of the associations of lymphohematopoietic malignancies with MCC may facilitate early clinical recognition.     

Malignant melanoma, breast cancer and other cancers in patients with Parkinson's disease

Previous studies report an atypical cancer pattern among patients with Parkinson's disease. Here, we evaluate the cancer pattern among people diagnosed with Parkinson's disease in an extension of our previous cohort study. For this Danish population-based cohort study, we identified 20,000 people with Parkinson's disease diagnosed in 1977-2006, from the National Danish Hospital Register. Cohort members were followed up for cancer in the Danish Cancer Registry until December 31, 2008, and their incidence rates of cancer were compared to age-, sex- and calendar period-specific rates in the general population as standardized incidence rate ratios (SIRs). In subanalyses, we estimated the risk for cancer among patients with early onset Parkinson's disease and we also compared breast tumor characteristics among women with Parkinson's disease to that of a control group. The overall cancer risk in our cohort was decreased [SIR = 0.86; 95% confidence interval (CI) = 0.83-0.90], as were those for smoking-related (SIR = 0.65; 95% CI = 0.60-0.70) and nonsmoking-related cancers (SIR = 0.79; 95% CI = 0.71-0.86). The cohort had increased risks for malignant melanoma (SIR = 1.41; 95% CI = 1.09-1.80), nonmelanoma skin cancer (SIR = 1.29; 95% CI = 1.18-1.39) and female breast cancer (SIR = 1.17; 95% CI = 1.02-1.34). Among patients with early onset Parkinson's disease, the risk for cancer was comparable to that of the general population. Of breast tumor characteristics, only grade of malignancy differed between Parkinson's disease women and controls. This study confirms a lower cancer risk among people with Parkinson's disease. Increased risks for malignant melanoma, nonmelanoma skin cancer and breast cancer might be due to shared risk factors with Parkinson's disease.     

Risk of new primary cancer in patients with oropharyngeal cancer.

The relative risk of subsequent cancers was evaluated for a total of 9,092 patients with lip and oropharyngeal cancer recorded between 1953 and 1989 in the nationwide Finnish Cancer Registry. The observed numbers of patients were compared with those expected on the basis of the incidence rates in the Finnish population. There were 1,130 patients (12%) with a new cancer. The standardised incidence ratio (SIR) of contracting a new primary cancer was 1.2 for lip cancer patients (95% CI 1.1-1.3) and 1.4 for patients with oropharyngeal cancer (95% CI 1.2-1.4). Among lip cancer patients, a statistically significant excess risk was found for subsequent cancers in the oropharyngeal area (SIR 1.9, 95% CI 1.1-3.1), larynx (SIR 2.0, 95% CI 1.2-2.9) and lung (SIR 1.4, 95% CI 1.3-1.6), i.e. for cancers with tobacco aetiology. Among patients with oropharyngeal cancer there was an excess of lip cancer (SIR, 3.5, 95% CI 1.5-6.9), lung cancer (SIR 1.8, 95% CI 1.3-2.3) and leukaemia (SIR 2.3, 95% CI 1.0-4.3). Radiotherapy for the first primary did not increase the risk of new cancer.     

Cancer incidence and mortality among members of the Danish resistance movement deported to German concentration camps: 65‐Year follow‐up

The widespread belief that a stressful life event increases cancer incidence and mortality was investigated in a unique cohort of all Danish male political prisoners, who survived the extremely stressful experience of life in German concentration camps between 1943 and 1945. A virtually complete cohort of all 1,322 Danish male political prisoners who survived deportation to German concentration camps were followed up for cancer incidence and all‐cause and cancer‐specific mortality from 1946 through 2010. Standardized ratios and 95% confidence intervals were calculated from the observed and expected numbers of cancers or deaths, the latter based on national rates. We observed slightly increased standardized cancer incidence ratio (SIR 1.16; 95% CI, 1.06–1.27), particularly of smoking‐ or alcohol‐related cancers (SIR 1.31; 95% CI, 1.15–1.49) and nonsignificantly increased SIR of immune system‐ and hormone‐related cancers (SIR 1.17; 95% CI, 0.80–1.65 and 1.05; 95% CI, 0.81–1.34 respectively). Both the standardized all‐cause mortality ratio (SMR 1.11; 95% CI, 1.05–1.18) and cancer specific mortality ratio (SCMR 1.17; 95% CI, 1.01–1.26) were slightly increased, particularly from smoking‐ or alcohol‐related cancers (SCMR 1.25; 95% CI, 1.06–1.45). The minor increased cancer incidence and cancer mortality among the survivors is probably not directly associated with exposure to this extreme stressful event, but may be indirectly mediated through behavioral responses to psychological stress, as reflected in the increased incidence of and mortality from tobacco‐ and alcohol‐related cancers.     

Multiple primary cancer incidence in Italy

Data collected from eleven Italian population-based cancer registries (overall population 7 200 000 inhabitants) were used to compute the incidence of second independent cancers (MP) in a cohort of cancer patients aged 15 years or more. Overall, 240 111 patients have been followed for 544 438 person-years during which 8766 second primary cancers were diagnosed leading to an observed to expected ratio (SIR) of MP of 1.08 (95% Confidence Interval (CI): 1.05–1.12). Restricting the analysis to metachronous cancers, there were 6974 second primary cancers diagnosed among 198 303 patients during 508,648 person-years with an SIR of 0.93 (95% CI: 0.90–0.96). According to the time since first cancer diagnosis, the SIR was significantly higher than expected during the first 2 months, then the overall risk was slightly lower than 1 up to 10 years after diagnosis. No differences were observed according to gender. The SIR significantly differed among the age groups with consistent excess risks in subjects younger than 65 years in comparison with older ones. Overall, significantly elevated SIR for metachronous cancers were evidenced for oral cavity and pharynx, larynx, connective, skin non-melanoma, ovary and kidney cancers. For each cancer site, the site-specific risk of further MP has been evaluated. The identification of strong site-specific associations may be useful for clinicians when following-up patients.     

Cancer incidence among alcoholic liver disease patients in Finland: A retrospective registry study during years 1996–2013

Both alcohol abuse and liver cirrhosis are known risk factors for various cancers. This article was aimed to assess the long‐term risk of malignancies among patients with severe alcoholic liver disease (ALD), i.e., alcoholic liver cirrhosis and alcoholic hepatitis. A cohort of 8,796 male and 3,077 female ALD patients from 1996 to 2012 was identified from the Finnish National Hospital Discharge Register. This nationwide cohort was combined with the data from the Finnish Cancer Registry for incidence of malignancies during the years 1996–2013. The cancer cases diagnosed were compared with the number of cancers in the general population. The number of malignancies in our cohort was 1,052 vs. 368 expected. There was statistically significant excess of cancers of the liver, (standardized incidence ratio [SIR] 59.20; 95% CI 53.11–65.61), pancreas (SIR 3.71; 95% CI 2.72–4.94), pharynx (SIR 9.25; 95% CI 6.05–13.56), mouth (SIR 8.31; 95% CI 4.84–13,29), oesophagus (SIR 7.92; 95% CI 5.49–11.07), tongue (SIR 7,21; 95% CI 3.60–12.89), larynx (SIR 5.20; 95% CI 2.77–8.89), lung (SIR 2.77; 95% CI 2.27–3.32), stomach (SIR 2.76; 95% CI 1.79–4.07), kidney (SIR 2.69; 95% CI 1.84–3.79) and colon (SIR 2.33; 95% CI 1.70–3.11). There was no decreased risk of any cancer among ALD patients. Severe ALD is associated with markedly increased risk of malignancies. The risk is especially high for hepatocellular carcinoma, but also significantly increased for cancers of the upper aerodigestive tract, pancreas and kidneys, and warrants cancer surveillance in selected cases.     

Risk of malignancy among patients with rheumatic conditions

Previous studies have described an increased risk of malignancy in subjects diagnosed with rheumatic conditions, most notably rheumatoid arthritis (RA). Our aim was to quantify and compare risks for site-specific malignancy among hospitalized patients with RA, osteoarthritis (OA) and other rheumatic conditions in a nationwide, population-based cohort. Subjects were identified from Scottish hospital in-patient records from 1981 to 1996 and followed up by computer linkage of the Scottish Cancer Registry and the national registry of deaths. Expected cancer incidence was calculated from national cancer rates and related to the observed incidence by the standardized incidence ratio (SIR). Among RA patients, there was an increased risk for hematopoietic [males SIR= 2.13, 95% confidence interval (CI) 1.7-2.7; females SIR = 1.76, 95% CI 1.5-2.1], lung (males SIR = 1.32, 95% CI 1.2-1.5; females SIR = 1.44, 95% CI 1.3-1.6) and prostate (SIR = 1.26, 95% CI 1.0-1.6) cancers. Reduced risk were seen for colorectal cancer (males SIR = 0.87, 95% CI 0.7-1.1; females SIR = 0.71, 95% CI 0.6-0.9) and, among females, stomach cancer (SIR = 0.70, 95% CI 0.5-1.0). The excess risk for hematopoietic cancer and the reduced risk for colorectal and stomach cancers were sustained over 10 years of follow-up. An overall decreased risk of cancer was observed for patients with OA; the greatest reductions were observed for colorectal (males SIR = 0.88, 95% CI 0.8-1.0; females SIR = 0.84, 95% CI 0.8-0.9), stomach (males SIR = 0.79, 95% CI 0.7-0.9; females SIR = 0.66, 95% CI 0.6-0.8) and lung (males SIR = 0.72, 95% CI 0.7-0.8; females SIR = 0.84, 95% CI 0.8-0.9) malignancies, with decreased risks generally still evident at 10 years of follow-up. Our results support several previous findings regarding the incidence of hematopoietic and colorectal malignancies in RA patients. In addition, we have shown a large decrease in stomach cancer among patients with OA and females with RA that warrants further investigation since it may provide clues to possible prevention strategies. To further our knowledge about the underlying mechanisms of altered risk in cancer patients with rheumatic conditions, population studies requiring primary data collection are required.     

Atypical cancer pattern in patients with Parkinson's disease

Among 14,088 patients, with a primary diagnosis of Parkinson's disease during the period 1977-98 identified from the National Register of Patients, 1282 cancers were subsequently recorded in the Danish Cancer Registry, compared with 1464 expected, with a standardised incidence ratio (SIR) of 0.88 (95% confidence interval (CI), 0.8-0.9). Significantly reduced risks were found for smoking-related cancers, for example, cancers of the lung (SIR, 0.38), larynx (0.47) and urinary bladder (0.52), although moderate reductions in risk were also seen for several nonsmoking-related cancers. In contrast, increased risks were seen for malignant melanoma (SIR, 1.95; 95% CI, 1.4-2.6), nonmelanocytic skin cancer (1.25; 1.1-1.4) and breast cancer (1.24; 1.0-1.5). The observed cancer pattern supports the hypothesis that constituents of tobacco smoke inhibit or delay the development of Parkinson's disease, but a low smoking prevalence appears to be only part of the explanation for the decreased cancer incidence. The increased relative risks of melanoma and nonmelanoma skin cancer are not likely to be artefactual, but further investigations of potential mechanisms are warranted.     

Incidence of interstitial pneumonitis among breast cancer patients: a 10-year Danish population-based cohort study

Chemotherapy and radiation therapy may increase risk for interstitial pneumonitis (IP) in breast cancer patients, but there are little current population-based data on IP incidence in these patients. We assessed population-based incidence rates (IRs) of IP among Danish breast cancer patients and compared these with IRs for the Danish general population. Through the Danish Cancer Registry, we identified all Danish breast cancer patients (n=35 823) diagnosed between 1994 and 2004. Treatment data were obtained from the Danish Breast Cancer Cooperation Group database, and data on IP, from the Danish National Registry of Patients. We computed IRs of IP among breast cancer patients and age-standardised incidence rate ratios (SIRs) comparing breast cancer patients with the general population. During follow-up, 28 breast cancer patients were registered with an IP diagnosis (IR=17.3 per 100,000 person-years (p-y) (95% confidence intervals (95% CI): 11.7-24.6)). When follow-up was restricted to 1 year after the first breast cancer diagnosis, eight patients with IP were identified (IR=23.4 per 100,000 p-y (95% CI: 11.0-44.1)). The SIR comparing breast cancer patients with the general population was 8.4 (95% CI: 5.7-11.9). Thus, although IP is a rare adverse event among breast cancer patients, its risk is substantially higher than that in the general population.     

Cancer risk among patients with multiple sclerosis: a population-based register study

Cancer occurrence in patients with multiple sclerosis (MS) has been little studied, but associations with brain tumours, breast cancer, Hodgkin lymphoma and nasopharyngeal carcinoma have been suggested. We took advantage of population-based registers of MS and cancer to assess the risk of cancer following diagnosis of MS. Patients registered in the Danish Multiple Sclerosis Register were linked with the Danish Cancer Register to obtain information on cancer occurrence. The ratio of the observed to the number of expected cancers based on population-based incidence rates, i.e., the standardised incidence ratio (SIR), served as measure of the relative cancer risk. A database comprising all Danish women born after April 1, 1935, with information on all live-born children, was used in the analyses of breast cancer to adjust for reproductive factors. Overall 1,037 cancers were observed in 11,817 MS patients during 153,875 person-years of follow-up vs. an expected number of 1,098 (SIR = 0.94 [95% confidence interval CI: (0.89-1.00)]. The risk of brain tumours and Hodgkin lymphoma was not increased. A 16% overall reduced cancer risk in men with MS was explained by reduced numbers of cancers of the digestive, respiratory and genital organs. Though the overall cancer risk was not increased [SIR = 1.01(0.94-1.09), n = 676], female MS patients had an increased risk of breast cancer [SIR = 1.21 (1.05-1.39), n = 193]. Adjusting for parity and age at first child delivery did not change this risk estimate materially. In general MS patients are not at increased risk of cancer. Women with MS, however, seem to have a small excess risk of breast cancer, which cannot be attributed to reduced parity or delayed first child birth.     

Secondary cancers after a lung carcinoid primary: a population-based analysis

Carcinoid tumors of the lung were first described in 1937, yet little is known about their etiology. The aim of the present investigation was to determine if there was excess risk of secondary cancers in a population-based sample after a lung carcinoid tumor diagnosis which may provide insight to the etiology. Subjects were 1882 cases diagnosed with carcinoid tumors of the lung between 1988 and 2000 whose information was obtained from the Surveillance, Epidemiology and End Results (SEER) Program database. Standardized incidence ratios were calculated by dividing the observed number of second primary cancers by the expected number of cancers. Excess risk of breast cancer was seen following diagnosis of a carcinoid tumor (SIR=1.80 95% CI 1.22-2.55). When stratified by time after diagnosis, excess risk of breast cancers in women was seen in the first 5 years after carcinoid diagnosis (SIR=1.68 95% CI 1.08-2.50) but fewer than expected breast cancers were diagnosed greater than 5 years after carcinoid diagnosis (SIR=0.29 95% CI 0.09-0.68). Prostate cancers also occurred 2.8 times more often than expected (95% CI 1.66-4.43), with risk being elevated only in the first 5 years post-carcinoid diagnosis. Development of lung carcinoids may be the result of genetic predisposition or environmental exposures, particularly those that are hormonally related. The role of genetics and sex hormones in lung carcinoid development, as well as the identification of other risk factors, should be explored.     

Hip and knee implantations among patients with osteoarthritis and risk of cancer: a record-linkage study from Denmark.

A nationwide cohort study of hip and knee replacement patients in Denmark was undertaken to assess any carcinogenic potential of these implants. A cohort of 22,997 osteoarthritis patients who received hip replacements and of 4,771 osteoarthritis patients who received knee replacements during the period 1977 through 1989 were identified using the nationwide Danish Hospital Discharge Registry. These patients were followed for cancer occurrence through 1993, using the Danish Cancer Registry. There was no overall excess of cancer in either the hip implant cohort [standardized incidence ratio (SIR) = 0.94; 95% confidence interval (CI)= 0.91-0.98] or the knee implant cohort (SIR = 0.97; 95% CI = 0.89-1.06). The risk reduction in both groups of patients reflected for the most part reduced risks for cancers of the respiratory system and the digestive tract, particularly stomach cancer (SIR = 0.69; 95% CI = 0.50-0.81 for hip replacement patients; SIR = 0.46; 95% CI = 0.20-0.91 for knee replacement patients). Elevated risks were observed for melanoma of the skin in both groups of patients. There was no clear excess risk for lymphohematopoietic cancers or malignant neoplasms of the bone or connective tissue among implant patients in either implant group. Contrary to an earlier study in Sweden, we did not find an excess risk for kidney or prostate cancers. In summary, these nationwide results indicate no overall cancer hazard among hip and knee implant patients, but limited follow-up warrants continued surveillance of individuals undergoing these increasingly common surgical procedures.     

Risk of second cancer among women with breast cancer

A large number of women survive a diagnosis of breast cancer. Knowledge of their risk of developing a new primary cancer is important not only in relation to potential side effects of their cancer treatment, but also in relation to the possibility of shared etiology with other types of cancer. A cohort of 525,527 women with primary breast cancer was identified from 13 population-based cancer registries in Europe, Canada, Australia and Singapore, and followed for second primary cancers within the period 1943-2000. We used cancer incidence rates of first primary cancer for the calculation of standardized incidence ratios (SIRs) of second primary cancer. Risk of second primary breast cancer after various types of nonbreast cancer was also computed. For all second cancer sites combined, except contralateral breast cancer, we found a SIR of 1.25 (95% CI = 1.24-1.26) on the basis of 31,399 observed cases after first primary breast cancer. The overall risk increased with increasing time since breast cancer diagnosis and decreased by increasing age at breast cancer diagnosis. There were significant excesses of many different cancer sites; among these the excess was larger than 150 cases for stomach (SIR = 1.35), colorectal (SIR = 1.22), lung (SIR = 1.24), soft tissue sarcoma (SIR = 2.25), melanoma (SIR = 1.29), non-melanoma skin (SIR = 1.58), endometrium (SIR = 1.52), ovary (SIR = 1.48), kidney (SIR = 1.27), thyroid gland (SIR = 1.62) and leukaemia (SIR = 1.52). The excess of cancer after a breast cancer diagnosis is likely to be explained by treatment for breast cancer and by shared genetic or environmental risk factors, although the general excess of cancer suggests that there may be additional explanations such as increased surveillance and general cancer susceptibility.