Risk factors for non-Hodgkin's lymphoma according to family history of haematolymphoproliferative malignancies

Kangmin Zhua, Robert S Levineb, Edward A Brannc, Yuan Gub, Lee S Caplanc, Irene Hallc and Marianna K Baumd

a Department of Health Evaluation Sciences, Pennsylvania State University, Hershey, Pennsylvania, USA.
b Department of Occupational and Preventive Medicine, Meharry Medical College, Nashville, Tennessee, USA.
c Centers for Disease Control and Prevention, Atlanta, Georgia, USA.
d University of Miami School of Medicine, Miami, Florida, USA.

Kangmin Zhu, Department of Helath Evaluation Sciences, A210, College of Medicine, Pennsylvania State University, PO Box 855, 600 Centerview Drive, Hershey, PA 17033-0855, USA

Abstract

Background Aetiological profiles of non-Hodgkin's lymphoma (NHL) may differ depending upon whether the disease is inheritance-related or sporadic. Because familial risk (a probable surrogate of inheritance-relatedness) of NHL is influenced by haematolymphoproliferative malignancies (HLPM), we evaluated whether non-familial risk factors differ between NHL with and without a family history of HLPM, using the Selected Cancers Study data.

Methods Cases were 1511 men aged 31–59 and diagnosed with NHL during 1984–1988. Controls were men without NHL, frequency-matched to cases by age range and cancer registry (n = 1910). These groups were compared: cases with a family history of HLPM and without, and controls without such a family history.

Results Polytomous logistic regression analyses showed that the odds ratio (OR) estimates of homosexual behaviour were 18.2 (95% confidence interval (CI) : 4.8–69.4) and 5.6 (95% CI : 3.3–9.5) for NHL with and without a family history of HLPM, respectively. The corresponding estimates were 3.9 (95% CI : 1.7–8.9) and 2.2 (95% CI : 1.5–3.1) for history of enlarged lymph nodes. Variables only related to NHL with a family history were use of heroin (OR = 15.6, 95% CI : 3.4–70.4), exposure to a chlorinated hydrocarbon pesticide (OR = 2.3, 95% CI : 1.0–5.0), occupational exposure to plywood, fibreboard or particleboard (OR = 2.0, 95% CI : 1.2–3.4) and history of liver diseases (other than hepatitis or cirrhosis) (OR = 6.5, 95% CI : 1.2–36.2). The association between homosexual behaviour and NHL among men with a family history was stronger for those aged 31–44, especially for B-cell type of the disease.

Conclusions This study suggests differences in the risk factor profiles between NHL with and without a family history of HLPM. The higher risks of NHL for homosexual behaviour and heroin use, surrogates of HIV infection, in men with a family history of HLPM imply that genetic susceptibility may be influential on the occurrence of HIV-related NHL.

Keywords Case-control studies, family history, non-Hodgkin's lymphoma, risk factors

Accepted 16 August 2000

Non-Hodgkin's lymphoma (NHL) is the sixth most common cancer in the US.1 Studies have demonstrated that human immunodeficiency virus (HIV) infection is a strong risk factor for NHL,2,3 accounting for part of the increasing incidence of the disease.1,4 Although inconsistent, epidemiological studies have also identified some potential non-genetic risk factors for NHL. These factors primarily include exposure to some pesticides or herbicides,58 radiation,9 blood transfusion,1012 smoking,13 hepatitis C virus infection,14,15 fat intake16 and use of some medications.17

However, no studies have assessed non-genetic risk factors for NHL according to whether the disease is inheritance-related or sporadic. It is reasonable to hypothesize that profiles of non-genetic risk factors differ depending upon whether a person carries susceptibility genes from his/her parents.18,19 For example, people with susceptibility genes may be vulnerable to effects of some factors whereas those without such genes may not be affected. Family history of disease, although not exclusively, may be inheritance-related and is therefore a probable surrogate of genetic susceptibility, particularly if the risk factors under consideration are unlikely to be associated with a shared family environment.

Previous studies have demonstrated that the risk of NHL is associated with family history of not only NHL but also Hodgkin's disease (HD) and haematological cancer with an overall relative risk estimate of 3–4 for a family history of these tumours.2024 These results suggest a familial aggregation of haematolymphoproliferative malignancies (HLPM) (lymphoma and haematological cancer or leukaemia). Such familial aggregation implies that HLPM share similar genetic changes and carcinogenic processes. This is possible because lymphoma and leukaemia have common cellular origin (haematopoietic stem cells)25,26 and some types of lymphoma and leukaemia have the same chromosome changes e.g. translocation at t (8,14) and t (11,14).25 Therefore it is reasonable to use family history of HLPM as a surrogate of inheritance-relatedness of NHL. This study aimed to examine risk factors for NHL according to family history of HLPM, using data from the Selected Cancers Study.

Materials and Methods

This study used data from a population-based case-control investigation conducted by the Selected Cancers Cooperative Study Group.27 Cases were men who were pathologically diagnosed with NHL during 1984–1988, who were 31–59 years old, and who lived in the areas covered by eight cancer registries in the US. In all, 2354 lymphoma patients were originally identified from the cancer registries. Of these patients, 2004 were interviewed and had microscope slides or blocks available. A lymphoma diagnosis was confirmed by a pathology panel for 1864 men, of whom 1511 were classified as having NHL. Controls were men selected through random digit dialling who were frequency matched to lymphoma cases by cancer registry and 5-year age interval. Some 2299 men were identified as eligible controls, among whom 83.1% completed the interview (n = 1910). Informed consent was obtained from the study subjects before an interview.

For this study, cases were divided into two subgroups according to family history of HLPM: those with (n = 83) and without (n = 1428) such a family history. Only controls who did not have a family history of HLPM (n = 1864) were used in analysis. Family history of HLPM is defined as a reported lymphoma or leukaemia among first-degree relatives (parents, sisters, brothers or children). Since pathological types could not be distinguished by some respondents for lymphoma (NHL versus HD) or leukaemia and since there were a relatively small number of study subjects with a family history, we could not make a detailed distinction of these malignancies for family history.

Information was collected primarily through telephone interviews. In-person interviews (2.4 % of cases with a family history, 5.1% of cases without a family history and 1.9% of controls) and next-of-kin interviews (13.3 % of cases with a family history, 18.4% of cases without a family history and none of controls) were made if participation could be obtained only in this manner or when a case had died. Data on risk factors before or at the reference date were collected. The reference date was the date of NHL diagnosis for cases and the date of interview for controls. Risk factors included demographic characteristics (age, ethnicity, education and marital status), medical history (mononucleosis, hepatitis, liver disease other than hepatitis or cirrhrosis, malaria, chloracne, chickenpox, allergy, rheumatoid arthritis, appendectomy, tonsillectomy, enlarged lymph nodes, blood transfusion, use of blood products other than a transfusion, use of androgen, use of clofibrate, and use of amphetamine), exposures to medical radiation, exposures to pesticides/ herbicides (chlorinated hydrocarbon pesticides, heterocyclic nitrogen pesticides, phenoxyherbicides, pesticides containing 2,4,5-T, pesticides containing 2,4-D, dinitroaniline pesticides, arsenical pesticides, substituted benzoic pesticides, carbamate or thiocarbamate pesticides, chloroacetanelide pesticides or organophosphate pesticides), other occupational exposures (dry cleaning, meat packing or processing, pulp mill/saw mill/ planing mill, chemical solvents, wood preservatives or wood treating chemicals, insulation or fire-proofing materials, nickel compounds or alloys, chromium compounds or alloys, formaldehyde, plywood, wood or saw dust, asbestos, shoe or leather dust, vinyl chloride, cutting oils, chlorophenols, using chemicals in hobby, or constructing things out of wood), personal habits and lifestyle (smoking, alcohol consumption, intravenous drug use and homosexual behaviour), type of non-prescription drugs used (amphetamines, amyl nitrite or poppers, barbiturates or downers, cocaine, heroin, or marijuana) and history of military service in Vietnam (a surrogate of military exposure to agent orange). Histories of mononucleosis, hepatitis, liver disease, enlarged lymph nodes, blood transfusion and medical radiation were based on the diagnosis or exposure 3 or 5 years prior to the reference date.

Polytomous logistic regression simultaneously comparing two groups of cases (with and without a family history of HLPM)28,29 with controls was used. We selected into the model variables for which the 95% confidence interval (CI) of an odds ratio (OR) estimate for either or both of the case subgroups excluded unity. A forward approach was used, in which a variable with an CI excluding one and with most significant likelihood test entered the model at each step. Distributions in immunophenotype differ between tumours with and without a family history of HLPM (82% and 72% were B-cell NHL for cases with and without a family history, respectively). We repeated the same analyses for the B-cell type of NHL to assess whether the magnitude of an association differed for this type, for which different histological types are biologically and therefore probably aetiologically related. Included in the B-cell group were small non-cleaved and cleaved lymphoma, small lymphocytic lymphoma, large non-cleaved and cleaved lymphoma, diffuse or follicular large cell lymphoma with intermediate grade, follicular mixed small and large cell lymphoma, Mantle zone lymphoma and Burkitt's lymphoma. This classification was based on the relationship between the Working Formulation classification and immunophenotypes of NHL.30 Human immunodeficiency virus infection is a strong risk factor for NHL2,3 and was not measured in this study. Because homosexual behaviour and drug use are highly related to HIV infection,31,32 they can be used as surrogates of the infection. Since the prevalence of HIV infection is higher in younger high-risk people than in their older counterparts,3335 we assumed that homosexual behaviour and drug use are better surrogates and therefore have higher relative risks in younger men. Thus, we repeated the analyses for men aged 31–44. To reduce the potential effects of HIV infection on results of other non-HIV-related variables, we also repeated the analyses excluding men who were homosexual or used illegal drugs that increase the risk of NHL.

Results

Table 1Go shows the distributions of demographic characteristics among NHL cases with and without a family history of HLPM and controls without such a family history. Compared to cases and controls without a family history, cases with a family history tended to be older. Cases with a family history were more likely to be never-married, compared with controls. The proportion of never-married men was higher among cases without a family history. While cases with a family history were more likely to be Caucasian, the three groups had similar educational levels. These demographic variables as well as cancer registry were adjusted in subsequent analyses.


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Table 1 Demographic characteristics of controls and non-Hodgkin's lymphoma cases with and without a family history of haematolymphoproliferative malignancy, the Selected Cancers Study, 1984–1988
 
Table 2Go shows the OR estimates and their CI of risk factors for NHL. Homosexual behaviour and history of enlarged lymph nodes were associated with increased risk of NHL in men both with and without a family history of HLPM, however, the association strength was greater in men with a family history. While NHL cases without a family history of HLPM were 5.6 times more likely to have homosexual behaviour (95% CI : 3.3–9.5) than controls without a family history, the corresponding OR estimate was 18.2 (95% CI : 4.8–69.4) for cases with such a family history. Exposures to heroin, chlorinated hydrocarbon pesticides and plywood increased the risk of NHL only among men with a family history of HLPM. For illegal use of heroin, the OR estimate was 15.6 (95% CI : 3.4–70.4) for cases with a family history while the estimate was 1.1 (95% CI : 0.6–2.0) for those without a family history. Liver diseases (other than hepatitis or cirrhosis) diagnosed at least 3 years prior to the reference date also are related only to NHL with a family history of HLPM. We also found an inverse association between history of allergy or illegal use of marijuana/hashish and NHL with a family history, and a positive association between illegal use of amyl nitrite or use of androgen and NHL without a family history. The OR estimates were similar between different family histories for other variables. After homosexual behaviour and illegal use of heroin were excluded from the analysis, the OR estimates for NHL with a family history increased from 6.5 (95% CI : 1.2–36.2) to 13.2 (95% CI : 2.2–79.3) for liver diseases other than hepatitis or cirrhosis and from 3.9 (95% CI : 1.7–8.9) to 5.3 (95% CI : 2.2–12.8) for enlarged lymph nodes. The other OR estimates remained similar (data not shown).


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Table 2 Odds ratio (OR) estimates and their CI of risk factors for non-Hodgkin's lymphoma (NHL) cases with and without a family history of haematolymphoproliferative malignancy among men aged 31–59, the Selected Cancers Study, 1984–1988
 
Table 3Go shows the OR estimates when data analysis was confined to the B-cell type of NHL. Except for an increase from 6.5 (95% CI : 1.2–36.2) to 12.5 (95% CI : 2.1–73.5) for other liver diseases, results were similar to those in Table 2Go.


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Table 3 Odds ratio (OR) estimates and their CI of risk factors for B-cell non-Hodgkin's lymphoma (NHL) cases with and without a family history of haematolymphoproliferative malignancy among men aged 31–59, the Selected Cancers Study, 1984–1988
 
When analyses were repeated for men aged 31–44, the OR estimates among men with and without a family history of HLPM were 31.4 (95% CI : 4.5–218.9) and 8.3 (95% CI : 4.2– 16.3) for homosexual behaviour, and 11.0 (95% CI : 1.8–66.0) and 0.9 (95% CI : 0.4–1.7) for heroin use. The corresponding estimates for B-cell type of NHL were 103.4 (95% CI : 11.8– 906.7) and 7.1 (95% CI : 3.3–15.3) for homosexual behaviour, and 17.9 (95% CI : 2.1–155.3) and 1.1 (95% CI : 0.5–2.4) for the use of heroin, respectively (data not shown).

Discussion

This study shows that the risk factor profiles may differ between NHL with and without a family history of HLPM. The most significant differences were shown for homosexual behaviour, heroin use, history of enlarged lymph nodes, exposures to chlorinated hydrocarbon herbicides or plywood, and history of liver diseases (other than hepatitis and cirrhosis). These variables increased the risk of NHL among men with a family history compared to those without a family history, suggesting the role of genetic susceptibility in the association of some non-genetic risk factors with NHL.

Previous studies have provided sound evidence that HIV infection is an important risk factor for NHL, especially B-cell type.3638 Homosexual behaviour and intravenous drug use are risk factors for HIV infection.31,32,3942 Heroin is usually injected,43 while marijuana is usually smoked, amyl nitrite is taken by nasal inhalation or in pills, and cocaine in nasal inhalation.43 Therefore, heroin use is more likely to be a risk factor for HIV infection. Our study found that homosexual behaviour and heroin use (as opposed to the use of marijuana, amyl nitrite or cocaine) increased the risk of NHL among men with a family history of HLPM. Intravenous drug use itself did not enter the model in this study, probably due to its high correlation with heroin use. This was confirmed by the fact that the OR among men with a family history was substantially decreased from 15.6 (95% CI : 3.4–70.4) to 8.7 (95% CI : 1.4–53.5) after intravenous drug use was added intentionally to the model. Although the independent impact of heroin use could not be excluded in this study, the similarity between homosexual behaviour and heroin use in the association with NHL strongly suggests the effects of HIV infection on the occurrence of NHL. A stronger association between homosexual behaviour and NHL (especially B-cell NHL) among men who were younger further supported this possibility.

Human immunodeficiency virus-related NHL involve a number of genetic lesions, including c-myc rearrangement, bcI-6 mutation, Ras mutation and p53 loss/mutation.4446 According to the ‘two-hit’ hypothesis,47 a recessive gene mutation leads to a heterozygous status of a cell (the first hit) and an additional somatic mutation of the gene renders the cell homozygous (the second hit), giving rise to a tumour. In our study, family history of HLPM may be a surrogate of ‘the first hit’ due to either inheritance or effect of exposure to environmental risk factors shared within family members. Homosexual behaviour and heroin use, surrogates of HIV infection, may induce subsequent mutations of the tumour-suppressor genes as a result of cytokine and immunological dysregulation due to the effect of HIV transactivating regulatory protein.46,48 Our results imply that genetic susceptibility may be important for the occurrence of HIV-related NHL. While HIV infection may also influence those not genetically susceptible, its effects may be greater in vulnerable people with ‘the first hit’.

Similar results were found for history of liver disease (other than hepatitis or cirrhosis) diagnosed at least 3 years prior to the reference date. A number of recent studies have found that hepatitis C virus infection may increase the risk of NHL,14,15,49 probably through stimulation of B cell expansion.50 Our study was conducted between 1984 and 1988, before which diagnostic methods for hepatitis C virus had not been established.51 It is not impossible that hepatitis C, which was not known during the study, was misclassified into non-hepatitis/cirrhosis liver disease in the study. If this assumption is tenable, our study may suggest an association between hepatitis C and NHL, especially in men with a family history of HLPM. A higher OR for the B-cell type of NHL in our data may support this possibility because hepatitis C virus affects B-cell lymphocytes.50 However, liver disease (other than hepatitis and cirrhosis) is a broad concept and includes various disease entities in the liver. Therefore, the association between liver disease and NHL cannot be readily explained and more detailed information about liver disease should be obtained in future research.

Exposures to chlorinated hydrocarbon pesticides or plywood were also associated with NHL in men with a family history of HLPM. While we did not find a previous study on plywood, a possible association between chlorinated hydrocarbon pesticides and NHL has been shown in some5,52 but not all53,54 of previous studies. In one previous study in women, pesticide-related risk was found to be greater in subjects with a family history of lymphatic or haematopoietic cancer.52 Our study suggests that an association of chlorinated hydrocarbon pesticides with NHL would exist only in individuals with genetic susceptibility. This may explain the negative results in some previous studies: when data do not make the distinction of genetic background the association between chlorinated hydrocarbon pesticides and NHL may be concealed or reduced.

Enlarged lymph nodes 3 years before the diagnosis of NHL tended to be related to NHL more strongly in men with a family history. Enlarged lymph nodes usually are a sign of lymphadenitis, immunological reactions or proliferative disorders, which commonly result from infection.50,5557 Some infections, e.g. Epstein-Barr virus and HTLV-1, have been linked to the occurrence of lymphoma.58,59 Therefore, enlargement of lymph nodes may be associated with NHL as a surrogate of infectious, and therefore immunological or proliferative abnormality. The association may be stronger in genetically susceptible men according to our data. However, caution should be taken in the explanation of the results. Because enlarged lymph nodes themselves might be an early sign of NHL they might be over-represented in cases. However, we do not have evidence to show that NHL with a family history is more likely to have an early manifestation of enlarged lymph nodes, which therefore confers a higher OR estimate. Another possibility that we do not exclude is recall bias: cases, particularly those with a family history, might be more likely to recall a history of enlarged lymph nodes, resulting in a falsely positive finding.

Our study showed that two factors, allergy and marijuana use, were related to decreased risk of NHL. These inverse associations had been found previously.6063 The inverse allergy-NHL association may represent an immune-NHL relationship and allergic reactions may reduce the risk of NHL via their effects on B-cell differentiation.62 In our study, such an inverse association was shown only in men with a family history, which needs to be confirmed and elucidated. More research is needed for allergy as well as marijuana use.

This study had some limitations. First, family history was used as a surrogate of genetic susceptibility. While family history is indeed an indicator of genetic susceptibility in many circumstances, it may also represent shared family environment. Therefore, we do not exclude the possibility that the identified differences between cases with and without a family history were contributed to by the interaction between an investigated exposure and some non-genetic risk factors shared within the family. Older age of cases with a family history than those without in our study seemed inconsistent with genetic effects. However, age at onset is influenced by a synthetic effect of all risk factors and different disease characteristics, and older age at onset does not refute the possible interaction between genetic susceptibility and specific non-genetic factors. More studies are obviously needed. Second, measurement errors on risk factors might be a problem. Recall bias might have influenced some of our results. However, while recall errors might be differential between cases and controls, they were less likely to be so between the two case groups defined by the family history of HLPM, especially for non-genetic factors. Therefore, recall bias alone might not account for the large differences in OR between the two case groups for some variables such as homosexual behaviour and heroin use. Proxy interviews for some cases might be another problem. However, the proportions of proxy interviews were not high and not obviously different between cases with and without the family history. Therefore, it might not substantially bias the results comparing the two case groups. Moreover, the results on homosexual behaviour and heroin use, the two major variables that were found to be associated with NHL, were not influenced by proxy interviews, because no proxy interviewees answered the questions on these variables. Third, homosexual behaviour and heroin use were assumed to be proxies of HIV infection. Thus, the true association of HIV infection with NHL might have been diluted. Moreover, we do not exclude the possibility that they are also surrogates of another unknown risk factor. Finally, lymphoma and leukaemia and their histological types could not be distinguished for family history and the relatively small sample size makes it impossible to analyse each type of NHL according to its family history. It may be envisaged that the OR estimate, e.g. for HIV-related variables, should be much higher for men with a family history if we could analyse data according to the same type of NHL for both cases and their family histories. This would need a very large number of study subjects and detailed information about NHL diagnosed in family members.

Despite these limitations, our results for some variables, especially homosexual behaviour and heroin use were unlikely explained entirely by artifact, because of the remarkable difference between men with and without a family history. The findings suggest the importance of considering genetic background in the evaluation of risks for NHL and more intense medical surveillance of NHL may be needed for HIV-infected individuals with a family history of HLPM. To further elucidate the inter-relationship between genetic susceptibility, non-genetic factors and risk of NHL, however, more epidemiological studies are needed, which have (1) a better lymphoma classification that can distinguish different biological entities more accurately, (2) large sample sizes for analysis based on NHL type, (3) laboratory measurements of genetic susceptibility, (4) more detailed and accurate measurement of non-genetic factors such as virus infections, and (5) investigations of not only cases and controls but also their family members.

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