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Since 1960, incidence of non-Hodgkin's lymphoma (NHL) has been increasing in most industrialized countries, but causes of this trend remain unclear. A role of the decreased exposure to infectious agents during childhood has been proposed. Our study evaluates the association between common childhood infectious diseases and the risk of NHL and its major subtypes by a reanalysis of the Italian multicenter case-control study. After exclusion of next-of-kin interviews, 1,193 cases, diagnosed between 1990 and 1993, and 1,708 population-based controls were included in the analyses. OR estimates were obtained by logistic regression, adjusting for gender, age, residence area, education, smoking habit and exposure to radiations, pesticides and aromatic hydrocarbons. Among B-cell lymphomas (n = 1,102) an inverse association was observed for rubella (OR = 0.80, 95% CI: 0.65-0.99), pertussis (OR = 0.74, 95% CI: 0.62-0.88) and any infection (OR = 0.75, 95% CI: 0.61-0.93). A negative trend by number of infections was observed, which was more evident among mature B-cell lymphoma (OR = 0.66 for three infections or more, 95% CI: 0.48-0.90). Our results indicate a potential protective role of common childhood infections in the etiology of B-cell NHL., (© 2019 UICC.)

Background: Non-Hodgkin lymphoma (NHL) comprises biologically and clinically heterogeneous subtypes. Previously, study size has limited the ability to compare and contrast the risk factor profiles among these heterogeneous subtypes., Methods: We pooled individual-level data from 17 471 NHL cases and 23 096 controls in 20 case-control studies from the International Lymphoma Epidemiology Consortium (InterLymph). We estimated the associations, measured as odds ratios, between each of 11 NHL subtypes and self-reported medical history, family history of hematologic malignancy, lifestyle factors, and occupation. We then assessed the heterogeneity of associations by evaluating the variability (Q value) of the estimated odds ratios for a given exposure among subtypes. Finally, we organized the subtypes into a hierarchical tree to identify groups that had similar risk factor profiles. Statistical significance of tree partitions was estimated by permutation-based P values (P NODE)., Results: Risks differed statistically significantly among NHL subtypes for medical history factors (autoimmune diseases, hepatitis C virus seropositivity, eczema, and blood transfusion), family history of leukemia and multiple myeloma, alcohol consumption, cigarette smoking, and certain occupations, whereas generally homogeneous risks among subtypes were observed for family history of NHL, recreational sun exposure, hay fever, allergy, and socioeconomic status. Overall, the greatest difference in risk factors occurred between T-cell and B-cell lymphomas (P NODE < 1.0×10(-4)), with increased risks generally restricted to T-cell lymphomas for eczema, T-cell-activating autoimmune diseases, family history of multiple myeloma, and occupation as a painter. We further observed substantial heterogeneity among B-cell lymphomas (P NODE < 1.0×10(-4)). Increased risks for B-cell-activating autoimmune disease and hepatitis C virus seropositivity and decreased risks for alcohol consumption and occupation as a teacher generally were restricted to marginal zone lymphoma, Burkitt/Burkitt-like lymphoma/leukemia, diffuse large B-cell lymphoma, and/or lymphoplasmacytic lymphoma/Waldenström macroglobulinemia., Conclusions: Using a novel approach to investigate etiologic heterogeneity among NHL subtypes, we identified risk factors that were common among subtypes as well as risk factors that appeared to be distinct among individual or a few subtypes, suggesting both subtype-specific and shared underlying mechanisms. Further research is needed to test putative mechanisms, investigate other risk factors (eg, other infections, environmental exposures, and diet), and evaluate potential joint effects with genetic susceptibility., (Published by Oxford University Press 2014.)

Background: A number of studies have shown possible associations between occupational exposures, particularly solvents, and lymphomas. The present investigation aimed to evaluate the association between exposure to solvents and lymphomas (Hodgkin and non-Hodgkin) in a large population-based, multicenter, case-control study in Italy., Methods: All newly diagnosed cases of malignant lymphoma in men and women age 20 to 74 years in 1991-1993 were identified in 8 areas in Italy. The control group was formed by a random sample of the general population in the areas under study stratified by sex and 5-year age groups. We interviewed 1428 non-Hodgkin lymphoma cases, 304 Hodgkin disease cases, and 1530 controls. Experts examined the questionnaire data and assessed a level of probability and intensity of exposure to a range of chemicals., Results: Those in the medium/high level of exposure had an increased risk of non-Hodgkin lymphoma with exposure to toluene (odds ratio = 1.8; 95% confidence interval = 1.1-2.8), xylene 1.7 (1.0-2.6), and benzene 1.6 (1.0-2.4). Subjects exposed to all 3 aromatic hydrocarbons (benzene, toluene, and xylene; medium/high intensity compared with none) had an odds ratio of 2.1 (1.1-4.3). We observed an increased risk for Hodgkin disease for those exposed to technical solvents (2.7; 1.2-6.5) and aliphatic solvents (2.7; 1.2-5.7)., Conclusion: This study suggests that aromatic and chlorinated hydrocarbons are a risk factor for non-Hodgkin lymphomas, and provides preliminary evidence for an association between solvents and Hodgkin disease.

In the context of a population-based case-control study in Italy, the authors investigated the possible association between the personal use of hair dyes and non-Hodgkin's lymphoma (NHL), leukemia, multiple myeloma, and Hodgkin's disease. They collected all incident cases of hematolymphopoietic malignancies; the control group was formed with a random sample of the general population. Overall, the authors interviewed 2,737 research subjects and 1,779 control subjects. Among women, the authors found no association between ever using hair dyes and the risk of hematolymphopoietic malignancies. However, for permanent hair dyes, the authors observed a slightly increased risk of lymphocytic leukemia (odds ratio [OR] = 1.3; 95% confidence interval [CI] = 0.8-2.2) and of follicular subtypes of NHL (OR= 1.3; 95% CI = 0.8-2.0). Women who used black hair dye colors were at an increased risk of developing leukemia (OR = 1.9; 95% CI = 1.0-3.4), in particular chronic lymphocytic leukemia (OR = 3.0; 95% CI = 1.1-7.5). In spite of the lack of information on the timing and frequency of hair dye use and the imprecision of the ORs, associations were suggested between leukemia and permanent black hair dye use and follicular NHL and the use of permanent hair dyes.

Background: In recent decades, the incidence of non-Hodgkin's lymphoma (NHL) has increased in all industrialized countries. Tobacco smoke contains several recognized or putative carcinogenic compounds that differ in concentration depending on which of the two main types, blond or black, is consumed. This investigation sought to evaluate the association between NHL and type of tobacco smoked (blond, black, or mixed), focusing on the Working Formulation (WF) subgroups., Methods: Reanalysis of Italian data from a recent multicenter population-based case-control study. The 1450 cases of NHL and 1779 healthy controls from 11 Italian areas with different demographic and productive characteristics were included in the study, corresponding to approximately 7 million residents. Odds ratios (ORs) adjusted for age, gender, residence area, educational level, and type of interview were estimated by unconditional logistic regression model., Results: A statistically significant association [OR = 1.4, 95% confidence interval (CI) 1.1-1.7] was found for blond tobacco exposure and NHL risk. A dose-response relationship was limited to men younger than 52 years (chi(2) for trend = 9.95, P < 0.001). Subjects starting smoking at an early age showed a higher risk in men younger than 65 years, whereas no clear trend was evident for the other age and gender subgroups. The analysis by WF categories showed the highest risks for follicular lymphoma in blond (OR = 2.1, 95% CI 1.4-3.2) and mixed (OR = 1.8, 95% CI 1.1-3.0) tobacco smokers and for large cell within the other WF group (OR = 1.6, 95% CI 1.1-2.4) only for blond tobacco., Conclusions: Smoking blond tobacco could be a risk factor for NHL, especially follicular lymphoma.

Background: The etiology of non-Hodgkin's lymphoma (NHL) and leukemia is still largely unknown, but exposure to chemicals, in particular pesticides, has been suggested to be a risk factor., Methods: A large population-based case-control study was conducted in Italy with the aim of investigating the associations between pesticide exposure and NHL, and solvents and leukemia. Data presented in this article refer to 1,575 interviewed cases and 1,232 controls in the nine agricultural study areas., Results: Exposure to nitro-derivatives and phenylimides among fungicides, hydrocarbon derivatives and insecticide oils among insecticides, and the herbicide amides are the chemical classes observed to be associated with the pathologies under investigation., Conclusions: The results of the case-control study suggest an increased risk for NHL and leukemia, and some chemical classes of pesticides, although few are statistically significant and some are based on few exposed cases. The results also show that men and women experience both similar and different risks for the same environmental agricultural exposures. Am. J. Ind. Med. 44:627-636, 2003., (Copyright 2003 Wiley-Liss, Inc.)

Objective: Tobacco use is the most prominent cause of respiratory cancers. Little is known, however, about the influence of smoking on hematolymphopoietic malignancies. To evaluate this relation, a population-based case-control study was carried out in 12 areas of Italy., Methods: Detailed interviews on tobacco smoking habits were administered to 1450 non-Hodgkin's lymphoma (NHL), 365 Hodgkin's disease (HD), 270 multiple myeloma (MM), and 649 leukemia (LEU) patients occurring from 1990 to 1993, and 1779 population controls., Results: We found a slightly increased risk for NHL in smokers (odds ratio 1.2, 95% confidence interval 1.0-1.4 for ever smokers), but a consistent positive association was shown only for follicular NHL. In this subtype, a significant excess risk was observed for ever versus never smokers, after adjustment for gender, age, geographic residence, education, and respondent (OR = 1.8, 95%, CI 1.3-2.7), with a positive exposure-response gradient for smoking duration (p < 0.01). The risk for follicular NHL was significantly elevated only among women, with ever smokers showing OR = 2.3 (CI 1.4-3.8), while for men we found OR = 1.3 (CI 0.69-2.3). No major differences were shown according to age. Female subjects also showed significant positive exposure-response trends for duration., Conclusion: Cigarette smoking could be a risk factor for follicular NHL among women. For HD, MM, or LEU, no clear association was observed.

We conducted a population-based, case-control study on hematolymphopoietic malignancies in 12 areas in Italy to investigate associations between different hematolymphopoietic malignancies and exposure to solvents and pesticides. We collected all incident cases 20-74 years of age from 12 areas, with a combined population of approximately 7 million residents. The control group was formed by a random sample of the study population. Data presented in this paper refer to 2,737 interviewed cases of 3,357 eligible cases and to 1,779 of 2,391 eligible controls. We analyzed risks associated with occupation using job-title information to evaluate disease pattern according to job category. An earlier publication presented results for women; here, we report the findings for men and discuss the overall patterns in both genders. The most consistent overall finding was an approximate doubling in relative risk for all four types of malignancies among male managers and related occupations. Several additional occupations were associated with elevated risk of one or more malignancies among men. These included cooks, waiters, and bartenders, and building caretakers and cleaners, for non-Hodgkin's lymphoma; textile workers and machinery fitters for Hodgkin's lymphoma; metal processors, material handlers, rubber workers, and painters for leukemia; and hairdressers, metal processors, tailors, electrical workers, and plumbers for multiple myeloma. The finding of increased risk of non-Hodgkin's lymphoma among both male and female cooks, waiters, and bartenders has not been previously reported; nor has the elevated risk of leukemia among material handlers. Among people engaged in agriculture, those employed as tractor drivers and as "orchard, vineyard, and related tree and shrub workers" appeared to be at increased risk for hematolymphopoietic malignancies.

Background: The annual incidence of non-Hodgkin's lymphomas (NHL) is increasing by 3%-4% in different parts of the developed world. Excesses of NHL have been observed in populations exposed to immunosuppressants and to HIV, but these causes do not explain the increasing trends. It is suggested that delayed infection could explain NHL trends, through an impairment of the Th1/Th2 lymphocyte patterns., Methods: In a population-based study on 1388 patients with NHL, 354 with Hodgkin's disease (HD) and 1718 healthy controls, the age of first occurrence of bacterial and viral diseases was investigated. Clinical records were perused in one centre to check the anamnestic data., Findings: The age of occurrence of bacterial and viral diseases was significantly higher among NHL patients than in the controls. The association between later age at first bacterial or viral disease was limited to small families (OR= 1.95; 95% confidence intervals 1.26, 3.00, for age 4-8 at first infection; OR=1.91; 1.19, 3.06, for age 9+, compared with less than 4). The association was more obvious for bacterial diseases (possibly for the lower degree of misclassification). High grade lymphomas showed the strongest association. The later age of occurrence of bacterial or viral diseases in NHL patients is consistent with a higher incidence of lymphomas observed in higher social groups. No clear association was found between HD and age at first bacterial or viral diseases., Interpretation: It is proposed that delayed infection could explain the increasing NHL trends, through an impairment of the Th1/Th2 lymphocyte patterns. The model of delayed infection has been proposed also to explain increasing prevalence rates of asthma.

Background: Viruses (such as Epstein-Barr virus) and pathological conditions (mainly involving immunosuppression) have been shown to increase the risk of haematolymphopoietic malignancies. Other associations (diabetes, tonsillectomy, autoimmune diseases) have been inconsistently reported., Methods: The association between different haematolymphopoietic malignancies (lymphomas, myelomas and leukaemias) and the previous medical history has been studied in a population-based case-control investigation conducted in Italy, based on face to face interviews to 2669 cases and 1718 population controls (refusal rates 10% and 19%, respectively). Controls were a random sample of the general population., Results: Previous findings were confirmed concerning the association between non-Hodgkin's lymphoma (NHL) and lupus erythematosus (odds ratio, OR=8.4; 95% CI 1. 6, 45), tuberculosis (OR=1.6; 1.05, 2.5) and hepatitis (1.8; 1.4, 2. 3). An association was found also between NHL and maternal (OR=2.8; 1.1, 6.9) or paternal tuberculosis (OR=1.7; 0.7, 3.9). Odds ratios of 4.0 (1.4, 11.8) and 4.4 (1.1, 6.6) were detected for the association between NHL and Hodgkin's disease, respectively, and previous infectious mononucleosis, but recall bias cannot be ruled out. No association was found with diabetes, tonsillectomy and adenoidectomy. An association with malaria at young age and "low grade" lymphatic malignancies is suggested. One interesting finding was the observation of four cases of poliomyelitis among NHL patients, one among Hodgkin's disease and one among myeloid leukaemia patients, compared with none among the controls (Fisher's exact test for NHL and Hodgkin's disease, p= 0.03, one tail)., Conclusions: Some of these findings are confirmatory of previous evidence. Other observations, such as the putative role of the polio virus and of malaria are new. A unifying theory on the mechanisms by which previous medical history may increase the risk of haematolymphopoietic malignancies is still lacking.

Helicobacter pylori has been suggested as a cause of gastric carcinoma and gastric non-Hodgkin's lymphoma (NHL). In a previous cohort study, a relative risk of six for gastric NHL was reported among subjects who tested positive for anti-H.pylori antibodies. The association between peptic ulcer and NHL has been studied in a population-based case-control investigation on hemato-lymphopoietic malignancies in Italy, based on face-to-face interviews to 2671 cases and 1718 controls (refusal rates 10 and 19%, respectively). Subjects who reported a diagnosis of peptic ulcer had a relative risk of 5.6 [95% confidence interval (CI) 3.8-8.0] for gastric NHL, whereas the estimate for non-gastric NHL was 1.3 (1.0-1.6). The association with recent diagnosis of ulcer was stronger, but the odds ratio (OR) was as high as 2.1 (95% CI 1.1-4.2) after >/=20 years since such diagnosis. After exclusion of the last 2 years before the diagnosis of NHL, and of ulcers diagnosed before 1978 (when gastroscopy became common in Italy), the OR was still 5.3 (95% CI 3.0-9.2). We found a strong effect modification by educational level, with ORs for ulcer more elevated in higher social groups. Gender was an effect modifier (OR = 4.1 in males, 9.2 in females; P = 0.03 for heterogeneity). The association with other gastrointestinal pathologies was much lower and statistically not significant. Almost all gastric lymphomas were B-cell NHLs of intermediate grade according to the working formulation; the majority belonged to the mucosa-associated lymphoid tissue (MALT) type. The association with ulcer was much stronger among MALT lymphomas, but only for recent ulcer diagnoses (2-10 years). Our study shows an increased risk for gastric NHL, very similar to the estimate reported in a previous cohort study. The risk was higher among more educated subjects.

The annual incidence of non-Hodgkin's lymphomas is increasing by 3 to 4% in different parts of the developed world, while rates for Hodgkin's disease, myelomas and leukemias are more stable. In the case of this group of malignancies, hypothesis generation on risk factors has been limited by the use of the ICD classification in mortality and incidence statistics. We have computed incidence rates in different Italian areas after careful re-classification of diagnoses, and considering specific histotypes (Working Formulation for NHL, Rye's classification for HD). While no particularly interesting pattern is suggested for Hodgkin's disease (even after considering specific Rye subgroups), multiple myeloma and leukemias, for non-Hodgkin's lymphomas the high rate in one agricultural area (Forli) was mainly due to the A sub-group in the Working Formulation (low-grade). In a heavily industrialized area (Varese), the high incidence rate was at least partly explained by a higher proportion of cases classified in the G sub-group (intermediate grade). Excesses of non-Hodgkin's lymphomas have been observed in populations exposed to phenoxy-acetic-acid herbicides, to insecticides and to organic solvents. One can hypothesize that different risk factors act on different stem cells and induce lymphoid malignancies belonging to different histologic sub-types.