Breast implants and a rare cancer: Did the FDA go far enough?

Breast implants have been the subject of controversy since they were first developed in the 1960s, with the controversy reaching a head in the late 1980s and early 1990s, when thousands of women with silicone implants reported a variety of ailments, including autoimmune disease and a variety of other systemic illnesses. These reports led to a rash of lawsuits and, ultimately, the banning of silicone breast implants for general use for breast augmentation in 1992. After that, silicone breast implants were only permitted in women requiring breast reconstruction or women enrolled in clinical trials studying breast implants. This ban was partially lifted in 2006, as evidence accumulated that the claims of autoimmune diseases and increased cancer risk due to silicone breast implants were not supported by clinical and scientific evidence and two products made by Allergan Corp. (formerly Inamed Corp.) and Mentor Corp. Not surprisingly, given that the furor over silicone breast implants as a cause of autoimmune and other systemic diseases is based on about as much solid scientific evidence as the antivaccine furor over vaccines as a cause of the "autism epidemic," there was widespread criticism of this decision. Even now, it is not difficult to find articles about breast implants with titles like Breast Implants: America's Silent Epidemic and websites like the Humantics Foundation and Toxic Breast Implants . I do note, however, that the number of such sites and articles does appear to be declining and, at least to my impression, seems to have decreased markedly over the last 10 years or so.

Having reviewed the literature and found evidence for a link between silicone breast implants and the systemic diseases attributed to them to be incredibly weak at best, I had little problem with the FDA's decision. Actually, the only thing I had a problem with at the time, my opinions of how breast implants interfere with breast cancer detection and treatment notwithstanding, is that the FDA was probably being more cautious than the evidence warranted.

Could it be that Orac was actually wrong about something?

I ask this question because last week there was a widely reported story about a warning that the FDA issued regarding breast implants. Indeed, on Wednesday, our press people were circulating copies of the advisory and asking if any of us were available to comment to the press before the evening news deadlines. Unfortunately (or fortunately, depending on your point of view), I was holed up for our NCI site visit rehearsal and thus in essence unavailable. So it was that the national media missed its opportunity to hear me opine my wisdom on the matter to a breathlessly waiting nation. Talk about dodging a proverbial bullet (our nation, that is). Be that as it may, this FDA advisory led to stories in the media like this one by ABC News, FDA Reports Link Between Breast Implants and a Rare Cancer:

The FDA advisory states:

After an intensive review of known cases of a rare form of cancer in breast implant recipients, the Food and Drug Administration says women with implants may have a very small, but increased risk of developing anaplastic large cell lymphoma, or ALCL.

FDA scientists reached that conclusion after examining scientific literature that focused on cases of ALCL in 34 women with breast implants, as well as information from agency reports, international regulatory agencies, scientific experts, and breast implant manufacturers.

But with an estimated five to 10 million breast implant recipients worldwide, agency experts say the known ALCL cases are too few to say conclusively that breast implants cause the disease. FDA believes there are about 60 of these ALCL cases worldwide, though that number is difficult to verify because not all of them were chronicled in scientific publications and some reports may have been duplicated.

This is the sort of epidemiological question that drives physicians and scientists crazy. The reason is quite simple. ALCL is a rare type of non-Hodgkin's lymphoma (NHL). Indeed, it is classified as a "rare disease," which for purposes of U.S. policy is defined as affecting less than 200,000 Americans. In actuality, ALCL affects far fewer Americans than that. According to the Surveillance, Epidemiology, and End Results (SEER) Program of the National Cancer Institute (NCI), approximately 1 in 500,000 women is diagnosed with ALCL in the the U.S. every year. ALCL of the breast is even more rare, with 3 in 100 million women per year being diagnosed with the disease. Not surprisingly, that means it's incredibly hard to get enough patient numbers to make firm conclusions regarding whether the risk of ALCL is truly higher in women with breast implants, and the FDA report, Anaplastic Large Cell Lymphoma (ALCL) In Women with Breast Implants: Preliminary FDA Findings and Analyses, reflects this uncertainty.

Reading the FDA's report, I was struck by how little there evidence is one way or the other because of the relative rarity of the disease. Basically, the evidence portion of the FDA report concentrates on case studies and the three existing studies that tried to determine whether there is an association between breast implants and ALCL. Given that the report strikes me as being pretty accessible to the lay person, I recommend reading it, because it reveals a careful sifting of the thin gruel of evidence and how the FDA came to its decision to issue this warning. I'll try to summarize its 21 pages for you and give you my take on the studies used to justify the warning, but go to the full report for details.

The FDA performed a review of the scientific literature. This included a search of PubMed, Embase, Web of Science, Cambridge Scientific Abstracts (CSA), EBSCO, and BIOSIS for published papers and abstracts about ALCL and breast implants. After duplicates were accounted for, the FDA found that the entire world scientific literature has reports of 34 women with breast implants who were diagnosed with ALCL of the breast. As pointed out above, the number might be as high as 60, as is described in the report:

In a thorough review of scientific literature published from January 1997 through May 2010, the FDA identified 34 unique cases of ALCL in women with breast implants throughout the world. The FDA's adverse event reporting systems also contain 17 reports of ALCL in women with breast implants. Additional cases have been identified through the FDA's contact with other regulatory authorities, scientific experts, and breast implant manufacturers. In total, the FDA is aware of approximately 60 case reports of ALCL in women with breast implants worldwide. The exact number is difficult to verify because reports from regulatory agencies and scientific experts often duplicate those found in the scientific literature.

It's estimated that there are between 5 and 10 million women in the world with breast implants. Given these numbers, the number of women with breast implants who have developed ALCL of the breast is higher than would be expected from SEER data alone. Moreover, another thread of association that is concerning derives from the spatial pattern noticed in these case reports:

Of the 34 cases, the median time from breast implant placement to ALCL diagnosis was 8 years, with a range from 1 year to 23 years. Most patients were diagnosed when they sought medical treatment for implant-related symptoms such as persistent seromas, capsular contractures, or peri-implant masses warranting breast implant revision operations. In each case, lymphoma cells were found in the effusion fluid (seroma) surrounding the implant, in the fibrous capsule, or within a peri-implant mass. Typically, there was no invasion beyond the fibrous capsule into the breast parenchyma.

It should also be noted that it couldn't be determined whether there was a higher risk of ALCL that could be attributed to silicone versus saline implants, as twenty-four had silicone implants, seven had saline, and the type of implants was unknown. Similarly, there didn't appear to be a correlation between the indication for implant placement and the risk of ALCL. Of the 34 cases, eleven patients had their implants placed for breast reconstruction, nineteen patients received implants for breast augmentation, and in four cases no reason for placement of the implants was reported.

Unfortunately, these case reports are not particularly illuminating.

Given that, perhaps the epidemiology will be more revealing. Except that it isn't. There are only three studies cited looking at whether there is an association between the presence of breast implants and ALCL of the breast. There were no prospective cohort studies. Indeed, all three studies were in essence retrospective studies. Of these, only one of them was designed to look specifically at a correlation between breast implants and ALCL of the breast, rather than observations of non-Hodgkin's lymphoma and other cancers in women with breast implants. This study (de Jong et al, 2008) is an individually matched case-control study that mined a nationwide population cancer database from the Netherlands. Since 1971, all reports on cytological and pathological diagnoses generated by every pathology department in the Netherlands have been stored in a central database (PALGA, Pathologisch Anatomisch Landelijk Geautomatiseerd Archief).

Going to show that lymphoma of the breast is a rare entity, between 1990 and 2006, only 429 cases of histologically proven lymphoma of the breast were found, and, of the 389 women eleven had a diagnosis of ALCL. Using these cases as the basis, de Jong et al performed an individually matched case-control study thusly:

Subsequently, we performed an individually matched case-control study, nested in the same cohort of 389 female patients. For each case patient with ALCL in the breast, we attempted to select 3 to 7 controls with other lymphomas in the breast, matched on age at diagnosis (±5 years) and year of diagnosis (±2 years). For all 47 potential controls, we obtained pathology reports. Furthermore, for all cases and controls, we sent a standardized questionnaire to the treating physician to obtain information on medical history, including previous malignancies, staging results, and presence of a breast prosthesis, including mammography results.

Conditional logistic regression analysis was performed to estimate the odds ratio (OR) of ALCL associated with breast prosthesis, using EGRET for Windows, 1999 (CYTEL Inc, Cambridge, Massachusetts).21â The OR was used as a valid risk estimate of relative risk and is therefore referred to as such. An estimate for absolute risk was made based on breast prosthesis sales figures for 1999 to extrapolate the number of women with breast prostheses.

Based on this analysis, de Jong et al estimated the odds ratio of ALCL associated with breast implants to be 18.2 (95% CI 2.1-156.8). What this means is that the odds of having a breast implant were 18.2 times higher in ALCL patients than in the control lymphoma patients. Personally, I have a few problems with this analysis. First, the matching was done on only two criteria, age and year of diagnosis.Although there was no statistically significant difference in age between the groups, there's no way of knowing if there were any confounding factors that were associated with ALCL of the breast. The numbers are just too small. Consequently, it's hard to say much about this series except that it is suggestive that there is an elevated risk of ALCL due to breast implants. As the authors themselves say:

Although an 18-fold increased odds for the development of a specific lymphoma in the breast may cause significant concern among women with breast prostheses, it should be realized that the absolute risk remains very low due to the exceedingly rare occurrence of ALCL in the population (estimated incidence at all sites 0.1/100,000 per year).

Which is about one in a million. Even if the estimate made by de Jong et al is accurate, that would put the risk at around 18 in a million.

As for the other two studies, they're not exactly studies. One (Brinton et al) is a systematic review of the literature looking for evidence of an association between breast implants and cancers at other sites. Brinton et al concluded that breast lymphomas in women with breast implants tend to be associated with the periprosthetic capsule, or in proximity to the implant. Moreover, in the general population, breast lymphomas tend to be a rare entity and most are of B-cell origin. In contrast, breast lymphomas in women with implants tend to be of T-cell origin. The second, Lipworth et al, examined five long term studies of women with breast implants including 43,000 women to assess the risk of lymphoma in these women. This review actually found that there was a slightly decreased risk of lymphoma in women with breast implants, but, as the FDA report noted, it had a at least two weaknesses. First, all the studies began following women more than 35 years before the study, and the entity of ALCL was not defined pathologically until 1985. Second, the number of women studied was inadequate to rule out a rare relationship between breast implants and ALCL.

As you can see, the evidence for a link between ALCL and breast implants is fairly sparse. Of the evidence, de Jong et al is probably the most suggestive, but even it is relatively weak, at least based on numbers alone. However, another piece of evidence comes from the characteristics of implant-associated lymphomas. More suggestive is the observation that such lymphomas were either found by the aspiration of lymphoma cells in the fluid surrounding the implant (it's not uncommon for implants to have a fluid collection surrounding them) or in the connective tissue capsule that develops around many breast implants. Add this to the seeming statistical association between breast implants and ALCL, and there might just be something there. It's not possible to conclude with any degree of certainty that there is such a risk right now; there are simply too few cases and ALCL is too rare, both in the general population and in women with breast implants.

Despite the controversy over the years over breast implants, particularly silicone breast implants, there has been no convincing evidence of a link between systemic diseases, such as autoimmune diseases or cancer. Indeed, since the 1990s, there have been at least a dozen comprehensive systematic reviews looking at a potential link between silicone breast implants and systemic diseases (conveniently listed at Wikipedia), none of which have found convincing evidence for a link. In 2006, Brinton et al found an increased risk of death from lung cancer and suicide in women with implants, but these risks were attributed to increased smoking and psychiatric disorders in women who have implants placed.

This report from the FDA suggests that there might be an increased risk of a rare cancer in women with breast implants, but the numbers are so low that it's difficult to conclude anything with much certainty, which is why the FDA concludes:

1. There is a possible association between breast implants and ALCL.
2. At this time, it is not possible to identify a specific type of implant associated with a lower or higher risk of ALCL.
3. There is uncertainty about the true cause of ALCL in women with breast implants.

Adding:

Based on available information, it is not possible to confirm with statistical certainty that breast implants cause ALCL. Because ALCL is so rare, even in breast implant patients, a definitive study would need to collect data on hundreds of thousands of women for more than 10 years. Even then, causality may not be conclusively established.

These are reasonable conclusions based on the current state of the evidence, which is inconclusive at best, weak at worst. Given the high degree of uncertainty, what the FDA has done is not entirely unreasonable, although one could argue that it's a tad alarmist. Basically, the FDA wants clinicians to consider ALCL in women with implants who have persistent seromas (fluid collections) around their implants, recommending that seroma fluid be sent for cytological analysis to rule out lymphoma. In addition, the FDA recommends that any confirmed cases of ALCL associated with implants be reported and is establishing a registry in collaboration with the American Society of Plastic Surgeons to track cases of implant-associated lymphoma. Even this might not be able to detect or confirm a link between implants and ALCL, given the rarity of the disease, but it is a start.

Even accepting the most pessimistic assumption, namely that there really is a significantly elevated risk of ALCL in women with breast implants due to the implants, which has been suggested but not by any means established, this risk, if it exists, should be put into perspective. For example, it should also be noted that, based on what we know, in women who choose implants for reconstruction after breast cancer surgery, the risk of recurrence of their breast cancer is orders of magnitude greater than any theoretical risk of ALCL due to implants. Indeed, in women who have never had cancer and choose implants for breast augmentation, the risk of developing breast cancer is also orders of magnitude higher than of developing ALCL. There is no evidence that implants increase the risk of breast cancer or breast cancer recurrence after breast cancer surgery.

In fact, the most significant risk due to breast implants is not the risk of systemic diseases, such as autoimmune diseases or cancer. Far more significant is the rate of local complications, such as capsular contracture or implant rupture. Due to such complications, many women with implants require reoperation. Indeed, reoperation rates have been estimated to be as low as 3% after seven years to as high as 20% over three years. These are by far the most significant risks due to breast implants.

I have observed in the past that the controversy over the safety of silicone breast implants is a lot like the manufactroversy regarding vaccines in that no amount of evidence will sway those who have become convinced that implants are responsible for a wide variety of autoimmune and other systemic diseases. On the other hand, I must concede that the local complications due to rupture or scarring can in some cases be quite disfiguring and debilitating. this newly reported association between implants and ALCL doesn't really change that assessment, given how tiny the risk is, even at its worst assessment. Surprisingly, I haven't seen anything on NaturalNews.com or Mercola.com about the FDA report yet. Maybe the report won't be used as the basis for another campaign of fear mongering.

Naaaaah. It's just a matter of time.