Clinical Review & Education

JAMA Surgery | Review

Breast Implant–Associated Anaplastic Large Cell Lymphoma

A Systematic Review
Ashley N. Leberfinger, MD; Brittany J. Behar, MD; Nicole C. Williams, MD, MBA; Kevin L. Rakszawski, MD;
John D. Potochny, MD; Donald R. Mackay, DDS, MD; Dino J. Ravnic, DO, MPH

Supplemental content
IMPORTANCE Breast implant–associated anaplastic large cell lymphoma (BIA-ALCL), a rare
peripheral T-cell lymphoma, is increasing in incidence. However, many practitioners who treat
patients with breast cancer are not aware of this disease.

OBJECTIVES To assess how BIA-ALCL develops, its risk factors, diagnosis, and subsequent
treatment and to disseminate information about this entity to the medical field.

EVIDENCE REVIEW A literature review was performed in an academic medical setting. All
review articles, case reports, original research articles, and any other articles relevant to
BIA-ALCL were included. Data on BIA-ALCL, such as pathophysiology, patient demographics,
presentation, diagnosis, treatment, and outcomes, were extracted. Particular focus was paid
to age, time to onset, implant type, initial symptoms, treatment, and survival. The search was
conducted in January 2017 for studies published in any year.

FINDINGS After duplicates were excluded, 304 relevant articles were assessed, and 115 were
included from the first documented case in August 1997 through January 2017. Thirty review
articles, 44 case reports or series, 15 original research articles, and 26 “other” articles (eg,
techniques, special topics, letters) were reviewed. A total of 93 cases have been reported in
the literature, and with the addition of 2 unreported cases from the Penn State Health Milton
S. Hershey Medical Center, 95 patients were included in this systematic review. Almost all
documented BIA-ALCL cases have been associated with a textured device. The underlying
mechanism is thought to be due to chronic inflammation from indolent infections, leading to
malignant transformation of T cells that are anaplastic lymphoma kinase (ALK) negative and
CD30 positive. The mean time to presentation is approximately 10 years after implant
placement, with 55 of 83 (66%) patients initially seen with an isolated late-onset seroma and
7 of 83 (8%) with an isolated new breast mass. Ultrasonography with fluid aspiration can be
used for diagnosis. Treatment must include removal of the implant and surrounding capsule.
More advanced disease may require chemotherapy, radiotherapy, and lymph node dissection.

CONCLUSIONS AND RELEVANCE Breast implant–associated anaplastic large cell lymphoma is a

rare cancer in patients with breast implants but is increasing in incidence. It is important for all
Author Affiliations: Division of
physicians involved in the care of patients with breast implants to be aware of this entity and Plastic Surgery, Department of
be able to recognize initial symptoms. Surgery, Penn State Health Milton S.
Hershey Medical Center, Hershey,
Pennsylvania (Leberfinger, Behar,
Potochny, Mackay, Ravnic);
Department of Pathology and
Laboratory Medicine, Penn State
Health Milton S. Hershey Medical
Center, Hershey, Pennsylvania
(Williams); Division of Hematology/
Oncology, Department of Medicine,
Penn State Health Milton S. Hershey
Medical Center, Hershey,
Pennsylvania (Rakszawski).
Corresponding Author: Dino J.
Ravnic, DO, MPH, Division of Plastic
Surgery, Department of Surgery,
Penn State Health Milton S. Hershey
Medical Center, 500 University Dr,
JAMA Surg. doi:10.1001/jamasurg.2017.4026 Hershey, PA 17033
Published online October 18, 2017. (dravnic@pennstatehealth.psu.edu).

(Reprinted) E1
© 2017 American Medical Association. All rights reserved.

Downloaded From: on 10/19/2017

 Clinical Review & Education Review
D
uring the past decade, more than 300 cases of anaplastic
large cell lymphoma (ALCL) associated with breast im-
plants, including 9 deaths, have been reported to the US
Food and Drug Administration (FDA), with more than half occurring
in patients after breast reconstruction for cancer.1 The exact inci-
dence is unknown due to the lack of standardized criteria for diagno-
sis; however, it is estimated to be 1 case per 30 000 women with
implants per year, with a median time to onset after implantation of
10.7 years.2,3 A prospective study4 on Natrelle (Allergan) 410 breast
implant risk factor analysis found that 4 patients of 17 656 who
received breast implants developed BIA-ALCL, suggesting that the
incidence may actually be closer to 1 case per 4000. The association
between breast implants and this rare peripheral T-cell lymphoma was
first noted in a 1997 article5 and has been since designated as breast
implant–associated ALCL (BIA-ALCL). Almost all known cases have
been linked to the use of textured implants.6
Breast implants are commonly perceived as a cosmetic inter-
vention. However, a large number of patients require implants for
cancer reconstruction after mastectomy. Implant-based breast re-
construction is typically performed in stages, which consist of ini-
tial tissue expander placement, followed by exchange for a perma-
nent implant. Most breast tissue expanders are currently textured,
and only textured implants are available in some countries. While
the FDA recommends periodic magnetic resonance imaging
follow-up of silicone implants to monitor for ruptures, it does not
address saline implants because rupture in these implant types is
typically clinically appreciated. Follow-up of either type of device is
frequently missed because patients and plastic surgeons may not
deem it necessary. However, patients with breast cancer typically
are adherent to medical and surgical oncologic clinical appoint-
ments. These health care professionals may be the first to encoun-
ter an implant abnormality but may unfortunately have little clini-
cal experience with how to monitor and examine implants. This may
cause an error or delay in diagnosis of BIA-ALCL, especially because
the median onset was more than a decade after implantation in our
systematic review. It is critical that physicians treating patients with
breast cancer be educated about the clinical presentation, diagnos-
tic criteria, and treatment modalities of this rare form of ALCL, which
is often curable when diagnosed early.
Methods
This systematic review was conducted according to Preferred
Reporting Items for Systematic Reviews and Meta-Analyses
(PRISMA) guidelines.7 A literature review was performed in an aca-
demic medical setting. Keywords searched were breast implant
associated anaplastic large cell lymphoma, lymphoma and breast
implants, and breast implant cancer through PubMed, EBSCOhost,
Web of Science, and Google Scholar. The search captured review
articles, case reports, original research articles, and any other ar-
ticles relevant to BIA-ALCL. The search was conducted in January
2017 for studies published in any year. Article reference lists were
also examined for applicable studies. Articles not published in Eng-
lish, commentaries or discussions, and studies on systemic ALCL were
excluded. Data on BIA-ALCL, such as pathophysiology, presenta-
tion, diagnosis, treatment, and outcomes, were extracted. Demo-
graphic and clinical data on the patients, including age, time to
E2 JAMA Surgery Published online October 18, 2017 (Reprinted)
© 2017 American Medical Association. All rights reserved.
Downloaded From: on 10/19/2017
Breast Implant–Associated Anaplastic Large Cell Lymphoma
Key Points
Question What is the incidence of breast implant–associated
anaplastic large cell lymphoma?
Findings In this systematic review of 115 articles and 95 patients,
the incidence of breast implant–associated anaplastic large cell
lymphoma remains controversial, but the diagnosis appears to be
increasing as both patients and practitioners become more aware
of this entity.
Meaning Before breast augmentation or reconstruction, surgeons
need to convey the risk of breast implant–associated anaplastic
large cell lymphoma to patients, with particular emphasis on the
established linkage to textured implants; patients must be
educated on the importance of routine surveillance after
implantation, and it is likely that increased follow-up will lead
to a further rise in this diagnosis.
onset, implant type, initial symptoms, treatment, and survival, were
also extracted, when possible. The data were recorded on an elec-
tronic data collection sheet, and duplicate articles were attempted
to be identified.
Results
After duplicates were excluded, 304 relevant articles were
assessed. After articles not published in English, commentaries or dis-
cussions, and studies on systemic ALCL were excluded, 115 articles
were included from the first documented case in August 1997 through
January 2017 (eFigure in the Supplement). Thirty review articles,
44 case reports or series, 15 original research articles, and 26 “other”
articles (eg, techniques, special topics, letters) were reviewed, with
93 cases reported in the literature. With the addition of 2 unre-
ported cases from Penn State Health Milton S. Hershey Medical
Center, 95 patients were included in this systematic review. Clinico-
pathological data were not available in every article; therefore, there
are varying denominators for various characteristics.
Pathophysiology
Development of BIA-ALCL is likely a complex process involving many
factors, including bacterial biofilm growth, textured implant sur-
face, immune response, and patient genetics. Textured implants
were first introduced in the late 1980s as a means to help prevent
capsular contracture, and their use significantly increased in the
1990s.8,9 The first case of BIA-ALCL was documented in a 1997
article.5 Anaplastic lymphoma kinase (ALK) is a tyrosine kinase re-
ceptor that is elevated in 60% of patients with systemic ALCL.10
However, it has never been reported with BIA-ALCL to date. The
absence of ALK in patients with BIA-ALCL suggests that its associa-
tion with breast implants is not coincidental. To our knowledge, no
cases have been documented from the pre–textured implant era,
which suggests a causal relationship with textured implants. All
implant manufacturers have had cases of ALCL associated with their
implants.1 Breast implant–associated anaplastic large cell lym-
phoma is thought to be related to inflammation possibly second-
ary to a reactive process due to the breast implant.11 It is well estab-
lished in the literature that chronic inflammation can lead to
jamasurgery.com
 Breast Implant–Associated Anaplastic Large Cell Lymphoma
Table 1. Clinicopathological Features of 95 Patients
With Breast Implant–Associated Anaplastic Large Cell Lymphoma
Included in the Systematic Review
Variable Value
Age at onset, mean, y (n = 94) 51
Time to onset, y (n = 85) 10
Type of surgery, No./total No. (%)
Reconstruction 43/80 (54)
Cosmetic 37/80 (46)
Type of implant, No./total No. (%)
Saline 31/80 (39)
Silicone 49/80 (61)
Initial presentation, No./total No. (%)
Seroma 55/83 (66)
Mass 7/83 (8)
Both seroma and mass 6/83 (7)
Other 15/83 (18)
lymphoma.12 Tissue ingrowth into the pores of textured implants is
thought to prolong chronic inflammation, and CD4 T cells have been
found to be the predominate cell type.13 In addition, recent studies
showed mutations in the JAK/STAT signaling pathway14 with SOCS1
(OMIM 603597), and other somatic mutations, including TP53
(OMIM 191170) and DNMT3A (OMIM 602769), are present in samples
from patients with BIA-ALCL.15
The time course for development of BIA-ALCL is also consis-
tent with the period required for a chronic biofilm to produce
inflammation, immune activation, and transformation to cancer.16
Textured implants develop a significantly higher load of bacterial
biofilm compared with smooth implants.17 In one study,16 analysis
of the contralateral breast without BIA-ALCL showed a similar
microbiome but significantly fewer bacteria. Hu et al16 found
Ralstonia species, a nonfermenting gram-negative bacillus, in 5 of
10 BIA-ALCL samples. Helicobacter pylori, which is known to cause
gastric lymphoma, is also a nonfermenting gram-negative bacillus18
and is thought to cause T-cell lymphoma. However, this theory has
not been fully substantiated as causal yet.19
Clinical Presentation
In our systematic review, the mean age at onset of BIA-ALCL was 51
years. Breast reconstruction patients were older (mean age, 57 years)
compared with cosmetic surgery patients (mean age, 46 years)
(P < .001), likely because of the increased prevalence of receiving
cosmetic implants at a younger age. The most common clinical pre-
sentation is a late peri-implant effusion,20,21 with patients first seen
with reports of breast enlargement. Sixty-six percent of patients in
our systematic review were initially seen with a seroma, 8% with a
mass, 7% with both a mass and seroma, and 18% with other enti-
ties (Table 1), including capsular contracture, 8,22,23 axillary
lymphadenopathy,24,25 skin lesions,26,27 and B-type symptoms (ie,
fever, lymphadenopathy, night sweats, and fatigue).28,29 In our
systematic review, 10% (9 of 95 patients) had axillary lymphade-
nopathy reported on initial presentation; however, Clemens et al30
described axillary metastases in 14.9% of patients in their recent
publication. While some studies implicate 2 different types of
BIA-ALCL (seroma vs mass),16 others suggest that these represent
less and more aggressive variants of the same cancer.31,32 The right
and left breast are affected equally, with 4 reported patients hav-
jamasurgery.com
© 2017 American Medical Association. All rights reserved.
Downloaded From: on 10/19/2017
Review Clinical Review & Education
ing bilateral breast involvement.23,33,34 In our systematic review,
most women had breast implants in place for a mean of approxi-
mately 10 years before diagnosis (8.6 years for reconstruction vs 9.9
years for cosmetic surgery, P = .29), with 43 of 80 (54%) in place
after reconstructive surgery for breast cancer and 37 of 80 (46%)
after cosmetic surgery. Patients with silicone implants seem to be
affected more often than those with saline implants, representing
49 of 80 (61%) and 31 of 80 (39%), respectively (Table 1). This may
be related to the greater use of textured anatomic silicone
implants more recently.
Assessment and Diagnosis
Ultrasound is usually the first study of choice to evaluate a woman
who reports breast swelling, but magnetic resonance imaging is also
sometimes used (Figure 1). In addition, ultrasound can be used for
image-guided fine-needle aspiration of fluid. On gross examina-
tion, the fluid often appears thick and cloudy. Cytological analysis
of peri-implant fluid shows large pleomorphic, epithelioid lympho-
cytes with abundant cytoplasm27 and an eccentric, kidney-shaped
nucleus (hallmark cells) with prominent nucleolus36 (Figure 2A).
Immunohistochemistry is used to confirm the diagnosis. Breast
implant–associated anaplastic large cell lymphoma is CD30 posi-
tive (Figure 2B), epithelial membrane antigen positive, and ALK
negative.37 CD30 is expressed on activated B cells and T cells.38
Epithelial membrane antigen is overexpressed in several cancers,
including breast cancer,39 and ALK (OMIM 105590) is a fusion gene
present in up to 70% of systemic ALCL.40 T-cell antigen expression
is variable, with the most frequently expressed markers being CD4,
CD3, CD45, and CD2, in decreasing order.36,41 Molecular analysis
shows monoclonal T-cell receptor (TCR) γ gene rearrangement.27 The
tumor cell layer on the surrounding capsule can be thin and discon-
tinuous, leading to false negative with capsule histology. In addi-
tion, in less aggressive cases, the tumor cell layer is usually con-
fined to the inner capsule (Figure 2C and D). When a mass is present,
the cells often exhibit a sheetlike growth, giving a multinodular
appearance with areas of geographic necrosis and sclerosis.27
Confirmed cases are reported to the American Society of Plastic
Surgeons’ Patient Registry and Outcomes for Breast Implants and
Anaplastic Large Cell Lymphoma Etiology and Epidemiology
(PROFILE) registry, which is kept in collaboration with the FDA, and
to the implant companies themselves.
After histologic confirmation of BIA-ALCL, further lymphoma
workup and staging are recommended. Each case should ideally be
discussed at a multidisciplinary team conference consisting of sur-
geons, medical oncologists, radiologists, and hematopathologists.
Routine laboratory work should include complete blood cell count
with differential, comprehensive metabolic panel, and lactate de-
hydrogenase level. For staging, positron emission tomography and
computed tomography (PET/CT) is the preferred imaging modality
to assess for systemic disease.42 The timing of PET/CT remains
debatable and is most frequently performed after surgery to allow
adequate time for postsurgical wound healing and to minimize the
risk of false-positive [18F]-fluorodeoxyglucose avidity.
Treatment
In our systematic review, 62 of 74 (84%) patients had at least a com-
plete capsulectomy and removal of the implant. Sixty-one percent
(45 of 74) of patients had some form of chemotherapy, with the most
(Reprinted) JAMA Surgery Published online October 18, 2017 E3
 Clinical Review & Education Review
Figure 1. Assessment of Patients With Late Peri-implant Seromas
A Schematic representation
Breast parenchyma
Fibrous capsule
Malignant lymphoma cells
Lymphoma cells within effusion fluid
Breast implant
C Affected breast axillary loculated (left), medial (middle), and inferior (right) fluid collection
A, Schematic representation by Thompson et al35 of effusion-associated
anaplastic large cell lymphoma after breast augmentation (reprinted with
permission from Haematologica). The septated effusion is contained between
the implant and the fibrous capsule that surrounds the implant. The malignant
cells are contained within the effusion fluid and adherent to the fibrous capsule
within a serofibrinous exudate. There is no invasion beyond the fibrous capsule
common therapy being cyclophosphamide, hydroxydaunorubicin,
vincristine, and prednisone (CHOP), and 22 of 74 (30%) received
adjuvant radiotherapy. In total, 46 of 67 (69%) patients were ini-
tially seen with stage I disease, 16 of 67 (24%) with stage II, 4 of 67
(6%) with stage III, and 1 of 67 (2%) with stage IV. Six patients
underwent neoadjuvant chemotherapy before planned capsulec-
tomy, and 1 patient required capsulectomy to be performed for
recurrence after chemotherapy.
Patients with systemic ALK-negative ALCL typically are initially
seen with advanced disease and have poor outcomes, which is in
contrast to BIA-ALCL, which has an indolent course and favorable
outcomes in most patients.43 Lymphoma benefiting from surgical
resection is in contrast to the normal paradigm for lymphoma man-
agement, which involves systemic chemotherapy, radiotherapy, or
both. Breast implant–associated anaplastic large cell lymphoma be-
haves more like a solid tumor than lymphoma. Therefore, Clemens
et al30 suggested using TNM staging, typically used for solid tu-
mors, instead of the Ann Arbor staging classification (Table 2)44 that
is used for lymphoma. Based on expert consensus from multiple
specialties, treatment guidelines were developed. Case reports from
our systematic review suggest that patients with localized disease
E4 JAMA Surgery Published online October 18, 2017 (Reprinted)
© 2017 American Medical Association. All rights reserved.
Downloaded From: on 10/19/2017
Breast Implant–Associated Anaplastic Large Cell Lymphoma
B Affected breast (left) and unaffected breast (right)
into the breast parenchyma. B, T2-weighted breast magnetic resonance images
of anaplastic large cell lymphoma in the affected right breast (left) and
unaffected left breast (right) of a patient. C, Ultrasound images of the patient’s
right breast axillary loculated fluid collection (left), medial fluid collection
(middle), and inferior fluid collection (right).
(seroma or stage I) seem to follow an indolent course; therefore, it
is reasonable to perform complete capsulectomy and implant re-
moval, without further intervention. Total capsulectomy is ad-
equate for resection. Typical margins used in traditional breast
cancer surgery are not required. After complete excision, surveil-
lance examinations every 3 to 6 months and interval imaging with
CT of the chest, abdomen, and pelvis or PET/CT every 6 months are
recommended for the first 2 years. If complete excision is not tech-
nically feasible or surgical pathology reveals incomplete excision or
partial capsulectomy, local radiotherapy is often used as adjuvant
therapy in the absence of systemic disease.42
Patients with more advanced disease, including a tumor mass
(stage II), lymph node involvement (stage II/III), or distant disease
(stage IV), should be referred to a medical oncologist for chemo-
therapy, radiotherapy, or both. CHOP chemotherapy with or with-
out radiotherapy has been successful in treating extended disease
(stage II-IV). Although there are no prospective data, 6 cycles of
CHOP are recommended.45 Other preferred regimens include
cyclophosphamide, hydroxydaunorubicin, vincristine, etoposide, and
prednisone (CHOEP) and dose-adjusted etoposide, prednisone,
vincristine, cyclophosphamide, and hydroxydaunorubicin
jamasurgery.com
 Breast Implant–Associated Anaplastic Large Cell Lymphoma
Figure 2. Cytology and Pathology
A Cytological analysis of breast seroma fluid B CD30-positive breast seroma fluid
C Breast capsule negative for capsule invasion D Breast capsule with CD30-positive tumor cells
Table 2. Ann Arbor Staging Classification for Lymphoma
Stage Description
I 1 Lymph node region or 1 extralymphatic site
II On the same side of the diaphragm, ≥2 lymph node
regions or localized extralymphatic extension
plus ≥1 lymph node region
III On both sides of the diaphragm, lymph node regions
with or without spleen involvement with or without
localized extralymphatic extension or both
IV Noncontiguous involvement of ≥1 extralymphatic site
with or without lymph node involvement
(EPOCH). Brentuximab vedotin, an antibody-drug conjugate
directed to CD30, has also gained favor for systemic therapy.
Prognosis
Except in advanced cases, BIA-ALCL usually has an indolent course.
Tumor nodules, axillary node involvement, bilateral breast involve-
ment, and an infiltrative pattern on capsule histology are associ-
ated with more aggressive behavior. Among 87 patients with
BIA-ALCL, Clemens et al30 showed that patients who underwent
complete surgical excision (total capsulectomy and implant re-
moval) had better overall survival (P = .022) and event-free
survival (P = .014) compared with partial capsulectomy with or
without chemotherapy and radiotherapy. In a study by Laurent
et al,37 the presence of a mass at diagnosis correlated with more ad-
vanced disease; therefore, survival rates were greater in those who
were initially seen with a seroma (11 of 11 with a seroma were alive
at 18 months, and 4 of 8 with a mass were alive at 2 years). In our
jamasurgery.com
© 2017 American Medical Association. All rights reserved.
Downloaded From: on 10/19/2017
Review Clinical Review & Education
A, Malignant lymphocyte with
eccentric kidney-shaped nucleus and
prominent nucleolus (anaplastic large
cell lymphoma hallmark cell) in breast
seroma fluid (Papanicolaou stain,
original magnification ×600).
Arrowheads indicate hallmark cells.
B, Breast seroma fluid (CD30
immunohistochemical stain, original
magnification ×400). C, Breast
capsule with minimal inflammation
and fibrosis negative for capsule
invasion (hematoxylin-eosin stain,
original magnification ×200).
D, Breast capsule luminal contents
(serofibrinous exudate) with
CD30-positive tumor cells (CD30
immunohistochemical stain, original
magnification ×400).
systematic review, 5 patients demonstrated recurrence of their
disease, and 5 patients died of their disease (n = 95). Nine deaths
among 359 patients have been reported to the FDA.6 The mean over-
all survival and disease-free survival are difficult to calculate due to
a lack of data and adequate follow-up, which varies from 1 month
to 20 years in our systematic review, with most documented less than
1 year from the time of diagnosis.
Discussion
More than 300 cases of BIA-ALCL have been reported to the FDA
(medical device reports of BIA-ALCL), but only 93 have been pub-
lished in the literature. With the inclusion of 2 additional cases
from Penn State Health Milton S. Hershey Medical Center, we
evaluated 95 patients in this systematic review. In 2015, a total of
305 856 breast augmentations and 106 338 reconstructions were
performed. 46 There are 5 to 10 million women with breast
implants currently worldwide,47 and rates of breast augmentation
and implant-based breast reconstruction are increasing every year.
Eighty-three percent of breast reconstructions in the United
States in 2010 were implant-based.48 Therefore, we expect to see
a rise in the number of cases of BIA-ALCL diagnosed. This is signifi-
cant because cosmetic patients frequently do not follow up with
their plastic surgeon after 1 postoperative year, although this para-
digm is changing among some practitioners. More commonly,
patients with breast cancer follow up with their breast surgeon or
medical oncologist far beyond the initial year after reconstruction
(Reprinted) JAMA Surgery Published online October 18, 2017 E5
 Clinical Review & Education Review Breast Implant–Associated Anaplastic Large Cell Lymphoma

Figure 3. Recommendations per the 2017 National Comprehensive Cancer Network Guidelines

Second
FNA of Indeterminate of
Effusion pathology
fluid lymphoma
Physical signs consultation
(effusion, breast US of breast or
Biopsy Negative for Refer to plastic
enlargement, mass) MRI or PET/CT Mass
mass lymphoma surgeon
>1 y after breast in select cases
Workup, staging, treatment, and
implants
Inconclusive Breast follow-up for breast
US MRI BIA-ALCL
implant–associated anaplastic large
• Observation cell lymphoma (BIA-ALCL).
Complete • H&P every 3-6 mo for 2 y C/A/P indicates chest, abdomen, and
excision • C/A/P CT or PET no more pelvis; CBC, complete blood cell
• Multidisciplinary team Localized
• Total capsulectomy and often than every 6 mo for 2y
• H&P to capsule count; CHOP, cyclophosphamide,
excision of associated Incomplete
• CBC with differential, hydroxydaunorubicin, vincristine,
mass with biopsy of excision
comprehensive and prednisone; CT, computed
suspicious nodes
metabolic panel
• Consider removal of • Discuss with tomography; FNA, fine-needle
• LDH
contralateral implant multidisciplinary team aspiration; H&P, history and physical;
• PET/CT
Extended • RT if only local residual LDH, lactic dehydrogenase;
disease disease
(stage II-IV) • Systemic therapy MRI, magnetic resonance imaging;
• CHOP or PET, positron emission tomography;
• Brentuximab vedotin RT, radiotherapy; and
US, ultrasonography.

is completed. In addition, if a woman is seen at the emergency
department or by a general practitioner with breast problems, she
is often first referred to a general surgeon or breast surgeon even
if she has breast implants. This represents a potential for delay in
diagnosis or misdiagnosis because these practitioners may be
unaware of the diagnosis of BIA-ALCL, be unfamiliar with the nec-
essary immunochemistry stains to request, and lack information
about the type of implant used. Most of the relevant published lit-
erature previously has been in plastic surgery journals; therefore,
there is a great need to disseminate information about this diagno-
sis to other medical and surgical specialties who may first encoun-
ter the patient with BIA-ALCL. Many patients also are unaware of
this entity. Penn State Health Milton S. Hershey Medical Center
currently lists BIA-ALCL as a possible complication on all consent
forms and informs patients about the risk, but many other institu-
tions may not.
Several points are agreed on by experts as noted in
the 2017 National Comprehensive Cancer Network guidelines.42
First, a delayed or recurrent seroma occurring more than 1 year
after breast implant placement should undergo aspiration, with
subsequent cytological analysis of fresh seroma fluid. Analysis
should include ALK testing and flow cytometry for CD30.
Management should be restricted to removal of the implant and
complete capsulectomy in patients with disease limited to the
capsule. Management of the contralateral breast remains contro-
versial, although most surgeons advise removal of both implants
and capsules because there have been cases of BIA-ALCL identi-
fied in the nonsymptomatic breast. Some surgeons also
advocate for lymph node dissection of involved nodes. Computed
tomography of the chest, abdomen, and pelvis, along with a PET
scan, can be performed to exclude systemic lymphoma 49 or
BIA-ALCL progression. Surveillance should consist of clinical
follow-up at least every 3 to 6 months for a minimum of 2 years,
with imaging no more often than every 6 months (Figure 3).
After this period, follow-up can be tailored as clinically
indicated. Because most cases have an indolent course,
identification of risk factors for more aggressive forms would
be helpful.
Another question regarding BIA-ALCL is when it is appropriate
to perform reconstruction after removal of the implant and cap-
sule for treatment of the entity (ie, whether there should be a wait-
ing period). Most patients want reconstruction, and this is a com-
mon question that arises during consultation. Time to reconstruction
varied greatly in our systematic review, with many cases having no
documentation of reconstruction or specifics on the reconstruc-
tion type. This question will be examined further as more cases of
BIA-ALCL are diagnosed and more data are produced. In addition,
because the current literature only describes linkage between
textured implants and BIA-ALCL, some surgeons will not offer tex-
tured devices because of the increased risk. Although there has not
been conclusive documentation to date of a textured tissue
expander causing pathogenesis, some practitioners have begun
using smooth tissue expanders.
In recent years, there has been a significant increase in the use
of anatomic implants, which are all textured, to offer the patient a
“tailor-made solution” with a more natural projection. However,
recent evidence showed no aesthetic superiority of anatomic
implants over round implants, and even plastic surgeons could not
tell which type that patients had.50 Currently, the FDA states that
the risk of BIA-ALCL in a patient with implants is small.6 The true
incidence is unknown, but the diagnosis is increasing. Recent
reports from the Australian Therapeutic Goods Administration,
which is the equivalent to the FDA, state that the incidence of
BIA-ALCL is as high as 1 case per 1000 women who have breast
implants in Australia,51 a rate that is much higher than that noted
within the United States. Currently, despite recognized linkage of
certain implant types to ALCL, no known restrictive action has
been taken by any regulatory agency worldwide. This places
health care professionals as the key participants in recommending
which type of implant should be used.
Limitations
This systematic review has several limitations. First, most cases of
BIA-ALCL are not documented in the literature. Second, the docu-
mentation varies, and many reports are missing key clinicopatho-
logical information.

E6 JAMA Surgery Published online October 18, 2017 (Reprinted) jamasurgery.com

© 2017 American Medical Association. All rights reserved.

Downloaded From: on 10/19/2017

 Breast Implant–Associated Anaplastic Large Cell Lymphoma
Conclusions
Because symptoms may be nonspecific, clinicians must have a high
index of suspicion for BIA-ALCL to prevent a delay in diagnosis.
ARTICLE INFORMATION
Accepted for Publication: June 17, 2017.
Published Online: October 18, 2017.
doi:10.1001/jamasurg.2017.4026
Author Contributions: Drs Leberfinger and Ravnic
had full access to all of the data in the study and
take responsibility for the integrity of the data and
the accuracy of the data analysis.
Study concept and design: Leberfinger, Potochny,
Mackay, Ravnic.
Acquisition, analysis, or interpretation of data: All
authors.
Drafting of the manuscript: Leberfinger, Behar,
Rakszawski, Ravnic.
Critical revision of the manuscript for important
intellectual content: All authors.
Statistical analysis: Leberfinger, Behar, Ravnic.
Administrative, technical, or material support: All
authors.
Study supervision: Williams, Potochny, Ravnic.
Conflict of Interest Disclosures: None reported.
Additional Contributions: We thank the patient for
granting permission to publish information shown
in Figure 1B and C and Figure 2.
REFERENCES
1. Srinivasa DR, Miranda RN, Kaura A, et al. Global
adverse event reports of breast implant–associated
ALCL: an international review of 40 government
authority databases. Plast Reconstr Surg. 2017;139
(5):1029-1039.
2. Brody GS, Deapen D, Taylor CR, et al. Anaplastic
large cell lymphoma occurring in women with
breast implants: analysis of 173 cases. Plast Reconstr
Surg. 2015;135(3):695-705.
3. Doren EL, Miranda RN, Selber JC, et al. U.S.
epidemiology of breast implant–associated
anaplastic large cell lymphoma. Plast Reconstr Surg.
2017;139(5):1042-1050.
4. McGuire P, Reisman NR, Murphy DK. Risk factor
analysis for capsular contracture, malposition, and
late seroma in subjects receiving Natrelle 410
form-stable silicone breast implants. Plast Reconstr
Surg. 2017;139(1):1-9.
5. Keech JA Jr, Creech BJ. Anaplastic T-cell
lymphoma in proximity to a saline-filled breast
implant. Plast Reconstr Surg. 1997;100(2):554-555.
6. US Food and Drug Administration. Breast
implant–associated anaplastic large cell lymphoma
(BIA-ALCL). https://www.fda.gov/MedicalDevices
/ProductsandMedicalProcedures
/ImplantsandProsthetics/BreastImplants
/ucm239995.htm. Accessed March 24, 2017.
7. Moher D, Liberati A, Tetzlaff J, Altman DG;
PRISMA Group. Preferred Reporting Items for
Systematic Reviews and Meta-analyses: the
PRISMA statement. PLoS Med. 2009;6(7):e1000097.
8. Lazzeri D, Agostini T, Bocci G, et al.
ALK-1–negative anaplastic large cell lymphoma
associated with breast implants: a new clinical
entity. Clin Breast Cancer. 2011;11(5):283-296.
jamasurgery.com
© 2017 American Medical Association. All rights reserved.
Downloaded From: on 10/19/2017
Appropriate cytological examination of late peri-implant seromas
is crucial to diagnose BIA-ALCL because capsule histology can
frequently give false-negative reports. Further research and long-
term follow-up of these patients is needed to determine the
optimal prognostic, treatment, and reconstructive guidelines.
9. O’Shaughnessy K. Evolution and update on
current devices for prosthetic breast
reconstruction. Gland Surg. 2015;4(2):97-110.
10. Wang YF, Yang YL, Gao ZF, et al. Clinical and
laboratory characteristics of systemic anaplastic
large cell lymphoma in Chinese patients. J Hematol
Oncol. 2012;5:38.
11. Story SK, Schowalter MK, Geskin LJ. Breast
implant–associated ALCL: a unique entity in the
spectrum of CD30+ lymphoproliferative disorders.
Oncologist. 2013;18(3):301-307.
12. Zucca E, Bertoni F, Vannata B, Cavalli F.
Emerging role of infectious etiologies in the
pathogenesis of marginal zone B-cell lymphomas.
Clin Cancer Res. 2014;20(20):5207-5216.
13. Hart AM, Lechowicz MJ, Peters KK, Holden J,
Carlson GW. Breast implant–associated anaplastic
large cell lymphoma: report of 2 cases and review of
the literature. Aesthet Surg J. 2014;34(6):884-894.
14. Blombery P, Thompson ER, Jones K, et al.
Whole exome sequencing reveals activating JAK1
and STAT3 mutations in breast implant–associated
anaplastic large cell lymphoma. Haematologica.
2016;101(9):e387-e390.
15. Di Napoli A, Jain P, Duranti E, et al. Targeted
next generation sequencing of breast
implant-associated anaplastic large cell lymphoma
reveals mutations in JAK/STAT signalling pathway
genes, TP53 and DNMT3A [published online
November 10, 2016]. Br J Haematol. 2016.
doi:10.1111/bjh.14431
16. Hu H, Johani K, Almatroudi A, et al. Bacterial
biofilm infection detected in breast
implant–associated anaplastic large-cell lymphoma.
Plast Reconstr Surg. 2016;137(6):1659-1669.
17. Jacombs A, Tahir S, Hu H, et al. In vitro and in
vivo investigation of the influence of implant
surface on the formation of bacterial biofilm in
mammary implants. Plast Reconstr Surg. 2014;133
(4):471e-480e.
18. Wang F, Meng W, Wang B, Qiao L. Helicobacter
pylori–induced gastric inflammation and gastric
cancer. Cancer Lett. 2014;345(2):196-202.
19. Brody GS. The case against biofilm as the
primary initiator of breast implant–associated
anaplastic large cell lymphoma. Plast Reconstr Surg.
2016;137(4):766e-767e.
20. Granados R, Lumbreras EM, Delgado M,
Aramburu JA, Tardío JC. Cytological diagnosis of
bilateral breast implant–associated lymphoma of
the ALK-negative anaplastic large-cell type: clinical
implications of peri-implant breast seroma
cytological reporting. Diagn Cytopathol. 2016;44
(7):623-627.
21. Letter H, Rop B, Edison MN, Turner P. Breast
implant–associated anaplastic large cell lymphoma:
a case report and literature review. Cureus. 2016;8
(3):e546. doi:10.7759/cureus.546
22. Wong AK, Lopategui J, Clancy S, Kulber D, Bose
S. Anaplastic large cell lymphoma associated with a
(Reprinted) JAMA Surgery Published online October 18, 2017
Review Clinical Review & Education
breast implant capsule: a case report and review of
the literature. Am J Surg Pathol. 2008;32(8):1265-
1268.
23. Santanelli di Pompeo F, Laporta R, Sorotos M,
et al. Breast implant–associated anaplastic large cell
lymphoma: proposal for a monitoring protocol.
Plast Reconstr Surg. 2015;136(2):144e-151e.
doi:10.1097/PRS.0000000000001416
24. 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(5):
831-833.
25. Tardío JC, Granados R. Axillary
lymphadenopathy: an outstanding presentation for
breast implant–associated ALK-negative anaplastic
large cell lymphoma. Int J Surg Pathol. 2015;23(5):
424-428.
26. Miranda RN, Lin L, Talwalkar SS, Manning JT,
Medeiros LJ. Anaplastic large cell lymphoma
involving the breast: a clinicopathologic study of 6
cases and review of the literature. Arch Pathol Lab
Med. 2009;133(9):1383-1390.
27. Alcalá R, Llombart B, Lavernia J, Traves V,
Guillén C, Sanmartín O. Skin involvement as the first
manifestation of breast implant–associated
anaplastic large cell lymphoma. J Cutan Pathol.
2016;43(7):602-608.
28. Carty MJ, Pribaz JJ, Antin JH, et al. A patient
death attributable to implant-related primary
anaplastic large cell lymphoma of the breast. Plast
Reconstr Surg. 2011;128(3):112e-118e.
29. Taylor KO, Webster HR, Prince HM. Anaplastic
large cell lymphoma and breast implants: five
Australian cases. Plast Reconstr Surg. 2012;129(4):
610e-617e.
30. Clemens MW, Medeiros LJ, Butler CE, et al.
Complete surgical excision is essential for the
management of patients with breast
implant–associated anaplastic large-cell lymphoma
[published correction appears in J Clin Oncol.
2016;34(8):888]. J Clin Oncol. 2016;34(2):160-168.
31. Jarjis RD, Hansen LB, Matzen SH. The
non-specific symptoms of breast implant–
associated anaplastic large cell lymphoma resulting
in delayed diagnosis: a case-based review. JPRAS
Open. 2015;6:1-4. doi:10.1016/j.jpra.2015.07.004
32. Aladily TN, Medeiros LJ, Amin MB, et al.
Anaplastic large cell lymphoma associated with
breast implants: a report of 13 cases. Am J Surg Pathol.
2012;36(7):1000-1008.
33. de Jong D, Vasmel WL, de Boer JP, et al.
Anaplastic large-cell lymphoma in women with
breast implants. JAMA. 2008;300(17):2030-2035.
34. Bautista-Quach MA, Nademanee A,
Weisenburger DD, Chen W, Kim YS.
Implant-associated primary anaplastic large-cell
lymphoma with simultaneous involvement of
bilateral breast capsules. Clin Breast Cancer. 2013;13
(6):492-495.
E7
 Clinical Review & Education Review
35. 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(11):1977-1979.
36. Provenzano E, Pinder SE. Modern therapies
and iatrogenic changes in breast pathology.
Histopathology. 2017;70(1):40-55.
37. Laurent C, Delas A, Gaulard P, et al. Breast
implant–associated anaplastic large cell lymphoma:
two distinct clinicopathological variants with
different outcomes. Ann Oncol. 2016;27(2):306-314.
38. Stein H, Foss HD, Dürkop H, et al. CD30+
anaplastic large cell lymphoma: a review of its
histopathologic, genetic, and clinical features. Blood.
2000;96(12):3681-3695.
39. Gendler SJ. MUC1, the renaissance molecule.
J Mammary Gland Biol Neoplasia. 2001;6(3):339-353.
40. Ma WW. LDK378: a promising next-generation
ALK inhibitor. http://www.targetedonc.com
/publications/targeted-therapies-cancer/2013
/december-2013/ldk378-a-promising-next
-generation-alk-inhibitor-with-fda-breakthrough
-therapy-designation. Published January 7, 2014.
Accessed January 8, 2017.
E8 JAMA Surgery Published online October 18, 2017 (Reprinted)
© 2017 American Medical Association. All rights reserved.
Downloaded From: on 10/19/2017
Breast Implant–Associated Anaplastic Large Cell Lymphoma
41. Taylor CR, Siddiqi IN, Brody GS. Anaplastic
large cell lymphoma occurring in association with
breast implants: review of pathologic and
immunohistochemical features in 103 cases. Appl
Immunohistochem Mol Morphol. 2013;21(1):13-20.
42. NCCN. National Comprehensive Cancer
Network. https://www.nccn.org/professionals
/physician_gls/pdf/t-cell.pdf. Accessed
January 8, 2017.
43. Miranda RN, Aladily TN, Prince HM, et al.
Breast implant–associated anaplastic large-cell
lymphoma: long-term follow-up of 60 patients.
J Clin Oncol. 2014;32(2):114-120.
44. Armitage JO. Staging non-Hodgkin lymphoma.
CA Cancer J Clin. 2005;55(6):368-376.
45. Cheah CY, Campbell BA, Seymour JF. Primary
breast lymphoma. Cancer Treat Rev. 2014;40(8):
900-908.
46. American Society of Plastic Surgeons. 2016
Plastic surgery statistics. https://www
.plasticsurgery.org/news/plastic-surgery-statistics.
Accessed January 15, 2017.
47. US Food and Drug Administration. FDA advises
women with breast implants. https://www.fda.gov
/ForConsumers/ConsumerUpdates/ucm240985
.htm. Published January 26, 2011. Accessed August
31, 2017.
48. Gurunluoglu R, Gurunluoglu A, Williams SA,
Tebockhorst S. Current trends in breast
reconstruction: survey of American Society of
Plastic Surgeons 2010. Ann Plast Surg. 2013;70(1):
103-110.
49. Hwang MJ, Brown H, Murrin R, Momtahan N,
Sterne GD. Breast implant–associated anaplastic
large cell lymphoma: a case report and literature
review. Aesthetic Plast Surg. 2015;39(3):391-395.
50. Hidalgo DA, Weinstein AL. Intraoperative
comparison of anatomical versus round implants in
breast augmentation: a randomized controlled trial.
Plast Reconstr Surg. 2017;139(3):587-596.
51. Australian Government Department of Health.
Breast implants and anaplastic large cell lymphoma:
update: additional confirmed cases of anaplastic
large cell lymphoma. https://www.tga.gov.au
/alert/breast-implants-and-anaplastic-large-cell
-lymphoma. Updated May 11, 2017. Accessed
August 31, 2017.
jamasurgery.com