Smoking and Risk of Non-Hodgkin's Lymphoma and Multiple MyelomaAuthor(s): Linda Morris Brown, George D. Everett, Robert Gibson, Leon F. Burmeister,Leonard M. Schuman, Aaron BlairReviewed work(s):Source: Cancer Causes & Control, Vol. 3, No. 1 (Jan., 1992), pp. 49-55Published by: SpringerStable URL: http://www.jstor.org/stable/3553349 .Accessed: 30/01/2012 14:27

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Cancer Causes and Control, 3, 49- 55

Smoking and risk of non-Hodgkin's lymphoma and multiple myeloma

Linda Morris Brown, George D. Everett, Robert Gibson, Leon F. Burmeister, Leonard M. Schuman, and Aaron Blair

(Received 9 September 1991; accepted in revised form 5 November 1991)

Population-based case-control interview studies of 622 White men with non-Hodgkin's lymphoma and 820 controls from Iowa and Minnesota (United States) and 173 White men with multiple myeloma and 452 con- trols from Iowa offered the opportunity to investigate the relationship of these cancers with smoking. Risks were significantly elevated for all lymphoma (odds ratio [OR] = 1.4), high-grade lymphoma (OR = 2.3), and unclassified lymphoma (OR = 2.8) for cigarette smokers. Dose-response gradients were not seen with inten- sity of cigarette use, but risks for these subtypes were greatest for cigarette smokers of longest duration. Similar elevations in risks were seen for tobacco users. The risk of multiple myeloma was not significantly elevated for either tobacco users or cigarette smokers. The findings from this study confirm the lack of an association between smoking and multiple myeloma and provide some support for an association between tobacco use and certain subtypes of non-Hodgkin's lymphoma.

Key words: Case-control study, cigarettes, epidemiology, etiology, multiple myeloma, non-Hodgkin's lym- phoma, smoking, tobacco, United States.

Recent attention has focused on the relationship be- tween smoking and leukemia,"- but only limited atten- tion has been paid to smoking and two related

lymphatic and hematopoietic cancers, non-Hodgkin's lymphoma (NHL) and multiple myeloma. To provide additional information on the role of smoking in the

etiology of these two tumors, we report results from case-control studies of White men with NHL in Iowa and Minnesota and multiple myeloma in Iowa.

Materials and methods

Subjects

During the period 1981-84, population-based case- control interview studies using the same questionnaire

were conducted for NHL, multiple myeloma, and leu- kemia in Iowa, and for NHL and leukemia in Min- nesota. Presented here are results for the NHL and multiple myeloma cases and the pooled controls. Details of the study methods and population have been described elsewhere.68- Briefly, all newly diagnosed cases of NHL or multiple myeloma were identified among White men aged 30 or older from the Iowa Health Registry and NHL from a special surveillance network of hospitals and pathology laboratories insti- tuted in Minnesota.

Two sources of controls were used to select a popu- lation-based stratified sample of White men without lymphatic or hematopoietic cancer: random-digit- dialing for living controls under age 651 and Medicare

Ms Brown and Dr Blair are with the Epidemiology and Biostatistics Program, National Cancer Institute. Dr Everett is with the Department of Internal Medicine, Orlando Regional Medical Center, Orlando, FL, USA. Drs Gibson and Schuman are in the Department of Epidemiology, University of Minnesota, Minneapolis, MN, USA. Dr Burmeister is in the Department of Preventive Medicine, University of lowa, Iowa City, IA, USA. Address correspondence to Ms Brown, Epidemiology and Biostatistics Program, National Cancer Institute, Executive Plaza North, Room 415C, Bethesda, MD 20892, USA. This work was supported in part by a grant from the National Institute of Environmental Health Sciences (ES 03099).

? 1992 Rapid Communications of Oxford Ltd Cancer Causes and Control. Vol 3. 1992 49

L. Morris Brown et al

records provided by the Health Care Financing Administration for living controls aged 65 and over. In addition, state death-certificate files were used to select deceased controls. Controls were frequency matched to the cases by five-year age group, vital status at time of interview, and state of residence.

A standardized questionnaire was used to obtain detailed information on the use of tobacco and alcohol, residential history, farm and non-farm occupational history, medical conditions, and family history of can- cer. Personal interviews lasting approximately 50 min were conducted with subjects, or with close relatives if

subjects were deceased or too ill to be interviewed. Interviews were completed for 89 percent of the NHL

cases, 84 percent of the multiple myeloma cases, and 78

percent of the controls. Slides from each interviewed case with a reported

diagnosis of NHL were diagnosed independently by four experienced pathologists using the Working For-

mulation,"o and a final diagnosis was reached by con- sensus. Details of these review procedures have been

published elsewhere." The 72 cases (10 percent) not confirmed as NHL by the panel were excluded from the analysis. Cases were grouped into four morpho- logic subtypes: diffuse, follicular, small lymphocytic, and other. Other lymphomas were divided into two

subtypes: high grade lymphomas, a grouping of histol-

ogies (large cell immunoblastic, lymphoblastic, and small noncleaved cell) characterized by poor prog- nosis;12 and unclassified lymphomas, NHL cases in which histologic material was inadequate to dis-

tinguish among subtypes. Pathologic material and laboratory reports were

reviewed by an expert pathologist to confirm diagnosis of multiple myeloma. Not included in the analyses are 25 cases of multiple myeloma for whom adequate information for diagnostic confirmation was unavailable.

The final study population consisted of 622 (438 living, 184 deceased) NHL cases and 1,245 (820 living, 425 deceased) controls from Iowa and Minnesota and 173 (101 living, 72 deceased) multiple myeloma cases and 650 (452 living, 198 deceased) controls from Iowa. Exposures such as smoking that increase overall mor- tality have been shown to be overrepresented in dead controls." Therefore, to eliminate this potential source of bias, results are presented with the deceased controls excluded.

Statistical analysis

Subjects who had used any tobacco product (cigarettes, cigars, pipes, chewing tobacco, or snuff) at least once a day for three months or more were defined as tobacco users. The first and last year of use, the age at first use,

and the usual amount used per day were ascertained for each type of tobacco used. Unconditional logistic regression" was used to calculate risks for the smoking variables of interest. Age (< 45, 45-64 > 65) and state (Iowa, Minnesota) were included in models to adjust for potential confounding. Other variables such as

farming, pesticides, alcohol, education, family history of cancer, and exposure to high-risk jobs or substances were not confounders of risk and were not included in the analysis.

Results Use of any tobacco product was reported by 81 percent of the NHL cases and 76 percent of the controls. Risks were elevated significantly for tobacco users for all

lymphoma, high grade lymphoma, and unclassified

lymphoma (Table 1). Risks associated with the cate-

gory of pipes or cigars and smokeless tobacco only were elevated for all subtypes and significantly elev- ated for all lymphoma, small lymphocytic lymphoma, and unclassified lymphoma. Odds ratios (OR) also were significantly elevated for use of cigarettes only (all lymphoma, unclassified) and cigarettes and other tobacco (high grade, unclassified).

Risks for all lymphoma, high-grade lymphoma, and unclassified lymphoma were elevated significantly for

cigarette smokers (Table 2). Risks did not increase with

increasing intensity of use for any subtype; however, risks for all lymphoma, follicular, high-grade, and unclassified lymphomas were greatest for those who had smoked for 46 years or more. The risks for current smokers were greater than those for ex-smokers. Results for the two states were similar.

When ORs were calculated using only living (self-) respondents, risks decreased slightly and there was no indication of dose-response with number of cigarettes smoked. For example, risks for all lymphoma decreased to 1.2 (95 percent confidence interval [CI]= 0.9-1.7) for cigarette smokers and 1.3, 1.3, and 1.2, respectively for <20, 20, and > 20 cigarettes smoked per day.

Use of tobacco was reported by 76 percent of the multiple myeloma cases and 77 percent of the controls (OR= 1.0, Table 3). Risks were not significantly elev- ated for use of any tobacco product.

Use of cigarettes was also similar for multiple myel- oma cases and controls, 68 percent and 70 percent, respectively (OR= 1.1, Table 4). Risks for multiple myeloma were not significantly elevated for any characteristic of cigarette use, and no risk exceeded 1.2. The exclusion of deceased cases reduced risks to 1.0 for cigarette smokers and 0.9, 1.1, 1.0 for the lightest to the heaviest cigarette smoking categories.

50 Cancer Causes and Control. Vol 3. 1992

Table 1. Risk of non-Hodgkin's lymphoma according to use of tobacco-'b Tobacco use Controls Lymphoma subtype

Other

Small All lymphoma Follicular Diffuse lymphocytic High grade Unclassified

Cases OR CI Cases OR CP Cases OR CI Cases OR C1 Cases OR CI Cases OR CI Non-tobacco user 197 116 1.0 - 39 1.0 - 43 1.0 - 18 1.0 - 7 1.0 - 9 1.0 - Tobaccouser 623 505 (A.4 t.1-1.8 156 1.3 0.9-1.9 154 1.1 0.8-1.6 67 1.2 0.7-2.0 50 2.3 1.0-5.1 78 2.7 1.3-5.6 Unknown 1 1

Types of tobacco used Smokeless

tobacco only 23 19 1.3 0.7-2.5 7 1.7 0.7-4.3 5 0.8 0.3-2.3 4 1.7 0.5-5.4 1 1.3 0.1 - 10.8 2 1.5 0.3-7.4 Pipes or

cigars only 40 29 1.2 0.8-2.1 8 1.0 0.4-2.3 7 0.7 0.3-1.8 8 2.1 0.8-5.1 2 1.4 0.3-7.1 4 2.1 0.6- 7,1 Pipes or

cigars and smokeless tobacco only 12 22 2.9 1.4-6.1 5 2.3 0.8-6.9 7 2.3 0.8-6.2 5 3.9 1.2-12.5 2 4.8 0.9-26.0 3 4.6 1.1 - 19.2

Cigarettes only 276 244 1.5 1.2-2.1 79 1.4 0.9-2.1 76 1.3 0.9-2.0 27 1.1 0.6-2.1 21 2.1 0.95.1 41 3.5 1.7-7.4 Cigarettes and

other tobacco 272 191 1.2 0.9-1.6 57 1.1 0.7-1.7 59 1.0 0.6-1.5 23 0.9 0.5-1.7 24 2.5 1.1-5.9 28 2.2 1.0-4.7

C-

CL 0

_,A

O.K

All odds ratios (OR) relative to risk for subjects who were nonusers of tobacco. All OR adjusted for age and state in a logistic analysis. Only living controls included in these analyses. CI = 95% confidence interval.

0

0

0

tJi

C-) C

C-

C-) C C

0

0

.0 .0

Table 2. Risk of non-Hodgkin's lymphoma according to cigarette smoking characteristics''b Characteristic Controls Lymphoma subtype

Other

Small All lymphoma Follicular Diffuse lymphocytic High-grade Unclassified

Controls Cases OR CI Cases OR C1L Cases OR CI' Cases OR Cl' Cases OR CI Cases OR CI Non-tobacco user 197 116 1.0 - 39 1.0 - 43 1.0 - 18 1.0 - 7 1.0 - 9 1.0 Cigarette smoker 548 435 1.4 1.0-1.8 136 1.2 0.8-1.8 135 1.1 0.8-1.7 50 1.0 0.6-1.7 45 2.3 1.0-5.2 69 2.8 1.4-5.7 Unknown 1 1

Number of cigarettes per day < 20 160 130 1.4 1.0-1.9 36 1.2 0.7-1.9 43 1.2 0.7-1.9 14 0.9 0.4-1.9 15 2.7 1.1-6.8 22 2.9 1.3-6.5 20 209 155 1.3 0.9-1.7 58 1.4 0.9-2.1 41 0.9 0.6-1.5 13 0.7 0.3-1.4 16 2.1 0.9-5.3 27 2.9 1.3 6.3 > 20 175 135 1.3 1.0-1.8 39 1.0 0.6-1.7 46 1.3 0.8-2.0 20 1.3 0.7-2.5 12 1.8 0.7-4.8 18 2.4 1.0-5.5 Unknown 4 15 3 5 3 2 2

Number of years smoked 1-20 148 106 1.2 0.9-1.7 39 1.2 0.7-2.0 33 1.1 0.6-1.8 11 0.9 0.4-2.1 9 1.6 0.6-4.4 14 2.1 0.9-5.1 21-35 165 111 1.2 0.8-1.6 39 1.1 0.7-1.8 34 1.0 0.6-1.7 17 1.2 0.6-2.4 13 2.1 0.8-5.4 8 1.1 0.4-2.9 36-45 116 94 1.4 0.9-2.0 30 1.2 0.7-2.0 28 1.2 0.7-2.0 10 0.9 0.4-1.9 9 2.1 0.8-6.0 17 3.3 1.4-7.7 >46 118 96 1.4 0.9-2.0 25 1.3 0.7-2.2 30 1.0 0.6-1.8 10 0.8 0.4-1.8 8 2.2 0.8-6.4 23 4.0 1.8-9.2 Unknown 1 28 3 10 2 6 7

Smoking status Current smoker 190 162 1.5 1.1 -2.0 58 1.4 0.9-2.3 42 1.1 0.7-1.8 16 1.0 0.5-2.0 17 2.4 1.0-6.0 29 3.8 1.7-8.3 Ex-smoker 357 263 1.2 0.9-1.6 76 1.1 0.7-1.7 90 1.1 0.8 - 1.7 33 1.0 0.5-1.7 27 2.1 0.9-5.0 37 2.2 1.0-4.6 Unknown I 10 2 3 1 1 3

All OR relative to risk for subjects who were nonusers of tobacco. All OR adjusted for age and state in a logistic analysis. Only living controls included in these analyses. CI = 95% confidence interval.

5(5

0

(5

to

Lymphoma, multiple myeloma and smoking

Table 3. Risk of multiple myeloma in Iowa-?b

Tobacco use Controls Cases OR CI'

Non-tobacco user 105 41 1.0 Tobacco user 347 132 1.0 0.7-1.6

Types of tobacco used Smokeless tobacco

only 8 5 1.9 0.5-6.6 Pipes or cigars only 22 6 0.6 0.2-1.6 Pipes or cigars and

smokeless tobacco only 4 3 1.5 0.3-7.0

Cigarettes only 169 70 1.3 0.8-2.0 Cigarettes and other

tobacco 144 48 0.9 0.5 - 1.4

All odds ratios (OR) relative to risk for subjects who were nonusers of tobacco. All OR adjusted for age in a logistic analysis.

b Only living controls included in these analyses. ' CI = 95% confidence interval.

Table 4. Risk of multiple myeloma in Iowa according to ciga- rette smoking characteristics",b

Characteristic Controls Cases OR CIC

Non-tobacco user 105 41 1.0 Cigarette smoker 313 118 1.1 0.7-1.6

Number of cigarettes per day < 20 101 30 0.8 0.4-1.3 20 118 46 1.1 0.7-1.9 > 20 92 35 1.2 0.7-2.1 Unknown 2 7

Number of years smoked 1-20 81 23 1.1 0.6-2.0 21-35 101 26 0.8 0.5-1.5 36-45 57 24 1.2 0.7-2.3 , 46 74 36 0.9 0.5-1.6 Unknown 9

Smoking status Current smoker 112 20 0.6 0.3-1.1 Ex-smoker 201 96 1.2 0.8-1.9 Unknown 2

-All odds ratios (OR) relative to risk for subjects who were non- smokers of cigarettes. All OR adjusted for age in a logistic analysis.

h Only living controls included in these analyses. 'CI = 95% confidence interval.

Discussion Our case-control studies of NHL and multiple myel- oma offered the opportunity to conduct detailed evalu- ations of tobacco as a risk factor among White male residents of Minnesota (NHL cases only) and Iowa. To our knowledge, this is the first report of smoking results for NHL categorized by morphology.

A possible association between NHL and smoking has been suggested by some studies,',56 but not

others.'"7-" While our results for all lymphoma (OR= 1.4) resemble those presented by Franceschi et al,16 the specific associations noted with high-grade and

unclassified lymphomas are new. Smoking may be related to high-grade lymphoma because it is the sub-

type with the poorest survival." Cigarette smoking has been associated with decreased survival in patients with a related malignancy, chronic myeloid leuke- mia.20,2' Whether this accounts for the associations seen in this study, however, is not known. Even less clear are possible reasons for the association with the unclassi- fied category of lymphoma. This category includes cases (probably including some high-grade lympho- mas) in which histologic material is inadequate to dis- tinguish among subtypes, as well as difficult cases for whom the panel of expert pathologists convened for this study could not reach a consensus on subtype." Since no intensity-response gradients were seen with either high-grade or unclassified lymphomas, these could be chance findings or may be the result of con- founding by some unknown cause. Risks of high-grade and unclassified lymphomas were somewhat higher for smokers of longest duration, but the patterns were inconsistent. The lack of dose-response could not be explained by the inability of proxies to recall accurately the quantity of tobacco used, because no gradients were observed when the analysis was restricted to self- respondents. Since small gradients in risk easily can be destroyed by nondifferential misclassification,22 exposure misclassification could be responsible for the lack of an intensity-response gradient. A new finding was the elevated risks for users of smokeless tobacco who also used pipes and/or cigars. This finding, while consistent across all subtypes, is based on small num- bers and may be spurious, especially since similar elev- ations in risk are not seen for users of 'pipes or cigars only' or 'smokeless tobacco only.'

The mechanism by which tobacco products might influence lymphatic cancers is unknown. Agricultural chemicals, organic solvents, and formaldehyde, pos- sible lymphomagens,'8, 23-26 are constituents of tobacco and tobacco smoke."'-2' Exposure to organic solvents also has been associated with cytogenetic changes in lymphoma cells.30 Cigarette smoking has been associ- ated with various immunologic alterations including alterations in T-cell subsets, elevated white blood counts, and lower percentages of natural killer cells.'-" These findings are noteworthy since excess risks of NHL have been associated with numerous states of

immunosuppression6-"8 including HIV-positive indi- viduals in whom the most common subtype found is high-grade lymphomas." It is possible, however, that smoking may not affect the lymphatic system in a dose- response manner. A study of natural killer cells found numbers to be decreased in smokers, but there was no evidence of a dose-response gradient with either inten- sity or duration of smoking.5

Cancer Causes and Control. Vol 3. 1992 53

L. Morris Brown et al

Most studies of multiple myeloma have found no indication of an elevated risk associated with use of

tobacco•", or cigarettes.54'', Notable exceptions were a case-control study of Flodin et aP14 who reported an increased risk for ex-smokers, but not current smok- ers, and a cohort study by Mills et al41 who reported elevated risks and a significant dose-response gradient with number of cigarettes smoked. In our study, no

significant elevations in risk for multiple myeloma were seen in relation to any form of tobacco, including cigarettes.

In conclusion, this case-control study of NHL revealed small increases in risks associated with ciga- rette smoking for all lymphoma and larger increases for the subtypes of high-grade and unclassified lym- phoma. Risks for all NHL subtypes were elevated for users of cigars or pipes and smokeless tobacco only. In contrast, cigarette smoking risks for multiple myeloma were not elevated and no significant associations were found for use of any other type of tobacco. Thus, the

findings from this study can be interpreted as confirm-

ing the lack of an association between smoking and

multiple myeloma and providing some support for an association between tobacco use and NHL. It is of interest that use of tobacco appears to be associated dif-

ferentially with the various lymphatic and hemato-

poietic tumors, since leukemia, NHL, and multiple myeloma all have common progenitor cells. These can- cers are known, however, to show other etiologic dif-

ferences.37,4647 Unknown factors may modify the

carcinogenic or immunologic effects of smoking on these different, but related diseases. Further research into mechanisms of tobacco-induced carcinogenesis and the etiology of these tumors is warranted.

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