Certain autoimmune and chronic inflammatory conditions, such as Sjögren's syndrome and rheumatoid arthritis (RA), have consistently
been associated with an increased risk of malignant lymphomas, but ...it is unclear whether elevated lymphoma risk is a phenomenon
that accompanies inflammatory conditions in general. Likewise, it is debated whether the increased risk identified in association
with some disorders pertains equally to all individuals or whether it varies among groups of patients with different phenotypic
or treatment-related characteristics. It is similarly unclear to what extent the increased lymphoma occurrence is mediated
through specific lymphoma subtypes. This update reviews the many findings on risks, risk levels, and lymphoma characteristics
that have been presented recently in relation to a broad range of chronic inflammatory, including autoimmune, conditions.
Recent results clearly indicate an association between severity of chronic inflammation and lymphoma risk in RA and Sjögren's
syndrome. Thus, the average risk of lymphoma in RA may be composed of a markedly increased risk in those with most severe
disease and little or no increase in those with mild or moderate disease. The roles of immunosuppressive therapy and EBV infection
seem to be limited. Furthermore, RA, Sjögren's syndrome, systemic lupus erythematosus, and possibly celiac disease may share
an association with risk of diffuse large B-cell lymphoma, in addition to well-established links of Sjögren's syndrome with
risk of mucosa-associated lymphoid tissue lymphoma and of celiac disease with risk of small intestinal lymphoma. However,
there is also obvious heterogeneity in risk and risk mediators among different inflammatory diseases. (Cancer Epidemiol Biomarkers
Prev 2006;15(11):2069–77)
Infectious mononucleosis (IM) has been associated with an increased risk of Hodgkin lymphoma (HL), implicating a role for Epstein-Barr virus (EBV) in HL development. Although essential to the ...understanding of the association, it has remained uncertain if the relationship is restricted to the EBV-positive subset of HL. We collected information on mononucleosis history and childhood socioenvironmental characteristics in a population-based study of 586 patients with classic HL and 3,187 controls in Denmark and Sweden. Tumor EBV status was established for 499 cases by immunohistochemistry and in situ hybridization techniques. Odds ratios (OR) for the relationship between HL risk and mononucleosis and other risk factors were estimated by logistic regression for HL in younger (18-44 years) and older (45-74 years) adults, overall and by tumor EBV status. All analyses were adjusted for country-specific measures of maternal education and mononucleosis history. IM was associated with an increased risk of EBV-positive OR, 3.23; 95% confidence interval (95% CI) 1.89-5.55 but not EBV-negative HL (OR, 1.35; 95% CI, 0.86-2.14). Risk of EBV-positive HL varied with time since IM and was particularly pronounced in younger adults (OR, 3.96; 95% CI, 2.19-7.18). IM-associated lymphomas occurred with a median of 2.9 years (1.8-4.9 years) after infection. The EBV specificity of the IM association was corroborated by a case-case comparison of IM history between younger adult EBV-positive and EBV-negative HL patients (OR(IM EBV+ HL versus EBV- HL), 2.68; 95% CI, 1.40-5.12). We found further evidence that IM is associated only with EBV-positive HL. This finding is compatible with the notion that EBV-positive and EBV-negative HL may have different etiologies.
Background: Some autoimmune and chronic inflammatory disorders are associated with increased risks of non-Hodgkin lymphoma (NHL). Because different NHL subtypes develop at different stages of ...lymphocyte differentiation, associations of autoimmune and inflammatory disorders with specific NHL subtypes could lead to a better understanding of lymphomagenic mechanisms. Methods: In a population-based case–control study in Denmark and Sweden, 3055 NHL patients and 3187 matched control subjects were asked about their history of autoimmune and chronic inflammatory disorders, markers of severity, and treatment. Logistic regression with adjustment for study matching factors was used to calculate odds ratios (ORs) and 95% confidence intervals (CIs) for NHL overall and for NHL subtypes. Results: Risks of all NHL were increased in association with rheumatoid arthritis (OR = 1.5, 95% CI = 1.1 to 1.9), primary Sjögren syndrome (OR = 6.1, 95% CI = 1.4 to 27), systemic lupus erythematosus (OR = 4.6, 95% CI = 1.0 to 22), and celiac disease (OR = 2.1, 95% CI = 1.0 to 4.8). All of these conditions were also associated with diffuse large B-cell lymphoma, and some were associated with marginal zone, lymphoplasmacytic, or T-cell lymphoma. Ever use of nonsteroidal anti-inflammatory drugs, systemic corticosteroids, and selected immunosuppressants was associated with risk of NHL in rheumatoid arthritis patients but not in subjects without rheumatoid arthritis. Also, multivariable adjustment for treatment had little impact on risk estimates. Psoriasis, sarcoidosis, and inflammatory bowel disorders were not associated with increased risk of NHL overall or of any NHL subtype. Conclusions: Our results confirm the associations between certain autoimmune disorders and risk of NHL and suggest that the associations may not be general but rather mediated through specific NHL subtypes. These NHL subtypes develop during postantigen exposure stages of lymphocyte differentiation, consistent with a role of antigenic drive in autoimmunity-related lymphomagenesis.
Celiac disease is associated with an increased risk of malignant lymphomas. The risk of lymphoproliferative malignancies in patients with small intestinal inflammation without villous atrophy and in ...patients with latent celiac disease is unknown.
We performed a cohort study using duodenal and jejunal biopsy data that were collected from all 28 Swedish pathology departments (July 1969 to February 2008). We identified two population-based cohorts composed of 28,989 individuals with biopsy-verified celiac disease (villous atrophy, Marsh stage 3) and 13,140 individuals with small intestinal inflammation without villous atrophy (Marsh 1 + 2) and a regional cohort of 3711 individuals with latent celiac disease (positive celiac disease serology and normal mucosa). Cancer data were obtained by linkage to the National Cancer Registry. We used Cox regression to estimate hazard ratios (HRs) for lymphoproliferative malignancy and any solid cancer among the three cohorts compared with a total of 227,911 age- and sex-matched reference individuals.
Although biopsy-verified celiac disease and intestinal inflammation were associated with lymphoproliferative malignancy (for celiac disease, HR = 2.82; 95% confidence interval CI = 2.36 to 3.37, n = 193; for inflammation, HR = 1.81; 95% CI = 1.42 to 2.31, n = 89), latent celiac disease was not associated with lymphoproliferative malignancy (HR = 0.97; 95% CI = 0.44 to 2.14, n = 7). The absolute rates of lymphoproliferative malignancies among persons with celiac disease, small intestinal inflammation, and latent celiac disease were 70.3 per 100,000 person-years, 83.4 per 100,000 person-years, and 28.0 per 100,000 person-years, respectively. Compared with individuals with celiac disease, individuals with small intestinal inflammation or latent celiac disease were at a statistically significantly lower risk of lymphoproliferative malignancy. Risk of any solid cancer was not increased beyond the first year of follow-up in any cohort. Celiac disease was associated with Hodgkin lymphoma and both T-cell and B-cell non-Hodgkin lymphomas.
The risk of lymphoproliferative malignancy in celiac disease is dependent on small intestinal histopathology, with no increased risk in latent celiac disease.
Background: The incidence of malignant lymphomas has been increasing rapidly, but the causes of these malignancies remain poorly understood. One hypothesis holds that exposure to ultraviolet (UV) ...radiation increases lymphoma risk. We tested this hypothesis in a population-based case–control study in Denmark and Sweden. Methods: A total of 3740 patients diagnosed between October 1, 1999, and August 30, 2002, with incident malignant lymphomas, including non-Hodgkin lymphoma, chronic lymphocytic leukemia, and Hodgkin lymphoma, and 3187 population controls provided detailed information on history of UV exposure and skin cancer and information on other possible risk factors for lymphomas. Odds ratios (ORs) with 95% confidence intervals (CIs) were calculated by logistic regression. Statistical tests were two-sided. Results: Multivariable-adjusted analyses revealed consistent, statistically significant negative associations between various measures of UV light exposure and risk of non-Hodgkin lymphoma. A high frequency of sun bathing and sunburns at age 20 years and 5–10 years before the interview and sun vacations abroad were associated with 30%–40% reduced risks of non-Hodgkin lymphoma (e.g., for sunbathing four times a week or more at age 20 versus never sunbathing, OR = 0.7, 95% CI = 0.6 to 0.9; for two or more sunburns a year at age 20 versus no sunburns, OR = 0.6, 95% CI = 0.5 to 0.8). These inverse associations increased in strength with increasing levels of exposure (all Ptrend≤.01). Similar, albeit weaker, associations were observed for Hodgkin lymphoma. There were no clear differences among non-Hodgkin lymphoma subtypes, although associations were stronger for B-cell than for T-cell lymphomas. A history of skin cancer was associated with a doubling in risks of both non-Hodgkin and Hodgkin lymphoma. Conclusions: A history of high UV exposure was associated with reduced risk of non-Hodgkin lymphoma. The positive association between skin cancer and malignant lymphomas is, therefore, unlikely to be mediated by UV exposure.
Purpose
The prognosis for patients with mantle cell lymphoma (MCL) is rather dismal where particularly elderly patients, often with comorbidities, have difficulties tolerating the intensive ...treatments needed for long-term remission. Our aim was to describe the frequency and spectrum of comorbidities among patients with MCL in a population-based setting, and assess the impact of comorbidities on treatment choice, lymphoma-specific and overall survival as well as causes of death in MCL patients by age and sex.
Methods
In the nationwide Swedish Lymphoma Register, we identified 1,385 MCL patients (1,009 males and 376 females) diagnosed 2000-2015 at all ages. Comorbid diseases within 10 years prior to diagnosis were identified from the national Swedish In- and Outpatient registers and included somatic diseases defined according to the Charlson comorbidity index (CCI; 0, 1 and 2+), with the addition of psychiatric disorders. Comorbidities were both categorized and presented individually. Hazard ratios (HR) with 95% confidence intervals (CIs) comparing lymphoma-specific and all-cause mortality among patients with different levels of CCI were estimated from flexible parametric survival models, adjusted for calendar year of diagnosis, age at diagnosis, sex, educational level, and MCL international prognostic index (MIPI). Model-based predictions were used to obtain cumulative probabilities of death due to lymphoma and other causes.
Results
In the cohort, 24% were <59 years of age, 32% between 60-69, 30% between 70-79 and 14% >80 years. In total, 606 out of 1,385 patients (44%) had a history of one or more comorbidities at the time of diagnosis, among which 388 (28%) had a CCI=2+. The most common specific comorbidities were prior malignancy (17%), (prostate cancer was most frequent), and prior coronary heart disease (14%). Moreover, 9% of the patients had diabetes, 7% had pulmonary disease, 3% renal disease, 3% connective tissue disease and 1% had dementia. In addition, 2% had a psychiatric disorder. With a mean follow-up of 3.7 years (range: 0.0-15.6), 633 (46%) patients died from lymphoma. Lymphoma was the major cause of death among males, irrespective of CCI (Figure 1A). Lymphoma was also the major cause of death among females with CCI=0 whereas among females with comorbidities (CCI≥1), approximately half of the patients died due to other causes (Figure 1B). A CCI=2+ was associated with worse overall and lymphoma-specific survival (adjusted lymphoma-specific HR=1.31; 95% CI: 1.04-1.65). Specific comorbidities associated with significantly worse lymphoma-specific survival were history of coronary heart disease, connective tissue disease, renal disease, dementia and psychiatric disorders (Figure 1C). Patients aged below 70 years at diagnosis who presented with no comorbidities were primarily treated according to the NLG-MCL2/3 protocol* (177 out of 437, 41%). However, this was not the case among patients in the same age range but with CCI=1 (24 out of 177, 34%) or CCI=2+ (13 out of 112, 12%). Primary treatment concepts for comorbid patients were CHOP, bendamustine, or chlorambucil with the addition of rituximab.
*NLG-MCL2/3= R-maxi-CHOP alternating with high dose cytarabine, rituximab, and consolidation with high-dose therapy and autologous stem-cell transplantation
Conclusions
A large fraction of MCL patients are elderly and comorbidity was present in almost half of the patients overall. A CCI of 2+ was an independent negative prognostic factor. Lymphoma-death was the major cause of death among males, motivating the need for MCL-specific treatment irrespectively of a high burden of comorbidities, while approximately 50% of comorbid-females died due to other reasons. Patients with comorbidities were less often treated according to intensive first-line chemotherapy protocols. In the introduction and development of new treatment regimens, consideration of toxicity and tolerability specifically in patients with comorbidities is warranted, particularly in patients with coronary heart disease, connective tissue disease and renal disorders.
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Ekstroem Smedby:Janssen Pharmaceuticals: Other: The Department have recieved partial funding from Janssen Pharmaceuticals. Eloranta:Janssen Pharmaceuticals: Other: S Eloranta is currently employed as a project coordinator and her salary is funded via a public-private real world evidence collaboration between Karolinska Institutet and Janssen Pharmaceuticals.
Aspirin (ASA) use has been associated with improved breast cancer survival in several prospective studies.
We conducted a nested case-control study of ASA use after a breast cancer diagnosis among ...women using Swedish National Registries. We assessed prospectively recorded ASA exposure during several different time windows following cancer diagnosis using conditional logistic regression with breast cancer death as the main outcome. Within each six-month period of follow-up, we categorized dispensed ASA doses into three groups: 0, less than 1, and 1 or more daily doses.
We included 27,426 women diagnosed with breast cancer between 2005 and 2009; 1,661 died of breast cancer when followed until Dec 31, 2010. There was no association between ASA use and breast cancer death when exposure was assessed either shortly after diagnosis, or 3-12 months before the end of follow-up. Only during the period 0-6 months before the end of follow-up was ASA use at least daily compared with non-use associated with a decreased risk of breast cancer death: HR (95% CI) =0.69 (0.56-0.86). However, in the same time-frame, those using ASA less than daily had an increased risk of breast cancer death: HR (95% CI) =1.43 (1.09-1.87).
Contrary to other studies, we did not find that ASA use was associated with a lower risk of death from breast cancer, except when assessed short term with no delay to death/end of follow-up, which may reflect discontinuation of ASA during terminal illness.
Background: A family history of hematopoietic malignancy is associated with an increased risk of non-Hodgkin lymphoma (NHL) and Hodgkin lymphoma (HL), although the magnitude of the relative risk is ...unclear. We estimated the association between familial hematopoietic cancer and risk of lymphoma using validated, registry-based family data, and we also investigated whether associations between some environmental exposures and risk of lymphoma vary between individuals with and without such a family history. Methods: In a population-based case–control study of malignant lymphoma, 1506 case patients and 1229 control subjects were linked to the Swedish Multi-Generation Register and then to the Swedish Cancer Register to ascertain history of cancer in first-degree relatives of patients with malignant lymphoma. Multiple logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for associations with the risk of lymphoma. Results: A history of hematopoietic malignancy in any first-degree relative was associated with an increased risk of all NHL (OR = 1.8, 95% CI = 1.2 to 2.5), common B-cell NHL subtypes, and HL. Relative risks were generally stronger in association with sibling hematopoietic cancer (OR for all NHL = 3.2, 95% CI = 1.3 to 7.6) than with parental hematopoietic cancer (OR = 1.6, 95% CI = 1.1 to 2.3). A family history of NHL or chronic lymphocytic leukemia (CLL) was associated with an increased risk of several NHL subtypes and HL, whereas familial multiple myeloma was associated with a higher risk of follicular lymphoma. There was no statistically significant heterogeneity in NHL risk associations with environmental factors between individuals with and without familial hematopoietic malignancy. Conclusions: The increased risk of NHL and HL among individuals with a family history of hematopoietic malignancy was approximately twofold for both lymphoma types. There was no evidence that etiologic associations varied between familial NHL and nonfamilial NHL.
Background: Case–control studies of familial cancer risk traditionally rely on self-reported family history of cancer, which may bias results due to differential recall between case patients and ...control subjects. To evaluate the reliability of self-reported data, we analyzed questionnaire and registry-based data on familial cancer from a population-based case–control study of malignant lymphoma. Methods: All 1508 lymphoma case patients and 1229 control subjects completed a telephone interview assessing cancer in family members. Participants were linked to the Swedish Multi-Generation Register and Cancer Register to identify confirmed cancer diagnoses in first-degree relatives. The sensitivity and specificity of self-reported familial cancer were calculated among case patients and control subjects and were compared using logistic regression. All statistical tests were two-sided. Results: Lymphoma case patients reported a family history of any cancer with statistically significantly higher sensitivity than control subjects (0.85, 95% confidence interval CI = 0.83 to 0.87 and 0.80, 95% CI = 0.77 to 0.82, respectively) but with marginally lower specificity (0.89, 95% CI = 0.87 to 0.91 and 0.92, 95% CI = 0.90 to 0.94, respectively). The sensitivity of self-reporting familial cancers by site ranged from less than 0.20 for rare malignancies to nearly 0.75 for more common types, whereas specificity was generally 0.98 or greater. For most sites, the reliability of self-report was similar in patients and control subjects. However, patients reported familial hematopoietic cancer with statistically significantly higher sensitivity (0.60, 95% CI = 0.57 to 0.62) than control subjects (0.38, 95% CI = 0.35 to 0.40). Odds ratios for the association between familial cancer and risk of non-Hodgkin lymphoma were consistently higher when based on self-reported, compared with registry data-based, family history of any cancer or of hematopoietic cancer. Conclusions: Reliability of self-reported family history of cancer varies between case patients and control subjects. Recall bias may thus produce biased results in case–control studies of familial cancer risk.
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