0
Original Investigation |

Monoclonal Gammopathy of Undetermined Significance and Exposure to Breast Implants FREE

Elizabeth W. Karlson, MD; Milenko Tanasijevic, MD; Susan E. Hankinson, ScD; Matthew H. Liang, MD, MPH; Graham A. Colditz, MD, DrPH; Frank E. Speizer, MD; Peter H. Schur, MD
[+] Author Affiliations

From the Department of Medicine, Division of Rheumatology, Immunology, and Allergy (Dr Schur), Robert B. Brigham Multipurpose Arthritis and Musculoskeletal Diseases Center (Drs Karlson and Liang), Channing Laboratory (Drs Hankinson, Colditz, and Speizer), and the Department of Pathology (Dr Tanasijevic), Brigham and Women's Hospital, and Harvard Medical School (Drs Karlson, Tanasijevic, Hankinson, Liang, Colditz, Speizer, and Schur), Boston, Mass.


Arch Intern Med. 2001;161(6):864-867. doi:10.1001/archinte.161.6.864.
Text Size: A A A
Published online

Background  Animal studies and uncontrolled case series in humans have suggested a possible association between breast implant exposure and monoclonal gammopathy.

Objective  To assess whether there is an increased risk of monoclonal gammopathy in women with silicone breast implants, we conducted a retrospective study of women exposed to breast implants and matched nonexposed women nested within a prospective cohort study (the Nurses' Health Study).

Methods  We used serum protein electrophoresis and immunoglobulin subtype by immunofixation to test 288 women exposed to breast implants and 288 age-matched, nonexposed women who previously had provided a blood sample (1989-1990) for monoclonal proteins.

Results  Among the women exposed to breast implants, 5 had monoclonal gammopathy of undetermined significance (MGUS) compared with 4 women among those not exposed (odds ratio, 1.25; 95% confidence interval, 0.27-6.39). The distribution of isotypes was similar across exposure groups. The exposed women with MGUS tended to be older than the nonexposed women (mean age, 60.4 years vs 52.5 years, respectively; P = .03). None of the 9 women with MGUS had reported multiple myeloma or other hematologic malignancies up through 1996.

Conclusions  We find little evidence to support a substantial increased risk of MGUS in women exposed to breast implants. Larger studies are needed to determine if a more modest relationship exists.

IN 1962, Potter and Boyce1 demonstrated that adjuvants (such as mineral oil) injected into mice caused chronic inflammation and in some strains, plasmacytomas. Since then, plasmacytomas have been induced in mice by intraperitoneal introduction of paraffin oils, pure alkanes, and solid lucite.2 Recently, Potter et al3 injected silicone gel as found in silicone breast implants into the peritoneal cavity of genetically susceptible strains of mice and caused plasmacytomas. In addition, cases of multiple myeloma developing at unusually young ages have occurred in women with silicone breast implants.46 These observations suggested a possible association between exposure to silicone gel and multiple myeloma and prompted the National Cancer Institute (Bethesda, Md) to establish a registry of patients with silicone implants and either multiple myeloma or monoclonal gammopathy7 and to call for further epidemiologic investigations.8

Twenty-four percent of patients with monoclonal gammopathy of undetermined significance (MGUS) eventually develop multiple myeloma, macroglobulinemia, amyloidosis, or related diseases.9 We investigated the possible association of MGUS and breast implants using archived plasma from 32 826 women enrolled in the Nurses' Health Study.

STUDY POPULATION

The Nurses' Health Study (made up of 121 700 female nurses aged 30 through 55 years at enrollment in 1976) is a prospective study of dietary, hormonal, lifestyle, and other risk factors for cancer, cardiovascular disease, and other chronic diseases. Participants receive biennial questionnaires to update exposure and disease status; the response rate as of 1996 remained at 90%. In 1988, all participants were asked to provide 30 mL of blood to be stored for future studies, and 32 826 blood samples were collected. This project was approved by the institutional review board of the Brigham and Women's Hospital, Boston, Mass.

STUDY DESIGN

The study is a retrospective cohort nested within the ongoing prospective cohort study (the Nurses' Health Study). The subjects were selected on the basis of their breast implant exposure status, and then their blood was tested for immunologic abnormalities to determine disease status.

SELECTION OF EXPOSED WOMEN

On the 1992 biennial questionnaire, 1890 women reported having undergone breast implant surgery and 1480 (78%) responded to a supplemental questionnaire regarding the date of surgery and complications since surgery. Of 1183 women who underwent breast implant surgery before the time of the blood collection (who provided information regarding date of implant) 76% reported having silicone gel–filled implants. We studied subjects with any type of breast implant and performed analyses by type of implant. We selected only women who reported having implants for cosmetic or prophylactic purposes. We excluded subjects without a blood sample (n = 670), and subjects who reported any condition potentially associated with hypergammaglobulinemia or monoclonal gammopathy, such as breast cancer, multiple myeloma, or other cancer (n = 460); connective tissue disease (n = 33); and breast implant surgery after breast cancer surgery (n = 386) before the time of the blood collection (exclusions not mutually exclusive). This left 288 exposed women who had blood collected after breast implant surgery; 235 (82%) with silicone gel–filled implants; and 53 (18%) with saline-filled, unknown, or other type of implant). The duration of exposure was calculated as the time from the breast implant surgery to the date the blood sample was collected.

SELECTION OF NONEXPOSED WOMEN

Using identical exclusion criteria, 26 258 women without breast implants were potential controls. Of these, 288 were randomly selected and matched to the exposed group by year of birth and the date the blood sample was returned to form the nonexposed group.

PROCESSING OF BLOOD SAMPLES

From 1989 to 1990, blood samples were delivered overnight to our laboratory where they were centrifuged into aliquot components of plasma, red blood cells, and white blood cells and then archived in liquid nitrogen freezers. Monoclonal proteins are known to be stable for up to 50 years if samples are frozen (Robert A. Kyle, personal communication, 1999).

SERUM PROTEIN STUDIES

Monoclonal gammopathy was detected by immunofixation using the Titan Agarose Gel Immunofixation Electrophoresis (Helena Laboratories, Beaumont, Tex). Immunofixations were interpreted independently by 2 blinded reviewers (M.T., P.H.S.). The heavy chain and light chain isotypes were determined. Monoclonal band size (tiny, small, moderate, and large) was assessed qualitatively by inspecting the gel. After the initial review of samples, interrater agreement was 97%. The 2 reviewers reached consensus on the remaining 3%.

BLINDING AND QUALITY CONTROL PROCEDURES

Plasma samples were labeled only with an identification number, and laboratory personnel were blinded to the group identity of the samples. Prior to the study, the reproducibility of the laboratory assay and interrater agreement was assessed by testing split samples of known positive and known negative controls. Ninety-eight percent of positive and negative controls were correctly identified. Included in every batch of study samples were random negative and positive controls. Of these, 100% of 48 positive controls and 100% of 52 negative controls were correctly identified with qualitative estimates of monoclonal band size (intensity) identical in 62% and off by only 1 size category in the remaining 38%.

STATISTICAL METHODS

We performed analyses according to the type of implant (silicone gel–filled, saline-filled, or other type) as well as any type of breast implant. We tested the association of MGUS and breast implant exposure using the Fisher exact test and computed exact univariate confidence intervals (CIs). An age-adjusted analysis was performed using multivariate logistic regression controlling for age as a continuous variable. Mean age according to exposure to breast implants and mean duration of exposure between women with MGUS and women without MGUS were compared by the t tests. All P values are 2-tailed.

At the time of the original blood collection, the mean age was 52.0 years for the exposed and 51.7 years for the nonexposed women. Mean ± SD and median duration of implant exposure was 11.72 ± 6 years and 12.13 years, respectively.

Among the exposed women with any type of breast implant, 5 (1.7%) of 288 women had MGUS compared with 4 (1.4%) of 288 women among the nonexposed (odds ratio, 1.25; 95% CI, 0.27-6.39; P>.99) (Table 1). The age-adjusted odds ratio was 1.23 (95% CI, 0.32-4.66; P = .76). Among women with silicone gel–filled implants, 3 (1.3%) of 235 had MGUS (odds ratio, 0.92; 95% CI, 0.13-5.49).

Table Graphic Jump LocationTable 1. Cases of MGUS Among Women With and Without Breast Implants, Nurses' Health Study*

The distribution of MGUS isotypes and qualitative estimates of band size were similar across exposure groups (data not shown). The 5 exposed women with MGUS tended to be older than the 4 nonexposed women (mean age, 60.9 years vs 53 years, respectively; P = .04). There was no significant difference in the duration of exposure to breast implants between those women with and without MGUS (11.07 vs 11.73 years; P = .81). None of the 9 women with MGUS had reported multiple myeloma or other hematologic malignancies on biennial questionnaires through 1996 (Table 2).

Table Graphic Jump LocationTable 2. Description of 5 Breast Implant−Exposed Women With MGUS*

Monoclonal gammopathy is a benign condition that occurs at a younger age than multiple myeloma occurs and is a precursor to multiple myeloma, macroglobulinemia, amyloidosis, or related diseases in up to 24% of cases.9 We found little evidence for an increased frequency of MGUS in women exposed to breast implants. The 5 women with breast implants who had MGUS were significantly older than the 4 women without silicone breast implants who had MGUS, suggesting that exposure to breast implants does not cause monoclonal gammopathy at younger than expected ages.

Our results stand in contrast to 3 case series and the National Cancer Institute's registry,47 whose findings might be due to referral, ascertainment, and/or detection bias. Five women with silicone breast implants and multiple myeloma referred to a cancer center were described: 2 women had MGUS prior to breast implant surgery, and 3 women were aged 45 years or younger, suggesting a higher than expected rate of multiple myeloma in the age range of 35 to 45 years.4 Among 324 patients with newly diagnosed multiple myeloma from another cancer center, 9 had silicone breast implants. The mean age at diagnosis was similar to controls without breast implant exposure.5 Of 34 female patients with multiple myeloma at a university medical center, 3 patients had silicone gel breast implants.6 Among 284 women with silicone gel–filled breast implants who were referred for rheumatic symptoms, 1.7% had MGUS.6 The National Cancer Institute's registry includes 18 women with multiple myeloma and silicone breast implants (including the above cases).7 The mean and median duration of exposure was 12 and 14 years, respectively, with a range of 2 to 25 years. Thus, the duration of exposures observed in our study falls within the range reported in the registry, and we demonstrated no significant association between exposure and MGUS and found no evidence for MGUS occurring at younger ages in women exposed to breast implants.

In contrast, 5 studies have failed to demonstrate an increased risk of monoclonal gammopathy or multiple myeloma in women with breast implants.1014 No cases of multiple myeloma were found in 1135 women with cosmetic implants from a Denmark study,10,11 in 1756 Swedish women with cosmetic implants,12 or in 3182 US women13 (type of implant not specified). A Mayo Clinic study of 749 women who received breast implants (82% silicone gel–filled implants) found no cases of MGUS, multiple myeloma, macroglobulinemia, primary amyloidosis, or lymphoproliferative disorder compared with 1 case of multiple myeloma and 4 cases of MGUS among 1498 controls.14

The present study is the first cohort study of the possible association between breast implants and MGUS using stored blood samples rather than medical records to identify outcomes, and the selection of subjects was unbiased by symptoms or diseases. Some limitations require discussion. Monoclonal gammopathy of undetermined significance occurs so infrequently that even this large cohort study had limited power to detect anything but large increases in relative risk. Although we studied all available plasma samples from women who had breast implants done for cosmetic purposes (n = 288), the upper bound of the CI (6.39) suggested that we could not rule out a relative risk of 6.39 (or less) for the risk of monoclonal gammopathy associated with breast implants. Finally, although unlikely, there may have been bias introduced by selecting women who were willing and able to give blood rather than women who were not. However, to result in a biased relative risk participation would need to vary by both breast implant status and MGUS status. In conclusion, we find little evidence for a substantial increased risk of MGUS in women with breast implants compared with women without implants.

Accepted for publication October 23, 2000.

This study was supported by grants AR42630, CA40356, CA49449, AR36308, and K08 AR 02074-1 from the National Institutes of Health, Bethesda, Md. Dr Karlson is the recipient of an Arthritis Foundation Investigator Award, Atlanta, Ga.

We thank Charles Fuchs, MD, for reviewing the manuscript, Christine Grudzien for her assistance, Gideon Aweh for his programming expertise, and the participants from the Nurses' Health Study for their ongoing participation in this study.

Reprints: Elizabeth W. Karlson, MD, 75 Francis St, Boston, MA 02115 (e-mail: ekarlson@rics.bwh.harvard.edu).

Potter  MBoyce  C Induction of plasma cell neoplasms in strain BALB/c mice with mineral oil and mineral oil adjuvants. Nature. 1962;1931086
Potter  M Perspectives on the origins of multiple myeloma and plasmacytomas in mice. Hematol Oncol Clin North Am. 1992;6211- 223
Potter  MMorrison  SWeiner  FZhang  XKMiller  FW Induction of plasmacytomas with silicone gel in genetically susceptible strains of mice. J Natl Cancer Inst. 1994;861058- 1065
Garland  LLBallester  OFVasey  FB  et al.  Multiple myeloma in women with silicone breast implants: serum immunoglobulin and interleukin-6 studies in women at risk. Curr Top Microbiol Immunol. 1996;210361- 366
Tricot  GJNaucke  SVaught  LVesole  DJagannath  SBarlogie  B Is the risk of multiple myeloma increased in patients with silicone implants? Curr Top Microbiol Immunol. 1996;210357- 359
Silverman  SVescio  RSilver  DRenner  SWeiner  SBerenson  J Silicone gel implants and monoclonal gammopathies: three cases of multiple myeloma and the prevalence of multiple myeloma and monoclonal gammopathy of undetermined significance. Curr Top Microbiol Immunol. 1996;210367- 374
Rabkin  CSSilverman  STricot  GGarland  LLBallerster  OPotter  M The National Cancer Institute silicone implant/multiple myeloma registry. Curr Top Microbiol Immunol. 1996;210385- 387
Salmon  SEKyle  RA Silicone gels, induction of plasma cell tumors, and genetic susceptibility in mice: a call for epidemiologic investigation of women with silicone breast implants. J Natl Cancer Inst. 1994;861040- 1041
Kyle  RA "Benign" monoclonal gammopathy: after 20 to 35 years of follow-up. Mayo Clin Proc. 1993;6826- 36
McLaughlin  JKFraumeni  JFOlsen Jr  JMellemkjaer  L Breast implants, cancer, and systemic sclerosis [letter]. J Natl Cancer Inst. 1994;861424
Friis  SMcLaughlin  JKMellemkjaer  L  et al.  Breast implants and cancer risk in Denmark. Int J Cancer. 1997;71956- 958
McLaughlin  JKFraumeni  JFJNyren  OAdami  HO Silicone breast implants and risk of cancer? [letter]. JAMA. 1995;273116
Deapen  DBrody  G Re: Induction of plasmacytomas with silicone gel in genetically susceptible strains of mice [letter]. J Natl Cancer Inst. 1995;87315- 316
Kyle  RA Monoclonal gammopathy of undermined significance. Curr Top Microbiol Immunol. 1996;210375- 383

Figures

Tables

Table Graphic Jump LocationTable 1. Cases of MGUS Among Women With and Without Breast Implants, Nurses' Health Study*
Table Graphic Jump LocationTable 2. Description of 5 Breast Implant−Exposed Women With MGUS*

References

Potter  MBoyce  C Induction of plasma cell neoplasms in strain BALB/c mice with mineral oil and mineral oil adjuvants. Nature. 1962;1931086
Potter  M Perspectives on the origins of multiple myeloma and plasmacytomas in mice. Hematol Oncol Clin North Am. 1992;6211- 223
Potter  MMorrison  SWeiner  FZhang  XKMiller  FW Induction of plasmacytomas with silicone gel in genetically susceptible strains of mice. J Natl Cancer Inst. 1994;861058- 1065
Garland  LLBallester  OFVasey  FB  et al.  Multiple myeloma in women with silicone breast implants: serum immunoglobulin and interleukin-6 studies in women at risk. Curr Top Microbiol Immunol. 1996;210361- 366
Tricot  GJNaucke  SVaught  LVesole  DJagannath  SBarlogie  B Is the risk of multiple myeloma increased in patients with silicone implants? Curr Top Microbiol Immunol. 1996;210357- 359
Silverman  SVescio  RSilver  DRenner  SWeiner  SBerenson  J Silicone gel implants and monoclonal gammopathies: three cases of multiple myeloma and the prevalence of multiple myeloma and monoclonal gammopathy of undetermined significance. Curr Top Microbiol Immunol. 1996;210367- 374
Rabkin  CSSilverman  STricot  GGarland  LLBallerster  OPotter  M The National Cancer Institute silicone implant/multiple myeloma registry. Curr Top Microbiol Immunol. 1996;210385- 387
Salmon  SEKyle  RA Silicone gels, induction of plasma cell tumors, and genetic susceptibility in mice: a call for epidemiologic investigation of women with silicone breast implants. J Natl Cancer Inst. 1994;861040- 1041
Kyle  RA "Benign" monoclonal gammopathy: after 20 to 35 years of follow-up. Mayo Clin Proc. 1993;6826- 36
McLaughlin  JKFraumeni  JFOlsen Jr  JMellemkjaer  L Breast implants, cancer, and systemic sclerosis [letter]. J Natl Cancer Inst. 1994;861424
Friis  SMcLaughlin  JKMellemkjaer  L  et al.  Breast implants and cancer risk in Denmark. Int J Cancer. 1997;71956- 958
McLaughlin  JKFraumeni  JFJNyren  OAdami  HO Silicone breast implants and risk of cancer? [letter]. JAMA. 1995;273116
Deapen  DBrody  G Re: Induction of plasmacytomas with silicone gel in genetically susceptible strains of mice [letter]. J Natl Cancer Inst. 1995;87315- 316
Kyle  RA Monoclonal gammopathy of undermined significance. Curr Top Microbiol Immunol. 1996;210375- 383

Correspondence

CME
Meets CME requirements for:
Browse CME for all U.S. States
Accreditation Information
The American Medical Association is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. The AMA designates this journal-based CME activity for a maximum of 1 AMA PRA Category 1 CreditTM per course. Physicians should claim only the credit commensurate with the extent of their participation in the activity. Physicians who complete the CME course and score at least 80% correct on the quiz are eligible for AMA PRA Category 1 CreditTM.
Note: You must get at least of the answers correct to pass this quiz.
You have not filled in all the answers to complete this quiz
The following questions were not answered:
Sorry, you have unsuccessfully completed this CME quiz with a score of
The following questions were not answered correctly:
Commitment to Change (optional):
Indicate what change(s) you will implement in your practice, if any, based on this CME course.
Your quiz results:
The filled radio buttons indicate your responses. The preferred responses are highlighted
For CME Course: A Proposed Model for Initial Assessment and Management of Acute Heart Failure Syndromes
Indicate what changes(s) you will implement in your practice, if any, based on this CME course.
NOTE:
Citing articles are presented as examples only. In non-demo SCM6 implementation, integration with CrossRef’s "Cited By" API will populate this tab (http://www.crossref.org/citedby.html).
Submit a Comment

Multimedia

Some tools below are only available to our subscribers or users with an online account.

Web of Science® Times Cited: 12

Related Content

Customize your page view by dragging & repositioning the boxes below.

Articles Related By Topic
Related Topics
PubMed Articles