Acquired disorders affecting the immune system and non-Hodgkin's lymphoma

PREVENTIVE

MEDICINE

Acquired

16, 96- 106 (1987)

Disorders Affecting Non-Hodgkin’s

the Immune Lymphomal

System and

JAMES M. TIELSCH, PH.D.,* MARTHA S. LINET, M.D., M.P.H. ,V2 AND MOYSES SZKLO, M.D.,DR.I?H.I *International Hopkins

Center for Epidemiologic and Preventive Ophthalmology, Wilmer Institute, The Johns School of Medicine, and tDepartment of Epidemiology, The Johns Hopkins School of Hygiene and Public Health, Baltimore, Maryland 21205

A case-control study was undertaken to determine whether a prior history of a variety of acquired disorders affecting the immune system was associated with an increased risk of non-Hodgkin’s lymphoma. Cases were identified over a 4-year period (1976-1979) at the Johns Hopkins Hospital and individually matched to hospital controls on age, sex, race, and year of diagnosis. For the 109 cases and matched controls who were traced and interviewed, positive associations suggesting an increase in risk were not detected. Instead, there was a suggestion of an inverse relationship. Odds ratios (ORs) were consistently less than 1 for associations between non-Hodgkin’s lymphoma and several chronic infectious diseases (OR = 0.65, 95% CI = 0.35, 1.20), chronic inflammatory diseases (OR = 0.88, 95% CI = 0.43, 1.79), autoimmune disorders (OR = 0.80, 95% CI = 0.19, 3.76), and allergic disorders (OR = 0.77, 95% CI = 0.45, 1.32). A statistically significant protective association was found for surgical removal of lymphoid tissue (OR = 0.50, 95% CI = 0.27, 0.91). Adjustment for potentially confounding variables did not change these results. These findings do not support the previously anecdotally reported impression that disorders producing a chronic antigenic stimulus are associated with the development of non-Hodgkin’s lymphoma. D 19x7 Academic

Press, Inc.

INTRODUCTION

Experimental evidence in animal systems suggests that a chronic stimulus to the immune system may produce an increased risk of lymphoma (10, 19, 21, 30), particularly in species with a susceptible genetic substrate (28). In humans, a number of investigations have suggested an increased risk of both non-Hodgkin’s lymphoma (NHL) and other lymphoproliferative malignancies in individuals with a variety of acquired disorders affecting the immune system, including a number of infectious, inflammatory, and autoimmune disorders (1, 3, 11, 15, 16, 18, 20, 38, 43). In addition, several epidemiologic studies have noted associations of viral, plasmodial, and parasitic diseases with malignant lymphomas, including NHL, Burkitt’s lymphoma, and Hodgkin’s disease (12, 39). The importance of immunologic factors in the etiology of lymphoproliferative abnormalities is also supported by findings of several studies showing positive associations between appendectomy or tonsillectomy and Hodgkin’s disease (13, 1 Supported in part by Public Health Service Grant ROlCA 26500 from the National Cancer Institute. This study was conducted with the assistance of the Oncology Information Service at The Johns Hopkins Comprehensive Cancer Center. z To whom reprint requests should be addressed at the Department of Epidemiology, The Johns Hopkins School of Hygiene and Public Health, 615 North Wolfe Street, Baltimore, Md. 21205. 96 0091-7435187 $3.00 Copyright All rights

0 1987 by Academic Press. Inc. of reproduction in any form reserved.

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14, 17, 34, 44), and between thymectomy and lymphoproliferative malignancies (41). A variety of autoimmune disorders appear to be characterized by decreases in suppressor T8 + cells and increases in the helper/suppressor (T4 + iT8 + ) ratios (6, 7, 16, 18, 27, 29, 35, 37, 42); such abnormalities in ratios and, perhaps, function of T cells may provide the basis for the increased risk of neoplasia, particularly lymphoproliferative malignancies, associated with these disorders. However, results of studies examining the relationship between altered immune function and neoplasia have not always been consistent. For example, some studies have suggested an inverse association between allergies and cancer (7, 22, 40), whereas others have not confirmed this association (5, 25, 26, 31, 33). Thus, it is important to carry out additional investigations aimed at exploring the connection between acquired immune system disorders and cancer. The possibility of expeditiously accessing both patients with NHL and hospital controls undergoing the same admission selection processes as cases in a major referral center in metropolitan Baltimore (The Johns Hopkins Hospital, JHH) prompted the present investigation. The purpose of the study was to examine the hypothesis that a history of acquired disorders or surgery involving the immune system affects risk of developing NHL. MATERIALS

AND METHODS

In this investigation, both cases and controls were selected from among patients hospitalized at The Johns Hopkins Hospital. Interviews were carried out to elicit information on the past history of acquired disorders affecting the immune system and surgical excision of lymphoid tissue. Case Selection Cases included newly diagnosed patients ages 18 years or older admitted to the JHH between January 1, 1976, and December 31, 1979. Cases were eligible for entry to the study if they had a histologic diagnosis of NHL confirmed by a senior pathologist at the JHH. All cases were classified according to the modified Rappaport scheme as described by Mann et al. (24). This case definition was met by 153 eligible cases, of which 109 (71.2%) were successfully traced and interviewed. Of patients not interviewed, 32 (20.9%) could not be traced, 10 (6.5%) refused participation, and 1 (1.3%) could not be included because the subject’s physician did not grant permission to contact the patient. Respondent and nonrespondent cases were similar on year of diagnosis, age, sex, stage and anatomic distribution of disease at diagnosis, cell type, and residence at time of diagnosis. Nonwhites, however, were more common among nonrespondents, 27 vs 7.3% among respondents. Selection

of Controls

Controls were chosen from among patients admitted to all inpatient services at the JHH excluding Psychiatry, Pediatrics, Oncology, Obstetrics, and the Renal Transplant Service. Controls were individually matched to cases on age (+- 5 years), sex, race, and year of diagnosis and were considered eligible if the matched hospitalization was the first admission for that particular diagnosis. Per-

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SZKLO

feet matching was achieved on sex, race, and year of diagnosis. Age matching was also very close, with 65.1% of pairs matched exactly and 90.8% matched within 1 year of age. The mean age difference between cases and controls was 0.06 years. The participation rate for controls (66.9%) was very similar to that for cases (71.1%). As for cases, inability to trace the subject was the most common (20.9%) reason for nonparticipation among controls. Additional reasons for nonparticipation included physician’s (3.1%) or subject’s (9.2%) refusal. For control subjects, respondents and nonrespondents were similar in terms of vital status or index diagnoses with few exceptions: A higher proportion of nonrespondents than respondents had nervous system and musculoskeletal disorders, and fewer nonrespondents had endocrine and metabolic and gastrointestinal disorders. However, respondents and nonrespondents were comparable with regard to the proportions with ophthalmologic and cardiovascular diseases, the two main diagnoses among controls. A higher proportion of nonrespondents (70.4%) than respondents (50.5%) were Baltimore residents at time of diagnosis. However, since 56.9% of cases who participated in the study were Baltimore residents, cases and controls were probably comparable with regard to likelihood of referral to JHH. Data Collection Data were collected from medical charts and telephone interviews. All telephone interviews were carried out by the same interviewer during the period September 1980 through October 1981. Information was sought mainly with regard to indices of chronic antigenic stimulation, such as previous medical history of chronic diseases and allergies, or surgery involving the immune system. All surgical histories reported during the interview were confirmed during review of the medical records. Additional questionnaire data included smoking, demographic variables, and an occupational history. All exposure data collected referred to the time prior to the NHL diagnosis for cases and prior to the index diagnosis for controls. Due to the serious nature of NHL (2) and the fact that cases were identified retrospectively, a large proportion of cases were deceased at the time of the study, 44 vs 9.2% of controls. For all deceased subjects, the interview was conducted with a surrogate. The most common surrogate was the spouse of the subject, who responded in 58.5% of cases. Children of the subject responded 24.6% of the time with the remaining 16.9% divided between parents and other relatives. Data Analysis The matched odds ratio (OR) and its 95% confidence interval (CI) were used as the measures of association and its precision, respectively (8). Multivariate analysis was carried out using the conditional logistic regression approach for matched sets developed by Breslow and Day (4). Tests for the homogeneity of odds ratios across strata also were done according to Breslow and Day (4). The main study variable, history of acquired disorders affecting the immune system, was defined as a previous history of chronic infectious, inflammatory, or autoimmune disease. A history of chronic infectious diseases was defined prior to

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data collection as a history of at least one of the following: tuberculosis, osteomyelitis, pyelonephritis, syphilis, mononucleosis, diverticulitis, chronic sinusitis, chronic bronchitis, chronic hepatitis, or any chronic parasitic infection, such as malaria. A chronic inflammatory disease history was considered positive if there was a positive history of at least one of the biliary tract diseases (not just gallstones), gout, nontropical sprue, or rheumatic heart disease. A history of autoimmune disease was defined as a history of at least one of the following: systemic lupus erythematosus, scleroderma, Sjogren’s disease, autoimmune hemolytic anemia, idiopathic thrombocytopenic purpura, dermatomyositis, ankylosing spondylitis, rheumatoid arthritis, Reiter’s syndrome, Hashimoto’s disease, Grave’s disease, or pernicious anemia. It is recognized that these conditions do not represent a comprehensive listing of all diseases in each of these categories, but rather the more frequently occurring disorders. Under the assumption that a history of more than one of these diseases would produce a stronger antigenic stimulus than a single exposure, a cumulative index of the number of such previous diseases was constructed. For the estimation of the odds ratio, the categories “no disease” or “one or more diseases” were used. However, for significance testing, we used Wilcoxon’s rank sum approach (36); the differences between matched cases and controls in each pair were based on the actual number of disorders. Severity and duration of these illnesses were not consistently reported on the medical record. Interview-based attempts to ascertain these data also proved unreliable due to the intermittent nature of a number of these disorders and because of the uneven distribution of surrogate respondents between cases and controls. A cumulative index of the number of allergic conditions was also developed, based on interview reports of the following: drug allergies, food and other allergies, hayfever, asthma, eczema, hives, severe or systemic reaction to insect stings, and prior therapy with allergy injections. The index was defined as the total number of allergic conditions listed. For the calculation of the OR and significance testing using Wilcoxon’s test, the same approaches were used as those described above. RESULTS

The baseline characteristics of NHL cases are shown in Table 1. As seen, most of the cases were white and between the ages of 50 and 69. The predominant cell type of NHL was histiocytic diffuse with about one-third all cases diagnosed in this category. Poorly differentiated lymphocytic and mixed lymphocytic-histiocytic nodular lymphomas also were fairly common in the case series, representing 27.5% of the total. Discharge diagnoses for control patients are seen in Table 2. Ophthalmologic and cardiovascular diseases represented more than one-half of these diagnoses, reflecting the frequency distribution of discharge diagnoses from the JHH inpatient services included in the present study. Among ophthalmologic patients, discharge diagnoses included retinal detachment (47%), cataract (31%), strabismus (1 lo/o), and other ocular disorders (11%). Cardiac and vascular disease patients

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LINET, TABLE

DISTRIBUTION

OF SELECTED

CHARACTERISTICS

Characteristic Sex Male Female Race White Nonwhite Age 18-39 40-49 50-59 60-69 70-79 80+ Cell type

Nodular PDLL IDLL Histiocytic Mixed Diffuse PDLL IDLL Histiocytic Mixed Undifferentiated Mixed PDLL Histiocytic Mixed Unknown PDLL Histiocytic Composite lymphoma

AND SZKLO 1 OF CASES

OF NON-HODGKIN’S

LYMPHOMA

n

%

59 50

54.1 45.9

101

92.7

8

7.3

13 12 35 33

11.9

11.0 32.1 30.3 12.8 1.8

14 2

16

14.7 0.9 0.9 12.8

I I 14 5 38 9 2

4.6 0.9 34.9 8.3 1.8

2 6 4

5.5 3.7

I

1.8

3 5 2

Note. PDLL = poorly differentiated lymphocytic lymphoma; IDLL tiated lymphocytic lymphoma; Mixed = mixed lymphocytic-histiocytic

2.8 4.6

1.8 = intermediately

differen-

lymphoma.

had discharge diagnoses of atherosclerotic coronary artery disease (22%), heart valve disorders (13%), heart rhythm disorders (13%), cerebrovascular disease (9%), peripheral vascular disease (22%), and other conditions (21%). Table 3 presents, for both the total 109 pairs and for the subset of 53 pairs in which both cases and controls were interviewed directly (that is, excluding surrogate interviews), matched odds ratios examining the association between NHL and history of acquired disorders affecting the immune system. For both the separate disease categories and for the total index of acquired immune-related disorders, no positive associations were found with NHL. Although there was a suggestion of an inverse relationship, none of the ORs reached statistical significance at the 01 = 0.05 level. When results were examined for only pairs who had

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101

DISORDERS

2

DISTRIBUTION OF DISCHARGE DIAGNOSES FOR MATCHED CONTROLS Diagnostic group

n

Infectious and parasitic disease Benign tumors Endocrine and metabolic disorders Nervous system disorders Ophthalmologic disorders Cardiac and vascular disorders Respiratory disorders G.I. system disorders G. U. system disorders Dermatologic disorders and plastic surgery Musculoskeletal disorders Other

2 4 4 5 36 23 4 9 7 4 6 5

3.7 3.7 4.6 33.0 21.1 3.7 8.3 6.4 3.7 5.5 4.6

109

100.0

Total

% 1.8

been interviewed directly, the findings were consistent with those for all pairs. Stratification on the matching factors indicated no significant interactions. Analyses were also conducted stratified by histologic pattern (nodular vs diffuse vs mixed) and cell type (lymphocytic vs histiocytic vs other). No major differences were found between groups, although the small size of these strata reduced the power to detect even fairly large differences in exposure frequencies. Allergic conditions and surgical removal of lymphoid tissue are examined in Table 4. For allergic conditions, although the direction of the association is not the same for all pairs and for those who were interviewed directly, ORs were

TABLE

3

ASSOCIATION OF GROUPS OF ACQUIRED DISORDERS AFFECTING THE IMMUNE SYSTEM AND NON-HODGKINS LYMPHOMA

Chronic infectious disease All pairs Directly interviewed pairs Chronic inflammatory diseases All pairs Directly interviewed pairs Autoimmune diseases All pairs Directly interviewed pairs Total index of chronic antigenic stimulation All pairs Directly interviewed pairs

Discordant pairs”

OR

95% CI

I7126 8115

0.65 0.53

(0.35, 1.20) (0.23. 1.26)

14/16 511I

0.88 0.45

(0.43. I .79) (0.02, 1.31)

415 314

0.80 0.75

(0.19, 3.76) (0.51, 4.43)

22130 1I/l9

0.73 0.58

(0.42, 1.27) (0.28. 1.221

Note. Wilcoxon rank sum test on paired difference in total index: Z = - 1.70, P = 0.09 (twotailed). a Discordant pairs are shown as case (+), control (-)/case (-), control (+).

102

TIELSCH,

LINET, TABLE

ASSOCIATION

OF A HISTORY OF ALLERGIC IMMUNE-SYSTEM-RELATED

SZKLO

4

CONDITIONS TISSUE WITH Discordant

Allergic

AND

AND HISTORY NON-HODGKIN’S

pairs”

OF SURGICAL LYMPHOMA

REMOVAL

OF

9.5% CI

OR

conditions

All pairs Directly

interviewed

pairs

Surgical history All pairs Directly interviewed

pairs

0 Discordant

pairs

are

shown

23130 14111

as case

0.77 1.27

(0.45, (0.58,

1.32) 2.80)

16132

0.50

7/11

0.64

(0.27, (0.25,

0.91) 1.64)

(+ ), control

(-)/case

( - ), control

( +).

close to unity and not statistically significant. For surgical history, an inverse association was seen, which reached statistical significance at the 0.05 level for all pairs. The surgical histories reported included tonsillectomy, adenoidectomy, appendectomy, and one case of splenectomy. Multiple adjustment for potentially confounding variables confirmed the apparent lack of a positive association of a prior history of immune-related or allergic conditions with NHL. For all pairs, the odds ratio for factors affecting the immune system, adjusted for respondent status (surrogate vs nonsurrogate), history of allergic conditions, and history of surgery to immune-system-related tissue, was 0.62 (P > 0.05). The odds ratio for allergic conditions using a similar adjustment was 1.67 (P > 0.05). Finally, the possibility that the inverse relationship of NHL to disorders affecting the immune system could have been caused by an abnormally high proportion of these disorders among controls was examined by comparing their prevalence rates among the three major diagnostic categories in control subjects: ophthalmologic, cardiac and vascular, and other. The three control subsets had similar proportions of individuals with a positive history of immune-system-related disorders, as follows: cardiac and vascular = 44.4%; ophthalmologic = 51.4%, and other = 57.1%. DISCUSSION

Results of the present case-control study do not support the hypothesis that a past history of acquired disorders affecting the immune system increases the risk of NHL. Cases were selected from among patients admitted to the main oncology center in a large metropolitan area, whereas controls were chosen from a variety of diagnoses in a patient pool admitted to the same hospital and, therefore, likely to undergo the same admission selection process as the cases. Although healthy population subjects are considered the best choice for controls (22), they are suitable mainly for case-control studies in which all or a random sample of cases from a population are ascertained. In addition, when studying a disease, such as NHL, that may present quite insidiously, surveillance bias may occur, in that cases with a prior history of acquired disorders affecting the immune system may be more likely to be under medical care surveillance and,

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thus, more likely to be diagnosed than those without these disorders (32). As the bias stems from the case selection, it was decided to select a control group (hospital patients) that had undergone the same selection for hospital admission as the case group, lending to “compensating bias” between cases and controls. In a situation of compensating bias, a similar exposure bias occurs in the numerator (odds in cases) and the denominator (odds in controls), and thus bias cancels out when the odds ratio is estimated (32). Selection of hospital patients as controls had an additional advantage in that it allowed choice of controls without regard to their vital status at time of interview. Furthermore, since both cases and controls were hospitalized patients, recall of past events was probably similar between cases and controls, hence minimizing the likelihood of recall bias. An additional advantage of the type of control group included in the present study is that it permitted a comparison between respondents and nonrespondents, since medical charts were available for both cases and controls. Use of hospitalized patients as controls is not, however, entirely free of problems. For example, if the control diseases were also related to disorders affecting the immune system, or if control patients with these disorders were under medical surveillance and thus more likely to be hospitalized, then a dilution of a true positive association, or even its reversal, could have occurred in the present study. To examine this possibility, the prevalence of a prior history of diseases related to the immune system was compared among the three major diagnostic categories in controls (cardiovascular, ophthalmologic, and other). No marked differences were found. This made it unlikely that failure to find a positive association with NHL, or the finding of a slight protective effect, could have been due to an abnormally high proportion of these disorders in the control patients. Finally, since for more cases than controls the information had to be obtained from a surrogate, surrogate response bias could spuriously eliminate a true positive association between NHL and immune-system-related disorders. However, this type of bias was probably not responsible for the observed results either, since results for all 109 pairs were not substantially different from those obtained for the 53 pairs who were interviewed directly. Results from this study are consistent with findings from two other recently completed case-control studies of lymphoproliferative malignancies. Grufferman et al. (personal communication) found a statistically significant protective effect for all chronic infectious, inflammatory, autoimmune, and allergic disorders combined in 153 cases of multiple myeloma compared with 459 hospital controls identified from two university teaching hospitals. Linet et al. (22a) found no statistically significant association between a history of subacute or chronic viral and bacterial infections and connective tissue or autoimmune disorders in 342 cases with chronic lymphocytic leukemia (CLL) compared with matched controls. These investigators noted a weak protective effect and a statistically significant protective effect for allergic disorders and surgical excision of lymphoid tissue, respectively, and CLL. Discrepancies among these three studies, including the current investigation, and previous reports may be due to a number of reasons. Differing distributions

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AND SZKLO

of histologic types of lymphoma, and concomitant differences in risk factors, between the current study and prior investigations may account for some of the discrepancy. Antibiotics and other agents used several years ago may not have completely eradicated many infections included in the recent studies, thus resulting in persistence of the antigenic challenge. More recent occurrence of these infections following treatment with appropriate antibiotics may be more properly classified as acute, rather than designated as chronic. The sample size and power of the current study may not have been adequate to demonstrate differences between cases and controls because the incidence and prevalence of many of the acquired disorders studied is relatively low. As noted above, results of studies examining the relationship between history of allergies and cancer has been conflicting. This may be a function of the heterogeneity of allergic disorders and/or the large discrepancy between peak ages of onset of allergic disorders and lymphoproliferative malignancies together with the occurrence of recall bias. Case definitions used in the three more recent studies may have been substantially different, although absence of detailed information in earlier studies makes this difficult to prove. Finally, differences in methods used to obtain information about acquired disorders involving the immune system between the older and the three recent studies may account for some of the discrepancy. In summary, epidemiologists have yet to identify risk factors for NHL that can account for a significant proportion of the disease seen in the population. Based on these results and on two other recently completed studies of lymphoproliferative malignancies, chronic lymphocytic leukemia and multiple myeloma, it seems unlikely that uncomplicated prolonged antigenic challenge is a major risk factor for these cancers. Future research will need to incorporate modern techniques to identify subgroups of the population with abnormal immunologic characteristics that can be followed to determine their risk of developing non-Hodgkin’s lymphomas and other lymphoproliferative malignancies. REFERENCES 1. Abbatt, J. D., and Lea, A. J. Leukaemogens. Lancer 2, 880-883 (1958). 2. Anderson, T., Bender, R. A., Fisher, R. I., DeVita, V. T., Chabner, B. A., Berand, C. W., Norton, L., and Young, R. C. Combination chemotherapy in non-Hodgkin’s lymphoma: Results of long-term follow-up. Canter- Treuf. Rep. 61, 1057-1066 (1977). 3. Blackburn, E. K., Callender, S. T., Dacie, J. V., Doll, R., Girdwood, R. H.. Mollin, D. L., Saracci, R., Stafford, J. L., Thompson, R. B., Varadi, S., and Wetherly-Mein, G. Possible association between pernicious anemia and leukemia: Prospective study of 1625 patients with a note on the very high incidence of stomach cancer. Inf. J. Cancer 3, 163-170 (1968). 4. Breslow, N. E., and Day, N. E. “Statistical Methods in Cancer Research.” IARC Scientific Publication No. 32, Lyon, 1980. 5. Dworin, M., Diamond, H. D., and Craver, L. F. Hodkin’s disease and allergy. Cuncer 8, 128-131 (1955). 6. Faure, M. R., Nicolas, J. F., Thivolet, J., Gaucnerand, M. A., and Czerneilewski, J. M. Studies of T-cell subsets in atopic dermatitis: Human T-cell subpopulations defined by specific monoclonal antibodies. C/in. Immunol. Immunoputhol. 22, 139-146 (1982). 7. Fisherman, E. W. Does the allergic diathesis influence malignancy’? J. A//er,g):y31, 74-78 (1960). 8. Fleiss, J. L. “Statistical Methods for Rates and Proportions.” Wiley, New York, 1973. 9. Fox, R. I., Carstens, S. A., Fong, S., Robinson, C. A., Howell, F., and Baughan, J. M. Use of

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