Subsequent cancers in patients diagnosed with cancer of unknown primary (CUP): etiological insights?

BackgroundPatterns of subsequent malignancies in patients with cancer of unknown primary (CUP) may provide etiological insight into the primary tumor. The objective of the present study is to quantify risks of the subsequent cancers in CUP patients since such studies are lacking.Patients and methodsA population-based cohort of CUP was identified from the Swedish Family-Cancer Database of year 2008. Standardized incidence ratios (SIRs) were calculated for developing the following malignancies in 31 357 CUP patients from 1975 to 2008.ResultsA total of 755 CUP patients developed subsequent cancers, showing a significantly increased overall SIR of 1.69 (95% confidence interval 1.57–1.81). Among the most common 32 malignancies, increased SIRs were noted for 16 sites. Over 10-fold increases were observed for squamous cell carcinoma at four sites, possibly as a result of uncontrolled human papillomavirus infection due to faltering immune surveillance. The highest SIRs were observed among CUP patients diagnosed at a younger age and during the first follow-up year.ConclusionsSwedish CUP survivors had a higher risk of developing many subsequent cancers. Different patterns of risk excess may be suggestive of possible roles for disease- and therapy-related immunosuppression, reappearance of hidden primary tumors, or genetic predisposition.     

Cancer of unknown primary (CUP): does cause of death and family history implicate hidden phenotypically changed primaries?

Background Cancer of unknown primary (CUP) is diagnosed at the metastatic stage. We aimed to identify hidden primary cancers in CUP patients by comparison with cancers in family members. We take use of the fact that the cause of death in CUP patients is often coded as the cancer in the organ of fatal metastasis. Patients and methods Forty-one thousand five hundred and twenty-three CUP patients were identified in the Swedish Family-Cancer Database, and relative risks (RRs) were calculated for cancer in offspring when family members were diagnosed with CUP and died of the cancer diagnosed in offspring. Results The RR for lung cancer in offspring was 1.85 when a family member was diagnosed with CUP and died of lung cancer. Significant familial associations were found for seven other cancers. Many familial associations were also significant when offspring CUP patients died of the cancer diagnosed in family members. Conclusions The cause of death after CUP diagnosis frequently matched the cancer found in a family member, suggesting that the CUP had originated in that tissue. The metastasis had probably undergone a phenotypic change, complicating pathological tissue assignment. These novel data suggest that some CUP cases are phenotypically modified primary cancers rather than cancers of unknown primaries.     

Immunosuppressive disorders and risk of anal squamous cell carcinoma: A nationwide cohort study in Denmark, 1978–2005

Compromised immune function may increase the risk of anal squamous cell carcinoma (SCC). We examined the risk of anal SCC in patients with HIV infection and other chronic disorders associated with immunosuppression. A population‐based cohort study was conducted using the Danish National Patient Registry and the Danish Cancer Registry (DCR). We identified all patients with a first‐time hospital contact or procedure for HIV infection, solid organ transplantation or autoimmune disease or a first‐time record of haematologic malignancy in the DCR, 1978–2005, and followed these for a subsequent anal SCC, starting follow‐up 1 year after diagnosis of the index disease. Standardised incidence ratios (SIRs) were computed as the ratio of observed to expected numbers of anal SCCs, based on national age‐, sex‐ and period‐specific rates. Among 4,488 patients with HIV, we observed 21 anal SCCs with 0.3 expected (SIR: 81.1 (95% confidence interval (CI): 51.6–121.9)). Risk of anal SCC was markedly increased among 5,113 solid organ recipients (SIR: 14.4 (CI: 7.0–26.4)) and 30,165 patients with haematologic malignancies (SIR: 2.3 (CI: 1.1–4.2)) but only moderately increased among 242,114 patients with autoimmune diseases (SIR: 1.3 (CI: 1.0–1.6)). SIRs varied according to type of autoimmune disease and were high in patients with Crohn's disease (SIR: 3.1 (CI: 1.2–6.4)), psoriasis (SIR: 3.1 (CI: 1.8–5.1)), polyarteritis nodosa (SIR: 8.8 (CI: 1.5–29.0)) and Wegener's granulomatosis (SIR: 12.4 (CI: 2.1–40.8)). In conclusion, we found HIV infection, solid organ transplantation, haematologic malignancies and a range of specific autoimmune diseases strongly associated with increased risk of anal SCC.     

Risk of cancer in patients with medically diagnosed hay fever or allergic rhinitis

Data on allergic conditions as risk or protective factors for cancer are controversial probably because most studies have used self‐reported data on mixed groups of allergies in a case–control setting. We define cancer risks in medically diagnosed hay fever/allergic rhinitis patients in a nationwide cohort study. A total of 138,723 hay fever/allergic rhinitis patients were identified from three Swedish health care databases and standardized incidence ratios (SIRs) were calculated for subsequent cancers identified from the Swedish Cancer Registry. Overall cancer risk was not changed (SIR 1.03). For individual cancers, the highest SIR was observed for nasal cancer (SIR 2.63), followed by testicular (1.46) and endocrine tumors (1.42), and kidney (1.31), prostate (1.18) and breast (1.11) cancers. The results were consistent in the three sources of data and all SIRs were above unity, albeit mainly not statistically significant. The SIRs for nervous system tumors were above unity and of borderline significance. SIRs were decreased for esophageal (0.50), liver (0.62) and lung (0.78) cancers, and the three sources of data agreed in the direction of the effect. The increased risks for testicular, renal, prostate and endocrine cancers may be explained by immunological mechanisms. Excess risk for these cancer accounts for a significant population attributable fraction. Nervous system cancers showed a borderline increase and none of the histological types were significantly decreased, providing strong evidence against the published case–control studies, which have reported protective effects. The reasons for the reduced risks for esophageal, liver and lung cancer remain to be explained.     

Cancer risk in amyloidosis patients in Sweden with novel findings on non-Hodgkin lymphoma and skin cancer

BackgroundSystemic amyloidoses include immunoglobulin light chain (AL) amyloidosis, serum amyloid (AA)-related amyloidosis and senile systemic amyloidosis (SSA). AL amyloidosis is associated with myeloma, and we showed recently that transthyretin-related hereditary amyloidosis was related to non-Hodgkin lymphoma (NHL). In SSA, amyloids constitute wild-type transthyretin. We wanted to analyze cancer risks in amyloidosis, particularly in SSA.Patients and methodsNonhereditary amyloidosis patients were identified from the Swedish Hospital Discharge and Outpatients Registers from years 1997 through 2010. Their cancer risk was assessed based on the Swedish Cancer Registry using standardized incidence ratio (SIR) between amyloidosis patients and the remaining population. To gain information about amyloidosis subtypes, we used the Swedish Prescribed Drug Register from years 2005 through 2010 to find out the specific medication prescribed.ResultsAmong 1400 identified amyloidosis patients, cancer risk was increased for myeloma, NHL and squamous cell skin cancer. Myeloma and skin cancers were diagnosed 7–8 years earlier than in the population, whereas NHL was diagnosed in elderly patients. The SIR was 204 for myeloma in patients who received AL amyloidosis medication, and it was 17.22 in patients receiving rheumatoid arthritis medication, suggesting AA amyloidosis. In remaining patients, including SSA, NHL risk was 14.78, including lymphoplasmacytic lymphoma and Waldenstrom macroglobulinemia (51.41) and diffuse large B-cell lymphoma (18.69). In these patients, endometrial cancer (7.04) and cancer of unknown primary site (6.56) were also increased.ConclusionsSSA is likely to be a main cause of NHL in the elderly population. The present findings suggest a novel mechanism for amyloidosis-related cancer, highlighting the role of chronic stimulation by amyloid.     

Risk of cancer of unknown primary among immigrants to Sweden

Incidence of cancer of unknown primary (CUP) varies globally, and environmental factors are suspected to be related to its development. Immigrant studies offer insights into disease etiology, but no studies have been published on CUP. We investigated CUP risk in immigrants to Sweden to search for etiological clues. The nationwide Swedish Family Cancer Database was used to calculate standardized incidence ratios for CUP in the first-generation immigrants compared with native Swedes from 1958 to 2008. A total of 2340 patients with CUP were identified among immigrants during a follow-up of 23 million person-years compared with 30 507 patients with CUP identified in native Swedes who were followed for 260 million person-years, showing an overall standardized incidence ratio of 0.88 (95% confidence interval: 0.85-0.93). The median age at immigration was 28 years for men and 27 for women. Significantly lower CUP risks, ranging from 0.18 to 0.89, were mainly observed among Finnish, German, and Asian immigrants. The decreased risks tended to be lower for women compared with men. Danes of both sexes had an increased risk. The increased or decreased CUP risks observed in this novel study suggested that early life environmental risk factors or genetic factors influence the development of CUP. The risk patterns were modified by sex. The observed differences may give clues about incidence rates in countries of origin for which incidence data are lacking.     

Risk factors for cancers of unknown primary site: Results from the prospective EPIC cohort

Cancer of unknown primary site (CUP) may be called an “orphan” disease, as it is diagnosed when metastases are detected while the primary tumor typically remains undetected, and because little research has been done on its primary causes. So far, few epidemiological studies, if any, have addressed possible risk factors for CUP. We analyzed data from the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort (N = 476,940). During prospective follow‐up, a total of 651 cases of incident cases of CUP were detected (ICD‐O‐2 code C809). Proportional hazards models were conducted to examine the associations of lifetime history of smoking habits, alcohol consumption, levels of education and anthropometric indices of adiposity with risk of being diagnosed with CUP. Risk of being diagnosed with CUP was strongly related to smoking, with a relative risk of 3.66 [95% C.I., 2.24–5.97] for current, heavy smokers (26+ cigarettes/day) compared to never smokers (adjusted for alcohol consumption, body mass index, waist circumference and level of education) and a relative risk of 5.12 [3.09–8.47] for cases with CUP who died within 12 months. For alcohol consumption and level of education, weaker associations were observed but attenuated and no longer statistically significant after adjusting for smoking and indices of obesity. Finally, risk of CUP was increased by approximately 30 per cent for subjects in the highest versus lowest quartiles of waist circumference. Our analyses provide further documentation, in addition to autopsy studies, that a substantial proportion of cancers of unknown primary site may have their origin in smoking‐related tumors, in particular.     

Association of cancer with moderately impaired renal function at baseline in a large,representative, population‐based cohort followed for up to 30 years

Patients with chronic renal failure show a greater incidence of malignancies. We evaluated whether moderately impaired renal function at baseline influenced risk of all cancers during long‐term follow in young persons. Our cohort included 33,346 subjects, aged 26–61 years at baseline, in a representative, population‐based study enrolling subjects from 1974 to 1992. Median follow‐up time was 28 years. Plasma creatinine was analyzed as a single measure at baseline. Incident cases of cancer were identified from the Swedish Cancer Registry. We studied 24,552 subjects from the cohort. To account for the unique sampling design, participants were divided by sex and age at baseline into 1,132 older men (age 60), 14,254 younger men (age 40–52), 7,498 older women (age 47–57) and 1,688 younger women (age 35–43). Glomerular filtration rate (GFR) was estimated using the CKD‐EPI formula. Patients were classified as having either normal to mildly impaired kidney function (eGFR ≥ 60 mL/min/1.73 m²), or moderate kidney dysfunction (eGFR<60 mL/min/1.73 m²). We calculated the risk of all cancers using competing risks regression. Overall, 6,595 participants were diagnosed with cancer, and 854 subjects (3.5%) had moderately impaired renal dysfunction at baseline. There was a significant association between moderately decreased GFR and subsequent risk of kidney cancer in younger men (hazard ratio, 3.38; 95% CI, 1.48 to 7.71; p = 0.004). However, we found no association with overall long‐term cancer risk. Our confirmation of an association between moderately impaired renal function and risk of kidney cancer in younger men requires further exploration of high‐risk groups and biological mechanisms.     

A population‐based assessment of mortality and morbidity patterns among patients with thymoma

Thymomas are rare tumors of the mediastinum; a limited number of small studies have evaluated the outcomes in these patients. We identified 668 patients with thymoma from the Swedish Cancer Registry, and 2,719 population‐based matched controls. We obtained information on autoimmunity from the nationwide inpatient/outpatient hospital discharge Registry. We constructed Kaplan‐Meier curves for survival analysis, conditional regression and Cox proportional hazards models to evaluate the association between thymoma and autoimmune diseases, and standardized incidence ratios (SIRs) to evaluate the risk for second cancers following thymoma. Compared with controls, patients with benign or malignant thymoma had a poorer (p < 0.001) 5‐year (79%, 53% vs. 91%), 10‐year (65%, 39% vs. 78%) and 20‐year (43%, 18% vs. 55%) overall survival. For thymoma patients, younger age at diagnosis and being diagnosed in recent years were associated with a better survival. Compared with controls, thymoma patients were more likely to have an autoimmune disease at some point during their lives (32.7% vs. 2.4%, respectively, p < 0.001), most frequently myasthenia gravis (24.5%), systemic lupus erythematosus (2.4%) and red cell aplasia (1.2%). Thymoma patients had twofold excess risk for second cancers compared with the general population, most notably: non‐melanoma skin cancer (SIR = 10.6, 95% confidence intervals (CI) = 6.0–17.3), non‐Hodgkin lymphoma (SIR = 6.8, 95% CI = 3.00–13.0), and cervical (SIR = 6.9, 95% CI = 1.4–20.1), endocrine (SIR = 4.7, 95% CI = 1.3–12.0), and prostate cancer (SIR = 3.0, 95% CI = 1.7–4.8). Despite the improved survival for thymoma patients over time, they have worse survival than controls. Thymoma patients are in need for follow‐up to detect and manage autoimmune diseases and cancer.     

Second Primary Tumors Following Thyroid Cancer a Swedish Record-Linkage Study

The incidence of second primary tumors was studied through record-linkage in 2 968 thyroid cancer patients reported to the Swedish Cancer Registry during the period 1958-1975. The cohort was matched with the Swedish Cancer Registry between 1959 and 1984. A total of 283 second primary tumors were reported more than one year after thyroid cancer diagnosis, and the standardized incidence ratio (SIR) was 1.18 (95% confidence interval = 1.03-1.31). A significantly elevated risk of cancer of the kidney, endocrine glands, and nervous system was noted. Men had a higher risk (SIR = 1.37; 95% CI = 1.06-1.70) than women (SIR = 1.11; 95% CI = 0.96-1.28). Patients who were 36-45 years at the time of the thyroid cancer diagnosis were at highest risk of developing a second primary tumor (SIR = 1.35; 95% CI = 0.99-1.81). Significantly elevated risks were seen 5-9 years after the thyroid cancer diagnosis (SIR = 1.44; 95% CI = 1.14-1.69), and the SIR was close to unity after ≥ 15 years of follow-up. Previously described elevated risks of subsequent leukemia and breast cancer were not confirmed in this study. Close medical surveillance, thyroid cancer treatment, hereditary factors, and a high frequency of autopsy could all contribute to the elevated risk of a second primary tumor in these patients.     

Site‐specific cancer deaths in cancer of unknown primary diagnosed with lymph node metastasis may reveal hidden primaries

Cancer of unknown primary site (CUP) is a fatal cancer ranking among the five most common cancer deaths. CUP is diagnosed through metastases, which are limited to lymph nodes in some patients. Cause‐specific survival data could guide the search for hidden primary tumors and help with therapeutic choices. The CUP patients were identified from the Swedish Cancer Registry between 1987 and 2008; 1,444 patients had only lymph node metastasis of defined histology (adenocarcinoma, squamous cell or undifferentiated). Site‐specific cancer deaths were analyzed by lymph node location and histology. Kaplan‐Meier survival curves were compared with metastatic primary cancer at related sites. Among the patients with metastasis to head and neck lymph nodes, 117 (59.1% of the specific cancer deaths) died of lung tumors. Patients with axillary lymph node metastasis died of lung and breast tumors in equal proportions (40.2% each). Also, squamous cell CUP in head and neck lymph nodes was mainly associated with lung tumor deaths (53.1%). With a few exceptions, survival of CUP patients with lymph node metastasis was indistinguishable from survival of patients with metastatic primary cancer originating from the organs drained by those nodes. The association between lymph node CUP metastases with cancer deaths in the drained organ and the superimposable survival kinetics suggests that drained organs host hidden primaries. Importantly, half of all site‐specific cancer deaths (266/530) were due to lung tumors. Thus, an intense search should be mounted to find lung cancer in CUP patients with lymph node metastases.     

Subsequent primary malignancies after endometrial carcinoma and ovarian carcinoma

BACKGROUND: Population-based data on subsequent neoplasms after women are diagnosed with endometrial and ovarian carcinomas are limited, particularly regarding specific histologic tumor types. METHODS: The nationwide Swedish Family-Cancer Database of 10.2 million individuals, which includes 19,128 invasive endometrial carcinomas and 19,440 ovarian carcinomas, was used to calculate standardized incidence ratios (SIRs) and 95% confidence intervals (95% CIs) for second primary carcinomas. SIRs were calculated for specific follow-up periods. Data on histopathologic types also were used. RESULTS: An excess of subsequent malignancies after women were diagnosed with endometrial carcinoma was noted at 11 sites. The highest SIRs were recorded for synchronous or metasynchronous ovarian carcinomas (SIR, 55.77; 95% CI, 48.82-63.43) and carcinomas of the small intestines (SIR, 14.71; 95% CI, 4.64-34.59). Primary ovarian carcinoma was followed by an increased risk of developing endometrial carcinoma, and the risks of developing many other malignancies also were increased after women were diagnosed with endometrial carcinoma, including intestinal malignancies, renal cell carcinoma, bladder carcinoma, squamous cell skin carcinoma, connective tissue malignancies, and leukemia. When ovarian endometrioid histology was diagnosed synchronously with primary endometrial carcinoma, the SIR was 140; when endometrial carcinoma was the subsequent neoplasm, the SIR was 87. A small familial component was found in the cooccurrence of endometrial carcinoma and ovarian carcinoma. CONCLUSIONS: The current data show a strong clustering of endometrial carcinomas and ovarian carcinomas, particularly involving tumors of endometrioid morphology. The patterns of second neoplasms also suggest that hereditary nonpolyposis colorectal carcinoma may contribute to the association between endometrial and ovarian malignancies. Increased risks for connective tissue tumors and leukemia may signal a response to treatment, and an increased risk for squamous cell skin carcinoma may signal a depressed immune function.     

Incidence and mortality in epithelial ovarian cancer by family history of any cancer

BACKGROUND:

Practically all data on familial risk in ovarian and other cancers are based on incident cancer, whereas familiality in cancer mortality is largely unknown. If fatal forms of cancer are a highly familial subtype, then familial risk for mortality may exceed that of incidence, which is relevant for clinical decision making and counseling.

METHODS:

Ovarian cancer patients in the nationwide Swedish Family Cancer Database were classified according to fatal and nonfatal (incident) family history. Familial risks for incident and fatal ovarian cancer were calculated for offspring based on their parental or sibling family history of any cancer using standardized incidence ratios (SIRs) for incidence and standardized mortality ratios (SMRs) for mortality. Offspring without family history were referents.

RESULTS:

The database included 24,757 mothers and 8138 daughters with ovarian cancer. When a mother had ovarian cancer, the SIR for incident ovarian cancer in daughters was 2.69, and when a sister had ovarian cancer it was 3.49. The SMRs for fatal cancer by fatal cancer in probands were 3.39 and 5.80, respectively. For fatal serous cancers among siblings, the SMR was 6.16, compared with 10.01 for the endometrioid type. Ovarian cancer was associated with maternal (SIR, 1.22; SMR, 1.56) and sororal breast cancer (SIR, 1.27). Another discordant association was between ovarian and paternal prostate cancer (SIR, 1.12; SMR, 1.66).

CONCLUSIONS:

Fatal familial risks were higher for concordant ovarian, ovarian‐breast, and ovarian‐prostate cancers than the corresponding incident risks. This may suggest that highly fatal subtypes exist for these cancers, calling for genetic dissection. Cancer 2011. © 2011 American Cancer Society.     

Cancer risk among patients with cystic fibrosis and their first‐degree relatives

Patients with cystic fibrosis (CF) are at increased risk of some cancers. Little is known about the cancer risks among carriers heterozygous for the CF mutation and it is hypothesized this may be associated with reduced cancer risk. Using Swedish general population‐based registers, we identified 884 patients with CF from 1968 to 2003 and 3,033 of their first‐degree relatives The subjects were followed from birth of index persons or 1958, whichever came later, until death, emigration or 2003, whichever came first. Cancer risks were compared with the general Swedish population using standardized incidence ratios (SIR) with 95% confidence intervals (CI). Patients, followed for an average of 21 years, were at a higher overall risk of cancer. Some 26 cancer diagnoses, after excluding multiple diagnoses of nonmelanoma skin cancer in one man, produced an overall SIR of 3.2 (95% CI 2.1–4.6). We found statistically significantly increased risks for kidney, thyroid, endocrine, lymphoma and nonmelanoma skin cancer. There was no modification of cancer risk among parents and siblings, with an average of 21 years of follow‐up. This study did not identify a heterozygote advantage for CF gene mutations in relation to cancer risk. © 2009 UICC     

Digitalis use and lung cancer risk by histological type in men

Lung cancer risk and tumor characteristics differ between sexes. Estrogen has been suggested to counteract lung cancer development. We aimed to test the hypothesis that digitalis use decreases lung cancer risk due to its estrogenic and other anticancer properties in men. This was a nationwide Swedish population‐based cohort study between July 1, 2005 and December 31, 2013. Data on the use of digitalis and organic nitrates in all male individuals were derived from the Swedish Prescribed Drug Registry. New lung cancer diagnoses among cohort participants were identified from the Swedish Cancer Registry. Cox proportional hazards regression was employed to estimate hazard ratios (HRs) with 95% confidence intervals (CIs) of lung cancer in digitalis users (exposed participants) compared to users of organic nitrates without digitalis medication (unexposed participants). The study cohort contained 74,437 digitalis users and 297,301 organic nitrates users. Long‐term use (≥2 years) of digitalis was associated with decreased HRs of total lung cancer (HR 0.55, 95% CI 0.39–0.79) and squamous cell carcinoma (HR 0.40, 95% CI 0.19–0.87). This large and population‐based study suggests decreased risks of lung cancer overall and squamous cell carcinoma associated with long‐term use of digitalis in men.     

Incidence of cancer of unknown primary in Sweden: analysis by location of metastasis

Increasing incidences of cancer of unknown primary (CUP) have been observed in Sweden previously. However, it is not known how the incidence trends for specific locations of metastasis vary. Site-specific data are available on the basis of the ninth international classification of diseases. CUP patients were identified between 1987 and 2008 from the Swedish Family-Cancer Database. Malignant neoplasms of ill-defined sites were diagnosed in 4042 patients, 1976 developed metastasis in lymph nodes, 9615 had metastasis in specified organs, and in 8052 patients, the malignant neoplasm was diagnosed without further specification. Age-standardized incidence rates for 23 685 patients were analyzed using a direct method of standardization. Overall, the incidence of CUP decreased from 6.98 to 6.00 per 100 000 from 1987 to 2008. The number of patients diagnosed with metastasis in specified organs decreased, whereas the number of patients diagnosed with CUP without further specification increased from 2.65 to 3.02 per 100 000. With improvements in diagnostic methods and imaging techniques for identification of cancer, the incidences of CUP have been decreasing because primary tumors can be specified more often. Computed tomography is typically sensitive in detecting lung, kidney, and colorectal cancers, which are known to have a genetic link with CUP. Prostate-specific antigen testing is used to detect prostate cancer, for which bone is a common metastatic site. Liver metastases are common if the primary tumor is located in the colorectum. If the primary tumor is found, this cancer site replaces the diagnosis of CUP within the Cancer Register and therefore CUP incidence is decreased.     

Endometrial cancer in the family-cancer database.

Endometrial cancer was studied in the Swedish Family-Cancer Database, updated in 1999 to cover individuals born after 1934 with their biological parents, totaling 9.6 million persons. Cancer data were obtained from the Swedish Cancer Registry from 1958 to 1996 and included over 20,000 cases of endometrial cancer. Seventy-six families were identified in which both the mother and the daughter had endometrial cancer, giving a familial standardized incidence ratio (SIR) of 3.19 for daughters and 2.78 for mothers. The risk depended inversely on the age at diagnosis, and the risk was almost 10 in daughters who were diagnosed before age 50 when their mothers were also diagnosed before that age. The discordant cancer site that associated with endometrial cancer between the two generations was colon, with a SIR of 1.44-1.68. However, when the maternal endometrial cancer was diagnosed before age 50, increased SIRs were observed in daughters or sons for rectal, pancreatic, nervous system, breast, and ovarian cancers. Second cancers were followed in females diagnosed with endometrial cancer, and the highest overall risks were observed for ovarian and connective tissue cancers; colorectal cancers were also clearly in excess. Among the other family members of the 76 families in which both mother and daughter were affected with endometrial cancer, there were 11 cases of colorectal cancer. When a sister was affected in such families, the SIR of endometrial cancer was 31.40, and the median diagnostic age was several years lower than in endometrial cancer families in which no colorectal cancers were found. Many of these families may have hereditary nonpolyposis colorectal carcinoma syndrome. However, the risk of endometrial cancer was increased even in families presenting no colorectal cancers.     

Occupation and risk of oesophageal adenocarcinoma and squamous‐cell carcinoma: The Nordic Occupational Cancer Study

To assess associations between occupation and risk of oesophageal adenocarcinoma (AC) and squamous‐cell carcinoma (SCC), data from the Nordic Occupational Cancer Study, a large population‐based cohort with long‐term follow‐up, was used. The Nordic Occupational Cancer Study includes 12.9 million individuals aged 30–64 years who participated in national censuses in Finland, Iceland, Norway and Sweden in 1960–1990. Individuals were assigned to one of the 54 occupational categories, and individuals with oesophageal cancer were identified through nationwide cancer registries with follow‐up through 2005. Country‐specific standardised incidence ratios (SIRs) with 95% confidence intervals (CIs) were estimated. During follow‐up, 4,722 ACs and 14,496 SCCs were observed. Among men, increased risks of AC and SCC were observed among waiters (SIR = 2.58, 95% CI 1.41–4.32 and SIR = 3.22, 95% CI 2.30–4.38 for AC and SCC, respectively), cooks and stewards (1.72, 1.04–2.69 and 2.53, 1.94–3.25), seamen (1.52, 1.16–1.95 and 1.77, 1.53–2.05), food workers (1.51, 1.18–1.90 and 1.21, 1.03–1.42), miscellaneous construction workers (1.24, 1.04–1.48 and 1.39, 1.25–1.54) and drivers (1.16, 1.01–1.33 and 1.23, 1.13–1.34). Decreased risks of AC and SCC were observed among technical workers, physicians, teachers, religious workers and gardeners. The SIR for AC was significantly different from that for SCC in six occupational categories. Among women, increased risks among food workers and waiters and decreased risks among teachers, nurses and assistant nurses were observed for SCC only. In both sexes, increased risks were observed among waiters and food workers, and decreased risks were observed among teachers. This large cohort study indicates that the risk of oesophageal cancer varies by occupation, but not by histological type in most occupational categories.     

Power and limits of modern cancer diagnostics: cancer of unknown primary

BackgroundCancer of unknown primary (CUP) is diagnosed at a metastatic stage but no diagnostic effort is spared to find the primary cancers because these will guide the treatment. Consequently, the diagnostic work-up for CUP is more comprehensive than for any other cancer, resulting in detection of second cancers unrelated to CUP. We want to use the detection rate of second cancers as a measure of efficacy of the diagnostic modalities in finding tumors, assuming that the detection rates have increased with modern technologies.Patients and methodsThe number of CUP patients identified in the nation-wide Swedish Database was 28 574 and relative risks (RRs) for second cancers were recorded in three periods from 1980 through 2008. The first 5 months after CUP were considered critical for second cancers to be diagnosed during the intense work-up for CUP.ResultsAmong second cancers, diagnosable by computed tomography or magnetic resonance imaging, there was a large 6.80-fold increase in RR immediately following CUP diagnosis from the period 1980–1989 to 2000–2008. Over the same periods, the increase in in situ tumors was 7.16-fold.ConclusionThese data suggest that improvements in the resolution and availability of powerful imaging techniques result in increasingly sensitive detection of tumors.     

Autoimmune diseases as comorbidities for liver,gallbladder, and biliary duct cancers in Sweden

Background

Autoimmune diseases are associated with many cancers but there is a lack of population-based studies with different autoimmune diseases that have a long follow-up. This is also true of hepatobiliary cancers, which include hepatocellular cancer (HCC) and rarer entities of gallbladder cancer (GBC), intra- and extrahepatic cholangiocarcinoma (iCCA and eCCA), and ampullary cancer.

Methods

Diagnostic data on 43 autoimmune diseases were collected from the Swedish Inpatient Register from 1987 to 2018, and cancer data were derived from the national cancer registry from 1997 onward. Relative risks were expressed as standardized incidence ratios (SIRs).

Results

In a population of 13.6 million, 1.1 million autoimmune diseases were diagnosed and subsequent hepatobiliary cancer was diagnosed in 3191 patients (17.2% of cancers). SIRs for HCC were 2.73 (men) and 2.86 (women), 3.74/1.96 for iCCA, 2.65/1.37 for GBC, 2.38/1.64 for eCCA, and 1.80/1.85 for ampullary cancer. Significant associations between autoimmune disease and HCC were observed for 13 autoimmune diseases, with the highest risks being for autoimmune hepatitis (48.92/73.53, men/women) and primary biliary cirrhosis (38.03/54.48). GBC was increased after six autoimmune diseases, with high SIRs for ulcerative colitis (12.22/3.24) and men with Crohn disease (9.16). These autoimmune diseases were also associated with a high risk of iCCA, which had seven other associations, and eCCA, which had five other associations. Ampullary cancer occurrence was increased after four autoimmune diseases.

Conclusion

An autoimmune disease is a common precursor condition for hepatobiliary cancers. This calls for careful control of autoimmune disease symptoms in each patient and encouragement to practice a healthy lifestyle.