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Pioneers of Breast Implant–Associated Anaplastic Large Cell Lymphoma: History from Case Report to Global Recognition

Miranda, Roberto N. MD; Medeiros, L. Jeffrey MD; Ferrufino-Schmidt, Maria C. MD; Keech, John A. Jr DO; Brody, Garry S. MD; de Jong, Daphne MD; Dogan, Ahmet MD; Clemens, Mark W. MD

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Plastic and Reconstructive Surgery: March 2019 - Volume 143 - Issue 3S - p 7S-14S
doi: 10.1097/PRS.0000000000005564
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Although relatively few physicians have ever encountered a case of breast implant–associated anaplastic large cell lymphoma (breast implant ALCL), the coverage of this uncommon malignancy in the literature, at national meetings, and in the news media may seem pervasive. Despite that breast implant ALCL has been recognized already 20 years ago, much of the U.S. medical community became aware of breast implant ALCL in January 2011 following a U.S. Food and Drug Administration (FDA) safety communication warning of the “possible association between breast implants and the development of anaplastic large cell lymphoma (ALCL).” This warning resulted from many years of research marked by various fortuitous observations. In this review of the early history of breast implant ALCL research, we summarize landmark studies that led to initial recognition and subsequent understanding of the disease and reintroduce, in their own words through a series of interviews, the researchers who first brought breast implant ALCL to world attention (Fig. 1).

Fig. 1.
Fig. 1.:
(Above, left) John Keech, DO, oncologist; (above, center) Ahmet Dogan, MD, pathologist; (above, right) Garry S. Brody, MD, plastic surgeon; (below, left) Daphne de Jong, MD, pathologist; (below, center) Roberto N. Miranda, MD, pathologist; and (below, right) L. Jeffrey Medeiros, pathologist.


In 1997, John Keech (Fig. 1, above, left), a medical oncologist in a community hospital, and the late Brevator Creech, a plastic surgeon, wrote a letter to this Journal, reporting an unusual finding in one of their patients with breast implants.1 A 41-year-old woman with a 6-year history of breast implants had a recurring mass in the right breast and associated with lymphadenopathy. A biopsy was obtained and diagnosed with anaplastic large cell lymphoma. The patient ultimately received chemotherapy and achieved complete remission.

John A. Keech, Jr, DO

The patient initially presented to Brev (Brevator Creech) because of mammary hypoplasia following a pregnancy and had a breast augmentation. Years later, the patient found some irregularity around one of the implants, a palpable mass, and a biopsy showed ALK negative anaplastic large cell lymphoma. This was a very unusual location for a lymphoma because it seemed to be related to the implant itself or the implant capsule and so we treated her as we would have treated a stage 1E non-Hodgkin lymphoma. We gave her cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) and radiation and she did well. We were very clear that it was not the breast tissue, but that this must somehow be related to the implant capsule. It was in the mid to late 90s, there was a flurry of excitement about silicone implants possibly causing autoimmune diseases. There were no data suggesting an increased risk of breast cancer, but we found 3 case reports of extranodal B-cell lymphoma occurring coincidentally around silicone implants. One night, Brev and I were having a beer and he said, “We should publish this, I think the case could get into the journal of Plastic and Reconstructive Surgery.” I would love to tell you that there was great science behind this discovery, but it actually happened over a beer. We just felt that this was so unusual that it should be recorded and so that is how the case got in the Journal. I did not appreciate the impact of what we reported until much later.


Over the next decade, sporadic case reports and small cases series were published regarding breast implants and ALCL.2–5 In 2008, Roden et al.6 from the Mayo Clinic reported 4 patients with breast implant ALCL presenting with only effusion; all underwent complete removal of the capsule and implant and achieved complete remission without the need for chemotherapy. In 2011, Poplewell et al.7 from the City of Hope reported 4 additional cases of breast implant ALCL. The combined number of cases made readers start to think these cases could be an entity.

Ahmet Dogan, MD

In the mid 2000s, we were working on trying to identify and characterize T-cell lymphomas. I (Fig. 1, above, center) was not aware of the previous case reports, and we had a new patient consultation with a very unusual morphology, with what we now recognize has all of the hallmarks of breast implant ALCL, and like everybody else before us, we thought this was an anaplastic lymphoma kinase (ALK)–negative peripheral ALCL. But the very next day, we had an in-house patient consultation with breast implants that showed the identical morphology. These 2 sequential cases were purely by chance. If the patients had been seen by 2 different people, they would not have noticed the connected features, but only by complete luck, it was seen by me. I was reminded of a very famous surgical pathologist, Dr. Juan Rosai, who taught me that “if you see two cases of an unusual morphology, you likely have just discovered a novel entity, but you will need many more cases to convince the rest of the world.”

I asked my fellow, Dr. Roden, to see whether we could find any other cases from our archives at the Mayo Clinic. We were able to put together this series that all showed identical morphology. We recognized the unique biology for the first time, and each one had identical characteristics and an indolent clinical course. From the start, we thought it was associated with the breast implant because of the unique morphology and relationship to the seroma. I had seen a lot of T-cell lymphomas, and yet I had never seen anything like this. I did not have any idea of the significance of what I was seeing at the time. I did not know anything about breast implants, about materials, and about surface textures. From our hematopathology group, I convinced everybody that this was real very easily. However, then came the many queries from industry, plastic surgeons, and plastic surgery societies, all asking “is this real?” I did not appreciate that this would lead to an FDA review and communication.

I think that the most critical aspect of breast implant ALCL is how the T cell sustains an uncontrolled proliferation which eventually turns out to be clonal. How do these cells initially expand? Some aspect of the physical interaction with the implant and the capsule leads to T-cell expansion which is very interesting to me. How is this signal delivered to the cell? It does not seem to be a proper antigen, and it is possibly dependent on the microenvironment cytokines. Second, what is the role of immune escape mechanisms perhaps created by the physical barrier of the scar capsule. There are unique lymphomas that only develop within a specific microenvironment, and perhaps that is happening here within the protected capsule space. These are fundamental questions that need to be answered.


In 2012, Brody8 (Fig. 1, above, right) reported his own experience as a surgeon for >40 years with patients with breast implants, and upon recognition of breast implant ALCL compounded with the experience of other surgeons in the United States. Brody8 included his observation that the appearance of breast implant ALCL coincided with texturing of the implant surface.

Garry Brody, MD

We had a group of plastic surgeons at the University of Southern California and my partner, Susan Downey, referred a patient to me with ALCL in an effusion around a textured breast implant, and that was the first case that we had. From nowhere I just had a hunch that the lymphoma was related to the textured implant. Within a couple of weeks, we had another case come to the University of Southern California. I began canvassing other plastic surgeons in the area and presenting at meetings. I began to get calls with more cases from colleagues referring patients because of my interest in this cancer. I had contacted all of the hospitals in Southern California looking for cases. The more I presented the findings, the more calls I would get with a case here and there. I then presented my early data at the California Society of Plastic Surgery. At first, I encountered a lot of skepticism when with some openly angered to the point of initially refusing to share their cases. I soon contacted the FDA whom I had worked with before and was given contacts to report to as things progressed. I also went to the World Health Organization in Lyon, France, to lobby for naming it as a distinct new disease entity.

In about 2010, when I had 4 cases, I approached the leadership at American Society of Plastic Surgeons, and they provided me with a generous grant for further study. At this point, I began to travel to medical centers around the world presenting the data and I was able to collect many new cases, with the most from Australia, New Zealand, United Kingdom, Brazil, and France. In 2016, I was awarded the Brown award by the American Association of Plastic Surgeons and the best article of 2015 by the Journal.


Already in 2008, de Jong et al.9 (Fig. 1, below, left) conducted a case–control study in the Netherlands that included 389 women with non-Hodgkin lymphoma in the breast over a 16-year span; 5 cases of ALCL were identified in patients with breast implants, and 6 other patients with ALCL lacked implants. For each of these 11 patients, the authors selected 1–5 controls with other lymphomas of the breast, matched for age and year of diagnosis. The calculated odds ratio was 18.2 (95% CI, 2.1–156.8) indicating that patients with breast ALCL were significantly more likely to have breast implants.9 De Jong et al.9 in 2008 estimated that the incidence of breast implant ALCL in the Netherlands was of approximately 1–3 per million per year. The same group repeated and extended the study 10 years later.10 Although the initial study was only based on 11 cases of breast ALCL of which 5 had implants, new risk estimates could be established using 43 breast ALCL of which 32 were implant carriers. Thereby, the odds ratio (relative risk) could be established at 421.8 (95% CI, 52.6–3,385.2), indicating an attributable risk. Since also a reliable estimate of breast implant carriers in the Netherlands could be made, an absolute risk could be determined at 29 cases per million at 50 years and 82 cases per million at 70 years. The number of women with implants needed to identify 1 breast implant ALCL case over a lifetime was 6,920.10

Daphne de Jong, MD

I first came across the disease in about 2002–2003, when my colleague sent me a complicated case of what we now know is a breast implant ALCL. The most amazing thing was that within 2 months, we had a second case, and so that really set us off. In the Netherlands, we have a national database of pathology specimens and diagnosis, and so searching for a very rare disease may be a lot of hard work, but is actually feasible in our country. We decided to mine the database, and we found more potential cases sufficient to perform an epidemiologic study together with our cancer epidemiology colleague Flora van Leeuwen, who has a research focus on the late effects of treatment for cancer. Back in 2008 for the first study, there were only 5 patients, and it is a miracle that we could actually derive reliable data from that set. With the updated study in 2018 published in JAMA Oncology on a much larger series of breast ALCL cases and appropriate controls, we could calculate a rather high relative risk, albeit that the absolute risk remains low. Now data are more convincing that there is indeed a direct correlation which may have consequences for the use of implants, but certainly has consequences for the way women together with their physicians may make decisions on choosing breast implants or not. To me, these studies are a prime example of the benefits of a multidisciplinary approach and could not have been successfully performed without this team all working together in a complementary manner.

In the future, I foresee that this disease may disappear. Once we have defined the mechanisms that cause breast ALCL and deciphered the role and specific features of implants, oncogenetic changes, and immunologic reactions, we may prevent breast ALCL, and the incidence may gradually decline. I do not know how many years this will take, though.


Talwalkar et al.11 reported on selected cases of breast lymphomas and noted that of 106 cases, 3 of the patients were ALCL. In a subsequent study, Miranda et al.12 (Fig. 1, below, center) focused on 6 patients with ALCL diagnosis in the breast; 3 of them were associated with breast implants.11

Roberto N. Miranda, MD

For me, this is a history of serendipity and luck. In 2007, I just moved to MD Anderson to work as a hematopathologist, and did not have an area of research, so I was open to being involved on any initiative to develop my academic career. Dr. L. Jeffrey Medeiros, Chairman of the Department of Hematopathology, asked me to help complete a article that reported 106 patients with lymphomas involving the breast.11 This was followed with deadlines to submit abstracts to our United States and Canadian Academy of Pathology annual meeting, and I decided to work on the ALCL cases of the previous series, a topic of interest to Dr. Medeiros. The abstract was rejected, but we pursued the publication of 6 patients with ALCL, 3 of whom had breast implants.12 Thanks to the reputation and expertise in the diagnosis of lymphomas of Dr. Medeiros and Dr. John T. Manning, Jr, in our department, we received more cases in consultation and reported our experience with 13 patients in 2012.13 While reviewing the charts, I found a letter from a patient sent to her clinical doctors stating that she presented with axillary and supraclavicular lymphadenopathy that recurred 3 times over 3 years, including once when she felt a mass next to her breast implant. She felt that the implant was causing the disease, but she felt her doctors disregarded her opinion and advised for more courses of chemotherapy. Finally, the patient went to a plastic surgeon and requested to have the implants and surrounding capsule removed. Her letter was dated 9 years after her surgery and stated her good health and “no implant, no cancer.” This letter impressed me so much and I wondered on what is known about therapy and management of this disease, so I did a focused review of the literature. I felt that the reports were more as a curiosity rather than as a clinical enigma, and I perceived there was no evidence-based medicine to manage this disease. Most of the reported cases focused on the pathologic diagnosis or described one of many therapeutic approaches. At that time, we decided to assess the long-term outcomes of patients by contacting corresponding authors of all published cases in the literature, and published our experience plus that of the researchers who contributed follow-up of their cases.14 We found that patients received a variety of management approaches: fine-needle aspiration, surgical drainage of the fluid, capsulectomy, implant replacement, complete resection, chemotherapy, radiation therapy, and stem cell transplant. Of great interest, we found that some patients who received surgery alone such as complete resection of the capsule and implant removal had 100% survival beyond 5 years after surgery, and at the same time, we demonstrated that not all patients with this disease require chemotherapy.14 Sometime in 2014, Dr. Mark Clemens, a plastic surgeon at MD Anderson, showed his keen interest in performing further studies with breast implant ALCL patients, and in collaboration with Dr. Kelly Hunt, a surgical oncologist also at MD Anderson, observed that the outcomes of breast implant ALCL reminded her of carcinoma in situ of the breast, an area of her expertise. The results of the retrospective evaluation of various therapeutic modalities demonstrated that complete resection of the capsule and implant removal are the cornerstones of therapy.15 This is a landmark study that provides a framework for clinical and pathologic assessment as well as for management of affected patients.

Where are we going now? Although the societies of plastic surgeons in United States, Europe, and Australia have shown an interest and awareness of breast implant ALCL, we believe that there are still cases that are undiagnosed, so more education is needed for physicians of various specialties such as surgeons, oncologists, radiologists, and pathologists.

L. Jeffrey Medeiros, MD

I (Fig. 1, below, right) saw my first case of breast implant ALCL in 1998. At the time, I was unaware of the case reported by Keech and Creech1 and I signed out this neoplasm as ALK-negative anaplastic large cell lymphoma. I essentially forgot about the case, but I was interested in breast lymphomas and put together a series of 106 cases from MD Anderson with an outstanding hematopathology fellow, Sameer Talwalkar. This series included 6 patients with ALCL involving the breast, of which 3 were associated with breast implants. When I read the series of 4 cases of breast implant ALCL from the Mayo Clinic, I finally started to see the possibility that breast implant ALCL was a true disease entity. As mentioned above, Dr. Miranda had joined our department and I asked him to help complete the article on breast lymphomas by Talwalkar et al.11 Dr. Miranda became very interested in the topic, as he stated above.

I remember attending a RAND Corporation meeting on breast implants and lymphoma in Arlington, Virginia. Garry Brody gave a nice talk on the subject at the meeting. I was impressed by the reluctance of some members of the audience to accept the idea. There were multiple types of reluctance. The surgeons in the audience were reluctant to accept the concept that breast implants had any risk whatsoever. As one surgeon told me, breast implants were “bread and butter” clinical practice and he could not imagine implants could be causing harm. Others in the audience had a difficult time reconciling the name “anaplastic large cell lymphoma,” which they knew to be an aggressive disease, with the apparent indolent clinical behavior. A third form of reluctance was shown by attendees with a very scientific perspective who said there was no evidence and that this could be coincidence. However, when I showed images of the 2 cases I brought, in which the tumor was closely related to the implants, the minds of these colleagues began to change.

When Dr. Miranda told me his plan to contact all of the authors of cases in the literature, I must admit that I was pessimistic, as I thought it unlikely everyone would be so cooperative, but I underestimated Dr. Miranda’s commitment to understanding this disease. It has been my pleasure to watch him make connections with many investigators around the world and put together excellent studies on this topic. I am grateful to be playing a small part in the overall effort.

In more recent times, there has been an exponential increase in the number of case reports of textured breast implants and ALCL throughout the world.16,17 Feldman et al.18 coauthored the 2017 release of the World Health Organization classification of lymphomas and acknowledged that breast implant ALCL is a provisional entity, providing a reference for wider recognition of this lymphoma. The U.S. FDA released a statement on March 21, 201819 reporting 414 cases of breast implant ALCL as of September 30, 2017. The report also states that the lifetime risk for breast implant ALCL is between 1 in 3,817 and 1 in 30,000 women with textured breast implants.19 As of September 2018, 582 cases of breast implant ALCL across 29 countries worldwide have been reported.17,20–23 Although our understanding of the disease continuous to grow, all this work would not be possible without the determination and drive of a few researchers over the last 2 decades who refused to accept dogma about breast implants, and dared to ask difficult questions for the safety of our patients. The series of seminal events in the understanding of breast implant ALCL is displayed in Table 1. A timeline of landmark studies on breast implant ALCL is displayed in Table 2.1,6,9–11,13–15,18,21,24–31

Table 1.
Table 1.:
Seminal Events in the Understanding of Breast Implant–Associated Anaplastic Large Cell Lymphoma
Table 2.
Table 2.:
Timeline of Landmark Studies on Breast Implant–Associated Anaplastic Large Cell Lymphoma


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24. Carty MJ, Pribaz JJ, Antin JH, et al.A patient death attributable to implant-related primary anaplastic large cell lymphoma of the breast. Plast Reconstr Surg. 2011;128:112e–118e.
25. Lechner MG, Megiel C, Church CH, et al.Survival signals and targets for therapy in breast implant-associated ALK–anaplastic large cell lymphoma. Clin Cancer Res. 2012;18:4549–4559.
26. Adrada BE, Miranda RN, Rauch GM, et al.Breast implant-associated anaplastic large cell lymphoma: sensitivity, specificity, and findings of imaging studies in 44 patients. Breast Cancer Res Treat. 2014;147:1–14.
27. Hu H, Johani K, Almatroudi A, et al.Bacterial biofilm infection detected in breast implant-associated anaplastic large-cell lymphoma. Plast Reconstr Surg. 2016;137:1659–1669.
28. Wang SS, Deapen D, Voutsinas J, et al.Breast implants and anaplastic large cell lymphomas among females in the California Teachers Study cohort. Br J Haematol. 2016;174:480–483.
29. Doren EL, Miranda RN, Selber JC, et al.U.S. epidemiology of breast implant-associated anaplastic large cell lymphoma. Plast Reconstr Surg. 2017;139:1042–1050.
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