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Keywords:

  • lymphoma;
  • non-Hodgkin;
  • diffuse large B-cell lymphoma;
  • estrogen;
  • progestin;
  • hormone replacement therapy;
  • menopause;
  • oral contraceptives;
  • hysterectomy

Abstract

  1. Top of page
  2. Abstract
  3. Material and methods
  4. Results
  5. Discussion
  6. Acknowledgements
  7. References

Reasons for higher incidence of lymphoid neoplasms among men than women are unknown. Because female sex hormones have immunomodulatory effects, reproductive factors and exogenous hormone use may affect risk for lymphoid malignancies. Previous epidemiologic studies on this topic have yielded conflicting results. Within the National Institutes of Health-AARP Diet and Health Study cohort, we prospectively analyzed detailed, questionnaire-derived information on menstrual and reproductive factors and use of oral contraceptives and menopausal hormone therapy among 134,074 US women. Using multivariable proportional hazards regression models, we estimated relative risks (RRs) for 85 plasma cell neoplasms and 417 non-Hodgkin lymphomas (NHLs) identified during follow-up from 1996 to 2002. We observed no statistically significant associations between plasma cell neoplasms, NHL, or the 3 most common NHL subtypes and age at menarche, parity, age at first birth, oral contraceptive use or menopausal status at baseline. For menopausal hormone therapy use, overall associations between NHL and unopposed estrogen and estrogen plus progestin were null, with the potential exception of an inverse association (RR = 0.49, 95% CI, 0.25–0.96) between use of unopposed estrogen and diffuse large B-cell lymphoma (DLBCL), the most common NHL subtype, among women with a hysterectomy. These data do not support an important role for reproductive factors or exogenous hormones in modulating lymphomagenesis. © 2008 Wiley-Liss, Inc.

Lymphoid neoplasms, including non-Hodgkin lymphomas (NHL), Hodgkin lymphomas and plasma cell neoplasms, are the sixth most commonly diagnosed group of cancers worldwide.1 Severe disruption of immune function is a well-established, strong risk factor for lymphomas, but much of lymphoid-neoplasm etiology remains unknown. The potential effects of modest immune perturbation on lymphomagenesis are not well understood.

In humans and animals, menses, pregnancy and exogenous hormone use affect immune function as reviewed in Refs.2, 3. This raises the possibility that reproductive factors and exogenous hormones modulate lymphomagenesis in women, which could help explain the lower incidence of almost all lymphoid neoplasm subtypes among women compared with men. Overall, associations between these factors and lymphoma risk are conflicting.4–26

Recent studies reported strong, statistically significant inverse associations between menopausal hormone therapy (MHT) and lymphoid neoplasms.20, 26 Odds ratios (ORs) of 0.6 (40% risk reductions compared with never-use) for diffuse large B-cell lymphoma (DLBCL),20, 26 Hodgkin lymphoma18 and all NHL combined13 could, if true, reveal etiologic or prevention clues. However, the validity of these findings is unclear. The types of available MHT and patterns of use have substantially changed since the 1960s,27 so associations with broadly defined “MHT” (especially from older studies) may reflect exposures that are not comparable across studies conducted during different time periods. Associations with specific subtypes of NHL are biologically plausible28, 29 but warrant cautious interpretation as they could be because of chance and often are difficult to replicate.30 Large, prospective studies with detailed data on use of specific MHT formulations and regimens have helped identify replicable associations between MHT and other cancers. We therefore evaluated MHT and other reproductive exposures as risk factors for lymphoid neoplasms and specific lymphoid neoplasm subtypes in the National Institutes of Health (NIH)-AARP Diet and Health Study.

Material and methods

  1. Top of page
  2. Abstract
  3. Material and methods
  4. Results
  5. Discussion
  6. Acknowledgements
  7. References

Study design/population

This study began in 1995–1996, when 3.5 million AARP members, male and female, ages 50–71, residing in 6 states (CA, FL, LA, NJ, NC and PA) and 2 metropolitan areas (Atlanta, GA and Detroit, MI) received a mailed questionnaire.31 The 567,169 AARP members (16.2%) who satisfactorily completed it received a second questionnaire, which collected detailed data on menstrual and reproductive factors and use of oral contraceptives and MHT, as well as other risk factors, in 1996–1997. A total of 334,908 AARP members (59.1%) completed that questionnaire. Overall, participants in the study were more likely to be non-Hispanic Caucasian, were slightly better educated, and had a slightly lower rate of current smoking compared with the general population.31 Participants are followed annually for change of address and linked to state cancer registries and the National Death Index (NDI).

To focus on the detailed MHT data from the second questionnaire, we excluded 188,117 men, 10,383 proxy respondents and 1,550 women who reported a personal history of cancer on either questionnaire (including 119 lymphoid neoplasms), and 784 women for whom all MHT data were missing. Therefore, analysis included 134,074 women.

Exposure ascertainment

The baseline questionnaire ascertained gynecologic surgeries, demographics, reproductive history, oral contraceptive use, menopausal status, smoking, family history of cancer and basic information (ever-never, recency and duration) about MHT use. The second questionnaire collected detailed MHT data. With those data, we used self-reported type, dates and duration of MHT use to classify exposure according to formulation (i.e., unopposed estrogen vs. estrogen plus progestin), regimen [sequential (fewer than 15 days of progestin per cycle) or continuous (at least 15 days of progestin per cycle), for use of estrogen plus progestin], duration and recency, as previously described.32 Exposure categories included women who reported use of only one MHT formulation (∼ 95% of MHT users); the ∼ 5% of women who reported multiple formulations were classified separately.

Cancer ascertainment

Probabilistic linkage to state cancer registries in the study states,33 plus 3 states to which relocation is common (AZ, NV and TX) identified incident cancers among participants. Linkage to NDI provided date and cause of death for fatal cancers.

Lymphoma classification

We defined incident lymphoid neoplasms using International Classification of Diseases for Oncology, Second and Third Edition (ICD-O-2 and ICD-O-3)34, 35 histology codes provided by the cancer registries. According to the World Health Organization classification36 and the International Lymphoma Epidemiology Consortium (InterLymph) guidelines,37 we grouped 634 total lymphoid neoplasm cases into plasma cell neoplasms (ICD-O-3 codes 9731–4; N = 85), Hodgkin lymphoma (9650–55, 9659, 9661–9667; N = 16), NHL (9591, 9670–1, 9673, 9675, 9678–80, 9684, 9687, 9689–91, 9695, 9698–9702, 9705, 9708–9, 9714, 9716–9, 9727–9, 9760–4, 9823, 9826–7, 9831–37, 9940; N = 417), and lymphoid neoplasms NOS (9590, 9822; N = 116). We also evaluated the 3 most common NHL subtypes: diffuse large B-cell lymphoma (DLBCL; 9678–80, 9684; N = 96), follicular lymphoma (9690–1, 9695, 9698; N = 105) and chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL; 9670, 9823; N = 84).

Statistical analysis

Cox proportional hazards regression, with age as the time scale and ties handled by complete enumeration,38 generated hazard ratios to estimate relative risks (RRs). Tests of proportional hazards revealed no departures. Follow-up began when the second questionnaire was received and scanned. Follow-up ended at the earliest of the following dates: diagnosis of lymphoid neoplasm (N = 634), movement out of a registry catchment area (N = 5,219), death (N = 4,496), diagnosis of a non-lymphoid hematopoietic neoplasm (ICD-O-3 codes 9740–58, 9800–5, 9840–9931, 9945–64, 9975–9989; N = 75), or June 30, 2002 (N = 123,650). We truncated follow-up in 2002 because we did not update MHT use during follow-up, and millions of women changed or stopped their MHT use after the July 2002 publication of Women's Health Initiative study results.39

Models included adjustment for age at baseline, race, education, menopausal status and use of oral contraceptives. Additional adjustment for calendar time or other potential confounders had little influence of RRs; so, these factors were dropped from statistical models. For each exposure, we evaluated potential associations with 5 outcomes: plasma cell neoplasms, NHL, and the 3 most common NHL subtypes: DLBCL, follicular lymphoma and CLL/SLL. We excluded Hodgkin lymphoma from further analysis due to too few cases (N = 16). In addition, for MHT, we investigated formulations (i.e., unopposed estrogen vs. estrogen plus progestin) 2 ways: first, among the entire cohort, and second, after stratifying on hysterectomy status at baseline. For the latter, unopposed estrogen was evaluated only among women with hysterectomy, and estrogen plus progestin was evaluated only among women with an intact uterus, to reflect the predominant prescribing patterns over the last 15 years.

Results

  1. Top of page
  2. Abstract
  3. Material and methods
  4. Results
  5. Discussion
  6. Acknowledgements
  7. References

The 134,074 women in the NIH-AARP Diet and Health Study accrued 719,035 total person-years during follow-up. The mean age at study entry was 63 years (range 51–72 years), and 91% of women were Caucasian. The 417 NHLs diagnosed during follow-up were similar to the number expected among US women of comparable age (based on 12 SEER registries, standardized incidence ratio (SIR) 1.05, 95% CI 0.95–1.16), whereas the 85 plasma cell neoplasms diagnosed during follow-up were fewer than expected (SIR 0.76, 95% CI 0.61–0.94), likely because our study population includes proportionally fewer non-white women than the SEER areas.

We observed no statistically significant associations between any of the outcomes and age at menarche, parity, age at first birth, oral contraceptive use, hysterectomy or menopausal status at baseline (Table I). No clear patterns of association emerged for age at first birth or parity when analyses were restricted to parous women (data not shown). Use of MHT, regardless of formulation, was also not significantly associated with plasma cell neoplasms, NHL overall or NHL subtypes (Table II). Risk estimates were unchanged after adjustment for race, menopausal status, oral contraceptive use, education and smoking.

Table I. Selected Demographic Characteristics and Reproductive Factors, and Relative Risk of Lymphoid Neoplasms, by Type, Among 134,074 Women in the NIH-AARP Diet and Health Study
 Plasma cell neoplasms (N = 85)Non-Hodgkin lymphoma (N = 417)Diffuse large B-cell lymphoma (N = 96)Follicular lymphoma (N = 105)CLL/SLL (N = 84)
No. cancer*Person- yearsRR295% CINo. cancers1Person- yearsRR295% CINo. cancers1Person-yearsRR295% CINo. cancer1Person- yearsRR295% CINo. cancer1Person- yearsRR295% CI
  • chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL); relative risk (RR).

  • 1

    No. cancers may not sum to total due to missing values for some variables.

  • 2

    RRs adjusted for age (continuous).

Age at study entry(years)
 <574136,100 50136,234 5136,097 21136,149 8136,113 
 57–6012138,442 77138,653 15138,467 18138,466 19138,465 
 61–6424163,598 92163,781 22163,596 19163,585 17163,570 
 65–6826185,148 133185,470 32185,183 32185,159 26185,159 
 ≥691994,150 6594,292 2294,162 1594,140 1494,123 
Race/ethnicity
 Caucasian72653,0951.00Ref.395654,0461.00Ref.92653,1781.00Ref.101653,1801.00Ref.77653,0991.00Ref.
 Other/unknown1364,3431.921.06–3.462264,3840.580.38–0.89464,3270.460.17–1.26464,3190.410.15–1.10764,3310.940.43–2.03
Education
 Less than high school737,2361.00Ref.2437,2941.00Ref.937,2571.00Ref.737,2331.00Ref.237,2261.00Ref.
 High School Grad21174,8130.680.29–1.60112175,0551.020.66–1.5922174,8150.550.26–1.2022174,7930.680.29–1.5928174,7983.070.73–12.88
 Some College29256,9220.690.30–1.57128257,2560.820.53–1.2735256,9600.640.31–1.3328256,9380.590.26–1.3626256,9302.000.48–8.45
 College Grad or higher24228,2280.680.29–1.58139228,5701.030.67–1.6027228,2450.590.28–1.2643228,2981.030.46–2.3028228,2532.500.59–10.50
Current Smoking Status
 Never40318,1151.00Ref.204318,6301.00Ref.39318,1341.00Ref.62318,1731.00Ref.44318,1301.00Ref.
 Former33282,3900.940.59–1.49154282,7380.860.70–1.0642282,4311.230.80–1.9028282,3880.510.33–0.8031282,3880.800.50–1.26
 Current1094,6840.930.47–1.874594,7780.780.56–1.07994,6850.860.42–1.771394,6890.710.39–1.30894,6660.640.30–1.36
Age at menarche (years)
 <1334349,7361.00Ref.207350,2661.00Ref.48349,8071.00Ref.56349,8061.00Ref.41349,7691.00Ref.
 13–1440297,5011.320.84–2.09172297,8860.960.78–1.1737297,4970.870.57–1.3342297,5030.880.59–1.3135297,4720.980.63–1.55
 ≥151064,2111.510.75–3.063464,2850.870.61–1.25964,2120.960.47–1.97664,2030.580.25–1.35864,2021.040.49–2.21
Parity
 Nulliparous11105,0901.00Ref.53105,2251.00Ref.10105,0981.00Ref.13105,1091.00Ref.14105,0951.00Ref.
 11273,2971.560.69–3.522873,3520.760.48–1.20873,2851.140.45–2.90773,2800.770.31–1.93473,2730.410.4–1.24
 223185,5481.150.56–2.36114185,8141.210.87–1.6729185,5731.610.78–3.2931185,5621.350.70–2.5719186,5360.760.38–1.51
 ≥334341,1250.820.42–1.62212341,6401.160.86–1.5744341,1711.180.59–2.3554341,1851.280.69–2.3546341,1590.950.52–1.73
Age at first birth (years)
 Nulliparous11105,0901.00Ref.53105,2251.00Ref.10105,0981.00Ref.13105,1091.00Ref.14105,0951.00Ref.
 <2014119,4441.120.51–2.4664119,5831.060.74–1.5316119,4591.420.64–3.1218119,4431.230.60–2.5212119,4350.740.34–1.61
 20–2435310,5440.970.49–1.90193311,0141.180.87–1.5946310,5901.410.71–2.7947310,5841.220.66–2.2634310,5490.780.42–1.46
 25–2917129,4231.100.51–2.3577129,6021.120.79–1.5915129,4221.080.48–2.4021129,4371.290.65–2.5921129,4351.150.59–2.27
 ≥30542,3050.990.34–2.852042,3480.890.53–1.49442,2990.880.28–2.81542,3040.940.33–2,63242,2900.340.08–1.49
Hysterectomy
 No47408,2471.00Ref.228408,8041.00Ref.52408,2791.00Ref.62408,2931.00Ref.50408,2521.00Ref.
 Yes37301,2531.030.67–1.58184301,6831.080.89–1.3142301,2911.060.70–1.5943301,2730.940.64–1.3934301,2450.900.58–1.40
Menopausal status at baseline
 Premenopausal226,2081.430.33–6.26826,2300.670.32–1.40326,2102.050.58–7.32326,2150.830.24–2.84126,2040.360.05–2.75
 Natural menopause, <45 years445,9540.610.21–1.762646,0240.920.60–1.41245,9500.330.08–1.391145,9751.710.85–3.45845,9691.180.54–2.59
 Natural menopause, 45–49 years14108,5620.970.51–1.8656108,6910.860.63–1.1920108,5851.490.82–2.7015108,5690.990.53–1.866108,5450.390.16–0.93
 Natural menopause, 50–54 years26193,6121.00Ref.116193,8681.00Ref.24193,6131.00Ref.27193,6151.00Ref.28193,6061.00Ref.
 Natural menopause, ≥55 years643,3710.930.38–2.262343,4350.840.54–1.31543,3740.830.32–2.16543,3680.830.32–2.17843,3781.230.56–2.69
 Surgical menopause32278,0490.880.53–1.48176278,4701.070.84–1.3537278,0801.100.66–1.8443278,0751.120.69–1.8130278,0400.760.45–1.26
 Natural menopause, aage unknown01,27311,2771.260.18–8.9911,2775.740.78–42.4601,27301,273
Oral contraceptive use
 Never55427,6021.00Ref.268428,2711.00Ref.68427,6751.00Ref.63427,6291.00Ref.56427,5901.00Ref.
 <5 year10122,9270.900.46–1.8059123,0550.890.66–1.1813122,9410.910.50–1.6715122,9430.860.48–1.5411122,9310.770.40–1.51
 5–9 years888,1331.010.48–2.154588,2420.940.68–1.30888,1370.780.37–1.651588,1551.200.67–2.15788,1430.690.31–1.53
 10+ years1169,7751.660.86–3.204169,8581.060.76–1.48569,7550.590.24–1.471169,7731.110.58–2.141069,7701.210.61–2.41
Table II. Menopausal Hormone Therapy use and Relative Risk of Lymphoid Neoplasms, by Type, Among 134,074 Women in the NIH-AARP Diet and Health Study
Hormone therapyNo. cancersPerson-yearsRR195% CIRR295% CI
  • chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL); relative risk (RR).

  • 1

    RRs adjusted for age (continuous).–

  • 2

    RRs adjusted for age (continuous), race, menopausal status, oral contraceptive use, education, smoking status, and other hormone therapy formulations.

  • Not shown: use of other or unknown hormone therapy types (N = 12 plasma cell neoplasms, RR = 1.15, 95% CI, 0–59–2.25; N = 47 NHL, RR= 0.91% CI, 0.65–1.27; N = 14 Diffuse large B-cell lymphoma, RR = 1.18,95% CI, 0.63–2.20; N = 11 follicular lymphoma, RR = 0.81, 95% CI, 0.41–1.60; N = 9 CLL/SLL, RR = 0.98, 95% CI, 0.46–2.08).

 Plasma cell neoplasms (N = 85)
No hormone therapy use38276,6781.00Ref.1.00Ref.
Estrogen only21203,3560.780.46–1.330.790.43–1.45
Estrogen and estrogen plus progestin230,1470.490.12–2.040.490.12–2.04
Estrogen plus progestin only12123,8960.910.47–1.770.920.46–1.81
 Non-Hodgkin lymphoma (N = 417)
No hormone therapy use171277,0991.00Ref.1.00Ref.
Estrogen only128203,6731.040.82–1.300.950.73–1.24
Estrogen and estrogen plus progestin1430,1840.760.44–1.300.730.42–1.26
Estrogen plus progestin only57124,0270.830.61–1.120.830.61–1.13
 Diffuse large B-cell lymphoma (N = 96)
No hormone therapy use43276,7071.00Ref.1.00Ref.
Estrogen only25203,3890.820.50–1.350.800.46–1.41
Estrogen and estrogen plus progestin330,1530.650.20–2.100.650.20–2.10
Estrogen plus progestin only11123,9000.730.37–1.430.720.36–1.44
 Follicular lymphoma (N = 105)
No hormone therapy use43276,6951.00Ref.1.00Ref.
Estrogen only31203,3880.990.62–1.570.900.52–1.55
Estrogen and estrogen plus progestin430,1520.860.31–2.400.790.28–2.23
Estrogen plus progestin only16123,9090.850.48–1.530.810.44–1.47
 CLL/SLL (N = 84)
No hormone therapy use34276,6651.00Ref.1.00Ref.
Estrogen only24203,3600.970.57–1.631.100.59–2.02
Estrogen and estrogen plus progestin430,1511.080.38–3.051.120.39–3.18
Estrogen plus progestin only13123,9070.930.49–1.780.920.47–1.79

We evaluated associations with MHT formulations after stratifying on hysterectomy status (Tables III and IV). We observed no statistically significant associations with plasma cell neoplasms, NHL overall, follicular lymphoma or CLL/SLL. Ever-use and current use of unopposed estrogen were statistically significantly associated with DLBCL (RR = 0.49, 95% CI, 0.25–0.96 and RR = 0.47, 95% CI, 0.22–0.98, respectively). For estrogen plus progestin, ever-use, duration of use, recency of use and regimen used generated null associations with plasma cell neoplasms, NHL overall and NHL subtypes.

Table III. Estrogen only Menopausal Hormone Therapy use and Relative Risk of Lymphoid Neoplasms, by type, Among Women with Hysterectomy in the NIH-AARP Diet and Health Study
Hormone therapyNo. cancers1Person-yearsRR295% CIRR395% CI
  • chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL); relative risk (RR).

  • 1

    No. cancers may not sum to total due to use of other hormone therapy formulations or missing data.

  • 2

    RRs adjusted for age (continous).

  • 3

    RRs adjusted for age (continuous), race, menopausal status, oral contraceptive use, education, smoking status, and other hormone therapy formulations.

 Plasma cell neoplasms (N = 37)
No hormone therapy use1163203.181.00Ref1.00Ref
Estrogen only18172352.830.640.30–1.360.630.29–1.37
Recency of use
 Former537043.490.850.30–2.410.840.30–2.41
 Current13133756.230.650.29–1.420.650.29–1.46
Duration of use
 <10 years575122.60.480.17–1.360.480.17–1.39
 >10 years1294678.380.780.35–1.740.791.35–1.78
 Non-Hodgkin lymphoma (N = 184)
No hormone therapy use4263304.161.00Ref.1.00Ref.
Estrogen only106172616.450.940.66–1.350.910.64–1.32
Recency of use
 Former2737119.441.160.72–1.861.140.71–1.84
 Current77133939.050.930.64–1.340.900.62–1.30
Duration of use
 <10 years4975256.331.070.71–1.601.060.71–1.60
 >10 years5694806.710.940.64–1.390.900.61–1.33
 Diffuse large B-cell lymphoma (N = 42)
No hormone therapy use1663226.791.00Ref.1.00Ref.
Estrogen only21172380.250.510.26–0.980.490.25–0.96
Recency of use
 Former737059.870.890.37–2.160.890.37–2.18
 Current13133763.510.480.23–1.000.470.22–0.98
Duration of use
 <10 years975145.080.640.28–1.450.630.28–1.44
 >10 years1294683.540.590.28–1.240.580.27–1.23
 Follicular lymphoma (N = 43)
No hormone therapy use863196.181.00Ref.1.00Ref.
Estrogen only25172371.251.140.51–2.541.020.45–2.29
Recency of use
 Former337042.140.540.15–1.950.520.14–1.86
 Current221337761.110.54–2.300.980.47–2.05
Duration of use
 <10 years1275147.81.030.45–2.380.970.42–2.25
 >10 years1394671.810.950.43–2.130.820.37–1.86
 CLL/SLL (N = 34)
No hormone therapy use763198.461.00Ref.1.00Ref.
Estrogen only19172354.331.020.43–2.431.100.45–2.64
Recency of use
 Former237043.740.580.12–2.770.610.13–2.95
 Current16133756.41.310.54–3.191.410.57–3.46
Duration of use
 <10 years1075140.741.490.56–3.961.580.59–4.21
 >10 years994331.971.020.38–2.731.090.40–2.95
Table IV. Estrogen Plus Progestin Only Menopausal Hormone Therapy use and Relative Risk of Lymphoid Neoplasms, by Type, Among Women with Intact Uteri in the NIH-AARP Diet and Health Study
Hormone therapyNo. cancers1Person-yearsRR295% CIRR395% CI
  • chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL); relative risk (RR).

  • 1

    No. cancers may not sum to total due to use of other hormone therapy formulations or missing data.

  • 2

    RRs adjusted for age (continuous) and other hormone therapy formulations.

  • 3

    RRs adjusted for age (continuous), race, menopausal status, oral contraceptive use, education, smoking status, and other hormone therapy formulations.

 Plasma cell neoplasms (N = 47)
No hormone therapy use26209,7461.00Ref.1.00Ref.
Estrogen plus progestin only12115,2211.160.58–2.351.240.60–2.58
Recency of use
 Former120,1590.510.07–3.760.550.08–4.11
 Current1194,2191.340.65–2.761.440.67–3.07
Duration of use
 <10 years1186,5321.610.78–3.351.720.81–3.63
 >10 years128,1540.300.04–2.250.310.04–2.32
Regimen of estrogen plus progestin
 Sequential (<15 days)441,5031.160.40–3.371.210.39–3.76
 Continuous422,5291.970.68–5.702.130.72–6.27
 Non-Hodgkin lymphoma (N = 228)
No hormone therapy use128210,0691.00Ref.1.00Ref.
Estrogen plus progestin only52115,3450.860.62–1.200.840.60–1.17
Recency of use
 Former920,1790.810.41–1.610.800.41–1.59
 Current4394,3220.880.62–1.250.850.59–1.23
Duration of use
 <10 years3686,6060.840.57–1.230.820.56–1.21
 >10 years1628,2040.930.55–1.560.890.52–1.52
Regimen of estrogen plus progestin
 Sequential (<15 days)1441,5380.670.38–1.160.640.36–1.13
 Continuous1522,5581.260.74–2.171.230.72–2.13
 Diffuse large B-cell lymphoma (N = 52)
No hormone therapy use26209,7541.00Ref.1.00Ref.
Estrogen plus progestin only11115,2261.070.52–2.201.080.52–2.27
Recency of use
 Former220,1641.020.24–4.301.060.25–4.48
 Current994,2191.100.51–2.371.100.49–2.45
Duration of use
 <10 years786,5271.020.43–2.401.040.44–2.48
 >10 years428,1641.190.41–3.431.180.39–3.51
Regimen of estrogen plus progestin
 Sequential (<15 days)341,5050.870.26–2.910.760.22–2.70
 Continuous322,5301.480.44–4.921.630.49–5.48
 Follicular lymphoma (N = 62)
No hormone therapy use35209,7751.00Ref.1.00Ref.
Estrogen plus progestin only15115,2340.820.44–1.520.770.41–1.46
Recency of use
 Former320,1630.920.28–3.010.890.27–2.93
 Current1294,2270.800.41–1.570.750.38–1.50
Duration of use
 <10 years1286,5390.900.46–1.780.850.43–1.68
 >10 years328,1600.620.19–2.030.590.18–1.95
Regimen of estrogen plus progestin
 Sequential (<15 days)441,5090.610.22–1.740.580.20–1.68
 Continuous322,5280.840.26–2.730.780.24–2.57
 CLL/SLL (N = 50)
No hormone therapy use27209,7431.00Ref.1.00Ref.
Estrogen plus progestin only12115,2320.890.45–1.800.860.42–1.75
Recency of use
 Former120,1600.410.06–3.000.400.05–2.96
 Current1194,2291.020.50–2.090.970.46–2.04
Duration of use
 <10 years886,5280.830.37–1.870.800.35–1.83
 >10 years428,1691.070.37–3.061.010.34–2.97
Regimen of estrogen plus progestin
 Sequential (<15 days)241,5060.430.10–1.810.410.09–1.78
 Continuous422,5301.510.52–4.351.410.48–4.14

Discussion

  1. Top of page
  2. Abstract
  3. Material and methods
  4. Results
  5. Discussion
  6. Acknowledgements
  7. References

This large cohort of US women with detailed exposure information revealed null associations between lymphoid neoplasms and most reproductive factors, including menarche, parity, oral contraceptives and menopausal status. Substantial changes in the types of available MHT and patterns of use over the last several decades27 complicate the comparisons with older studies of MHT and lymphoid neoplasm risk. Almost all MHT use consisted of unopposed estrogen therapy until the 1970s, when the discovery of increased endometrial cancer risks among women taking estrogen therapy led to sharp declines in MHT use.27 The combined estrogen-plus-progestin formulations emerged in the 1980s, and use of unopposed estrogen (among women with hysterectomy) and estrogen plus progestin (among women with an intact uterus) steadily increased until the early 2000s, when clinical trial data documented unfavorable risk-benefit profiles for MHT use among postmenopausal women.27 Few previous studies have considered MHT formulation or accounted for hysterectomy status, a strong predictor of unopposed estrogen use.13–21, 23, 26

Although our overall findings for MHT use were null, our risk estimates were generally less than one for all lymphoid neoplasm types, which is consistent with most of the previous literature on this topic. In analyses restricted to women with hysterectomy, we observed inverse associations between unopposed estrogen and NHL (RR = 0.63, 95% CI, 0.29–1.37) and DLBCL (RR = 0.49, 95% CI, 0.25–0.96). These results are most comparable with 4 previous studies that evaluated risk by MHT formulation20 or collected data when essentially all reported MHT use was unopposed estrogen (i.e., 1980s through the early 1990s).13, 15, 26 Of those studies, 3 also reported inverse associations with NHL,13, 20, 26 and the 2 that considered NHL subtypes also found significant associations for DLBCL.20, 26 In contrast, we and others did not observe the positive association between unopposed estrogen use and follicular lymphoma that was reported by Cerhan et al.15 Although some previous studies have observed somewhat stronger associations with current or long-duration use,15, 16, 18, 20, 21, 24 the absence of consistent statistical significance and dose-response by duration or recency argue against a true association or a simple, uncomplicated relationship between MHT and lymphoma. Nevertheless, the potential inverse association between unopposed estrogen use and DLBCL, which could also be due to chance, warrants further study. Our data on unopposed estrogen and the other main subtypes, plasma cell neoplasms, CLL/SLL and Hodgkin's lymphoma, were too imprecise to draw firm conclusions about these potential associations.

In contrast to the unopposed estrogen data, our analysis of estrogen plus progestin use revealed null associations with plasma cell neoplasms, NHL overall and specific NHL subtypes. These findings could be because of low statistical power, especially for the NHL subtypes. For the entire cohort of 134,074 women and the outcome of NHL overall, we had ∼ 86% statistical power to detect a RR = 0.7 for ever-use of unopposed estrogen and 57% power to detect a RR = 0.7 for ever-use of estrogen plus progestin. For women with hysterectomy and NHL overall as the outcome, we had 56% power to detect a RR = 0.7 for ever-use of unopposed estrogen. For women with an intact uterus and NHL overall as the outcome, we had 51% power to detect a RR = 0.7 for ever-use of estrogen plus progestin. If our null associations with estrogen plus progestin are confirmed in future studies (to date, none of the other studies of NHL and MHT have reported data on estrogen plus progestin use among women with an intact uterus) then the potential contrast between inverse associations with unopposed estrogen and null associations with estrogen plus progestin would suggest possible distinct roles for estrogen and progestin in lymphomagenesis. This suggestion is particularly intriguing in light of evidence suggesting that estrogen, but not progestin, influences B-cell development and antibody production.2, 40

Previous data on menstrual and reproductive factors and risk of lymphoid neoplasms are inconsistent.4, 10, 11, 13, 14, 21, 22, 24, 25 Study design, participant demographics and exposure ascertainment do not appear to explain the inconsistencies, as both significant and null associations have been reported in older and newer studies, among younger and older women, and in case-control and cohort designs. Although decreased risk of Hodgkin lymphoma has been associated somewhat more consistently with reproductive factors such as higher parity and earlier age at first birth,5–9, 11, 12, 18 we did not have a sufficient number of Hodgkin lymphoma cases in this older adult cohort for analysis. The inverse association we observed between DLBCL and increasing duration of oral contraceptive use might not be real because it was based on small numbers and not statistically significant. Nonetheless, the potential for 2 different exogenous hormones (i.e., oral contraceptives and unopposed estrogen) to decrease risk of DLBCL warrants further study.

Our study's strengths—e.g., large sample size, prospective design and subtype-specific analyses—increase the validity of these results. Detailed data on specific formulations and regimens minimized misclassification of exogenous hormone use and allowed us to evaluate contemporary MHT use in detail, instead of relying on broad exposure categories that capture diverse patterns of MHT use over time. We lacked follow-up data on hormone therapy use after baseline, but we assume that many current users in 1996 and 1997 continued their use at least through mid-2002.32 Selection bias might particularly affect analyses of reproductive factors and lymphoma in previous case-control studies.41 Low response to our mailed questionnaires could theoretically produce similar bias, but this seems unlikely because response was not associated with reproductive factors.32 Some other limitations, such as small numbers of some NHL subtypes, affect most single studies of NHL.

Our primarily null associations between menstrual and reproductive factors, use of oral contraceptives and specific detailed measures of MHT and precise NHL subtypes add substantial weight to the previous suggestions from other studies that reproductive factors and exogenous hormones generally are not strong risk factors for lymphoid neoplasms. Before the observed inverse associations between exogenous hormones and DLBCL can be considered indicative of hormonal exposures reducing risk for some lymphoid neoplasms, they should be replicated in sufficient detail, both for specific MHT exposures and NHL subtypes, across diverse study designs or in pooled analyses. Other hormone-related risk factors that might contribute to the observed sex differences in susceptibility to lymphoid neoplasms warrant continued consideration.

Acknowledgements

  1. Top of page
  2. Abstract
  3. Material and methods
  4. Results
  5. Discussion
  6. Acknowledgements
  7. References

Cancer incidence data from the Atlanta metropolitan area were collected by the Georgia Center for Cancer Statistics, Department of Epidemiology, Rollins School of Public Health, Emory University. Cancer incidence data from California were collected by the California Department of Health Services, Cancer Surveillance Section. Cancer incidence data from the Detroit metropolitan area were collected by the Michigan Cancer Surveillance Program, Community Health Administration, State of Michigan. The Florida cancer incidence data used in this report were collected by the Florida Cancer Data System under contract to the Department of Health (DOH). The views expressed herein are solely those of the authors and do not necessarily reflect those of the contractor or DOH. Cancer incidence data from Louisiana were collected by the Louisiana Tumor Registry, Louisiana State University Medical Center in New Orleans. Cancer incidence data from New Jersey were collected by the New Jersey State Cancer Registry, Cancer Epidemiology Services, New Jersey State Department of Health and Senior Services. Cancer incidence data from North Carolina were collected by the North Carolina Central Cancer Registry. Cancer incidence data from Pennsylvania were supplied by the Division of Health Statistics and Research, Pennsylvania Department of Health, Harrisburg, Pennsylvania. The Pennsylvania Department of Health specifically disclaims responsibility for any analyses, interpretations, or conclusions.

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  3. Material and methods
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  5. Discussion
  6. Acknowledgements
  7. References
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