Plastic and Reconstructive Surgery Advance Online Article
Doi: 10.1097/PRS.0b013e3182172418
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.3
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1.
2.
3.
4.
RAND Health, RAND Corporation, Santa Monica, CA
Pardee RAND Graduate School, RAND Corporation, Santa Monica, CA
RAND Health, RAND Corporation, Boston, MA
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
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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 execution 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: "None 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 02116
Phone: 617-338-2059 x4222
Fax: 617-357-7470
Email: [email protected]
Abstract:
Background
In recent years, there have been growing concerns about a possible association of nonHodgkin’s lymphoma (NHL)—in particular, anaplastic large cell lymphoma (ALCL)—and breast
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implants. The purpose of this study was to identify and analyze all reported cases of NHL
occurring in patients with breast implants.
Methods
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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
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expert nominations. After references were reviewed and assessed for inclusion or exclusion,
case-based data were independently abstracted, reconciled, and adjudicated by multiple
investigators. The data were then synthesized and analyzed.
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Results
Of 884 identified articles, only 83 were relevant to NHL involving the breast and 34 were
included in our study. Thirty-six 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 unexplained seroma or mass, was
negative for Anaplastic Lymphoma Kinase (ALK) expression, 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.
Introduction
Since Duvic et al. published a case series in 1995 of 3 women with breast implants who
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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
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all newly-diagnosed NHLs worldwide2 and 0.9%3 of the estimated 65,540 cases of NHL
diagnosed in the U.S. in 2010.3 Lymphomas of the breast are extremely rare, comprising 0.04-
0.5% of all breast cancers and approximately 1-2% of all extranodal lymphomas.4-6 Despite the
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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
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but not yet published a series of 34 cases.7 Whether or not a small but positive association
between breast implants and ALCL development exists 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 exact 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 2006. Based on an estimate of 100,000300,000 Dutch women with breast implants, the authors calculated an ALCL incidence of 0.1-
0.3 per 100,000 women with implants per year.9 Next, 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: 2.1-156.8).9 On the
other hand, several large, epidemiologic cohort studies of North American and European
women with breast implants have not shown an increased overall risk of NHL development
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(Table 1). Pooled analysis of these studies included over 43,000 women with breast implants
with a mean follow-up of 8.3-16.6 years revealed 48 observed NHL cases, none of which were
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primary breast lymphomas.10 Based on these numbers, a standardized incidence ratio of 0.89
(95% confidence interval: 0.67-1.18) was calculated, suggesting no increased overall risk of
NHL development among women with implants.10
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Epidemiologic studies can support or refute the existence 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
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experiments and clinical registries and trials. Because breast ALCL in women with implants
occurs infrequently and the evidence on the existence 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 2010. For PubMed, we used the following search term strategy: (Lymphoma, T-
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/exp)
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*
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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
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(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
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written in English were considered. Of the initial 884 titles, 83 articles discussed ALCL and
breast implants. Fourteen additional articles were provided by 2 expert plastic surgeons (V.L.Y.
and K.C.C.).
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Article Selection & Case Abstraction
Two clinician researchers (B.K. and C.R.) independently reviewed all selected
references for study inclusion or exclusion, 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. Next,
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 exempt by the Human Subjects Protection
Committee/Institutional Review Board at RAND.
Results
Literature Search
From the literature search, 884 titles were initially identified, of which 83 were selected for
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review and 14 supplied by clinical experts (Figure 1). Articles were excluded for several
reasons, including written in a language other than English (n=2), duplicate article (n=1) or data
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(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, 11-31 which included 36 cases of ALCL and other NHLs involving the breast: 29 (81%)
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were ALCL, 2 (5%) were follicular lymphoma, 1 (3%) 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
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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).
Case Presentation
Fourteen (48%) of 29 ALCL cases were noted to have presented with a seroma,1 (3%)
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
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positive cytology findings in the aspirated fluid. No data about presence or absence of seroma
was reported in the 7 non-ALCL cases. Seven (24%) of the 29 ALCL cases reported data
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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
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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
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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 2 (7%) 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%) nonALCL 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 0.2-1.7). Mean symptom duration among 5
non-ALCL cases for which it was reported was 5.4 years (range 0.5-17).
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
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(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
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(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
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data about whether implant exchange 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).
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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 examination [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 extranodal; 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,
and only 1 case (3%) was stage IVE, defined as NHL that involves the breast, at least one other
extranodal 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 extranodal organ and lymph
nodes on both sides of the diaphragm) at diagnosis.
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Cancer Treatment & Outcomes
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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%)
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with data received chemotherapy. Eleven (85%) of 13 patients were treated with
cyclophosphamide, hydroxydaunorubicin, vincristine, and prednisone (CHOP); 1 (8%) with
CHOP and ifosfamide, carboplatin, and etoposide (ICE); and 1 (8%) patient’s regimen was not
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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
1.1-12). 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.
Discussion
Until now, ALCL has been thought to manifest as two different clinical entities—systemic
ALCL, in which lymphadenopathy and frequent extranodal involvement (including of the skin) is
present; and primary cutaneous ALCL (PCALCL), in which the disease is limited to the skin.32
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Although the histopathology of ALCL is not uniform, both types express CD30, a tumor necrosis
factor receptor and tumor marker found in Hodgkin’s lymphoma and some ALCLs; however,
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ALK, a tyrosine kinase receptor, is expressed in 60-85% of systemic ALCLs but rarely in
PCALCLs.33-34 Chromosomal rearrangements involving the ALK gene, which underlie the
expression of the protein in ALK-positive (ALK+) ALCL, lead to constitutive activation of an ALK
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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
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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 better41 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,
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
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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
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observation. This is a somewhat surprising finding given the usual poor prognosis of extranodal
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
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systemic ALK- ALCL 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 implant-
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associated ALCL manifesting as an unexplained 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.
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
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and/or present as an unexplained seroma or mass, be ALK-, and have a relatively indolent
course. This suggests that implant-associated ALCL is more similar to cutaneous ALCL than
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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.
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Ultimately, understanding the biology, treatment and prognosis of implant-associated
ALCL will require substantial research efforts, such as in vitro experiments using immortalized
implant-associated ALCL cell lines, collection of detailed clinical information in breast implant
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registries, and well-designed epidemiologic studies. But developing and executing 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 expert consultation process known as the RAND/UCLA Appropriateness Method45 to
integrate the available information with expert opinion. Since the 1980s, this method has been
used across the world to take on many complex topics in health care, such as organ
transplantation46-48 and carotid endarterectomy.49 In October 2010, we brought together leading
experts 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.
References
1.
Duvic M, Moore D, Menter A, Vonderheid EC. Cutaneous T-cell lymphoma in
association with silicone breast implants. J Am Acad Dermatol 1995;32:939-42.
2.
Armitage JO, Weisenburger DD. New approach to classifying non-Hodgkin's
lymphomas: clinical features of the major histologic subtypes. Non-Hodgkin's Lymphoma
D
E
Classification Project. J Clin Oncol 1998;16:2780-95.
3.
Altekruse SF, Kosary CL, Krapcho M, et al, (eds.). SEER Cancer Statistics Review,
T
P
1975-2007. Bethesda, MD: National Cancer Institute; 2010.
4.
Cohen PL, Brooks JJ. Lymphomas of the breast. A clinicopathologic and
immunohistochemical study of primary and secondary cases. Cancer 1991;67:1359-69.
5.
E
C
Brogi E, Harris NL. Lymphomas of the breast: pathology and clinical behavior. Semin
Oncol 1999;26:357-64.
6.
7.
Wiseman C, Liao KT. Primary lymphoma of the breast. Cancer 1972;29:1705-12.
C
A
Brody G, Deapen D, Gill P, et al. T-cell non Hodgkin's anaplastic lymphoma associated
with one style of breast implants. In: 89th Annual Meeting, American Association of
Plastic Surgeons. San Antonio, TX; 2010.
8.
National Clearinghouse of Plastic Surgery Statistics. 2010 Report of the 2009 Statistics.
Arlington Heights, IL; 2010.
9.
de Jong D, Vasmel WL, de Boer JP, et al. Anaplastic large-cell lymphoma in women with
breast implants. JAMA 2008;300:2030-5.
10.
Lipworth L, Tarone RE, McLaughlin JK. Breast implants and lymphoma risk: a review of
the epidemiologic evidence through 2008. Plast Reconstr Surg 2009;123:790-3.
11.
Lechner M, Lade S, Brody G, Epstein A. Breast Implant-Associated T Cell Anaplastic
Large-Cell Lymphoma: Case Report and Establishment of a Novel Cell Line (Tlbr-1).
Journal of Investigative Medicine 2010;58:317.
12.
Hanson SE, Gutowski KA. Primary T-cell lymphoma associated with breast implant
capsule. Plast Reconstr Surg 2010;126:39e-41e.
13.
Li S, Lee AK. Silicone implant and primary breast ALK1-negative anaplastic large cell
lymphoma, fact or fiction? Int J Clin Exp Pathol 2009;3:117-27.
14.
Mora P, Melo AC, Amorim GLS, Scheliga AA. Primary T-cell anaplastic lymphoma
D
E
associated to a Breast implant: case report. Haematologica 2009;94:658-9.
15.
Miranda RN, Lin L, Talwalkar SS, Manning JT, Medeiros LJ. Anaplastic large cell
T
P
lymphoma involving the breast: a clinicopathologic study of 6 cases and review of the
literature. Arch Pathol Lab Med 2009;133:1383-90.
16.
Gualco G, Chioato L, Harrington WJ, Jr., Weiss LM, Bacchi CE. Primary and secondary
E
C
T-cell lymphomas of the breast: clinico-pathologic features of 11 cases. Appl
Immunohistochem Mol Morphol 2009;17:301-6.
17.
Farkash EA, Ferry JA, Harris NL, et al. Rare lymphoid malignancies of the breast: a
C
A
report of two cases illustrating potential diagnostic pitfalls. J Hematop 2009;2:237-44.
18.
Bishara MR, Ross C, Sur M. Primary anaplastic large cell lymphoma of the breast
arising in reconstruction mammoplasty capsule of saline filled breast implant after radical
mastectomy for breast cancer: an unusual case presentation. Diagn Pathol 2009;4:11.
19.
Alobeid B, Sevilla DW, El-Tamer MB, Murty VV, Savage DG, Bhagat G. Aggressive
presentation of breast implant-associated ALK-1 negative anaplastic large cell
lymphoma with bilateral axillary lymph node involvement. Leuk Lymphoma 2009;50:8313.
20.
Wong AK, Lopategui J, Clancy S, Kulber D, Bose S. Anaplastic large cell lymphoma
associated with a breast implant capsule: a case report and review of the literature. Am J
Surg Pathol 2008;32:1265-8.
21.
Roden AC, Macon WR, Keeney GL, Myers JL, Feldman AL, Dogan A. Seromaassociated primary anaplastic large-cell lymphoma adjacent to breast implants: an
indolent T-cell lymphoproliferative disorder. Mod Pathol 2008;21:455-63.
22.
Newman MK, Zemmel NJ, Bandak AZ, Kaplan BJ. Primary breast lymphoma in a patient
with silicone breast implants: a case report and review of the literature. J Plast Reconstr
D
E
Aesthet Surg 2008;61:822-5.
23.
Olack B, Gupta R, Brooks GS. Anaplastic large cell lymphoma arising in a saline breast
T
P
implant capsule after tissue expander breast reconstruction. Ann Plast Surg 2007;59:567.
24.
Fritzsche FR, Pahl S, Petersen I, et al. Anaplastic large-cell non-Hodgkin's lymphoma of
E
C
the breast in periprosthetic localisation 32 years after treatment for primary breast
cancer--a case report. Virchows Arch 2006;449:561-4.
25.
Kraemer DM, Tony HP, Gattenlohner S, Muller JG. Lymphoplasmacytic lymphoma in a
C
A
patient with leaking silicone implant. Haematologica 2004;89:ELT01.
26.
Sahoo S, Rosen PP, Feddersen RM, Viswanatha DS, Clark DA, Chadburn A. Anaplastic
large cell lymphoma arising in a silicone breast implant capsule: a case report and
review of the literature. Arch Pathol Lab Med 2003;127:e115-8.
27.
Gaudet G, Friedberg JW, Weng A, Pinkus GS, Freedman AS. Breast lymphoma
associated with breast implants: two case-reports and a review of the literature. Leuk
Lymphoma 2002;43:115-9.
28.
Keech JA, Jr., Creech BJ. Anaplastic T-cell lymphoma in proximity to a saline-filled
breast implant. Plast Reconstr Surg 1997;100:554-5.
29.
Said JW, Tasaka T, Takeuchi S, et al. Primary effusion lymphoma in women: report of
two cases of Kaposi's sarcoma herpes virus-associated effusion-based lymphoma in
human immunodeficiency virus-negative women. Blood 1996;88:3124-8.
30.
Sendagorta E, Ledo A. Sezary syndrome in association with silicone breast implant. J
Am Acad Dermatol 1995;33:1060-1.
31.
Cook PD, Osborne BM, Connor RL, Strauss JF. Follicular lymphoma adjacent to foreign
body granulomatous inflammation and fibrosis surrounding silicone breast prosthesis.
Am J Surg Pathol 1995;19:712-7.
32.
D
E
Jacobsen E. Anaplastic large-cell lymphoma, T-/null-cell type. Oncologist 2006;11:83140.
33.
T
P
Pittaluga S, Wlodarska I, Pulford K, et al. The monoclonal antibody ALK1 identifies a
distinct morphological subtype of anaplastic large cell lymphoma associated with
2p23/ALK rearrangements. Am J Pathol 1997;151:343-51.
34.
E
C
DeCoteau JF, Butmarc JR, Kinney MC, Kadin ME. The t(2;5) chromosomal translocation
is not a common feature of primary cutaneous CD30+ lymphoproliferative disorders:
comparison with anaplastic large-cell lymphoma of nodal origin. Blood 1996;87:3437-41.
35.
C
A
Morris SW, Kirstein MN, Valentine MB, et al. Fusion of a kinase gene, ALK, to a
nucleolar protein gene, NPM, in non-Hodgkin's lymphoma. Science 1994;263:1281-4.
36.
Bai RY, Ouyang T, Miething C, Morris SW, Peschel C, Duyster J. Nucleophosminanaplastic lymphoma kinase associated with anaplastic large-cell lymphoma activates
the phosphatidylinositol 3-kinase/Akt antiapoptotic signaling pathway. Blood
2000;96:4319-27.
37.
Falini B, Pileri S, Zinzani PL, et al. ALK+ lymphoma: clinico-pathological findings and
outcome. Blood 1999;93:2697-706.
38.
Vose J, Armitage J, Weisenburger D. International peripheral T-cell and natural killer/Tcell lymphoma study: pathology findings and clinical outcomes. J Clin Oncol
2008;26:4124-30.
39.
Savage KJ, Harris NL, Vose JM, et al. ALK- anaplastic large-cell lymphoma is clinically
and immunophenotypically different from both ALK+ ALCL and peripheral T-cell
lymphoma, not otherwise specified: report from the International Peripheral T-Cell
Lymphoma Project. Blood 2008;111:5496-504.
40.
Willemze R, Jaffe ES, Burg G, et al. WHO-EORTC classification for cutaneous
lymphomas. Blood 2005;105:3768-85.
41.
Liu HL, Hoppe RT, Kohler S, Harvell JD, Reddy S, Kim YH. CD30+ cutaneous
D
E
lymphoproliferative disorders: the Stanford experience in lymphomatoid papulosis and
primary cutaneous anaplastic large cell lymphoma. J Am Acad Dermatol 2003;49:1049-
T
P
58.
42.
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.
E
C
A European Multicenter Study of 47 patients. Cancer 1993;71:2097-104.
43.
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-
C
A
pathological entity. Haematologica 2010;95:1977-9.
44.
Medeiros LJ, Elenitoba-Johnson KS. Anaplastic Large Cell Lymphoma. Am J Clin Pathol
2007;127:707-22.
45.
Fitch K, Bernstein SJ, Aguilar MS, Burnand B, LaCalle JR. The RAND/UCLA
Appropriateness Method User's Manual. Santa Monica, CA: RAND Corporation; 2001.
46.
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;40:2021-3.
47.
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;39:1927-9.
48.
Santori G, Valente R, Cambiaso F, Ghirelli R, Gianelli Castiglione A, Valente U.
Preliminary results of an expert-opinion elicitation process to prioritize an informative
system funded by Italian Ministry of Health for cadaveric donor management, organ
allocation, and transplantation activity. Transplant Proc 2004;36:433-4.
49.
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;14:707-27.
T
P
D
E
C
A
E
C
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
D
E
Table 2. Characteristics of ALCL and other NHL cases
T
P
Figure 2. ALCL and CD30+ cutaneous lymphoproliferative disorders, along with ALK
status. Key: ALCL = Anaplastic Large Cell Lymphoma; PCALCL = Primary Cutaneous
E
C
ALCL; LyP = Lymphomatoid Papulosis
Figure 3. ALCL involving fibrous capsule and seroma surrounding breast implant.
C
A
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;95:1977-9.
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
Key for Figures, Tables, and Online Supplemental Digital Content Titles: NHL = Non-Hodgkin’s
Lymphoma, ALCL = Anaplastic Large Cell Lymphoma, ALK = Anaplastic Lymphoma Kinase
D
E
T
P
C
A
E
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Table 1. Epidemiologic cohort studies of women with breast implants and NHL10
Reference
Location
Study
Period
Lipworth et
al., 2009
50
(1)
Denmark,
Sweden
19652002
Deapen et
al., 200751
Los Angeles
19531994
Brisson et
52
al., 2006
Ontario,
Quebec
19741997
Pukkala et
al., 200253
Finland
19701999
Brinton et
54
al., 2001
Georgia,
Alabama,
North
Carolina,
Florida,
Washington, D.C.
19601996
Lipworth et
al., 2009
10
(2)
North
America,
Northern
Europe
19532002
Mean
Follow-Up
(Range) (yrs.)
16.6 (0.1-37.8)
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
15.5 (0.0423.0)
E
C
8.3 (up to 29)
Pooled analysis of
43,537 women with
breast implants from
above studies
Range of
mean followup: 8.3-16.6
years
12.9
Number of
Observed
Cases
9
D
E
SIR, 1.29
(0.42–3.01)
T
P
13.8 Ontario,
15.4 Quebec
(up to 24)
2171 women with
breast implants; Finnish
reference population
7447 women with
breast implants before
1989; 2203 women with
other cosmetic
procedures at same
practices
C
A
Estimated
Relative Risk
(95% CI)
SIR, 1.22
(0.56–2.32);
none of the 9
cases were
primary breast
NHLs
5
Implant
patients: SIR,
0.75
(0.49–1.11);
comparison
group: SIR,
0.78 (0.48–
1.20);
RR,* 0.97
(0.53–1.76)
SIR, 3.7 (0.810.7)
25; 20
Implant
patients: SIR,
0.81 (0.261.57);
comparison
group: SIR,
0.90 (0.252.30); RR,*
†
0.55 (NS )
0.89 (0.671.18)
6; 4
3
48
Key: CI = Confidence Interval; SIR = Standardized Incidence Ratio; RR = Relative Risk; NS = Not 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 2008. Plast Reconstr Surg 2009;123:790-3.
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:
(n=9)
(n=2)
Mean years (range)
11.7 (1-23)
10.5 (7-14)
Prior cancer (non-T-cell lymphoma):
Yes
12 (41%)
1 (14%)
8=breast, affected
x
x
1=breast, contralateral
x
-1=breast, side unknown
x
-1=breast, contralateral
x
-and Hodgkin’s lymphoma
1=Hodgkin’s lymphoma
x
-No
1 (3%)
-Not reported
16 (55%)
6 (86%)
Time between first prior cancer and breast
(n=10)
(n=1)
diagnosis:
Mean years (range)
14.7 (7-32)
9
Prior T-cell lymphoma:
Yes
2 (7%)
1 (14%)
1=cutaneous ALCL
x
-1=systemic ALCL
x
-1=Mycosis Fungoides
-x
No
--Not reported
27 (93%)
6 (86%)
Time between T-cell lymphoma and breast
(n=2)
(n=1)
diagnosis:
Mean years (range)
1.8 (1-2.5)
4
Affected breast:
Left
12 (41%)
2 (29%)
Right
16 (55%)
1 (14%)
Bilateral
1 (3%)
2 (29%)
Not reported
-2 (29%)
Placement of implant:
Subglandular
--Subpectoral
2 (7%)
1 (14%)
Not reported
27 (93%)
6 (86%)
Years having implant:
(n=27)
(n=7)
Mean years (range)
6.9 (0.2-19)
10.6 (0.3-22)
Surface:
Smooth
--Textured
6 (21%)
1 (14%)
Not reported
23 (79%)
6 (86%)
Covering:
Silicone
1 (3%)
1 (14%)
Polyurethane, foam
5 (17%)
1 (14%)
Polyurethane, not specified
-2 (29%)
Not reported
23 (79%)
3 (43%)
Type of implant:
Saline
16 (55%)
-Silicone
11 (38%)
6 (86%)
Not reported
2 (7%)
1 (14%)
Manufacturer/model:
Dow-Corning
-2 (29%)
McGhan (1=Style 168; 4=unspecified)
4 (14%)
1 (14%)
Meme, Surgitek, Bristol-Meyers-Squibb
-1 (14%)
Nagor (1=SFX-HP250; 1=R)
2 (7%)
-Replicon
-1 (14%)
Rolfil PIP Hydrogel
1 (3%)
-Not reported
22 (76%)
2 (29%)
Key: ALCL = Anaplastic Large Cell Lymphoma (including 1 ALCL/Primary Effusion Lymphoma); NHL = Non-Hodgkin’s Lymphoma
D
E
T
P
E
C
C
A
(including 2 Follicular Lymphomas, 1 Lymphoplasmacytic Lymphoma, 2 Sézary Syndromes, and 2 Mycosis Fungoides)
Online Supplemental Digital Content
ALCL*
(n=29)
Other TCL
(n=7)
FL
(n=2)
LPL
(n=1)
MF
(n=2)
Age at
diagnosis:
Mean years
(range)
50.5
(28-87)
46.9
(35-56)
49.5
(43-56)
55
44
(35-53)
≤ 31
31 – 35
36 – 40
41 – 45
46 – 50
51 – 55
56 – 60
61 – 65
> 65
2 (7%)
2 (7%)
3 (8%)
6 (16%)
3 (8%)
3 (8%)
3 (8%)
3 (8%)
4 (14%)
-1 (14%)
1 (14%)
1 (14%)
1 (14%)
2 (29%)
1 (14%)
---
---1 (50%)
--1 (50%)
---
7 (100%)
Gender:
Female
Textured
Not reported
Prior implant
polyurethane
covering:
Not reported
Prior implant
type:
Total
(n=36)
43
(38-48)
49.8
(28-87)
--1 (50%)
-1 (50%)
-----
2 (6%)
3 (8%)
4 (11%)
7 (19%)
4 (11%)
5 (14%)
4 (11%)
3 (8%)
4 (11%)
D
E
T
P
-----1
(100%)
----
-1 (50%)
---1 (50%)
----
2 (100%)
1
(100%)
2 (100%)
2 (100%)
36 (100%)
NR
NR
NR
NR
NR
4 (11%)
32 (89%)
NR
NR
NR
NR
NR
--
1 (3%)
28 (97%)
NR
NR
NR
NR
NR
1 (3%)
35 (97%)
7 (24%)
22 (76%)
NR
NR
NR
NR
NR
7 (19%)
29 (81%)
NA
NA
NA
NA
NA
E
C
29 (100%)
C
A
Race:
White
Not reported
BMI:
Not reported
Current/previ
ous smoker:
Yes
Not reported
Prior implant:
Yes
Not reported
Prior implant
size:
Not reported
Prior implant
surface:
SS
(n=2)
4 (14%)
25 (86%)
NR
NR
(n=9
implants
in 7 pts.)
-(n=9
implants
in 7 pts.)
NA
NA
NA
NA
NA
1 (11%)
8 (89%)
1 (11%)
8 (89%)
NA
NR
(n=9
implants
NA
NA
NA
NA
-(n=9
implants
Saline
Silicone
Double-lumen
silicone
Not reported
Prior implant
manufacturer
:
Not reported
Years having
any implant:
Mean years
(range)
Prior cancer
(non-T-cell
lymphoma):
Yes
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)
(n=2)
10.5
(7-14)
10.5
(7-14)
12 (41%)
x
x
x
x
1 (14%)
x
----
1 (50%)
x
----
1=bre
ast,
contralateral
1=bre
ast, side
unknown
1=bre
ast,
contralateral
and
Hodgkin’s
disease
1=Hod
gkin’s disease
No
Not reported
Time between
first prior
cancer and
breast
diagnosis:
Mean years
(range)
Prior
radiation:
Yes
No
Not reported
Prior
chemotherap
y:
Yes
No
Not reported
Implant
x
1 (3%)
16 (55%)
--6 (86%)
--1 (50%)
(n=10)
(n=1)
(n=1)
14.7
(7-32)
9
9
(n=12)
2 (17%)
2 (17%)
8 (67%)
(n=1)
1 (100%)
---
(n=1)
1 (100%)
---
(n=12)
7 (58%)
2 (17%)
3 (25%)
(n=1)
-1 (100%)
--
(n=1)
-1 (100%)
--
(n=7)
(n=1)
(n=1)
NR
C
A
E
C
NR
-(n=11)
11.5
(1-23)
D
E
NR
T
P
NR
in 7 pts.)
1 (11%)
2 (22%)
1 (11%)
5 (56%)
NR
13 (36%)
NR
1 (3%)
22 (61%)
(n=11)
NA
NA
NA
NA
NA
NA
NA
14.1
(7-32)
NA
(n=13)
3 (23%)
2 (15%)
8 (62%)
NA
(n=13)
7 (54%)
3 (23%)
3 (23%)
(n=8)
timing to
therapy:
After
Before
Prior T-cell
lymphoma:
Yes
1=cuta
neous ALCL
1=syst
emic ALCL
1=MF
No
Not reported
Time between
T-cell
lymphoma
and breast
diagnosis:
Mean years
(range)
Affected
breast:
Left
Right
Bilateral
Not reported
Placement of
implant:
Subglandular
Subpectoral
Not reported
Years having
implant:
Mean years
(range)
5 (71%)
2 (29%)
1 (100%)
--
2 (7%)
x
x
--27 (93%)
1 (14%)
--x
-6 (86%)
(n=2)
(n=1)
1.8
(1-2.5)
4
NR
1 (50%)
1 (50%)
---
-1 (14%)
6 (86%)
-1 (50%)
1 (50%)
(n=27)
6.9
(0.2-19)
(n=7)
10.6
(0.3-22)
10
(6-14)
2 (7%)
10 (37%)
10 (37%)
2 (7%)
3 (11%)
1 (14%)
1 (14%)
1 (14%)
2 (29%)
2 (29%)
--1 (50%)
1 (50%)
--
16 (55%)
10 (34%)
3 (10%)
3 (43%)
1 (14%)
3 (43%)
-1 (50%)
1 (50%)
(n=10)
2 (20%)
4 (40%)
4 (40%)
(n=1)
-1 (100%)
--
(n=1)
-1 (100%)
--
(n=6)
NA
NA
6 (75%)
2 (25%)
--
3 (8%)
NR
1 (50%)
--x
-1 (50%)
-2 (100%)
-33 (92%)
D
E
T
P
NA
2 (29%)
1 (14%)
2 (29%)
2 (29%)
-2 (7%)
27 (93%)
NA
(n=1)
E
C
12 (41%)
16 (55%)
1 (3%)
--
C
A
<1
1–5
6–10
11–15
> 15
Reason for
initial
implant:
Cosmetic
Mastectomy
Not reported
Mastectomy
reconstructio
n:
Immediate
Delayed
Not reported
Reconstructi
1 (100%)
--
NA
4
NR
1 (50%)
-1 (50%)
--
(n=3)
NA
2.5
(1-4)
--1 (50%)
1 (50%)
14 (39%)
17 (47%)
3 (8%)
2 (6%)
NR
NR
NR
-3 (8%)
33 (92%)
17
16.7
(11.4-22)
1.8
(0.3-3.3)
(n=34)
8.1
(0.2-22)
NR
---1 (50%)
1 (50%)
1 (50%)
1 (50%)
----
3 (9%)
11 (32%)
11 (32%)
4 (12%)
5 (15%)
NR
1 (50%)
-1 (50%)
2 (100%)
---
19 (53%)
11 (31%)
6 (17%)
NA
(n=11)
2 (18%)
5 (45%)
4 (36%)
NA
NA
(n=7)
on expander
used:
Yes, type
unspecified
Not reported
Size of
affected
implant:
Mean cc
(range)
Surface:
Smooth
Textured
Not reported
Covering:
Silicone
Polyurethane,
foam
Polyurethane,
not specified
Not reported
Type of
implant:
Saline
Silicone
Not reported
Manufacturer/
model:
Dow-Corning
McGhan
(1=Style 168;
4=unspecified)
Meme,
Surgitek,
BristolMeyersSquibb
Nagor
(1=SFXHP250; 1=R)
Replicon
Rolfil PIP
Hydrogel
Not reported
# surgical
revisions to
affected
breast:
Mean number
(range)
Not reported
Recent breast
trauma:
Yes
Not reported
1 (17%)
5 (83%)
NR
NR
NA
NA
NA
(n=3)
483
(250-650)
NR
NR
NR
NR
NR
-6 (21%)
23 (79%)
-1 (14%)
6 (86%)
-1 (50%)
1 (50%)
1 (3%)
5 (17%)
-23 (79%)
1 (14%)
1 (14%)
2 (29%)
3 (43%)
1 (50%)
-1 (50%)
--
C
A
-6 (86%)
1 (14%)
-1 (50%)
1 (50%)
2 (29%)
1 (14%)
1 (14%)
-1 (14%)
-2 (29%)
-1 (50%)
--1 (50%)
---
NR
-1
(100%)
--
NR
(n=3)
483
(250-650)
D
E
NR
-7 (19%)
29 (81%)
-1 (50%)
-1 (50%)
2 (6%)
6 (17%)
2 (6%)
26 (72%)
-2 (100%)
--
-2 (100%)
--
16 (44%)
17 (47%)
3 (8%)
2 (100%)
-------
--1 (50%)
---1 (50%)
2 (6%)
5 (14%)
1 (3%)
2 (6%)
1 (6%)
1 (6%)
24 (67%)
NR
T
P
E
C
16 (55%)
11 (38%)
2 (7%)
-4 (14%)
-2 (7%)
-1 (3%)
22 (76%)
NR
1 (14%)
6 (86%)
--1 (50%)
1 (50%)
(n=7)
1.7 (1-3)
22
NR
NR
NR
NR
NR
(n=7)
1.7 (1-3)
22
1 (3%)
28 (97%)
NR
NR
NR
NR
NR
1 (3%)
35 (97%)
Pain:
Yes
No
Not reported
Swelling:
Yes
No
Not reported
Redness:
Yes
No
Not reported
Capsular
contraction:
Yes (1=II;
1=IV;
1=unspecified)
No
Not reported
Palpable
mass:
Yes
No
Not reported
Other:
Yes:
Erythematous
lesion(s)/ulcer
-Scaling of
palms and
soles
-Urticaria,
exfoliative
erythroderma
-Recurrent
low-grade
fever
Subcutaneous
nodules
Not reported
Duration of
symptoms:
Mean years
(range)
Antibiotics:
Yes
No
Not reported
Aspiration:
Yes
No
Not reported
Affected
6 (21%)
2 (7%)
21 (72%)
2 (29%)
-5 (71%)
1 (50%)
-1 (50%)
14 (48%)
-15 (52%)
NR
4 (14%)
-25 (86%)
4 (57%)
-3 (43%)
NR
2 (7%)
-27 (93%)
1 (14%)
-6 (86%)
1 (50%)
-1 (50%)
7 (24%)
5 (17%)
17 (59%)
1 (14%)
-6 (86%)
1 (50%)
-1 (50%)
NR
NR
E
C
(n=7)
0.8
(0.2-1.7)
(n=5)
5.4
(0.5-17)
C
A
2 (7%)
-27 (93%)
12 (41%)
-17 (59%)
NR
NR
NR
NR
NR
NR
1 (50%)
-1 (50%)
8 (22%)
2 (6%)
26 (72%)
NR
NR
NR
14 (39%)
-22 (61%)
NR
2 (100%)
---
2 (100%)
---
8 (22%)
-28 (78%)
D
E
T
P
2 (6%)
x
x
27 (94%)
5 (71%)
x
x
x
x
-2 (29%)
--2 (100%)
NR
NR
NR
3 (9%)
-33 (91%)
8 (22%)
5 (14%)
23 (64%)
NR
NR
NR
1
(100%)
---x
---
2 (100%)
x
------
2 (100%)
-x
x
----
29 (81%)
17
3
(2-4)
1.9
(0.5-3.3)
(n=12)
2.7
(0.2-17)
NR
2 (6%)
-34 (94%)
NR
12 (33%)
-24 (67%)
NR
NR
NR
NR
7 (19%)
implant
exchanged:
Yes
No
Not reported
Contralateral
implant
exchanged:
Yes
No/Not
applicable
Not reported
Affected
implant
ruptured
before
surgery:
Yes
No
Not reported
Contralateral
implant
ruptured
before
surgery:
Yes
No/Not
applicable
Not reported
Affected
implant
ruptured
during
surgery:
Yes
No/Not
applicable
Not reported
Contralateral
implant
ruptured
during
surgery:
Yes
No/Not
applicable
Not reported
Surgical
removal of
affected
implant:
Yes
No
Not reported
Surgical
5 (17%)
2 (7%)
22 (76%)
NR
2 (7%)
2 (7%)
25 (86%)
NR
2 (7%)
9 (31%)
18 (62%)
2 (29%)
1 (14%)
4 (57%)
NR
NR
C
A
-2 (29%)
5 (71%)
-4 (57%)
3 (43%)
NR
NR
NR
NR
NR
1
(100%)
---
-1 (50%)
1 (50%)
NR
-1
(100%)
--
-8 (28%)
21(72%)
-2 (29%)
5 (71%)
NR
NR
20 (69%)
1 (3%)
8 (28%)
5 (71%)
1 (14%)
1 (14%)
1 (50%)
-1 (50%)
1
(100%)
---
NR
NR
2 (6%)
2 (6%)
32 (89%)
D
E
1 (50%)
-1 (50%)
4 (11%)
10 (28%)
22 (61%)
-1 (50%)
1 (50%)
-1 (50%)
1 (50%)
-8 (22%)
28 (78%)
-1 (50%)
1 (50%)
-2 (100%)
--
-16 (44%)
20 (56%)
-1 (50%)
1 (50%)
-1 (50%)
1 (50%)
-10 (28%)
26 (72%)
1 (50%)
1 (50%)
--
2 (100%)
---
25 (69%)
2 (6%)
9 (38%)
T
P
NR
E
C
-6 (21%)
23 (79%)
-12 (41%)
17 (59%)
NR
5 (14%)
2 (6%)
29 (81%)
removal of
contralateral
implant:
Yes,
concurrent
Yes,
sequential
Yes, not
specified
No/Not
applicable
Not reported
Capsulectom
y:
Yes
No
Not reported
Mass:
Yes
No
Not reported
Size of mass:
Mean cm
(range)
Cancer
associated
with capsule:
Yes
Not applicable
Not reported
Capsule
inflammation:
Yes
Not applicable
Not reported
Seroma:
Yes
No
Not reported
Positive
cytology from
aspirated
fluid:
Yes
No
Not reported
Stage:
I
II
III
IV
Not reported
3 (10%)
1 (3%)
1 (3%)
2 (6%)
22 (76%)
--
5 (71%)
--1 (14%)
1 (14%)
--
21 (72%)
3 (10%)
5 (17%)
3 (43%)
1 (14%)
3 (43%)
9 (31%)
5 (17%)
15 (52%)
(n=6)
3.5 (1-10)
20 (69%)
3 (10%)
6 (21%)
ALK status:
Negative
14 (48%)
1 (3%)
14 (48%)
(n=14)
11 (79%)
1 (7%)
2 (14%)
21 (72%)
4 (14%)
-1 (3%)
3 (10%)
25 (86%)
1
(100%)
------
NR
NR
NA
NA
2 (29%)
2 (29%)
3 (43%)
2 (29%)
2 (29%)
3 (43%)
NR
NR
1 (50%)
--1 (50%)
---
2 (100%)
------
1 (50%)
1 (50%)
--
2 (100%)
---
24 (67%)
4 (11%)
8 (22%)
NR
NR
8 (22%)
1 (3%)
1 (3%)
3 (9%)
23 (64%)
--
D
E
T
P
NR
E
C
C
A
5 (17%)
3 (10%)
21(72%)
1 (50%)
---1 (50%)
--
NR
NR
NA
NA
NA
9 (25%)
5 (14%)
22 (61%)
(n=6)
3.5 (1-10)
-1
(100%)
--
1 (50%)
1 (50%)
--
1 (50%)
-1 (50%)
22 (61%)
5 (14%)
9 (25%)
-1
(100%)
--
1 (50%)
1 (50%)
--
1 (50%)
-1 (50%)
7 (19%)
5 (14%)
24 (67%)
NR
NR
NR
NR
NR
NA
NA
NA
NA
NA
14 (39%)
1 (3%)
21 (58%)
(n=14)
11 (79%)
1 (7%)
2 (14%)
1 (14%)
--6 (86%)
--
---2 (100%)
--
---1
(100%)
--
1 (50%)
--1 (50%)
--
---2 (100%)
--
22 (61%)
4 (11%)
-7 (19%)
3 (8%)
25 (86%)
Positive
Not reported
Radiation:
Yes
No
Not reported
Chemotherap
y/other:
Yes:
11=C
HOP
1=CH
OP + ICE
1=Not
specified
Other:
Photo
phoresis and
interferon
PUVA
and interferon
No
Not reported
Reconstructi
on:
Yes, LDF with
expander of
unknown type
No
Not reported
Reimplantatio
n:
Yes
No
Not reported
Size of new
implant:
Mean cc
(range)
Surface:
Not reported
Type:
Saline
Silicone
Not reported
Manufacturer/
model:
Not reported
Follow-up
reported:
Yes
No
Duration of
follow-up:
Mean years
-4 (14%)
NA
NA
12 (41%)
4 (14%)
13 (45%)
2 (29%)
2 (29%)
3 (43%)
-1 (50%)
1 (50%)
13 (45%)
x
x
x
---4 (14%)
12 (41%)
----2 (29%)
x
x
1 (14%)
4 (57%)
-------1 (50%)
1 (50%)
C
A
2 (6%)
3 (10%)
24 (83%)
NR
NR
NA
NA
-4 (14%)
NR
1 (50%)
1 (50%)
--
1 (50%)
-1 (50%)
14 (39%)
6 (17%)
16 (44%)
----1 (50%)
-x
-1 (50%)
----1 (50%)
x
--1 (50%)
13 (36%)
---2 (6%)
--5 (14%)
16 (44%)
NR
1 (3%)
4 (11%)
31 (86%)
D
E
T
P
E
C
1 (3%)
4 (14%)
24 (83%)
NA
NR
NR
NR
NR
NR
NR
NR
NR
2 (6%)
3 (8%)
31 (86%)
NR
NA
NA
NA
NA
NA
--
NR
(n=2)
1 (50%)
1 (50%)
--
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
-(n=2)
1 (50%)
1 (50%)
--
NR
NA
NA
NA
NA
NA
--
16 (55%)
13 (45%)
4 (57%)
3 (43%)
NR
NR
2 (100%)
--
2 (100%)
--
20 (56%)
16 (44%)
(n=13)
2.1
(0.1-9)
(n=3)
5.5
(1.1-12)
NA
NA
(n=1)
3.3
(n=2)
6.6
(1.1-12)
(n=16)
2.7
(0.1-12)
(range)
(n=16)
Recurrence
(n=4)
(n=2)
(n=2)
1 (6%)
1 (25%)
NA
NA
1 (50%)
-of disease:
Yes
12 (75%)
2 (50%)
-2 (100%)
No
3 19%)
1 (25%)
1 (50%)
-Not reported
Vital status:
(n=16)
(n=4)
(n=2)
(n=2)
Alive
16 (100%)
3 (75%)
NA
NA
1 (50%)
2 (100%)
Dead
-1 (25%)
1 (50%)
-Table A. Detailed summary of ALCL and other NHL cases in patients with breast implants,
(n=20)
2 (10%)
14 (70%)
4 (20%)
(n=20)
19 (95%)
1 (5%)
D
E
Supplemental Digital Content 1
T
P
Key: NR = Not Reported; NA = Not 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
E
C
Mass Index; CHOP = Cyclophosphamide, Hydroxydaunorubicin, Oncovin, Prednisone; ICE = Ifosfamide,
Carboplatin, Etoposide; PUVA = Psoralen and UltraViolet A; LDF = Latissimus Dorsi Flap
C
A
Online Supplemental Digital Content
Table B. Individual cases of ALCL and other NHL in patients with breast implants, Supplemental Digital
Content 2
D
E
T
P
E
C
C
A
Key: F = Female; R = Right; L = Left; NR = Not Reported; NA = Not Applicable; ALCL = Anaplastic Large Cell
Lymphoma; FL = Follicular Lymphoma; LPL = Lymphoplasmacytic Lymphoma; SS = Sézary Syndrome; MF =
Mycosis Fungoides
Figure 1
D
E
T
P
C
A
E
C
Figure 2
D
E
T
P
C
A
E
C
Figure 3
D
E
T
P
C
A
E
C