Date: 11 Jun 2000 08:01:38 -0000

There are 6 messages in this issue.

Topics in this digest:

3. USSW: Reported Complications of Silicone Gel Breast Implants

4. USSW: International Archives of Allergy & Immunology

5. USSW: Carcinoma

6. USSW: Silicone Breast Implants and Collagen Diseases

7. USSW: Silicone Gel Filled Breast Implants and Connective Tissue Disease

8. USSW: Desmoid tumor of the breast following augmentation mammaplasty

Message: 3

21 pages

Barbara G. Silverman, MD, MPH; S. Lori Brown, PhD, MPH; Rosalie A. Bright, ScD; Ronald G. Kaezmarek, MD, MPH; Janet B. Arrowsmith-Lowe, MD; and David A. Kessler, MDPurpose: To review the range of local and systemic complication attributed to silicone breast implants and to evaluate the epidemiologic literature on these complications.

Data Sources: Epidemiologic studies of the potential risks of silicone breast implant identified by MEDLINE search and literature review.

Study Selection: Epidemiologic studies with cohort, case-control, and cross-sectional designs. When epidemiologic studies were unavailable (as for estimates of local complications), case series were reviewed.

Data Extraction: Epidemiologic studies evaluated for methodologic quality. including such characteristics as study design, sample size and selection, determination of silicone exposure and outcome variables, and duration of follow-up.

Data Synthesis: The epidemiologic literature on the potential complications of silicone breast implants has concentrated primarily on connective tissue disorders and cancer, estimates of the true incidence of local complications, such as rupture. capsular contracture, and breast pain. are unavailable. Studies of scleroderma and other defined connective tissue disease's suggest that implant recipients have no substantially increased risk for these disorders; however, the epidemiologic literature is insufficient to rule out an association between breast implants and connective-tissue disease like syndromes. Overall, the rate of breast cancer does not seem to be increased in women with silicone breast implants. However, the risk to women as they reach the postmenopausal years is not yet known.

Conclusions: Information is insufficient To adequately advise women who currently have or are seeking to obtain breast implants about the overall risk of these devices No epidemiologic study has indicated that the rate of well-defined connective tissue disease or breast cancer has greatly increased in women with silicone breast implants, but no studies have ruled out a moderately increased risk for these diseases. No studies have adequately addressed the crucial issue of local complications such as rupture and capsular contracture, although evidence increasingly points to a higher risk for rupture as implants age.

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Silicone breast implants have been used for reconstruction and cosmetic enhancement of the breast since the early 1960s (1). Synthetic polymers of silicone oxide with organic sidechains (polydimethylsiloxane) can he formed into gels by lengthening polymer chains or can be further modified into a solid, rubber-like material (elastomer) by cross-linking the polymer chains (2). silicone gel breast implants are composed of a silicone elastomer envelope filled with silicone gel, and saline implants consist of a silicone elastomer envelope filled with a saline solution. Until recently, most implants used for cosmetic and reconstructive purposes contained silicone gel.

The body of anecdotal literature describing local and systemic complications of silicone gel breast implants is increasing (3, 4). but epidemiologic evidence to support these reports remains sparse. The 1976 Medical Device Amendments to the Food, Drug and Cosmetic Act require that medical devices be shown to be safe and effective before marketing (5). Because silicone breast implants were introduced before the law was enacted, they were allowed to remain on the market ("grandfathered"): however, they will eventually need to meet the same safety requirements as new devices (5). Because of growing concern about the safety of silicone gel implants, a brief moratorium on their use was implemented in January 1992 until new information received by the Food and Drug Administration (FDA) could be presented to an advisory panel (6). This new information included case reports of autoimmune disease in women with breast implants and evidence that some early models of gel-filled implants leaked excessively. Although the moratorium was lifted in April I992 the continued lack of adequate safety data led the FDA to act on the advisory panel's recommendation that the availability of silicone gel implants be restricted to participants in controlled clinical trials, including women having reconstructive surgery (7) and a limited number of women having augmentative surgery. A detailed description of the regulatory history of Silicone gel breast implants is beyond the scope of this review but is available from other sources (5, 6, 8).

Several categories of problems related to silicone gel breast implants continue to be of concern, including 1) local effects such as implant rupture, capsular contracture, and pain; 2) the association between silicone gel implants and the development of systemic autoimmune or connective tissue disease; and 3) the association between silicone gel implants and the developmentof or delay in the diagnosis of breast cancer.

We present an overview of he most common adverse outcomes that have been reported with silicone gel breast implants. In the cases of connective tissue diseases and breast cancer we have given preference to published epidemiologic studies with cross-sectional, cohort or case-control designs over case series and anecdotal reports. For our discussions of local complications, including rupture, and other issues of interest for which epidemiologic studies are not yet available, we limited our review to sources that were judged to be the most current and of the highest quality rather th an attempting an exhaustive review of all potential complications that have been reported in women with silicone gel breast implants. WE focus on silicone gel breast implants rather than saline-filled implants because 1) most implanted devices contain silicone gel, 2) silicone implants have been the most intensively studied in epidemiologic investigations and case series and 3) silicone implants have been the focus of the greatest health concerns.

We searched the MEDLINE database (1975-1995) and reviewed the literature to identify epidemiologic studies wills cohort, case-control, and cross sectional designs. We reviewed case series where epidemiologic studies were unavailable (as for estimates of local complications). We evaluated epidemiologic studies for methodologic quality, including characteristics such as study design, sample size and selection, determination of exposure and outcome variables, and duration of follow-up.

Estimates of the prevalence of silicone breast implants in the United States have been difficult to obtain. Data from the 1988 Medical Device Implant Supplement to the National Health interview Survey (9) yielded an estimate of 304,000 women (95% Cl, 239,000 to369,000) with 530,000 silicone implants (CI, 444,000 to 616,000). Because this survey emphasized "medical devices...[that] help the body function or treat illness or injury it may have under counted cosmetic implants. Bright and colleagues (9), using market reports (10, 11) and expected mortality and implant removal rates,concluded that the true number of breast implant recipients in the United States in 1988 was about 1 million.

Using data from a 1989 mailed survey of 40,000 households, Cook and colleagues (12) estimated that 815,700 women (CI, 715,800 to 974,700) had breast implants at the time of thesurvey, for a prevalence of 8 per 1000 women. Although the wording of the questionnaire that was used may have resulted in the inclusion of persons who received devices other than breast implants and although the response rate was only 68%, this survey provides the best available data on the prevalence of breast implants in U.S. women By applying market data that suggest an increase in the prevalence of breast implants in the United States of 17% per year (10, 11) to the adjusted estimate of Bright and colleagues (9) and the estimate of Cook and co-workers (12), the estimated prevalence of breast Implants in early 1992 is 11 to 12 per 1000 women.Gabriel and associates (13) estimated that the prevalence of breast implants among females 15 years of age and older in the racially homogeneous population of Olmsted County, Minnesota was approximately 1% as of 1 January 1992.

In a 1995 report, Terry and colleagues (14) extrapolated from 1988 New York State ambulatory and hospital surgery data to conclude that approximately 890,000 U.S. women received cosmetic breast implants between 1963 and 1988. However the potential for error in the coding of procedures, the assumption that surgical practices in New York are representative of those of the United States as a whole, and other methodologic flaws call this estimate into question.

Local Reactions: Implant Failure, Silicon Migration, Capsular Contracture, and Other Effects

In general, implant failure is defined as a rupture of the prosthesis that causes silicone gel to spill into the surrounding tissue The symptoms of rupture include nodules, decreased breast size, asymmetry, and pain (sometimes characterized as burning) or tenderness. In some cases, however, symptoms may be absent (15) Implant age (16). closed capsulotomy (a technique that uses manualpressure to break up fibrous scar tissue around the implant)(16-18), trauma or injury to the breast (15, 16), and mammography (15, 16) have been implicated in ruptures. However, in many cases rupture may be spontaneous or caused by normal wear and tear on the elastomer envelope.

Physical examination is not sensitive for diagnosing rupture of silicone gel Implants (19). Although mammography (15,16), ultrasonography (19,20), and magnetic resonance imaging (21,22) have been studied for their ability to identify implant rupture, their true sensitivity and specificity are unknown. Using screening mammography, Destouet and colleagues (23) identified implant failure in 16 (5%) of 350 asymptomatic breast implant recipients. Only 5 of these 16 women chose to have their implants removed (explanted); rupture was confirmed in all cases (23). Harris and coworkers(19) retrospectively reviewed mammography findings for 336 silicone breast implant recipients and reported that 6.5% had sonographic or mammographic evidence of silicone leaks. This estimated may have been biased upward because many of the study participants had symptoms related to their implants.

The "gold standard" for confirmation of rupture is explantation and inspection of the implant. Several studies have used women whose implants were removed to estimate rupture rates (Table 1). de Camara and colleagues (16) studied a series of 31 patients of a large multispecialty practice, all of whom had sought evaluation for various symptoms related to breast implants. In this group, which had a total of 51 implants, the condition of an implant at surgery was significantly related to the age of the implant. After 1 to 9 years, 35.7% of implants aged 1 to 9 years were ruptured; after 10 to 17 years, 95.7% of implants had either ruptured or showed evidence of leaking silicone (16). Peters and associates (17) described a second series of 57 women with 102 implants; among these women, 25.6% of implants aged 2 to 10 years and 53.6% of implants aged 11 to 26 years had ruptured. Of implants aged 11 to 26 years, 64.3% were either ruptured or leaking. In a third series, Robinson and colleagues (24) evaluated 495 implant recipients, 300 of whom elected to have the implant removed. Although in some cases the women opted for explantation because they suspected an implant-related health problem, others based their decision on a general concern about silicone gel implants. The investigators reported frank ruptures in 51% of participants; overall, 71% of the women in this series had either frank rupture or severe silicone bleed at explantation. The rupture rate did not differ between asymptomatic patients and patients with implant-related symptoms. The risk for rupture increased with the age of the implant, a finding that led Robinson and colleagues (24) to conclude that women with implants should have them removed as a prophylactic measure, preferably within 8 years of implantation, to reduce the risk for rupture or severe bleed. Although explantation studies incompletely reflect the general population of recipients and use varying definitions of rupture and leakage, they provide some information on the causes of rupture. Some evidence suggests that as implants age, they are more susceptible to rupture from external pressure, as assessed by compressive testing techniques on intact, explanted prostheses(25).

Prosthetic rupture is not the only means by which silicone may escape to surrounding tissues. Silicone may diffuse, or bleed, through the silicone elastomer envelope in the absence of a tear or rupture (26). Evidence also indicates that the silicone shell of the implant may shed silicone fragments. Textured silicone shells appear to be more likely than smooth shells to shed fragments (27,28). Another problem that has been reported in connection with silicone injection (29-33), as well as with silicone breast implants (34-36), is migration of silicone to distant sites, formation of silicone granulomas or pseudotumors, and transport of silicone gel to regional lymph nodes (37, 38).

The wide range of estimates of rupture and overall failure in the published literature can be attributed to several factors, including differences in the patient samples and types of implants studied, the methods used to detect rupture, and the duration of follow-up after breast implantation. This last point is crucial, because the most recent research (24) strongly suggests that aging of the implant is an important factor in rupture; thus, longer follow-up would result in the detection of higher rupture rates. Any study of implants to determine the true rate of failure must stratify the data by the age and type of implant. For all of these

reasons, rupture rates previously reported to the FDA are of questionable value (39). Because ruptures are potentially silent and their ultimate effects on health are unknown, improved screening and diagnostic tests are necessary to provide more information on rates of rupture in general and the influence of rupture on other local and systemic complications. Studies currently in progress are expected to shed further light on this issue as techniques with greater sensitivity and specificity for diagnosing rupture are developed.

The formation of a capsule around a silicone implant is part of the expected inflammatory response to any foreign body, even one composed of a material considered "inert" (40,41). Capsular contracture, resulting in moderate to extreme hardening of the breast, tightness, mild to sever pain, and deformity or distortion of the breast, is the most common local reaction after implantation (42). Diagnosis and measurement of the severity of contracture is inherently subjective, ;making comparison of studies that have used different diagnostic criteria difficult; the widely used Baker scale (43), which ranks implant outcomes on a scale from 1 (a breast with a soft and natural appearance) to IV (a hard breast with obvious spherical distortion), requires that the observer use some judgement when classifying the implants of individual patients. Anecdotal reports of contracture incidence as low as 0.6% (44) and as high as 100% (45) have been published; neither of these two reports was accompanied by data on the duration of follow-up, diagnostic criteria, and follow-up technique. Few controlled trials have studied this issue. In Asplund's randomized, clinical trial comparing silicone gel with saline implants (46), patients and an evaluator were blinded to the type of implant used and patients were followed for at least 6 months. A 54% contracture rate was documented (Baker classes III and IV) in the silicone gel group. Long-term follow-up of 34 of the 35 study patients (minimum follow-up, 5.5 years) showed no additional cases of contracture (47). This follow-up and restriction of the study to patients having reconstructive surgery after mastectomy make it difficult to generalize these results to the wider population of implant recipients. Coleman and colleagues (48) obtained similar results in a randomized, controlled clinical trial comparing smooth with textured silicone implants in 50 women having bilateral augmentation. After 12 months, a blinded panel of observers found contracture rates (Baker classes III and IV) of 58% for smooth implants and 8% for textured implants (48).

Several other reports involving more participants have been based on reviews of the patient records of a single practice or physician (49-55). These studies have tended to concentrate on different variations in treatment protocols that may have affected outcome. In addition, these studies as a group are complicated by flaws such as high or unspecified loss of patients to follow-up, short or uncertain duration of follow-up, and potential bias in the diagnosis of contracture caused by the lack of blinded reviewers and other factors affecting the reliability of their estimates, which range from 2.5% for a textured implant (52) to 81% for a smooth, gel-filled prosthesis (51).

Capsular contracture does not seem to require the presence of silicone gel, because contracture has been shown to occur with saline-filled implants (46, 51). Some investigators (56) have noted an association between the amount of silicone bleeding from the prosthesis and the intensity of the inflammatory response of the capsule, and silicone has been shown to be present in the capsule (57, 58). Use of local antibacterial agents can reduce the incidence of capsular contracture with saline implants, suggesting that periprosthetic bacterial contamination may be a contributing factor (59). Movement of the implant in the tissue bed (40) and a smooth rather than textured implant surface (8, 48) have also been implicated as causes of capsular contracture. Treatment of contracture appears to be ineffective because recurrence may be high, perhaps exceeding 50% (42). Closed capsulotomy (60) has been

used in the past; this procedure is not currently recommended, because it is known to cause rupture and may forcefully extrude silicone gel from the elastomer (16-18). Reoperation may thus be required to disrupt or remove a capsule (61).

Many other local complications have been reported, including breast pain (9, 24, 62), infection, delayed wound healing, hematoma, seratoma, changes in breast or nipple sensation (63) and galactoccic formation or galactorrhea (64). In addition, adverse outcomes, such as wrinkling, shifting, displacement, or extrusion of the implant, and unsatisfactory cosmetic results (63) have also been reported. The true incidence rates of these events are unknown.

Many individual case reports and case series have implicated breast augmentation and reconstruction, particularly the implantation of silicone breast implants, in the development of connective tissue disease-like syndromes (3, 4, 65, 66). Some reports have involved confirmed diagnoses of such known disorders as systemic sclerosis, rheumatoid arthritis, and systemic lupus erythematosus, whereas others ;have described as entity called "human adjuvant disease." Although the term "human adjuvant disease" has been widely used to describe constitutional and rheumatic symptoms in patients exposed to silicone or paraffin, it has been discredited as lacking precise and reproducible criteria (67).

The following is a critical review of epidemiologic studies that used cohort, case-control, and cross-sectional designs to study the potential for connective tissue disease in association with silicone breast implants. We have included published studies that used epidemiologic methods to compare the incidence or prevalence of connective tissue disease in breast implant recipients and a comparison group (Table 2). Although anecdotal reports and case series are valuable as first indicators of potential device problems, they are insufficient to study associations between exposures and presumed effects. Such reports are beyond the scope of this review and have been excluded.

Goldman and colleagues (68) reviewed the records of female patients in a single practice that cared for both primary care and rheumatology patients, and they found that patients with silicone breast implants were no more likely than those without implants to have received a diagnosis of a known connective tissue disorder. On the basis of this finding, the investigators concluded that breast implants and excess connective tissue diseases are not associated. This conclusion is questionable, however, because it is based on a study of a referral population in which the comparison group had a presumably high incidence of rheumatologic symptoms. This approach does not consider t he possibility of an association between atypical symptom complexes and breast implantation. Furthermore, it is not clear that the investigators used a consistent method for determining a history of breast implantation in the patient group studied.

Weisman and coworkers (66) surveyed 378 patients who had had cosmetic breast augmentation between 1970 and 1981. The survey did not include a comparison group of women who had not been exposed to silicone. Of the 125 patients who responded, none reported any of the diseases of interest (including rheumatoid arthritis, systemic lupus erythematosus, and scleroderma) after augmentation; 3 respondents did report fibromyalgia. The investigators do not appear to have determined the reasons for lack of response. Given the small sample size, the poor response rate (especially given that persons not responding to questionnaire surveys may have been deceased or more seriously ill than those who responded), and the lack of an appropriate comparison group, the study results cannot establish or dismiss a link between breast implants and connective tissue disorders.

Similar flaws limit the value of questionnaire studies by Wells and associates (69) and Giltay and colleagues (70). In a survey of patients from a single plastic surgery practice, Wells and associates (69) compared the incidences of 23 symptoms of connective tissue disease and the diagnoses of arthritis, systemic lupus erythematosus, scleroderma, or the Raynaud phenomenon between patients who had had cosmetic surgery involving silicone exposure and patients who had no silicone exposure. The investigators concluded that their survey showed no association between silicone used in cosmetic procedures and connective tissue

disorders.

Gilray and colleagues (70) identified all patients of a single plastic surgery department of a university hospital who had received a silicone breast implant between January 1978 and December 1990, and they matched each to a patient of the same age who had had a cosmetic surgery procedure not involving silicone during the same year. Participants were asked about symptoms suggestive of connective tissue disease and the use of antirheumatic drugs and medical consultations for rheumatic problems. Women exposed to silicone were significantly more likely than women in the comparison group to report "rheumatic complaints," such as joint pain lasting at least 3 months, burning eyes, and skin abnormalities worsened by sun exposure. Recipients were slightly more likely than women in the comparison group to seek medical consultation, either from general practitioners or specialists, and to take "antirheumatic" drugs for their symptoms; these differences were not statistically significant. However, the researchers concluded t hat women exposed to silicone were no more likely than women not exposed to silicone to show evidence of serious rheumatic disease.

In the surveys of Wells and Giltay and their colleagues, low rates of response and a lack of information on nonresponders, some of whom may have been deceased or seriously ill, may have resulted in incomplete ascertainment of connective tissue disease.

Schusterman and colleagues (71) prospectively studied patients having breast reconstruction with silicone implants or autogenous tissue after mastectomy. After average follow-up periods of 2.5 years for the silicone implant recipients and 1.9 years for the autogenous tissue group, the researchers found no difference in the incidence of diagnosed rheumatic diseases. The ability of the study to detect true differences in the two groups was limited by the small sample size and short duration of follow-up, although the researchers state that they intend to continue to follow this group. Furthermore, the fact that all study participants had had breast cancer limits the extent to which results can be generalized to the general population of implant recipients; an estimated 80% of breast implants are used for cosmetic rather than reconstructive purposes (3).

Gabriel and colleagues (72) conducted a large cohort study of the potential association between connective tissue disorders and breast implants among 749 residents of Olmsted County, Minnesota, who received implants between 1 January 1964 and 31 December 1991.

Review of the medical records of implant recipients and of an age-matched comparison group showed no increased incidence of connective tissue disease (relative risk, 1.06; CI, 0.334 to 2.97), Hashimoto thyroiditis (relative risk, 1.01; CI, 0.46 to 2.09), or cancer (relative risk, 1.10; CI, 0.55 to 2.11) in women who received implants compared with those who did not. This study was an improvement over previous cohort studies in that it was population based and studied many more implant recipients; however, the sample size was still inadequate to detect rare outcomes, and the duration of follow-up (average, 7.8 years for case-patients and 8.3 years for controls) was inadequate to detect outcomes with long latencies. Furthermore, the report did not indicate that a history of connective tissue disease was an exclusion criterion for either patient group. Finally, although complete medical records were available for all follow-up care provided in Olmsted County, use of these records alone made it impossible to detect syndromes or symptom complexes not consistently recorded in medical records and would have resulted in an undercounting of complications in implant recipients who sough follow-up care elsewhere. Despite these flaws, the results of the study by Gabriel and colleagues tend to rule out a marked risk for well-defined connective tissue diseases related to silicone breast implants.

More recently, Sanchez-Guerrero and colleagues (73) studied 87,501 women from the cohort of the Nurses' Health Study, 876 of whom had silicone gel implants. The 1990 questionnaire included questions on breast implantation. On the basis of responses to biennial questionnaires administered between 1976 and 1992, the investigators identified a group of participants reporting a physician diagnosis of such connective tissue disorders as systemic lupus erythematosus, rheumatoid arthritis, and scleroderma, as well as rheumatic or musculoskeletal disease. In 1992, 5086 women (6% of the total cohort) reporting such conditions were sent a "screening questionnaire" intended to collect more specific information on self-reported signs and symptoms of disease.

Sanchez-Guerrero and colleagues (73) ruled out a moderately increased risk for definite connective tissue disease or self-reported signs and symptoms of such disease in breast implant recipients. However, the investigators sought information on signs and symptoms suggestive of connective tissue disease only in the group reporting a diagnosis of a defined connective tissue disease and not in the entire cohort or in a random sample thereof. The 94% of study participants who were not given the opportunity to complete a "screening questionnaire" were considered, for the purposes of the data analysis, to have had no self-reported symptoms, an assumption that probably resulted in an underestimate of the prevalence of such symptoms. Therefore, although the study provides additional evidence against a markedly increased risk for certain connective tissue disorders in implant recipients, it could not address whether symptoms of atypical connective tissue disorders may occur more frequently in such recipients.

Many of the disease entities that have been linked to silicone breast implants are rare and therefore difficult to detect, even in large cohort studies. For example, estimates of t he annual incidence of scleroderma in the United States vary from 2 to 10 per 1 million persons (74). For this reason, several investigators have used a case-control design to study these potential outcomes. Dugowson and co-workers (75) surveyed 349 patients with rheumatoid arthritis and 1456 controls (described as "similarly aged") on a history of silicone breast implants and reported an odds ratio of 0.41 (CI, 0.05 to 3.13). It is not clear whether case-patients and controls were asked about a history of breast implantation in a similar manner. Strom and associates (76) resurveyed case-patients with systemic lupus erythematosus and controls from an earlier study of risk factors for that disease and reported that 0.8% of the case-patients and note of t he controls had received a breast implant. Of the case-patients with systemic lupus erythematosus and age-matched controls (friends of the case-patients), who had been gathered for the earlier study, 76% of t he former and 78% of the latter were available for a second interview. More case-patients than controls could not be interviewed because they were deceased, confused, or incapacitated (9.8% compared with 1.4%), where-as more controls than case-patients could not be located (18.2% compared with 12.3%). The investigators used a control group compiled for another study, the Cancer and Steroid Hormone Study, to calculate odds ratios, and they concluded that breast implants conferred no increased risk for systemic lupus erythematosus (odds ratio, 4.5; 90% CI, 0.21 to 27.3). The wide CI indicates the limited power of this study to rule out increased risk and makes it difficult to draw any conclusions from the results.

The potential association between breast implants and scleroderma has been studied extensively by the case-control method. In a preliminary report of a case series, Wigley and colleagues (77) calculated a 0.66% prevalence of augmentation mammoplasty among 741 patients with a diagnosis of systemic sclerosis at university research centers in Baltimore and Pittsburgh and concluded that this prevalence was not significantly different from that in t he general population. Hochberg and coworkers (78) expanded on the Wigley study with a multi-center case-control study comparing 869 patients who had systemic sclerosis with 2061 age, race, and sex-matched community controls. The adjusted odds ration for the association between scleroderma and breast implants, as reported in this study's brief abstract, was 1.25 (CI, 0.62 to 2.53). Two population-based studies of scleroderma conducted in Michigan (79) and in Sydney, Australia (80), used intensive case-finding to identify patients with scleroderma and compared them with controls on the presence of several potential risk factors, including breast implants. The Australian investigators (80) found that the prevalence of augmentation mammoplasty, adjusted for socioeconomic status, in a group of 251 patients with scleroderma was 1.54%, a value not significantly different from that of a group of age-and sex-matched controls living in Sydney, Similarly, the Michigan investigators (79) compared 274 case-patients who had scleroderma with 1184 controls and calculated an odds ratio of 0.72 (CI, 0.16 to 3.21). However, these investigators sought a history of breast implantation until t he time of interview for the controls and until the time of diagnosis for the case-patients. This difference may have increased the likelihood of eliciting the exposure of interest in controls compared with case-patients.

Published epidemiologic studies of the potential association between connective tissue disease and silicone breast implants represent a range of methodologic approaches, focus on various outcomes, and, as has been noted here, vary widely in quality. Some of the problems common to these different studies include 1) sample sizes inadequate to rule out rare outcomes, 2) study methods inappropriate for detecting atypical syndromes, 3) poor choice of comparison group, and 4) inadequate duration of follow-up or information-gathering techniques that may have biased the detection of implants ro clinical outcomes. Given the enormous concern over the potential for connective tissue disease in association with silicone breast implants, it is tempting to use meta-analysis to pool the results of published studies in order to derive an estimate of overall risk. This approach may be appropriate for summarizing a group of high-quality studies that individually lack statistical power, but a meta-analysis of observational studies (which may contain considerable bias in ascertaining exposures and outcomes and problems controlling for confounders) is problematic at best (81,82). A recently published meta-analysis (83) that includes the studies discussed here is notable in that it gives little consideration to the design and methodologic problems of the individual studies that may have affected the quality of the summary risk estimates calculated.

An inability to mathematically poof the results of these studies does not preclude drawing certain conclusions. For example. Taken together these studies suggest no substantial increase in t he risk for scleroderma or other well-defined connective tissue diseases overall as a result of breast implantation. However, no study has specifically addressed atypical connective tissue diseases, and the few studies that have attempted to consider symptoms that may indicate atypical syndromes have had design flaws that rendered them inconclusive.

Risk for Breast Cancer

Concern over the potential carcinogenicity of silicone has prompted several cohort studies of the potential link between silicone breast implants and breast cancer. Four of these studies are listed in Table 3 Berkel and colleagues (84) used health care claims data to identify a cohort of 11,676 breast implant recipients in Alberta, Canada. On the basis of cancer registry data from the same province, the investigators calculated the expected number of breast cancer cases in the cohort and compared this value with the actual number of cases observed. expressing the comparison as the standardized incidence rate, a representation of the percentage of expected cases that have actually occurred. For the entire cohort, the standardized incidence rate was 48% (P < 0.01); in the subgroup of implant recipients with at least 10 years of available follow-up data, the calculated standardized incidence rate was reportedly 16% (no P value was provided). However, the implication that there is an inverse association between breast implants and breast cancer is unsupported for several reasons. Because both recipients of gel-filled implants and recipients of saline-filled implants were included in the cohort, the possible effect of gel-filled implants may have been masked. Furthermore, the study was susceptible to confounding by such factors as family and reproductive history. Of particular concern is that persons with a family history of breast cancer may have been less likely to receive cosmetic implants because of concern that the presence of an implant would interfere with mammographic screening in this high-risk group.

Another methodologic flaw of the study is that persons who moved from Alberta after receiving breast implants were not considered to be lost to follow-up, even though cancer cases in these women would not have been detected. In addition, the average duration of follow-up of 10.2 years (maximum, 18 years) was inadequate to address the possible long-term association between silicone breast implants and breast cancer. Finally, because 86% of the women in the study cohort were younger than 40 years of age, the study cannot exclude the possibility that a carcinogenic effect of breast implants will manifest in postmenopausal breast cancer.

A recent reanalysis of the Alberta Health Care data (85) used a more restrictive definition of breast implant recipients, took greater care to confirm person-years of follow-up, and considered several induction periods. This study concluded that the risk for breast cancer neither increased nor decreased significantly in women with breast implants regardless of whether an induction period of 0, 5, or 10 years was used for analysis (standardized incidence rates, 76% [CI, 55% to 102%]; 85% [CI, 58% to 119%]; and 68% (01, 32% to 125%], respectively).

Deapen and Brody (86) conducted a retrospective cohort study of 3112 implant recipients selected from the records of 35 plastic surgeons in Los Angeles County. The observed number of cases of breast cancer and of all other cancers combined was not significantly different from expected numbers based on ins Angeles County Cancer Registry incidence data (standardized incidence rare for breast cancer, 66% [CI, 41% to 301%]; standardized incidence rate for all other cancer 90% [CI, 66% to 120%])- However, a statistically significant increase in the incidence of cancers of the lung (standardized incidence rate, 212%; CI, 109% to 370%) and vulva (standardized incidence rate, 526%; CI, 171% to 1228%) were seen in the implant group compared with the general population. As in the study by Berkel and colleagues (84), the researchers did not control for potential confounder; such as family history of breast cancer and reproductive history. The study also did not address the potential long-term carcinogenicity of breast implants; the median duration of follow-up was only 10.6 years, and only 67 participants were followed for 20 or more years. In contrast to the Alberta study, however, women who moved out of the boundaries of the Los Angeles County Cancer Registry were classified as lost to follow-up. Finally, because only about one third of Los Angeles County plastic surgeons participated in the study, selection bias may have occurred. Although the investigators' finding of an increased risk for cancer of the lung and vulva in the breast implant group is of interest, the absolute number of cases (12 cases of lung cancer and 5 cases of cancer of the vulva) was relatively small. The value of this finding is also limited by the lack of information on potential confounders of the association between breast implants and these cancers. Examples of such confounders include 1) cigarette smoking for lung cancer and, to a lesser extent, cancer of the vulva and 2) human papilloma virus infection for cancer of the vulva (87).

The possible association between breast cancer and implants has also been examined in patients who received implants after mastectomy. Petit and colleagues (88) compared 146 women who had mastectomy and reconstruction with silicone implants with 146 women who had mastectomy alone. Women not exposed to silicone were matched, whenever possible, to women who had been exposed on the basis of age at diagnosis (within 10 years) and stage of primary tumor. After a median of 10 years of follow-up after reconstruction, the risk for death from any cause did not significantly differ between groups (relative risk, 0.6; CI, 0.3 to 1.1). However, the rates of death from breast cancer and of distant metastases in the exposed group were one half those in the unexposed group, a significant difference (relative risks, O.5 [CI, 0.3 to 1-0) and 0.5 [CI, 0.3 to 0.8). respectively). These results suggest that the use of silicone implants for reconstruction in women with a diagnosis of breast cancer is not associated with an increased risk for death or the development of second primary cancers.

Malone and colleagues (89) and Mclaughlin and coworkers (90, 91) have published, as letters to the editor, results of additional epidemiologic studies that did not find an association between breast implants and breast cancer. Although these findings are encouraging, analysis of these studies is hampered by the lack of detail provided in the brief reports.

Mammography is the primary method used for the early detection of breast cancer (92). As the population of women with breast implants ages, their risk for breast cancer and their need for regular screening increases. The presence of a silicone breast implant has been shown to interfere with complete imaging of the breast (9393). Displacement of the silicone implant posteriorly during mammography, a technique introduced by Eklund and colleagues in 1988 (96), has been shown to improve visualization of breast tissue over the standard compression technique. However, Silverstein and coworkers (97) compared postaugmentation mammoplasty films taken with both compression and displacement techniques with preaugmentation films in 62 breast implant recipients and found that, regardless of the technique used, much of the breast tissue was obscured by the implant. When the compression method was used, the presence of a breast implant resulted in a 35% decrease in the visible area compared with the visible area on preaugmentation films; when the displacement method was used, the visible area was decreased by 25%. The best images were obtained from women with submuscular implants and no substantial capsular contracture (97). Compression and displacement methods complement one another, because posterior breast tissue tends to be visualized best with Standard compression and anterior tissue can be seen best with the displacement technique (98).

Several reviews of case series of women who have had augmentation have received a diagnosis of breast cancer have been done (97, 99-103); most of these studies (97, 99, 102,103) concluded that mammography has reduced sensitivity for detecting palpable masses in women who have had augmentation. However, all of these retrospective studies included patients who received their diagnosis before the introduction of special views such as the displacement technique of Eklund and colleagues (96). There is disagreement as to whether the presence of implants delays the diagnosis in a clinically important manner, prospective data in women who have and have not received implants who are receiving equal screening are required to settle this issue.

Despite concerns about the sensitivity of mammography in implant recipients, the value of mammography is such that women who have received implants should be screened according to the same schedule recommended for women without implants (96). It has also been suggested that women older than 30 years of age considering augmentation mammoplasty have mammography before (100, 103) and after implantation (100). Current mammography screening guidelines stress that at least four views (two using the compression technique and two using the displacement technique) rather than the usual two views be done on all women who have had augmentation. Additional views may be required in patients in whom a rigid capsule has formed around the implant (92). The more intensive pre- and postoperative screening required for women who have had augmentation will result in higher radiation exposure over the long-term, an additional concern for women checking implants.

Another concern is the possibility of implant rupture during the compression procedure. Several cases of such occurrences have been reported. For example, Andersen and colleagues (15) describe one patient whose implant ruptured during mammography, and de Camara and coworkers (16) report that three women had severe pain during mammography that may have indicated implant rupture.

Although silicone breast implants have been used for cosmetic and reconstructive purposes for more than 30 years, several questions about the potential health risks of these devices remain unanswered. The epidemiologic research on breast implants to date has focused primarily on the potential for systemic complications, particularly cancer and connective tissue disease. The results of several large studies have shown no greatly increased short-term risk for defined, physician-diagnosed connective tissue diseases or breast cancer in association with silicone breast implants. Although these findings provide some reassurance, they do not settle the issue completely, because no study has had a sample size sufficient to compare the incidence rates of rare connective tissue or autoimmune disorders in women who have received implants with rates in the general population of women. Furthermore, because most studies have focused on well-defined connective tissue diseases, they cannot rule out the possibility of an elevated risk for one or more distinct, atypical connective tissue disease-like syndromes that do not meet the standardized diagnostic criteria used in most studies.

Although the literature on t he association between connective tissue diseases and cancer is increasing, no epidemiologic study has examined local complications of breast implantation (such as rupture, capsular contracture, and breast pain), even though these are undoubtedly the most common sequelae of breast implantation. Research to date, based primarily on case series, has been insufficient to accurately determine either the incidence rates of local complications of breast implants or the proportion of implant recipients for whom explantation will be required to treat these conditions. Published studies of implant failure have suggested a prevalence of failure ranging from 5% to 70%. The estimate of 5%, derived by Destouet and colleagues (23) from the study of a group of asymptomatic women having screening mammography, is probably an absolute minimum. At the opposite extreme, the estimate of Robinson and colleagues (24) suggests a rate of implant failure that exceeds 70% in both symptomatic and asymptomatic women. This study and others (16, 17) point to the importance of implant age as a determining factor in assessing the risk for rupture. The lack of reliable data on local complications is especially troubling, given that the frequency of these problems may more strongly affect the numbers of women affected and the attendant illnesses than do other more publicized and well-studied concerns, such as connective tissue diseases. It is hoped t hat several cohort studies currently in progress, although they focus primarily on cancer and connective tissue disorders, will also provide needed data on local effects and help to characterize the expected lifespan of these devices (104).

Because breast implants benefit many women, prospective recipients must have enough information on potential risks to decide whether the expected benefits of the procedure will outweigh thoses risks. Reports that rates of implant failure increase markedly with age may indicate that these devices have a limited overall life expectancy, a particularly important consideration for younger recipients. The current state of knowledge of the complications of silicone breast implants makes local effects a top priority on the research agenda. However, research is also needed to further address the potential for a long-term association between silicone implants and rare or atypical connective tissue disease syndromes or breast cancer and to explore the possibility that the presence of breast implants impedes the early detection of cancer.

Addendum. In a recent study, Hennekens and colleagues used data from the Harvard Women's Health Study to study the association between a history of silicone breast implants and self-reported history of connective tissue disease (JAMA. 1996; 276:616-21). Despite methodologic problems such as a low rated of response to the mailed survey questionnaire and the lack of medical record confirmation of events of interest, their finding of a relative risk for any connective tissue disease of 1.24 (CI, 1.08 to 1.41) is consistent with our conclusion that current research has tended to rule out large increases in risk for connective tissue disease caused by breast implants while not entirely excluding the possibility of such adverse events. The study did not address atypical syndromes or local effects.

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Acknowledgments: The authors thank Ruth B. Merkatz, PhD, RN, Louise A. Brinton, PhD, Sahar M. Dawisha, MD, Larry Kessler, ScD, and D. Bruce Burlington, MD, for their review of and comments on the manuscript.

Requests for Reprints: Barbara G. Silverman, MD, MPH, Center for Devices and Radiological Health, HFZ-541, U.S. Food and Drug Administration, 1350 Piccard Drive, Rockville, MD 20850.

Current Author Addresses: Drs. Silverman, Brown, Bright, and Kaczmarck: U.S. Food and Drug Administration, Center for Devices and Radiological Health, HFZ-541, U.S. Food and Drug Administration, 1350 Piccard Drive, Rockville, MD 20850. Dr. Arrowsmith-Lowe: Center for Biologics Evaluation and Research, HFM-380. U.S. Food and Drug Administration. 1401 Rockville Pike, Rockville, MD 20852-1448. Dr. Kessler: U.S. Food and Drug Administration, HF-1, 5600 Fishers Lane, Rockville, MD 20857.

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Message: 4

Abstract: Source: International Archives of Allergy & Immunology - 103(1):105-8,1994

Authors: Teuber, Gershwin

Institution: Division of Rheumatology, Allergy, and Clinical Immunology,University of Calif.,Davis

Tite:Autoantibodies and clinical rheumatic complaints in two children of women with silicone gel breast implants

Abstract:Considerable interest and efforts are directed at determining the extent to which silicone gel breast implants may contribute to the risk of developing autoimmune disease.There is also comparable interest in determining the extent to which silicone may alter the natural history of an established autoimmune disease.Recently, there has been concern over the possibility that children of women with silicone breast implants might somehow be adversely affected because of either trans-mammary or trans-placental delivery of silicone during either breast feeding or pregnancy. Herein, we describe two children of mothers with silicone breast implants, both female, aged approximately 3 and 9 years, both of whom had long-standing myalgias that were unexplained and did not fit current clinical criteria for juvenile arthritis.Both were found to have positive antinuclear antibodies. Additionally, the 9 year-old girl was found to have a significantly high titer of antibodies against denatured human type II collagen; indeed, her titer was six standard deviations above the mean for normal controls. There have been numerous previous studies which have documented an adverse impact of trace metals, chemicals and some medications on the morphologic and neurologic development of children exposed in utero. Much less information exists on potential toxicity experienced by a neonate through breast feeding, although examples of toxic transmission have been reported. In Western Europe, but not the US, women with silicone breast implants are advised not to breast feed.Further research should address these concerns and, in particular, women with silicone breast implants, with evidence of leakage or rupture, should refrain from breast feeding until further data are obtained.

[Non-text portions of this message have been removed]

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Message: 5

Abstract:

Authors: Shousha, Schoenfeld, Moss, Shore,Sinnett Institution: Department of Histopathology,Charing Cross Hospital,London,United Kingdom.

Title:Light and electron microscopic study of an invasive cribriform carcinoma with extensive microcalcification developing in a breast with silicone augmentation.

Source: Ultrastructural Pathology.18(5):519-23,1994 Sep.-Oct.

Although recent epidemiologic studies suggest that silicone augmentation of the breast is not associated with an increased risk of mammary carcinoma,cases of breast carcinoma arising in augmented breasts are being increasingly encountered as a large number of patients who had augmentation are getting older.A case of a 51-yr.-old woman with a 20-yr.history of breast augmentation who developed an invasive cribriform carcinoma associated with extensive microcalcification is presented.The patient had submammary silicone implants 20 yrs.ago that were replaced,because of local complications,in subpectoral postions 10 yrs.later.Dispersive X-ray microanalysis failed to demonstrate silicone in sections of the tumor and adjacent breast tissue.Appropriately fixed tumor tissue was available for electron microscopic examination.The tumor cells were rich in mitochondria,and their luminal surfaces were endowed with abundant microville,but the cell surfaces that came closest to the calcified microspheriols were devoid of microvilli and had cellular buddings between the microspheriols.It is suggested that the tumor cells might have been actively involved in the process of microcalcification.

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Message: 6

Authors: Haga, Haaland

Source: Tidsskr Nor Laegeforen - Norwegian Feb.28, 1992 112(6):763-4

Abstract: Connective tissue disease has been reported to occur following implantation of silicone gel-filled prostheses to augment the breast. In this case report and review of the literature, 2 patients are described in whom connective tissue disease developed within one and three years respectively after cosmetic surgery. One developed dermatomyositis with lung fibrosis, and the other developed cutaneous lupus and a Sjogren-like syndrome. Both suffered serious complications due to vasculitis. Although evidence of a causal relationship between the implantation and the development of connective tissue disease is circumstantial, removal of the silicone prosthesis has been reported to result in subsequent remission.

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Message: 7

Authors: Spiera,Gibofsky,Spiera. Hospital for Special Surgery Cornell Univ.Medical College

Source: J.Rheumatol Feb.1994 Vol.21 - Pgs.239-245

Abstract: Objective. To review the literature examining the association of silicone gel filled implants and connective tissue disease.

Methods: Computerized literature searches and manual review of bibliographies.

Results: Numerous concerns have arisen regarding the safety of silicone gel filled breast implants.The structure of these prostheses is reviewed.Silicones are not biologically inert.Injectable as well as implantable silicones have proven capable of eliciting inflammatory and fibroproliferative responses.Silicone leakage from silicone gel filled implants is well documented as is distant migration of silicone in the host.In the past decade,over 60 cases of connective tissue disease following mammoplasty with silicone gel filled implants have been reported. About half of these patients developed scleroderma or scleroderma-like illnesses. This reported overrepresentation of scleroderma compared to other rheumatic diseases mimics the Japanese experience with injectable silicones. Possible biological rationale for the association is presented.

Conclusion: The physical and biological properties of silicone gel filled implants and their behavior in vivo is compatible with the hypothesis that they may contribute to the development of connective tissue disease. The association seems most likely with scleroderma; however, there is yet inadequate epidemiological data to definitively establish causality.

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Abstract:

Authors:Schuh,Radford

Institution: Parkcrest Surgical Associates,St.Louis,Missouri Title: Desmoid tumor of the breast following augmentation mammaplasty. Source:Plastic & Reconstructive Surgery. 93(3):603-5,1994 Mar.

Fewer than 100 cases of desmoid tumor of the breast have been reported. We report the first recorded case of desmoid associated with silicone gel-filled implants.