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Monoclonal Gammopathy of Undetermined Significance and Exposure to Breast Implants
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
Arch Intern Med. 2001;161:864-867.
ABSTRACT
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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.
INTRODUCTION
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.4-6 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.
PARTICIPANTS AND METHODS
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.
RESULTS
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).
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Table 1. Cases of MGUS Among Women With and Without Breast Implants,
Nurses' Health Study*
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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).
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Table 2. Description of 5 Breast Implant-Exposed Women With MGUS*
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COMMENT
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,4-7
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.10-14
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.
AUTHOR INFORMATION
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{at}rics.bwh.harvard.edu).
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.
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