Anaplastic Large Cell Lymphoma and Breast Implants: A Systematic Review ACCEPTED

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1 Plastic and Reconstructive Surgery Advance Online Article Doi: /PRS.0b013e Anaplastic Large Cell Lymphoma and Breast Implants: A Systematic Review Benjamin Kim, M.D., M.Phil. 1,2,4 Carol Roth, R.N., M.P.H. 1 Kevin C. Chung, M.D., M.S. 6 V. Leroy Young, M.D., F.A.C.S. 5 Kristin van Busum, M.P.A. 3 Christopher Schnyer, M.P.P. 3 Soeren Mattke, M.D., D.Sc RAND Health, RAND Corporation, Santa Monica, CA 2. Pardee RAND Graduate School, RAND Corporation, Santa Monica, CA 3. RAND Health, RAND Corporation, Boston, MA 4. Division of Hematology-Oncology, Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA 5. Body Aesthetic Research Center, St. Louis, MO 6. Section of Plastic Surgery, Department of Surgery, University of Michigan Health System, Ann Arbor, MI Running title: Anaplastic Large Cell Lymphoma and Breast Implants Key Words: Lymphoma, Large-Cell, Anaplastic; Breast Implants/Adverse Effects; Review Support for this study was provided by the Plastic Surgery Educational Foundation (PSEF) and the Aesthetic Surgery Education and Research Foundation (ASERF) through unrestricted grants from Allergan, L.L.C.; Mentor Worldwide, L.L.C.; and Sientra, Inc. Neither the study sponsors nor the listed companies had roles in the design or eecution of this study. Soeren Mattke, the primary author, is an employee of RAND Corporation. As a work-made-forhire institution, RAND owns all copyright to its employees' works. Authors cannot legally transfer copyright as they do not own the copyright. Copyright is retained by RAND Corporation. FD: "ne of the authors have a financial interest in any of the products, devices, or drugs mentioned in this manuscript Word Count: Abstract = 235, Article = 3067 Corresponding Author: Soeren Mattke, M.D., D.Sc. RAND Corporation 20 Park Plaza #720 Boston MA Phone: Fa: mattke@rand.org

2 Abstract: Background In recent years, there have been growing concerns about a possible association of non- Hodgkin s lymphoma (NHL) in particular, anaplastic large cell lymphoma (ALCL) and breast implants. The purpose of this study was to identify and analyze all reported cases of NHL occurring in patients with breast implants. Methods We conducted a systematic literature review of reported cases of NHL in patients with breast implants. Publications were identified with a search algorithm, forward searches, and epert nominations. After references were reviewed and assessed for inclusion or eclusion, case-based data were independently abstracted, reconciled, and adjudicated by multiple investigators. The data were then synthesized and analyzed. Results Of 884 identified articles, only 83 were relevant to NHL involving the breast and 34 were included in our study. Thirty-si cases of NHL in patients with implants were found, of which 29 (81%) were ALCLs. Although detailed clinical information was lacking in many cases, ALCL oftentimes involved the capsule and/or presented as an uneplained seroma or mass, was negative for Anaplastic Lymphoma Kinase (ALK) epression, and had a relatively indolent clinical course when it developed adjacent to a breast implant. Conclusions A form of ALCL, which clinically behaves more like the less-aggressive cutaneous form of ALK-negative ALCL rather than the more-aggressive systemic form, may be associated with breast implants. Future research on the epidemiology and biology of this rare disease is clearly needed to better understand its nature.

3 Introduction Since Duvic et al. published a case series in 1995 of 3 women with breast implants who developed cutaneous T-cell lymphoma, 1 there have been growing concerns that implants are associated with the development of primary non-hodgkin s lymphoma (NHL), most notably anaplastic large cell lymphoma (ALCL), of the breast. ALCL is a rare disease, comprising 2% of all newly-diagnosed NHLs worldwide 2 and 0.9% 3 of the estimated 65,540 cases of NHL diagnosed in the U.S. in Lymphomas of the breast are etremely rare, comprising % of all breast cancers and approimately 1-2% of all etranodal lymphomas. 4-6 Despite the rarity of both ALCL and primary breast lymphomas, multiple cases of ALCL developing adjacent to breast implants have been reported, including by Brody et al., who have recently presented but not yet published a series of 34 cases. 7 Whether or not a small but positive association between breast implants and ALCL development eists is of interest to women, plastic surgeons, implant manufacturers, federal regulatory agencies, and the public because the number of women with breast implants is large. In 2009 alone, a reported 289,328 breast augmentation, 86,424 reconstruction, and 87,386 lift procedures were performed in the U.S.; 8 unfortunately, the eact number of women who received implants is not known because only some breast reconstructions and lift procedures utilized implants. To date, no population-based estimate of the incidence of ALCL in women with breast implants in the U.S. has been reported; however, de Jong et al. have published an epidemiologic study of ALCL in women with breast implants in the Netherlands. 9 They identified 11 women with breast ALCL, of whom 5 had implants at the time of diagnosis, in their country s comprehensive lymphoma database from 1990 to Based on an estimate of 100, ,000 Dutch women with breast implants, the authors calculated an ALCL incidence of 0.1-

4 0.3 per 100,000 women with implants per year. 9 Net, they matched the breast ALCL cases with controls diagnosed with other breast NHLs and determined that the odds ratio for a woman with implanted breasts to develop ALCL was 18.2 (95% confidence interval: ). 9 other hand, several large, epidemiologic cohort studies of rth American and European women with breast implants have not shown an increased overall risk of NHL development (Table 1). Pooled analysis of these studies included over 43,000 women with breast implants On the with a mean follow-up of years revealed 48 observed NHL cases, none of which were primary breast lymphomas. 10 Based on these numbers, a standardized incidence ratio of 0.89 (95% confidence interval: ) was calculated, suggesting no increased overall risk of NHL development among women with implants. 10 Epidemiologic studies can support or refute the eistence of associations between potential etiologic factors and disease development; however, they are not designed to test hypotheses and determine causative relationships, which are the aims of laboratory eperiments and clinical registries and trials. Because breast ALCL in women with implants occurs infrequently and the evidence on the eistence and strength of the association between breast implants and ALCL development is inconclusive, we set out to perform a systematic literature review of ALCL and other NHL cases occurring in women with breast implants as an initial step to assess the current, published knowledge of this disease. Methods Search Strategy We conducted a literature search of the PubMed, Embase, Web of Science (Science Journals & Proceedings) databases to identify all citations relating to breast implants and ALCL or other NHLs. For PubMed and Embase, we searched references from 1966; for Web of Science, we searched from 1980; and for Web of Science Proceedings, we search from 1990 through July For PubMed, we used the following search term strategy: (Lymphoma, T-

5 Cell OR lymphoma*[tiab]) AND (breast implants/adverse effects OR silicone gels/adverse effects OR silicones/adverse effects) OR breast AND (implant or implants or prosthes* or endoprosthes*)) AND lymphoma*. For Embase, we used: (breast AND endoprosthesis/ep) OR (breast AND implant*) OR (breast* AND silicon*) AND t cell lymphoma OR lymphoma* NOT coronary stent. Finally, for Web of Science, we used: Topic=(breast AND lymphoma* AND (implant* OR prosthes* OR endoprosthes* OR silicon*)). We also conducted forward searches on 2 articles Duvic et al. 1 and de Jong et al. 9 using Web of Science. Research (categorized as epidemiologic studies or scientific papers) and non-research (case reports or case series) articles from peer-reviewed journals, conference abstracts, and unpublished manuscripts were retrieved from the literature search. Only human-based topics and articles written in English were considered. Of the initial 884 titles, 83 articles discussed ALCL and breast implants. Fourteen additional articles were provided by 2 epert plastic surgeons (V.L.Y. and K.C.C.). Article Selection & Case Abstraction Two clinician researchers (B.K. and C.R.) independently reviewed all selected references for study inclusion or eclusion, which was determined by whether or not articles reported a minimum level of information age, gender, presence of breast implant, and type of lymphoma on cases of ALCL or other NHLs occurring in patients with breast implants. Net, the reviewers recorded all available case-based data in an abstraction tool independently and compared and reconciled their data, with unresolved differences adjudicated by a third researcher (S.M.). Finally, a detailed, summative table was created containing frequencies, means, and ranges for each abstracted variable, as applicable. This study was reviewed and considered eempt by the Human Subjects Protection Committee/Institutional Review Board at RAND.

6 Results Literature Search From the literature search, 884 titles were initially identified, of which 83 were selected for review and 14 supplied by clinical eperts (Figure 1). Articles were ecluded for several reasons, including written in a language other than English (n=2), duplicate article (n=1) or data (n=4), insufficient clinical information (n=4), or not containing a case of ALCL or other NHL in a patient with breast implants (n=62). The total number of articles included in the analysis was 34, 1, 9, which included 36 cases of ALCL and other NHLs involving the breast: 29 (81%) were ALCL, 2 (5%) were follicular lymphoma, was lymphoplasmacytic lymphoma, 2 (5%) were mycosis fungoides, and 2 (5%) were Sézary syndrome (Table 2) (See Table A, Supplemental Digital Content 1, which shows a Detailed summary of ALCL and other NHL cases in patients with breast implants, INSERT LINK HERE) (See Table B, Supplemental Digital Content 2, which shows Individual cases of ALCL and other NHL in patients with breast implants, INSERT LINK HERE). Patient Characteristics Characteristics of the patients, information on their past medical history, and data on their implant types are summarized in Table 2. Because data elements were frequently not reported in articles and because of small numbers of cases in each group, statistical comparisons between women with implants who were diagnosed with ALCL versus other NHLs were not made. More detailed information is provided in Tables A and B in the Supplemental Digital Content online (INSERT LINK 1 HERE, INSERT LINK 2 HERE).

7 Case Presentation Fourteen (48%) of 29 ALCL cases were noted to have presented with a seroma, ALCL case did not present as a seroma and data was not reported in the remaining 14 (48%) ALCL cases. Eleven (79%) of these 14 ALCL cases that presented as seromas showed positive cytology findings in the aspirated fluid. data about presence or absence of seroma was reported in the 7 non-alcl cases. Seven (24%) of the 29 ALCL cases reported data indicating that the patient had a palpable breast mass on presentation, 5 (17%) reported absence of a mass and information was missing for the remaining 17 (59%) ALCL cases. In 9 of 29 (31%) ALCL cases, a mass was documented at the time of surgery, no mass was found in 5 (17%) ALCL cases and data were not reported for the remaining 15 (52%) patients. Sizes of the masses were reported for 6 ALCL cases, with a mean size of 3.5 cm (range 1-10). Among non-alcl patients, 1 case was reported to have presented with a breast mass and no such information was available for the other 6 (86%) non-alcl cases. Less frequently cited symptoms among ALCL cases were pain [6/29 (21%); no pain in 2/29 (7%), not reported in 21/29 (72%)], redness [4/29 (14%), [not reported in 25/29 (86%)], and capsule contracture [2/29 (7%), not reported in 27/29 (93%)]. Among non-alcl patients, pain and contracture were rare, but redness was reported for 4 (57%) of 7 cases [not reported in 3/7 (43%) non-alcl cases]. Other symptoms (e.g., skin lesions, fever) were reported in only of 29 ALCL cases but in 5 (71%) of 7 patients with other NHLs [not reported in 27/29 (93%) ALCL and 2/7 (29%) non- ALCL cases]. Duration of symptoms was rarely noted. In the 7 cases where it was, mean duration in years for ALCL cases was 0.8 (range ). Mean symptom duration among 5 non-alcl cases for which it was reported was 5.4 years (range ).

8 Surgery Very little data were available about whether or not the affected or contralateral implants were known or thought to be ruptured prior to or during surgery, with only 14 (39%) out of all 36 cases addressing this. Four affected implants were reported as ruptured prior to surgery: 2 (18%) out of the 11 ALCL cases and 2 (67%) out of the 3 non-alcl cases for whom data was available. In 20 (95%) of the 21 cases of ALCL, the affected implant was removed, and in 1 (5%) case, it was left in place [not reported in 8/29 (28%) ALCL cases]. Among the 6 other NHL cases with data, the affected implant was removed in 5 (83%) and left in place in 1 (17%) [not reported in 1/7 (14%) non-alcl cases]. In 22 (76%) and 24 (83%) of the 29 ALCL cases, no data about whether implant echange or reconstruction, respectively, was undertaken after the diagnosis was made was reported; in reported cases, however, there were no details about the types of replacement implants used (e.g., size, surface, type, manufacturer/model). Pathology Most reports of ALCL [21/29 (72%)] did not indicate whether or not the capsule was associated with inflammation. In 20 (69%) out of 23 ALCL cases with data, ALCL was associated with the capsule on histologic eamination [not reported in 6/29 (21%) ALCL cases]. Other NHLs were noted as being associated with the capsule in 2 (50%) out of 7 cases with data [not reported in 3/7 (43%) other NHL cases]. Results of immunohistochemical staining for Anaplastic Lymphoma Kinase (ALK) were reported for 25 (86%) of the 29 cases of ALCL, and all were ALK-negative (ALK-). Staging information at diagnosis was provided for 26 (90%) of the 29 ALCL cases. Twenty-one (72%) ALCL cases were stage IE, defined as NHL that only affects an organ or site other than the lymph nodes (defined as etranodal; breast, in this case) but has not spread to other organs or lymph nodes, 4 (14%) were stage IIE, defined as NHL that involves the breast and one or more lymph node groups on the same side of the diaphragm,

9 and only 1 case (3%) was stage IVE, defined as NHL that involves the breast, at least one other etranodal organ (such as the liver, bone marrow, or lungs), and lymph nodes on both sides of the diaphragm. In contrast, 6 (86%) of the 7 non-alcl cases were stage IV, defined as NHL that does not involve the breast but does involve at least one other etranodal organ and lymph nodes on both sides of the diaphragm) at diagnosis. Cancer Treatment & Outcomes Information about radiation treatment was not reported for 45% (13/29) of ALCL cases and 12 the 16 cases with data (75%) received radiation therapy. Information about chemotherapy was not reported for 41% (12/29) of ALCL cases and 13 of the 17 cases (76%) with data received chemotherapy. Eleven (85%) of 13 patients were treated with cyclophosphamide, hydroydaunorubicin, vincristine, and prednisone (CHOP); 1 (8%) with CHOP and ifosfamide, carboplatin, and etoposide (ICE); and 1 (8%) patient s regimen was not specified. Only 16 (55%) out of the 29 cases of ALCL included information about patient followup and outcomes. Mean duration of reported follow-up in years was 2.1 (range 0.1-9). Four (57%) out of the 7 non-alcl cases had follow-up data with a mean duration of 5.5 years (range ). Of the 16 ALCL cases with follow-up data, 12 (75%) had no recurrence, 1 (6%) had a recurrence, and 3 (19%) did not have information regarding recurrence. Among 4 non-alcl cases, 1 (25%) had a recurrence, 2 (50%) had no recurrence, and 1 (25%) did not have information regarding recurrence. All 16 ALCL patients with follow-up data were reported to be alive at the time of last contact, and 3 (75%) of the 4 non-alcl patients were reported to be alive.

10 Discussion Until now, ALCL has been thought to manifest as two different clinical entities systemic ALCL, in which lymphadenopathy and frequent etranodal involvement (including of the skin) is present; and primary cutaneous ALCL (PCALCL), in which the disease is limited to the skin. 32 Although the histopathology of ALCL is not uniform, both types epress CD30, a tumor necrosis factor receptor and tumor marker found in Hodgkin s lymphoma and some ALCLs; however, ALK, a tyrosine kinase receptor, is epressed in 60-85% of systemic ALCLs but rarely in PCALCLs Chromosomal rearrangements involving the ALK gene, which underlie the epression of the protein in ALK-positive (ALK+) ALCL, lead to constitutive activation of an ALK fusion protein and contribute to the pathogenesis of ALK+ ALCL The pathogenesis of ALK- ALCL, on the other hand, is not well-understood. Most patients diagnosed with ALK+ ALCL are under the age of 30 and are male (male/female ratio: 6.5:1), 37 whereas systemic ALK- ALCL commonly occurs in older individuals, with a median age at diagnosis of 58 years. 38 ALK+ ALCL has a significantly better prognosis than systemic ALK- ALCL, with a 5-year overall survival rate of 70% versus 49%, respectively, when treated with systemic chemotherapy such as CHOP. 39 PCALCL has been categorized under the new WHO/EORTC classification system as a CD30+ cutaneous lymphoproliferative disorder, 40 a term that represents the spectrum of CD30+ skin lesions from benign lymphomatous papulosis (LyP) to borderline cases to malignant PCALCL (Figure 2). Although PCALCL is a malignant condition, the disease oftentimes follows an indolent course, with disease-specific survival rates at 5 and 10 years of 85% or better 41 and spontaneous regression in rare cases. 42 Our systematic literature review has yielded 36 cases of non-hodgkin s lymphoma (NHL) occurring in women with breasts implants, with 29 (80.6%) of the NHLs being ALCLs. All of the women who had breast implants and developed ALCL in our literature review had ALK- disease,

11 when ALK status was reported. In addition, most of the women for whom data were reported had ALCL localized in the capsule a fibrous layer of tissue that forms around the implant after surgery and/or a seroma pocket of fluid surrounding the implant but contained within the fibrous capsule (Figure 3). Although follow-up information on these women was not always included and the time interval varied from case to case, no women for whom vital status was reported died from her ALK- ALCL in spite being treated with a variety of different treatments including surgical removal of the affected implant, chemotherapy, radiation therapy, and observation. This is a somewhat surprising finding given the usual poor prognosis of etranodal ALK- ALCL cases. Some authors have therefore suggested that breast ALCL cases associated with a seroma or effusion around an implant have clinical courses more akin to PCALCL than systemic ALK- ALCL 21 and should be regarded as a distinct clinicopathologic entity. 43 There are several limitations to our study. First, because there may have been limited knowledge among plastic surgeons, pathologists, and oncologists in the past of implantassociated ALCL manifesting as an uneplained seroma or mass, some patients with the disease may not have been diagnosed. Second, there may have been inconsistencies in how individual hematopathologists interpreted pathology slides for each case because ALK- ALCL is immunophenotypically heterogeneous, 44 potentially leading to over- or under-diagnosis of ALCL compared to what would have occurred if central pathologic review had been available. In addition, not all cases of ALCL that develop adjacent to breast implants are reported to the manufacturers or in the literature, skewing estimates of its true incidence downward. Finally, there may have been additional ALCL cases in patients with breast implants that were not indentified or included in this study; however, based on our review of bibliographies and forward searches of references in articles included in our study, the number of cases we missed is likely to be very small or zero. It is important to note that this systematic literature review is not an epidemiologic study and is insufficient to accurately assess the incidence of ALCL in patients with breast implants or the total number of women at risk of this disease.

12 As an initial step to understand the risk factors, etiology, clinical management, and prognosis of this disease, we have performed a systematic literature review of ALCL and other NHLs occurring in patients with breast implants, which has revealed limited reporting on many data elements of interest. Although detailed clinical information is oftentimes lacking in case reports or series, ALCL that develops adjacent to a breast implant seems to involve the capsule and/or present as an uneplained seroma or mass, be ALK-, and have a relatively indolent course. This suggests that implant-associated ALCL is more similar to cutaneous ALCL than systemic ALCL and may therefore only require surgical removal of the affected implant and capsule and clinical follow-up, as opposed to aggressive adjuvant chemotherapy and/or radiation therapy. Ultimately, understanding the biology, treatment and prognosis of implant-associated ALCL will require substantial research efforts, such as in vitro eperiments using immortalized implant-associated ALCL cell lines, collection of detailed clinical information in breast implant registries, and well-designed epidemiologic studies. But developing and eecuting such a research agenda will take time, and women and their surgeons are looking for immediate guidance. To provide such guidance against a background of very limited evidence, we used a structured epert consultation process known as the RAND/UCLA Appropriateness Method 45 to integrate the available information with epert opinion. Since the 1980s, this method has been used across the world to take on many comple topics in health care, such as organ transplantation and carotid endarterectomy. 49 In October 2010, we brought together leading eperts from the fields of biomaterials, immunology, pathology, hematology/oncology, and epidemiology to critically evaluate and weigh in on specific questions regarding implantassociated ALCL. This systematic literature review informed the panelists and provided the backdrop to their discussion, the results of which will be reported in a forthcoming article.

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17 lymphoma, not otherwise specified: report from the International Peripheral T-Cell Lymphoma Project. Blood 2008;111: Willemze R, Jaffe ES, Burg G, et al. WHO-EORTC classification for cutaneous lymphomas. Blood 2005;105: Liu HL, Hoppe RT, Kohler S, Harvell JD, Reddy S, Kim YH. CD30+ cutaneous lymphoproliferative disorders: the Stanford eperience in lymphomatoid papulosis and primary cutaneous anaplastic large cell lymphoma. J Am Acad Dermatol 2003;49: Beljaards RC, Kaudewitz P, Berti E, et al. Primary cutaneous CD30-positive large cell lymphoma: definition of a new type of cutaneous lymphoma with a favorable prognosis. A European Multicenter Study of 47 patients. Cancer 1993;71: Thompson PA, Lade S, Webster H, Ryan G, Prince HM. Effusion-associated anaplastic large cell lymphoma of the breast: time for it to be defined as a distinct clinicopathological entity. Haematologica 2010;95: Medeiros LJ, Elenitoba-Johnson KS. Anaplastic Large Cell Lymphoma. Am J Clin Pathol 2007;127: Fitch K, Bernstein SJ, Aguilar MS, Burnand B, LaCalle JR. The RAND/UCLA Appropriateness Method User's Manual. Santa Monica, CA: RAND Corporation; Santori G, Fontana I, Valente R, Ghirelli R, Valente U. Application of the RAND/UCLA Appropriateness Method to evaluate an information system for kidney/pancreas transplantation in adult recipients. Transplant Proc 2008;40: Santori G, Andorno E, Valente R, Ghirelli R, Valente U. Application of the RAND/UCLA appropriateness method to evaluate an informative system for liver transplantation in adult and pediatric recipients. Transplant Proc 2007;39: Santori G, Valente R, Cambiaso F, Ghirelli R, Gianelli Castiglione A, Valente U. Preliminary results of an epert-opinion elicitation process to prioritize an informative

18 system funded by Italian Ministry of Health for cadaveric donor management, organ allocation, and transplantation activity. Transplant Proc 2004;36: Shekelle PG, Chassin MR, Park RE. Assessing the predictive validity of the RAND/UCLA appropriateness method criteria for performing carotid endarterectomy. Int J Technol Assess Health Care 1998;14:

19 Figures and Tables Legend Table 1. Epidemiologic cohort studies of women with breast implants and NHL Figure 1. Literature flow diagram for ALCL and other NHL cases Table 2. Characteristics of ALCL and other NHL cases Figure 2. ALCL and CD30+ cutaneous lymphoproliferative disorders, along with ALK status. Key: ALCL = Anaplastic Large Cell Lymphoma; PCALCL = Primary Cutaneous ALCL; LyP = Lymphomatoid Papulosis Figure 3. ALCL involving fibrous capsule and seroma surrounding breast implant. Thompson PA, Lade S, Webster H, et al. Effusion-associated anaplastic large cell lymphoma of the breast: time for it to be defined as a distinct clinico-pathological entity. Reprinted with permission from Haematologica. 2010;95: Online Supplemental Digital Content Supplemental Digital Content 1- Table A Detailed summary of ALCL and other NHL cases in patients with breast implants Supplemental Digital Content 2- Table B Individual cases of ALCL and other NHL in patients with breast implants

20 Key for Figures, Tables, and Online Supplemental Digital Content Titles: NHL = n-hodgkin s Lymphoma, ALCL = Anaplastic Large Cell Lymphoma, ALK = Anaplastic Lymphoma Kinase

21 Table 1. Epidemiologic cohort studies of women with breast implants and NHL 10 Reference Lipworth et al., 2009 (1) 50 Location Denmark, Sweden Study Period Deapen et Los Angeles al., Brisson et al., Ontario, Quebec 15.5 ( ) Pukkala et Finland al., Brinton et al., Lipworth et al., 2009 (2) Ontario, Implant 15.4 Quebec patients: SIR, (up to 24) 0.75 ( ); comparison group: SIR, 0.78 ( ); RR,* 0.97 ( ) 8.3 (up to 29) SIR, 3.7 ( ) Georgia, Alabama, rth Carolina, Florida, Washington, D.C. rth America, rthern Europe Study Population Pooled analysis of 3486 Swedish and 2736 Danish women with breast implants from 1965 to 1993; Swedish and Danish reference populations 3139 Caucasian women with breast implants from 1953 to 1980; general population rates 24,558 women with breast implants; 15,893 women with other cosmetic procedures at same practices; general population rates 2171 women with breast implants; Finnish reference population 7447 women with breast implants before 1989; 2203 women with other cosmetic procedures at same practices Pooled analysis of 43,537 women with breast implants from above studies Mean Follow-Up (Range) (yrs.) Estimated Relative Risk (95% CI) 16.6 ( ) SIR, 1.22 ( ); none of the 9 cases were primary breast NHLs SIR, 1.29 ( ) 12.9 Implant patients: SIR, 0.81 ( ); comparison group: SIR, 0.90 ( ); RR,* 0.55 (NS ) Range of 0.89 (0.67- mean followup: ) years Number of Observed Cases ; ; 4 48 Key: CI = Confidence Interval; SIR = Standardized Incidence Ratio; RR = Relative Risk; NS = t Stated. *Relative risk estimated from internal comparison with other cosmetic procedure patients. Confidence interval not presented in article but upper bound stated to include 1.0. Adapted from Lipworth L, Tarone RE, McLaughlin JK. Breast implants and lymphoma risk: a review of the epidemiologic evidence through Plast Reconstr Surg 2009;123:790-3.

22 Table 2. Characteristics of ALCL and other NHL cases ALCL (n=29) Other NHL (n=7) Age at diagnosis: Mean years (range) 50.5 (28-87) 46.9 (35-56) Years having any implant: Mean years (range) (n=9) 11.7 (1-23) (n=2) 10.5 (7-14) Prior cancer (non-t-cell lymphoma): 8=breast, affected 1=breast, contralateral 1=breast, side unknown 1=breast, contralateral and Hodgkin s lymphoma 1=Hodgkin s lymphoma t reported 12 (41%) 16 (55%) 6 (86%) Time between first prior cancer and breast diagnosis: Mean years (range) (n=10) 14.7 (7-32) (n=1) 9 Prior T-cell lymphoma: 1=cutaneous ALCL 1=systemic ALCL 1=Mycosis Fungoides t reported 27 (93%) 6 (86%) Time between T-cell lymphoma and breast diagnosis: Mean years (range) (n=2) 1.8 (1-2.5) (n=1) 4 Affected breast: Left Right Bilateral t reported 12 (41%) 16 (55%) Placement of implant: Subglandular Subpectoral t reported 27 (93%) 6 (86%) Years having implant: Mean years (range) (n=27) 6.9 (0.2-19) (n=7) 10.6 (0.3-22) Surface: Smooth Tetured t reported 6 (21%) 23 (79%) 6 (86%) Covering: Silicone Polyurethane, foam Polyurethane, not specified t reported 5 (17%) 23 (79%) 3 (43%) Type of implant: Saline Silicone t reported 16 (55%) 11 (38%) 6 (86%) Manufacturer/model: Dow-Corning McGhan (1=Style 168; 4=unspecified) Meme, Surgitek, Bristol-Meyers-Squibb Nagor (1=SFX-HP250; 1=R) Replicon Rolfil PIP Hydrogel t reported 4 (14%) 22 (76%) Key: ALCL = Anaplastic Large Cell Lymphoma (including 1 ALCL/Primary Effusion Lymphoma); NHL = n-hodgkin s Lymphoma (including 2 Follicular Lymphomas, 1 Lymphoplasmacytic Lymphoma, 2 Sézary Syndromes, and 2 Mycosis Fungoides)

23 Online Supplemental Digital Content Age at diagnosis: Mean years (range) ALCL* (n=29) 50.5 (28-87) Other TCL (n=7) 46.9 (35-56) FL (n=2) 49.5 (43-56) LPL (n=1) MF (n=2) (35-53) SS (n=2) 43 (38-48) Total (n=36) 49.8 (28-87) > 65 3 (8%) 6 (16%) 3 (8%) 3 (8%) 3 (8%) 3 (8%) 4 (14%) 1 (100%) 2 (6%) 3 (8%) 4 (11%) 7 (19%) 4 (11%) 5 (14%) 4 (11%) 3 (8%) 4 (11%) Gender: Female 29 (100%) 7 (100%) 1 36 (100%) (100%) Race: White t reported 4 (14%) 25 (86%) NR NR NR NR NR 4 (11%) 32 (89%) BMI: t reported NR NR NR NR NR NR Current/previ ous smoker: 28 (97%) NR NR NR NR NR 35 (97%) t reported Prior implant: t reported 7 (24%) 22 (76%) NR NR NR NR NR 7 (19%) 29 (81%) Prior implant size: NA NA NA NA NA t reported NR Prior implant surface: Tetured t reported Prior implant polyurethane covering: t reported Prior implant type: (n=9 implants in 7 pts.) 1 (11%) 8 (89%) NR (n=9 implants NA NA NA NA NA NA NA NA NA NA (n=9 implants in 7 pts.) 1 (11%) 8 (89%) (n=9 implants

24 Saline Silicone Double-lumen silicone t reported Prior implant manufacturer : t reported Years having any implant: Mean years (range) Prior cancer (non-t-cell lymphoma): 8=bre ast, affected in 7 pts.) 1 (11%) 2 (22%) 1 (11%) 5 (56%) NA NA NA NA NA NR NA NA NA NA NA (n=9) 11.7 (1-23) 12 (41%) (n=2) 10.5 (7-14) 10.5 (7-14) NR NR NR in 7 pts.) 1 (11%) 2 (22%) 1 (11%) 5 (56%) (n=11) 11.5 (1-23) 13 (36%) 1=bre ast, contralateral 1=bre ast, side unknown 1=bre ast, contralateral and Hodgkin s disease 1=Hod gkin s disease t reported 16 (55%) 6 (86%) NR NR NR 22 (61%) Time between (n=10) (n=1) (n=1) (n=11) first prior cancer and NA NA NA 14.1 breast (7-32) (7-32) diagnosis: Mean years (range) Prior (n=12) (n=1) (n=1) (n=13) radiation: 2 (17%) 1 (100%) 1 (100%) 3 (23%) 2 (17%) 2 (15%) 8 (67%) NA NA NA 8 (62%) t reported Prior (n=12) (n=1) (n=1) (n=13) chemotherap 7 (58%) 7 (54%) y: 2 (17%) 1 (100%) 1 (100%) 3 (23%) 3 (25%) NA NA NA 3 (23%) t reported Implant (n=7) (n=1) (n=1) (n=8)

25 timing to therapy: After Before Prior T-cell lymphoma: 1=cuta neous ALCL 1=syst emic ALCL 1=MF t reported Time between T-cell lymphoma and breast diagnosis: Mean years (range) Affected breast: Left Right Bilateral t reported Placement of implant: Subglandular Subpectoral t reported Years having implant: Mean years (range) 5 (71%) 27 (93%) (n=2) 1.8 (1-2.5) 12 (41%) 16 (55%) 27 (93%) (n=27) 6.9 (0.2-19) 1 (100%) 1 (100%) 6 (86%) NR NR (n=1) 4 NA NA 6 (86%) (n=7) 10.6 (0.3-22) NR NA NA NA 6 (75%) 2 (25%) (n=1) 4 NA NR NR NR 10 (6-14) ( ) 1.8 ( ) 3 (8%) 33 (92%) (n=3) 2.5 (1-4) 14 (39%) 17 (47%) 3 (8%) 2 (6%) 3 (8%) 33 (92%) (n=34) 8.1 (0.2-22) < > (37%) 10 (37%) 3 (11%) NR 3 (9%) 11 (32%) 11 (32%) 4 (12%) 5 (15%) Reason for initial implant: Cosmetic 16 (55%) 10 (34%) 3 (10%) 3 (43%) 3 (43%) NR 19 (53%) 11 (31%) 6 (17%) Mastectomy t reported Mastectomy reconstructio n: Immediate (n=10) 2 (20%) 4 (40%) 4 (40%) (n=1) 1 (100%) (n=1) 1 (100%) NA NA NA (n=11) 2 (18%) 5 (45%) 4 (36%) Delayed t reported Reconstructi (n=6) (n=7)

26 on epander used:, type unspecified t reported Size of affected implant: Mean cc (range) Surface: Smooth Tetured t reported Covering: Silicone Polyurethane, foam Polyurethane, not specified t reported Type of implant: Saline Silicone t reported Manufacturer/ model: Dow-Corning McGhan (1=Style 168; 4=unspecified) Meme, Surgitek, Bristol- Meyers- Squibb Nagor (1=SFX- HP250; 1=R) Replicon Rolfil PIP Hydrogel t reported # surgical revisions to affected breast: Mean number (range) t reported Recent breast trauma: t reported 1 (17%) 5 (83%) NR NR NA NA NA (n=3) 483 ( ) 6 (21%) 23 (79%) 5 (17%) 23 (79%) 16 (55%) 11 (38%) 4 (14%) 22 (76%) NR NR NR NR NR 6 (86%) 3 (43%) 6 (86%) NR NR NR NR 1 (100%) NR (n=7) 1.7 (1-3) 22 NR NR NR NR NR 6 (86%) (n=3) 483 ( ) 7 (19%) 29 (81%) 2 (6%) 6 (17%) 2 (6%) 26 (72%) 16 (44%) 17 (47%) 3 (8%) 2 (6%) 5 (14%) 2 (6%) 1 (6%) 1 (6%) 24 (67%) 28 (97%) NR NR NR NR NR (n=7) 1.7 (1-3) (97%)

27 Pain: t reported Swelling: t reported Redness: t reported Capsular contraction: (1=II; 1=IV; 1=unspecified) t reported Palpable mass: t reported Other: : - Erythematous lesion(s)/ulcer -Scaling of palms and soles -Urticaria, efoliative erythroderma -Recurrent low-grade fever - Subcutaneous nodules t reported Duration of symptoms: Mean years (range) Antibiotics: t reported Aspiration: t reported Affected 6 (21%) 21 (72%) 5 (71%) NR 14 (48%) 15 (52%) NR NR NR NR NR 4 (14%) 25 (86%) 27 (93%) 7 (24%) 5 (17%) 17 (59%) 2 (6%) (94%) (n=7) 0.8 ( ) 4 (57%) 3 (43%) NR NR 6 (86%) 6 (86%) 5 (71%) NR (n=5) 5.4 (0.5-17) NR NR NR NR NR NR 1 (100%) NR 17 3 (2-4) 1.9 ( ) 27 (93%) NR NR NR NR NR 8 (22%) 2 (6%) 26 (72%) 14 (39%) 22 (61%) 8 (22%) 28 (78%) 3 (9%) 33 (91%) 8 (22%) 5 (14%) 23 (64%) 7 (19%) 12 (41%) 17 (59%) NR NR NR NR NR 29 (81%) (n=12) 2.7 (0.2-17) 2 (6%) 34 (94%) 12 (33%) 24 (67%)

28 implant echanged: t reported Contralateral implant echanged: /t applicable t reported Affected implant ruptured before surgery: t reported Contralateral implant ruptured before surgery: /t applicable t reported Affected implant ruptured during surgery: /t applicable t reported Contralateral implant ruptured during surgery: /t applicable t reported Surgical removal of affected implant: t reported Surgical 5 (17%) 22 (76%) NR NR NR NR NR 25 (86%) NR NR NR NR NR 9 (31%) 18 (62%) 6 (21%) 23 (79%) 12 (41%) 17 (59%) 8 (28%) 21(72%) 4 (57%) NR 1 (100%) 5 (71%) NR NR 4 (57%) 3 (43%) NR 1 (100%) 5 (71%) NR NR 5 (14%) 2 (6%) 29 (81%) 2 (6%) 2 (6%) 32 (89%) 4 (11%) 10 (28%) 22 (61%) 8 (22%) 28 (78%) 20 (69%) 8 (28%) 5 (71%) 1 (100%) 16 (44%) 20 (56%) 10 (28%) 26 (72%) 25 (69%) 2 (6%) 9 (38%)

29 removal of contralateral implant:, concurrent, sequential, not specified /t applicable t reported Capsulectom y: t reported Mass: t reported Size of mass: Mean cm (range) Cancer associated with capsule: t applicable t reported Capsule inflammation: t applicable t reported Seroma: t reported Positive cytology from aspirated fluid: t reported Stage: I II III IV t reported 3 (10%) 2 (6%) 22 (76%) 21 (72%) 3 (10%) 5 (17%) 5 (71%) 1 (100%) 3 (43%) 3 (43%) NR NR 9 (31%) 5 (17%) 15 (52%) NR NR NR NR NR (n=6) 3.5 (1-10) NA NA NA NA NA 20 (69%) 3 (10%) 6 (21%) 5 (17%) 3 (10%) 21(72%) 3 (43%) NR 3 (43%) NR 1 (100%) 1 (100%) 14 (48%) 14 (48%) NR NR NR NR NR (n=14) 11 (79%) 1 (7%) 2 (14%) NA NA NA NA NA 8 (22%) 3 (9%) 23 (64%) 24 (67%) 4 (11%) 8 (22%) 9 (25%) 5 (14%) 22 (61%) (n=6) 3.5 (1-10) 22 (61%) 5 (14%) 9 (25%) 21 (72%) 4 (14%) 3 (10%) 6 (86%) 1 (100%) 7 (19%) 5 (14%) 24 (67%) 14 (39%) 21 (58%) (n=14) 11 (79%) 1 (7%) 2 (14%) 22 (61%) 4 (11%) 7 (19%) 3 (8%) ALK status: Negative 25 (86%) 25 (86%)

30 Positive t reported 4 (14%) NA NA NA NA NA 4 (14%) Radiation: t reported 12 (41%) 4 (14%) 13 (45%) 3 (43%) NR 14 (39%) 6 (17%) 16 (44%) Chemotherap y/other: : 11=C HOP 1=CH OP + ICE 1=t specified Other: 13 (45%) 4 (14%) 12 (41%) 4 (57%) NR 13 (36%) 2 (6%) 5 (14%) 16 (44%) Photo phoresis and interferon PUVA and interferon t reported Reconstructi on:, LDF with epander of 4 (14%) 24 (83%) NR NR NR NR NR 4 (11%) 31 (86%) unknown type t reported Reimplantatio n: 2 (6%) 3 (10%) 24 (83%) NR NR NR NR NR 2 (6%) 3 (8%) 31 (86%) t reported Size of new implant: NR NA NA NA NA NA Mean cc (range) Surface: t reported NR NA NA NA NA NA Type: Saline Silicone t reported (n=2) NA NA NA NA NA (n=2) Manufacturer/ model: NR NA NA NA NA NA t reported Follow-up reported: Duration of follow-up: Mean years 16 (55%) 13 (45%) (n=13) 2.1 (0.1-9) 4 (57%) 3 (43%) NR NR (n=3) 5.5 (1.1-12) NA NA (n=1) 3.3 (n=2) 6.6 (1.1-12) 20 (56%) 16 (44%) (n=16) 2.7 (0.1-12)

31 (range) Recurrence (n=16) (n=4) (n=2) (n=2) of disease: 1 (6%) 1 (25%) NA NA 12 (75%) 2 (50%) 3 19%) 1 (25%) t reported Vital status: (n=16) (n=4) (n=2) (n=2) Alive 16 (100%) 3 (75%) NA NA Dead 1 (25%) Table A. Detailed summary of ALCL and other NHL cases in patients with breast implants, Supplemental Digital Content 1 Key: NR = t Reported; NA = t Applicable; ALCL = Anaplastic Large Cell Lymphoma; TCL = T-Cell Lymphoma; MF = Mycosis Fungoides; FL = Follicular Lymphoma; PEL = Primary Effusion Lymphoma; LPL = Lymphoplasmacytic Lymphoma; SS = Sézary Syndrome; * = 1 case of ALCL/PEL; BMI = Body Mass Inde; CHOP = Cyclophosphamide, Hydroydaunorubicin, Oncovin, Prednisone; ICE = Ifosfamide, Carboplatin, Etoposide; PUVA = Psoralen and UltraViolet A; LDF = Latissimus Dorsi Flap (n=20) 2 (10%) 14 (70%) 4 (20%) (n=20) 19 (95%) 1 (5%)

32 Online Supplemental Digital Content Table B. Individual cases of ALCL and other NHL in patients with breast implants, Supplemental Digital Content 2 Key: F = Female; R = Right; L = Left; NR = t Reported; NA = t Applicable; ALCL = Anaplastic Large Cell Lymphoma; FL = Follicular Lymphoma; LPL = Lymphoplasmacytic Lymphoma; SS = Sézary Syndrome; MF = Mycosis Fungoides

33 Figure 1

34 Figure 2

35 Figure 3