Special Topic Breast Implant–Associated Anaplastic Large Cell Lymphoma: A Systematic Review Courtney A. Gidengil, M.D., M.P.H. Zachary Predmore, B.A. Soeren Mattke, M.D., D.Sc. Kristin van Busum, M.P.A Benjamin Kim, M.D., M.Phil. Boston, Mass.; and San Francisco, Calif.
Background: There is substantial evidence that a type of anaplastic large cell lymphoma (ALCL) is associated with breast implants. However, the course in patients with breast implants seems to be unusually benign compared with other systemic ALCL. The purpose of this study was to identify and analyze recently published cases of breast implant–associated ALCL, with an emphasis on diagnosis, staging, treatment, and outcomes. Methods: The authors conducted a systematic literature review of reported cases of ALCL in patients with breast implants. Publications were identified with a search algorithm and forward searches. Case-based data were abstracted independently and reconciled by multiple investigators. Results: Of 248 identified articles, only 102 were relevant to breast implant– associated ALCL, and 27 were included in this study. Fifty-four cases of ALCL in patients with breast implants were identified. Detailed clinical information was lacking in many cases. Most presented with a seroma (76 percent), and approximately half were associated with the capsule (48 percent). Most presented as stage IE (61 percent). All but one case were ALK-negative. Most received chemotherapy (57 percent) and radiation therapy (48 percent), and 11 percent received stem cell transplants. Approximately one-quarter recurred, and 9 percent died. Conclusions: Since the publication of guidance related to breast implant–associated ALCL in 2010, a number of cases have been reported. Despite the typically benign course, many of the cases have been treated with radiation therapy and/or chemotherapy. Increasing awareness of this disease entity among clinicians would be helpful, along with standardizing an approach to diagnosis, staging, and treatment. (Plast. Reconstr. Surg. 135: 713, 2015.) CLINICAL QUESTION/LEVEL OF EVIDENCE: Risk, V.
C
oncern over the association of breast implants and anaplastic large cell lymphoma (ALCL) has been growing since the publication of a case series of three women with breast implants and cutaneous T-cell lymphoma in 1995.1 Since then, a number of case reports and case series, along with an extensive systematic literature review2 and report of a structured expert panel,3 have strengthened the evidence for this association. However, this form of ALCL appears to have a more benign course than systemic ALCL, behaving more like a primary cutaneous form of ALK-negative ALCL. In fact, the lymphoma often From RAND Health, RAND Corporation; the Division of Infectious Diseases, Boston Children’s Hospital; and the Division of Hematology-Oncology, University of California, San Francisco. Received for publication June 17, 2014; accepted September 26, 2014. Copyright © 2014 by the American Society of Plastic Surgeons DOI: 10.1097/PRS.0000000000001037
regresses after removal of the implant and capsule, without any systemic treatment.2,3 Despite calls for nonaggressive treatment, including guidance from the U.S. Food and Drug Administration, women may still be receiving aggressive therapy for this disease. ALCL is a rare Disclosure: Support for this study was provided by unrestricted grants from Allergan, Inc. The study sponsor had no role in the design of execution of this study. The authors have no other commercial associations or financial disclosures. Supplemental digital content is available for this article. Direct URL citations appear in the text; simply type the URL address into any Web browser to access this content. Clickable links to the material are provided in the HTML text of this article on the Journal’s Web site (www. PRSJournal.com).
www.PRSJournal.com
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Plastic and Reconstructive Surgery • March 2015 disease, constituting only 2 percent of all newly diagnosed non-Hodgkin lymphomas worldwide.4 Lymphomas in the breast are even more rare, accounting for only 1 to 2 percent of all extranodal lymphomas and 0.04 to 0.5 percent of all breast cancers.5–7 Thus, the vast majority of plastic surgeons and oncologists are unlikely to have ever encountered this relatively rare entity. As a result, there have been a number of anecdotal reports of women receiving chemotherapy and radiation therapy for what may well be an indolent disease. Lack of familiarity is one barrier to treating this disease appropriately, but another factor is the scant literature available on ALCL in breast implants. The largest systematic review on this topic identified only 29 cases of breast implant– associated ALCL and only six population-based epidemiologic studies.2 Since that review, we have identified another four epidemiologic studies,8–10 none of which identified any cases of ALCL in large populations of women with breast implants (Table 1).8–11 Given the infrequency of this disease, the lack of cases in population-based studies is not altogether surprising. Fortunately, a number of case reports and case series have been published since our last systematic review. Systematically reviewing these additional cases would help to deepen the understanding of this uncommon disease entity and provide richer background information for clinicians that are faced with this disease. The goal of our study was to review the recent literature for cases of ALCL in women with breast implants to better identify risk factors, course, management, and outcomes associated with this disease entity.
PATIENTS AND METHODS Search Strategy We conducted a search of the PubMed, Embase, Web of Science (including Science Citation Index
and Conference Proceedings Citation Index), and SCOPUS (Health Sciences and Physical Sciences) databases to identify all cases of breast implant– associated ALCL reported since our last systematic review. The search start date was June 6, 2010, because that was the end date of our last search.2 The end date for the search was January 8, 2014. For PubMed, we searched for references from June 6, 2010; for Embase, Web of Science, and SCOPUS, we searched references from 2010. For PubMed, we used the following search term strategy: ((Lymphoma, T-Cell OR lymphoma*[tiab]) AND (breast implants/adverse effects[MeSH] OR silicone gels/adverse effects[MeSH] OR silicones/adverse effects[MeSH])) OR ((breast AND (implant or implants or prosthes* or endoprosthes*)) AND lymphoma*). For Embase, we used: (((breast AND endoprosthesis/exp)OR (breast AND implant*) OR (breast* AND silicon*)) AND (“t cell lymphoma” OR lymphoma*)) NOT “coronary stent”. For Web of Science, we used: Topic=(breast AND lymphoma*) AND Topic=(implant* OR prosthes* OR endoprosthes* OR silicon*). Finally, for SCOPUS, we used: (TITLE-ABS-KEY(breast AND lymphoma*) AND TITLE-ABS-KEY((implant* OR prosthes* OR endoprosthes* OR silicon*))). We then conducted a forward search on our previous review using Web of Science. In addition, we completed a search of the “grey literature” (the unpublished, noncommercial, hard-to-find information that organizations such as professional associations, research institutes, think tanks, and government departments produce) using Lexis/Nexis, New York Academy of Medicine, and Google Scholar. We searched Lexis/Nexis Academic (Focus on Industry News) from 2010 using the search terms breast implant lymphoma. We searched New York Academy of Medicine Grey Literature Database using the terms breast implant* lymphoma. Finally, we
Table 1. Epidemiologic Cohort Studies of Women with Breast Implants Reference
Location
Pan et al., 20128
Canada
Study Period
1974–1989 (follow-up through 2007) 2000–2005 Berry and Stanek, United 9 Kingdom (follow-up 2013 through 2012) United 1999–2008 Chummun and ingdom (follow-up K McLean, 201310 through 2012) Denmark 1973–2010 Vase et al., 201311
Study Population
Follow-Up (yr)
Estimated RR No. of Observed (95% CI) Cases of ALCL
24,558 women with breast implants 460 women with PIP breast implants 44 women with PIP implants
Mean, 23.7 (range, 0.1–34.0)
N/A
0
Range, 6–12
N/A
0
Mean, 7
N/A
0
19,885 women with breast implants
Mean, 7.7
0 (0–10.3)
0
RR, relative risk; ALCL, anaplastic large cell lymphoma; PIP, Poly Implant Prothèse; N/A, not applicable.
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Volume 135, Number 3 • Breast Implants and ALCL searched Google Scholar using the terms breast implant* lymphoma. Search results were categorized as research (epidemiologic studies or scientific articles) and nonresearch (case reports or case series) articles from peer-reviewed journals, reviews, letters to the editor, conference abstracts, and unpublished manuscripts. Only human-based topics and articles written in English were considered. A total of 248 titles were identified from the search, six were mined from citations, and six were found in the grey literature. One hundred forty-six of the 248 articles were deemed irrelevant and removed, one was not in English, four were duplicates, and one was unavailable. In addition, the six grey literature articles were all irrelevant. In total, 102 articles were selected for review Article Selection and Case Abstraction One researcher (Z.P.) reviewed all relevant references to identify articles containing case information. For each identified case, two clinician reviewers (B.K. and C.G.) independently recorded all available case-based data in an abstraction tool, and then compared and reconciled their data. Criteria for including a case required that at least some additional information other than diagnosis was available (e.g., history, symptoms, follow-up). Data elements abstracted included information about patient demographics, medical history, implant characteristics, presenting symptoms, diagnosis and staging, treatment, and patient outcomes. Detailed summary tables were created, which contained frequencies, means, and ranges for each abstracted variable, as applicable. This study was reviewed and considered exempt by the Human Subjects Protection Committee/Institutional Review Board at RAND.
RESULTS Literature Search In total, 248 titles were returned by the literature search (Fig. 1). Of these, 102 were selected for review. Ultimately, 27 studies presenting 54 new cases of breast implant–associated ALCL were identified.12–38 Twenty of the 27 studies (74 percent) came from journal articles, four (15 percent) came from a conference abstract, and three (11 percent) came from research letters. Twentyone (78 percent) were case reports and six (22 percent) were case series. Three abstracts were found to contain the same cases as three of the journal articles. In these cases, we counted only the journal article, and added any information from the
abstract into the case information abstracted from the journal article. Patient Characteristics Characteristics of the patients, information on their medical history, and data on their implant types are summarized in Table 2. More detailed information is provided in Table A, Supplemental Digital Content 1, which shows selected features of ALCL cases in patients with breast implants, http://links.lww.com/PRS/B217.) Of the women who developed ALCL, 27 (50 percent) underwent the original implant surgery for cosmetic augmentation, 22 (41 percent) for reconstruction after cancer surgery, and one (2 percent) for prophylaxis of breast cancer; four (7 percent) reported no data. Of the 23 procedures performed for reconstruction or prophylaxis, six (26 percent) were immediate, three (13 percent) were delayed, and 14 (61 percent) did not report the timing. Five (22 percent) had an expander used, although the type was not specified for any of the cases. Implant Characteristics The number of years that the cases had an implant was reported for most (81 percent) cases. The average number of years with the affected implant was 8 years (range, 1 to 27 years). The average number of years with any implant was 11 years (range, 2 to 32 years). Of those cases that reported the number of surgical revisions to the affected breast (83 percent), the mean number of revisions was 0.4 (range, zero to three). Data were not consistently reported on the placement of the implant or the size, surface, and implant covering. Eighty percent of the cases had no data about implant placement (i.e., subglandular, subpectoral, or submuscular). The sizes of implants used were noted in only 11 of the 54 ALCL cases (20 percent). When reported, the mean size was 391 cc (range, 250 to 640 cc). No data were available for 55 percent of ALCL cases regarding the surface of the affected implant. Of the 24 cases with data, 22 (92 percent) of the implants were reported to have a textured surface. The implant covering was also rarely reported. Of the three (6 percent) that were reported, two reported a silicone covering and one reported a polyurethane foam covering. The type of implants used among the ALCL cases was saline in 44 percent and silicone in 31 percent (24 percent did not report implant type). Twenty-three of the 54 ALCL cases (43 percent)
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Plastic and Reconstructive Surgery • March 2015
Fig. 1. Literature flow for published ALCL cases. PIP, Poly Implant Prothèse.
had data about the implant manufacturer/model. Of these 23, five (9 percent of 54) reported Allergan, one (2 percent) reported Allergan and CUI Corp., two (4 percent) reported Allergan/ Inamed/McGhan, two (4 percent) reported Allergan/McGhan, one (2 percent) reported Inamed, two (4 percent) reported Inamed/McGhan, six (11 percent) reported McGhan, three (6 percent) reported Nagor, and one (2 percent) reported Silimed. Of note, not all manufacturers labeled their implants in the past; thus, when not reported, it is unknown whether this was simply not reported by choice or not reported because the implant was not labeled.
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Case Presentation Ten of 54 ALCL cases (18 percent) reported data indicating that the patient had a palpable breast mass on presentation (Table 3). In 15 cases (28 percent), a mass was documented at the time of surgery. Sizes of the masses were reported for eight cases, with a mean size of 4.4 cm (range, 0.4 to 10 cm). Swelling was fairly common and reported in 39 cases (62 percent). Less frequently cited symptoms among ALCL cases were pain in 15 (28 percent), redness in five (9 percent), capsular contracture in four (7 percent), and constitutional symptoms in one (2 percent). Other symptoms (e.g., axillary adenopathy, rash,
Volume 135, Number 3 • Breast Implants and ALCL Table 2. Characteristics of ALCL Cases
Table 2. (Continued) Value (%)
No. Age at diagnosis, yr Mean Range Years having any implant Mean Range Prior cancer (non–T-cell lymphoma) Yes* Breast DCIS Affected Bilateral Side not reported Breast cancer Affected Contralateral Side not reported No Not reported Time between first prior cancer and breast diagnosis, yr Mean Range Prior lymphoma or lymphoma-like condition Yes No Not reported Affected breast Left Right Bilateral Not reported Reason for initial implant Cosmetic Mastectomy for breast cancer Prophylaxis for breast cancer Not reported Placement of affected implant Subglandular Subpectoral Not reported Years having implant Any implant Mean Range Affected implant Mean Range Surface Smooth Textured Not reported Covering Silicone Polyurethane Not reported Type of implant Saline Silicone Not reported Manufacturer/model Allergan Allergan, CUI Corp. Allergan, Inamed, McGhan
54 53 29–77 11 2–32 22 (40) 5 3 1 1 18 3 7 9 2 (4) 30 (56) 12 6–27 1 (2) 2 (4) 51 (94) 19 (35) 25 (46) 2 (4) 8 (15) 27 (50) 22 (41) 1 (2) 4 (7) 3 (6) 8 (15) 43 (80) 11 2–32 8 1–27 2 (4) 22 (41) 30 (56) 4 (7) 1 (2) 49 (91) 24 (44) 17 (31) 13 (24) 5 (9) 1 (2) 2 (4) (Continued)
Value (%) Allergan, McGhan Inamed Inamed, McGhan McGhan Nagor Silimed Not reported
2 (4) 1 (2) 2 (4) 6 (11) 3 (6) 1 (2) 31 (57)
DCIS, ductal carcinoma in situ. *Totals may not sum to 100% because of rounding and also because two patients had two episodes of breast cancer. One patient had both breast DCIS (affected side) and the later breast cancer (contralateral side). In addition, one patient with breast cancer had it first on the affected side, and then later on the contralateral side.
lethargy) were reported in 14 cases (26 percent). Duration of symptoms was rarely noted (24 percent); when reported, the mean duration was 7 months (range, 1 to 24 months). Diagnosis and Surgical Management The affected implant was reported as removed in 48 of the 54 reported cases of ALCL (89 percent) (Table 3). Of the cases that had implants removed, seven (15 percent) had delayed implant removal (i.e., after chemotherapy or months into the diagnosis). The remaining six cases (11 percent of 54) provided no data regarding removal. In no cases were the implants reported to be left in place on the affected side. In 22 of the cases of ALCL (41 percent), the contralateral implant was removed either concurrently with the affected implant (37 percent) or sequentially (4 percent). It was not removed in four of the cases (7 percent). However, most reports (52 percent) gave no information about the status of the contralateral implant. Few cases had information about whether implant exchange or reconstruction was undertaken after the diagnosis was made (20 percent). Forty-one ALCL cases (76 percent) were noted to have a seroma either at presentation or at the time of surgery. Twenty-four of these (59 percent) showed positive cytology findings in the aspirated fluid. Twenty-one of the cases (39 percent) indicated that the capsule was associated with inflammation. In 26 cases (48 percent), ALCL was associated with the capsule on histologic examination. Staging information at diagnosis was provided for 39 cases (72 percent). Thirty-three (61 percent) were stage IE and six (11 percent) were stage IIE. ALK status was reported for 46 cases (89 percent), and 45 of 46 were ALK-negative. The one case that was ALK-positive was later found to be ALK-negative on subsequent specimens.
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Plastic and Reconstructive Surgery • March 2015 Table 3. Clinical Course of Patients with ALCL Value (%)* No. Duration of symptoms Mean Range Not reported Surgical removal of affected implant Yes No Not reported Surgical removal of contralateral implant Yes, concurrent Yes, sequential No/not applicable Not reported Seroma Yes No Not reported Mass Yes No Not reported Size of mass, cm Mean Range Not reported Lymph node investigation performed Yes No Not reported Stage IE IIE Not reported Radiation therapy Yes If yes, site of radiation therapy Chest wall Chest wall and axilla Axilla Not reported No Not reported Chemotherapy/other Yes CHOP CHOP, cisplatin, gemcitabine CHOP, cyclophosphamide CHOP, ESHAP CHOP, gemcitabine, ifosfamide, vinorelbine CHOP, ifosfamide, aracytine, methotrexate CHOP, ICE CHOP, ICE, Cytoxan ABVD, gemcitabine, cisplatin, brentuximab Not reported No Not reported Stem cell transplant Yes No Not reported Clinical follow-up reported Yes (frequency not reported) No Duration of follow-up, yr Mean Range
54 7 mo 1–24 mo 41 (76) 48 (89) 0 (0) 6 (11) 20 (37) 2 (4) 4 (7) 28 (52) 41 (76) 3 (6) 10 (18) 15 (28) 19 (25) 20 (37) 4.4 0.4–10 7 (47) 8 (15) 35 (65) 11 (20) 33 (61) 6 (11) 15 (28) 26 (48) 10 1 1 14 19 (35) 9 (17) 31 (57) 14 1 1 1 1 1 1 1 1 8 16 (30) 7 (13) 6 (11) 36 (67) 12 (22) 43 (80) 11 (20) 2.2 0.25–12
CHOP, cyclophosphamide, hydroxydaunorubicin, vincristine, and prednisone; ESHAP, etoposide, methylprednisolone, cytarabine, and cisplatin; ICE, ifosfamide, carboplatin, and etoposide; ABVD, Adriamycin, bleomycin, vinblastine, and dacarbazine. *Totals may not sum to 100% because of rounding.
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Treatment Of all of the 54 cases, 31 (57 percent) received chemotherapy, although information about chemotherapy was not reported for 13 percent of the cases. Sixteen (30 percent) received no chemotherapy. When chemotherapy regimens were reported, the regimens were noted to consist mostly of cyclophosphamide, hydroxydaunorubicin, vincristine, and prednisone (plus/minus other chemotherapeutic agents). For 41 percent of cases that received chemotherapy, information about specific agents making up the regimens was not reported. Approximately half of the cases (48 percent) received radiation therapy, mostly to the chest wall. Nineteen (35 percent) did not receive radiation therapy, although for one of the patients this was because treatment was declined. Information on radiation therapy was not reported for nine cases (17 percent). Six cases (11 percent) received a stem cell transplant for treatment of their ALCL, and 36 (67 percent) did not. For 12 cases (22 percent), this information was not reported. Outcomes Some sort of clinical follow-up was reported for 43 cases (80 percent), although frequency of follow-up was never reported. Only 10 cases (19 percent) reported any imaging follow-up. When reported, mean duration of follow-up was 2.2 years (range, 0.25 to 12 years). Of the 43 cases with follow-up data, 28 (65 percent) had no recurrence, 11 (26 percent) had a recurrence, and four (9 percent) did not have information regarding recurrence. Of the 11 patients with reported recurrences, four (36 percent) were local recurrences, and the remaining 64 percent were distant, meaning outside of the breast/capsule. Thirty-six of the 43 cases with follow-up data, or 84 percent, were reported to be alive at the time of last contact, whereas five of the 43 had died (12 percent). Of the five patients who died, two were stage IE at diagnosis and two were stage IIE at diagnosis. Stage at diagnosis was not reported for one of the patients. Four of the five patients had a recurrence reported (the fifth patient had no information on recurrence), of which three of four were distant recurrences.
DISCUSSION Our systematic literature review identified 54 cases of ALCL occurring in women with breast implants. Most presented with a seroma, and approximately half had involvement of the
Volume 135, Number 3 • Breast Implants and ALCL seroma by histopathology. The affected implant was removed the majority of the time, and the contralateral implant was removed less frequently. All but one case was found to be ALK-negative. Many of the cases resolved with implant removal alone, but chemotherapy and/or radiation therapy was administered in over half of all cases. Although the literature was all published during 2010 and later, many of the case reports and series reported cases that occurred well before 2010. Thus, the treating clinicians would not yet be aware of U.S. Food and Drug Administration guidance,39 or possibly even of the breast implant– associated ALCL disease entity. Given the risks of radiation therapy and chemotherapy, consensus on when this therapy should be offered would be very helpful to treating clinicians. In contrast to our previous systematic review, in which no cases of death because of ALCL were reported,2 we identified five deaths in association with ALCL. However, little clinical detail was provided about these deaths. In at least one case, it was unclear whether the patient had primary ALCL of the breast, or lymphoma that localized to the breast and thus happened to be identified there. Given that breast implant–associated ALCL is thought to generally have a benign course, it is extremely important to understand risk factors for death (e.g., stage at presentation, history of lymphoma or lymphoma-like conditions). This would allow clinicians to have a higher index of suspicion for aggressive disease early on, and perhaps suggest the need for very close follow-up, systemic chemotherapy, and/ or radiation therapy. We identified only a small number of deaths, but obtaining more detailed information on such patients, and ensuring longterm follow-up for all ALCL patients, would allow for more effective identification of at-risk patients. Our study does have limitations, some of which are inherent in a systematic review of published literature. We could only capture cases that are available to us in the literature, which may be affected by publication bias. Although impossible to confirm, it seems likely that cases of breast implant– associated ALCL with poor outcomes may be more likely to be published. Thus, the mortality and recurrence rates in the cases we review here are likely to be far higher than those observed across the population of breast implant–associated ALCL. Other sources of data—such as the Manufacturer and User Facility Device Experience database—may avoid this bias but often have duplicate cases reported by manufacturers, users, health care providers, and others. A separate limitation that is unrelated to publication bias is that there
is likely to be heterogeneity in how potential cases of ALCL are diagnosed. This may result in either overdiagnosis or underdiagnosis of ALCL. Finally, any findings related to risk factors for ALCL (e.g., implant surface) must be placed within the context of the overall prevalence of the same risk factor. For example, we found that 92 percent of implants in ALCL patients were textured, but the interpretation of this finding is limited without knowledge of the overall prevalence of textured implants in the general breast implant population. We note that there are still very few cases of breast implant–associated ALCL reported in the literature, which makes identification of risk factors for and optimal management of this disease difficult. What case reports do exist rarely report complete diagnostic or clinical information. Sometimes, these data are not available to reporting clinicians, such as when the patient is lost to followup or transitions their care to another provider. Given that case reports and case series are often written by clinicians with varying backgrounds, and thus differing areas of interest, perhaps a better approach to gathering systematic information on this entity would be to start a disease registry. We recommend that manufacturers and regulators collaborate when possible to share data about cases of ALCL and/or implant registries. This would enable the collection of a larger number of cases and eliminate the possibility of duplicate cases being reported in different registries. Although identifying a larger number of cases would allow for a better understanding of this disease entity and its clinical course, the rarity of breast implant–associated ALCL means that it will likely be difficult to draw strong conclusions about optimal management based on empiric evidence alone. In addition, clinicians are seeing patients with breast implant–associated ALCL now, and need guidance on the best approach to the disease. For these reasons, assembling experts in the fields of hematopathology, molecular pathology, oncology, and plastic surgery who are familiar with this disease entity would be very helpful. This systematic literature review served as a basis for a structured expert panel using the RAND/UCLA Appropriateness Method in March of 2014. Our goal was to integrate available information from our review with expert opinion, and come to a consensus on issues such as nomenclature, staging, and disease management. Courtney A. Gidengil, M.D., M.P.H. RAND Corporation 20 Park Plaza, Suite 920 Boston, Mass. 02116 [email protected]
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21. George EV, Pharm J, Houston C, et al. Breast implantassociated ALK-negative anaplastic large cell lymphoma: A case report and discussion of possible pathogenesis. Int J Clin Exp Pathol. 2013;6:1631–1642. 22. Hanson SE, Gutowski KA. Primary T-cell lymphoma associated with breast implant capsule. Plast Reconstr Surg. 2010;126:39e–41e. 23. Hurst E, Wadehra V, Menon G, Collis N, Lennard A. Breast implant associated anaplastic large cell lymphoma [ALCL]. Hematol Oncol. 2013;31:243. 24. Lazzeri D, Agostini T, Giannotti G, et al. Null-type anaplastic lymphoma kinase-negative anaplastic large cell lymphoma arising in a silicone breast implant capsule. Plast Reconstr Surg. 2011;127:159e–162e. 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. Lee M, Cooper B, Becker D. Keeping abreast of axillary masses. Lancet 2012;380:1530. 27. Mies C, Goyal A, Bagg A, et al. Breast implant capsule-associated anaplastic large cell lymphoma (BIC-ALCL). Lab Ivest. 2012;92:54A. 28. Neppalli AK, Koshy NV. Breast implant associated ALK negative anaplastic large t cell lymphoma. J Invest Med. 2013;61:407. 29. Parthasarathy M, Orrell J, Mortimer C, Ball L. Chemotherapyresistant breast implant-associated anaplastic large cell lymphoma. BMJ Case Rep. 2013;2013:ii. 30. Popplewell L, Thomas SH, Huang Q, Chang KL, Forman SJ. Primary anaplastic large-cell lymphoma associated with breast implants. Leuk Lymphoma 2011;52:1481–1487. 31. Singh E, Frost E, Morris EJ, Raza S. Anaplastic lymphoma masquerading as breast abscess in a patient with silicone implants. Breast J. 2013;19:543–545. 32. Smith TJ, Ramsaroop R. Breast implant related anaplastic large cell lymphoma presenting as late onset peri-implant effusion. Breast 2012;21:102–104. 33. Sørensen K, Murphy J, Lennard A, Wadehra V, Menon GK, Collis N. Anaplastic large cell lymphoma in a reconstructed breast using a silicone implant: A UK case report. J Plast Reconstr Aesthet Surg. 2014;67:561–563. 34. Talagas M, Charles-Petillon F, Uguen A, et al. Fine needle aspiration cytology of ALK negative T-cell anaplastic large-cell lymphoma associated with breast implant. Acta Cytol. 2013;57:53. 35. Taylor KO, Webster HR, Prince HM. Anaplastic large cell lymphoma and breast implants: Five Australian cases. Plast Reconstr Surg. 2012;129:610e–617e. 36. 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 clinico-pathological entity. Haematologica 2010;95:1977–1979. 37. Weathers WM, Wolfswinkel EM, Hatef DA, Lee EI, Hollier LH, Brown RH. Implant-associated anaplastic large cell lymphoma of the breast: Insight into a poorly understood disease. Can J Plast Surg. 2013;21:95–98. 38. Zakhary JM, Hamidian Jahromi A, Chaudhery S, Kim M. Anaplastic large cell lymphoma in the setting of textured breast implant: A call for patients and physicians education. J La State Med Soc. 2013;165:26–29. 39. U.S. Food and Drug Administration. Anaplastic large cell lymphoma (ALCL) in women with breast implants: Preliminary FDA findings and analyses. Available at: http://www.fda. gov/MedicalDevices/ProductsandMedicalProcedures/ ImplantsandProsthetics/BreastImplants/ucm239996.htm. Accessed January 28, 2015.
Background: There is substantial evidence that a type of anaplastic large cell lymphoma (ALCL) is associated with breast implants. However, the course in patients with breast implants seems to be unusually benign compared with other systemic ALCL. The purpose of this study was to identify and analyze recently published cases of breast implant–associated ALCL, with an emphasis on diagnosis, staging, treatment, and outcomes. Methods: The authors conducted a systematic literature review of reported cases of ALCL in patients with breast implants. Publications were identified with a search algorithm and forward searches. Case-based data were abstracted independently and reconciled by multiple investigators. Results: Of 248 identified articles, only 102 were relevant to breast implant– associated ALCL, and 27 were included in this study. Fifty-four cases of ALCL in patients with breast implants were identified. Detailed clinical information was lacking in many cases. Most presented with a seroma (76 percent), and approximately half were associated with the capsule (48 percent). Most presented as stage IE (61 percent). All but one case were ALK-negative. Most received chemotherapy (57 percent) and radiation therapy (48 percent), and 11 percent received stem cell transplants. Approximately one-quarter recurred, and 9 percent died. Conclusions: Since the publication of guidance related to breast implant–associated ALCL in 2010, a number of cases have been reported. Despite the typically benign course, many of the cases have been treated with radiation therapy and/or chemotherapy. Increasing awareness of this disease entity among clinicians would be helpful, along with standardizing an approach to diagnosis, staging, and treatment. (Plast. Reconstr. Surg. 135: 713, 2015.) CLINICAL QUESTION/LEVEL OF EVIDENCE: Risk, V.
C
oncern over the association of breast implants and anaplastic large cell lymphoma (ALCL) has been growing since the publication of a case series of three women with breast implants and cutaneous T-cell lymphoma in 1995.1 Since then, a number of case reports and case series, along with an extensive systematic literature review2 and report of a structured expert panel,3 have strengthened the evidence for this association. However, this form of ALCL appears to have a more benign course than systemic ALCL, behaving more like a primary cutaneous form of ALK-negative ALCL. In fact, the lymphoma often From RAND Health, RAND Corporation; the Division of Infectious Diseases, Boston Children’s Hospital; and the Division of Hematology-Oncology, University of California, San Francisco. Received for publication June 17, 2014; accepted September 26, 2014. Copyright © 2014 by the American Society of Plastic Surgeons DOI: 10.1097/PRS.0000000000001037
regresses after removal of the implant and capsule, without any systemic treatment.2,3 Despite calls for nonaggressive treatment, including guidance from the U.S. Food and Drug Administration, women may still be receiving aggressive therapy for this disease. ALCL is a rare Disclosure: Support for this study was provided by unrestricted grants from Allergan, Inc. The study sponsor had no role in the design of execution of this study. The authors have no other commercial associations or financial disclosures. Supplemental digital content is available for this article. Direct URL citations appear in the text; simply type the URL address into any Web browser to access this content. Clickable links to the material are provided in the HTML text of this article on the Journal’s Web site (www. PRSJournal.com).
www.PRSJournal.com
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Plastic and Reconstructive Surgery • March 2015 disease, constituting only 2 percent of all newly diagnosed non-Hodgkin lymphomas worldwide.4 Lymphomas in the breast are even more rare, accounting for only 1 to 2 percent of all extranodal lymphomas and 0.04 to 0.5 percent of all breast cancers.5–7 Thus, the vast majority of plastic surgeons and oncologists are unlikely to have ever encountered this relatively rare entity. As a result, there have been a number of anecdotal reports of women receiving chemotherapy and radiation therapy for what may well be an indolent disease. Lack of familiarity is one barrier to treating this disease appropriately, but another factor is the scant literature available on ALCL in breast implants. The largest systematic review on this topic identified only 29 cases of breast implant– associated ALCL and only six population-based epidemiologic studies.2 Since that review, we have identified another four epidemiologic studies,8–10 none of which identified any cases of ALCL in large populations of women with breast implants (Table 1).8–11 Given the infrequency of this disease, the lack of cases in population-based studies is not altogether surprising. Fortunately, a number of case reports and case series have been published since our last systematic review. Systematically reviewing these additional cases would help to deepen the understanding of this uncommon disease entity and provide richer background information for clinicians that are faced with this disease. The goal of our study was to review the recent literature for cases of ALCL in women with breast implants to better identify risk factors, course, management, and outcomes associated with this disease entity.
PATIENTS AND METHODS Search Strategy We conducted a search of the PubMed, Embase, Web of Science (including Science Citation Index
and Conference Proceedings Citation Index), and SCOPUS (Health Sciences and Physical Sciences) databases to identify all cases of breast implant– associated ALCL reported since our last systematic review. The search start date was June 6, 2010, because that was the end date of our last search.2 The end date for the search was January 8, 2014. For PubMed, we searched for references from June 6, 2010; for Embase, Web of Science, and SCOPUS, we searched references from 2010. For PubMed, we used the following search term strategy: ((Lymphoma, T-Cell OR lymphoma*[tiab]) AND (breast implants/adverse effects[MeSH] OR silicone gels/adverse effects[MeSH] OR silicones/adverse effects[MeSH])) OR ((breast AND (implant or implants or prosthes* or endoprosthes*)) AND lymphoma*). For Embase, we used: (((breast AND endoprosthesis/exp)OR (breast AND implant*) OR (breast* AND silicon*)) AND (“t cell lymphoma” OR lymphoma*)) NOT “coronary stent”. For Web of Science, we used: Topic=(breast AND lymphoma*) AND Topic=(implant* OR prosthes* OR endoprosthes* OR silicon*). Finally, for SCOPUS, we used: (TITLE-ABS-KEY(breast AND lymphoma*) AND TITLE-ABS-KEY((implant* OR prosthes* OR endoprosthes* OR silicon*))). We then conducted a forward search on our previous review using Web of Science. In addition, we completed a search of the “grey literature” (the unpublished, noncommercial, hard-to-find information that organizations such as professional associations, research institutes, think tanks, and government departments produce) using Lexis/Nexis, New York Academy of Medicine, and Google Scholar. We searched Lexis/Nexis Academic (Focus on Industry News) from 2010 using the search terms breast implant lymphoma. We searched New York Academy of Medicine Grey Literature Database using the terms breast implant* lymphoma. Finally, we
Table 1. Epidemiologic Cohort Studies of Women with Breast Implants Reference
Location
Pan et al., 20128
Canada
Study Period
1974–1989 (follow-up through 2007) 2000–2005 Berry and Stanek, United 9 Kingdom (follow-up 2013 through 2012) United 1999–2008 Chummun and ingdom (follow-up K McLean, 201310 through 2012) Denmark 1973–2010 Vase et al., 201311
Study Population
Follow-Up (yr)
Estimated RR No. of Observed (95% CI) Cases of ALCL
24,558 women with breast implants 460 women with PIP breast implants 44 women with PIP implants
Mean, 23.7 (range, 0.1–34.0)
N/A
0
Range, 6–12
N/A
0
Mean, 7
N/A
0
19,885 women with breast implants
Mean, 7.7
0 (0–10.3)
0
RR, relative risk; ALCL, anaplastic large cell lymphoma; PIP, Poly Implant Prothèse; N/A, not applicable.
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Volume 135, Number 3 • Breast Implants and ALCL searched Google Scholar using the terms breast implant* lymphoma. Search results were categorized as research (epidemiologic studies or scientific articles) and nonresearch (case reports or case series) articles from peer-reviewed journals, reviews, letters to the editor, conference abstracts, and unpublished manuscripts. Only human-based topics and articles written in English were considered. A total of 248 titles were identified from the search, six were mined from citations, and six were found in the grey literature. One hundred forty-six of the 248 articles were deemed irrelevant and removed, one was not in English, four were duplicates, and one was unavailable. In addition, the six grey literature articles were all irrelevant. In total, 102 articles were selected for review Article Selection and Case Abstraction One researcher (Z.P.) reviewed all relevant references to identify articles containing case information. For each identified case, two clinician reviewers (B.K. and C.G.) independently recorded all available case-based data in an abstraction tool, and then compared and reconciled their data. Criteria for including a case required that at least some additional information other than diagnosis was available (e.g., history, symptoms, follow-up). Data elements abstracted included information about patient demographics, medical history, implant characteristics, presenting symptoms, diagnosis and staging, treatment, and patient outcomes. Detailed summary tables were created, which contained frequencies, means, and ranges for each abstracted variable, as applicable. This study was reviewed and considered exempt by the Human Subjects Protection Committee/Institutional Review Board at RAND.
RESULTS Literature Search In total, 248 titles were returned by the literature search (Fig. 1). Of these, 102 were selected for review. Ultimately, 27 studies presenting 54 new cases of breast implant–associated ALCL were identified.12–38 Twenty of the 27 studies (74 percent) came from journal articles, four (15 percent) came from a conference abstract, and three (11 percent) came from research letters. Twentyone (78 percent) were case reports and six (22 percent) were case series. Three abstracts were found to contain the same cases as three of the journal articles. In these cases, we counted only the journal article, and added any information from the
abstract into the case information abstracted from the journal article. Patient Characteristics Characteristics of the patients, information on their medical history, and data on their implant types are summarized in Table 2. More detailed information is provided in Table A, Supplemental Digital Content 1, which shows selected features of ALCL cases in patients with breast implants, http://links.lww.com/PRS/B217.) Of the women who developed ALCL, 27 (50 percent) underwent the original implant surgery for cosmetic augmentation, 22 (41 percent) for reconstruction after cancer surgery, and one (2 percent) for prophylaxis of breast cancer; four (7 percent) reported no data. Of the 23 procedures performed for reconstruction or prophylaxis, six (26 percent) were immediate, three (13 percent) were delayed, and 14 (61 percent) did not report the timing. Five (22 percent) had an expander used, although the type was not specified for any of the cases. Implant Characteristics The number of years that the cases had an implant was reported for most (81 percent) cases. The average number of years with the affected implant was 8 years (range, 1 to 27 years). The average number of years with any implant was 11 years (range, 2 to 32 years). Of those cases that reported the number of surgical revisions to the affected breast (83 percent), the mean number of revisions was 0.4 (range, zero to three). Data were not consistently reported on the placement of the implant or the size, surface, and implant covering. Eighty percent of the cases had no data about implant placement (i.e., subglandular, subpectoral, or submuscular). The sizes of implants used were noted in only 11 of the 54 ALCL cases (20 percent). When reported, the mean size was 391 cc (range, 250 to 640 cc). No data were available for 55 percent of ALCL cases regarding the surface of the affected implant. Of the 24 cases with data, 22 (92 percent) of the implants were reported to have a textured surface. The implant covering was also rarely reported. Of the three (6 percent) that were reported, two reported a silicone covering and one reported a polyurethane foam covering. The type of implants used among the ALCL cases was saline in 44 percent and silicone in 31 percent (24 percent did not report implant type). Twenty-three of the 54 ALCL cases (43 percent)
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Fig. 1. Literature flow for published ALCL cases. PIP, Poly Implant Prothèse.
had data about the implant manufacturer/model. Of these 23, five (9 percent of 54) reported Allergan, one (2 percent) reported Allergan and CUI Corp., two (4 percent) reported Allergan/ Inamed/McGhan, two (4 percent) reported Allergan/McGhan, one (2 percent) reported Inamed, two (4 percent) reported Inamed/McGhan, six (11 percent) reported McGhan, three (6 percent) reported Nagor, and one (2 percent) reported Silimed. Of note, not all manufacturers labeled their implants in the past; thus, when not reported, it is unknown whether this was simply not reported by choice or not reported because the implant was not labeled.
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Case Presentation Ten of 54 ALCL cases (18 percent) reported data indicating that the patient had a palpable breast mass on presentation (Table 3). In 15 cases (28 percent), a mass was documented at the time of surgery. Sizes of the masses were reported for eight cases, with a mean size of 4.4 cm (range, 0.4 to 10 cm). Swelling was fairly common and reported in 39 cases (62 percent). Less frequently cited symptoms among ALCL cases were pain in 15 (28 percent), redness in five (9 percent), capsular contracture in four (7 percent), and constitutional symptoms in one (2 percent). Other symptoms (e.g., axillary adenopathy, rash,
Volume 135, Number 3 • Breast Implants and ALCL Table 2. Characteristics of ALCL Cases
Table 2. (Continued) Value (%)
No. Age at diagnosis, yr Mean Range Years having any implant Mean Range Prior cancer (non–T-cell lymphoma) Yes* Breast DCIS Affected Bilateral Side not reported Breast cancer Affected Contralateral Side not reported No Not reported Time between first prior cancer and breast diagnosis, yr Mean Range Prior lymphoma or lymphoma-like condition Yes No Not reported Affected breast Left Right Bilateral Not reported Reason for initial implant Cosmetic Mastectomy for breast cancer Prophylaxis for breast cancer Not reported Placement of affected implant Subglandular Subpectoral Not reported Years having implant Any implant Mean Range Affected implant Mean Range Surface Smooth Textured Not reported Covering Silicone Polyurethane Not reported Type of implant Saline Silicone Not reported Manufacturer/model Allergan Allergan, CUI Corp. Allergan, Inamed, McGhan
54 53 29–77 11 2–32 22 (40) 5 3 1 1 18 3 7 9 2 (4) 30 (56) 12 6–27 1 (2) 2 (4) 51 (94) 19 (35) 25 (46) 2 (4) 8 (15) 27 (50) 22 (41) 1 (2) 4 (7) 3 (6) 8 (15) 43 (80) 11 2–32 8 1–27 2 (4) 22 (41) 30 (56) 4 (7) 1 (2) 49 (91) 24 (44) 17 (31) 13 (24) 5 (9) 1 (2) 2 (4) (Continued)
Value (%) Allergan, McGhan Inamed Inamed, McGhan McGhan Nagor Silimed Not reported
2 (4) 1 (2) 2 (4) 6 (11) 3 (6) 1 (2) 31 (57)
DCIS, ductal carcinoma in situ. *Totals may not sum to 100% because of rounding and also because two patients had two episodes of breast cancer. One patient had both breast DCIS (affected side) and the later breast cancer (contralateral side). In addition, one patient with breast cancer had it first on the affected side, and then later on the contralateral side.
lethargy) were reported in 14 cases (26 percent). Duration of symptoms was rarely noted (24 percent); when reported, the mean duration was 7 months (range, 1 to 24 months). Diagnosis and Surgical Management The affected implant was reported as removed in 48 of the 54 reported cases of ALCL (89 percent) (Table 3). Of the cases that had implants removed, seven (15 percent) had delayed implant removal (i.e., after chemotherapy or months into the diagnosis). The remaining six cases (11 percent of 54) provided no data regarding removal. In no cases were the implants reported to be left in place on the affected side. In 22 of the cases of ALCL (41 percent), the contralateral implant was removed either concurrently with the affected implant (37 percent) or sequentially (4 percent). It was not removed in four of the cases (7 percent). However, most reports (52 percent) gave no information about the status of the contralateral implant. Few cases had information about whether implant exchange or reconstruction was undertaken after the diagnosis was made (20 percent). Forty-one ALCL cases (76 percent) were noted to have a seroma either at presentation or at the time of surgery. Twenty-four of these (59 percent) showed positive cytology findings in the aspirated fluid. Twenty-one of the cases (39 percent) indicated that the capsule was associated with inflammation. In 26 cases (48 percent), ALCL was associated with the capsule on histologic examination. Staging information at diagnosis was provided for 39 cases (72 percent). Thirty-three (61 percent) were stage IE and six (11 percent) were stage IIE. ALK status was reported for 46 cases (89 percent), and 45 of 46 were ALK-negative. The one case that was ALK-positive was later found to be ALK-negative on subsequent specimens.
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Plastic and Reconstructive Surgery • March 2015 Table 3. Clinical Course of Patients with ALCL Value (%)* No. Duration of symptoms Mean Range Not reported Surgical removal of affected implant Yes No Not reported Surgical removal of contralateral implant Yes, concurrent Yes, sequential No/not applicable Not reported Seroma Yes No Not reported Mass Yes No Not reported Size of mass, cm Mean Range Not reported Lymph node investigation performed Yes No Not reported Stage IE IIE Not reported Radiation therapy Yes If yes, site of radiation therapy Chest wall Chest wall and axilla Axilla Not reported No Not reported Chemotherapy/other Yes CHOP CHOP, cisplatin, gemcitabine CHOP, cyclophosphamide CHOP, ESHAP CHOP, gemcitabine, ifosfamide, vinorelbine CHOP, ifosfamide, aracytine, methotrexate CHOP, ICE CHOP, ICE, Cytoxan ABVD, gemcitabine, cisplatin, brentuximab Not reported No Not reported Stem cell transplant Yes No Not reported Clinical follow-up reported Yes (frequency not reported) No Duration of follow-up, yr Mean Range
54 7 mo 1–24 mo 41 (76) 48 (89) 0 (0) 6 (11) 20 (37) 2 (4) 4 (7) 28 (52) 41 (76) 3 (6) 10 (18) 15 (28) 19 (25) 20 (37) 4.4 0.4–10 7 (47) 8 (15) 35 (65) 11 (20) 33 (61) 6 (11) 15 (28) 26 (48) 10 1 1 14 19 (35) 9 (17) 31 (57) 14 1 1 1 1 1 1 1 1 8 16 (30) 7 (13) 6 (11) 36 (67) 12 (22) 43 (80) 11 (20) 2.2 0.25–12
CHOP, cyclophosphamide, hydroxydaunorubicin, vincristine, and prednisone; ESHAP, etoposide, methylprednisolone, cytarabine, and cisplatin; ICE, ifosfamide, carboplatin, and etoposide; ABVD, Adriamycin, bleomycin, vinblastine, and dacarbazine. *Totals may not sum to 100% because of rounding.
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Treatment Of all of the 54 cases, 31 (57 percent) received chemotherapy, although information about chemotherapy was not reported for 13 percent of the cases. Sixteen (30 percent) received no chemotherapy. When chemotherapy regimens were reported, the regimens were noted to consist mostly of cyclophosphamide, hydroxydaunorubicin, vincristine, and prednisone (plus/minus other chemotherapeutic agents). For 41 percent of cases that received chemotherapy, information about specific agents making up the regimens was not reported. Approximately half of the cases (48 percent) received radiation therapy, mostly to the chest wall. Nineteen (35 percent) did not receive radiation therapy, although for one of the patients this was because treatment was declined. Information on radiation therapy was not reported for nine cases (17 percent). Six cases (11 percent) received a stem cell transplant for treatment of their ALCL, and 36 (67 percent) did not. For 12 cases (22 percent), this information was not reported. Outcomes Some sort of clinical follow-up was reported for 43 cases (80 percent), although frequency of follow-up was never reported. Only 10 cases (19 percent) reported any imaging follow-up. When reported, mean duration of follow-up was 2.2 years (range, 0.25 to 12 years). Of the 43 cases with follow-up data, 28 (65 percent) had no recurrence, 11 (26 percent) had a recurrence, and four (9 percent) did not have information regarding recurrence. Of the 11 patients with reported recurrences, four (36 percent) were local recurrences, and the remaining 64 percent were distant, meaning outside of the breast/capsule. Thirty-six of the 43 cases with follow-up data, or 84 percent, were reported to be alive at the time of last contact, whereas five of the 43 had died (12 percent). Of the five patients who died, two were stage IE at diagnosis and two were stage IIE at diagnosis. Stage at diagnosis was not reported for one of the patients. Four of the five patients had a recurrence reported (the fifth patient had no information on recurrence), of which three of four were distant recurrences.
DISCUSSION Our systematic literature review identified 54 cases of ALCL occurring in women with breast implants. Most presented with a seroma, and approximately half had involvement of the
Volume 135, Number 3 • Breast Implants and ALCL seroma by histopathology. The affected implant was removed the majority of the time, and the contralateral implant was removed less frequently. All but one case was found to be ALK-negative. Many of the cases resolved with implant removal alone, but chemotherapy and/or radiation therapy was administered in over half of all cases. Although the literature was all published during 2010 and later, many of the case reports and series reported cases that occurred well before 2010. Thus, the treating clinicians would not yet be aware of U.S. Food and Drug Administration guidance,39 or possibly even of the breast implant– associated ALCL disease entity. Given the risks of radiation therapy and chemotherapy, consensus on when this therapy should be offered would be very helpful to treating clinicians. In contrast to our previous systematic review, in which no cases of death because of ALCL were reported,2 we identified five deaths in association with ALCL. However, little clinical detail was provided about these deaths. In at least one case, it was unclear whether the patient had primary ALCL of the breast, or lymphoma that localized to the breast and thus happened to be identified there. Given that breast implant–associated ALCL is thought to generally have a benign course, it is extremely important to understand risk factors for death (e.g., stage at presentation, history of lymphoma or lymphoma-like conditions). This would allow clinicians to have a higher index of suspicion for aggressive disease early on, and perhaps suggest the need for very close follow-up, systemic chemotherapy, and/ or radiation therapy. We identified only a small number of deaths, but obtaining more detailed information on such patients, and ensuring longterm follow-up for all ALCL patients, would allow for more effective identification of at-risk patients. Our study does have limitations, some of which are inherent in a systematic review of published literature. We could only capture cases that are available to us in the literature, which may be affected by publication bias. Although impossible to confirm, it seems likely that cases of breast implant– associated ALCL with poor outcomes may be more likely to be published. Thus, the mortality and recurrence rates in the cases we review here are likely to be far higher than those observed across the population of breast implant–associated ALCL. Other sources of data—such as the Manufacturer and User Facility Device Experience database—may avoid this bias but often have duplicate cases reported by manufacturers, users, health care providers, and others. A separate limitation that is unrelated to publication bias is that there
is likely to be heterogeneity in how potential cases of ALCL are diagnosed. This may result in either overdiagnosis or underdiagnosis of ALCL. Finally, any findings related to risk factors for ALCL (e.g., implant surface) must be placed within the context of the overall prevalence of the same risk factor. For example, we found that 92 percent of implants in ALCL patients were textured, but the interpretation of this finding is limited without knowledge of the overall prevalence of textured implants in the general breast implant population. We note that there are still very few cases of breast implant–associated ALCL reported in the literature, which makes identification of risk factors for and optimal management of this disease difficult. What case reports do exist rarely report complete diagnostic or clinical information. Sometimes, these data are not available to reporting clinicians, such as when the patient is lost to followup or transitions their care to another provider. Given that case reports and case series are often written by clinicians with varying backgrounds, and thus differing areas of interest, perhaps a better approach to gathering systematic information on this entity would be to start a disease registry. We recommend that manufacturers and regulators collaborate when possible to share data about cases of ALCL and/or implant registries. This would enable the collection of a larger number of cases and eliminate the possibility of duplicate cases being reported in different registries. Although identifying a larger number of cases would allow for a better understanding of this disease entity and its clinical course, the rarity of breast implant–associated ALCL means that it will likely be difficult to draw strong conclusions about optimal management based on empiric evidence alone. In addition, clinicians are seeing patients with breast implant–associated ALCL now, and need guidance on the best approach to the disease. For these reasons, assembling experts in the fields of hematopathology, molecular pathology, oncology, and plastic surgery who are familiar with this disease entity would be very helpful. This systematic literature review served as a basis for a structured expert panel using the RAND/UCLA Appropriateness Method in March of 2014. Our goal was to integrate available information from our review with expert opinion, and come to a consensus on issues such as nomenclature, staging, and disease management. Courtney A. Gidengil, M.D., M.P.H. RAND Corporation 20 Park Plaza, Suite 920 Boston, Mass. 02116 [email protected]
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