Supplement
Aesthetic Surgery Journal
2019 NCCN Consensus Guidelines on the 2019, Vol 39(S1) S3–S13
© 2019 The American Society for
Aesthetic Plastic Surgery, Inc.
Diagnosis and Treatment of Breast Reprints and permission:
[email protected]Implant-Associated Anaplastic Large DOI: 10.1093/asj/sjy331
www.aestheticsurgeryjournal.com
Cell Lymphoma (BIA-ALCL)
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Mark W. Clemens, MD, FACS; Eric D. Jacobsen, MD; and
Steven M. Horwitz, MD
Abstract
National Comprehensive Cancer Network (NCCN) guidelines represent the consensus standard of care for diagnosis and management of the majority of known
cancers. NCCN guidelines on breast implant-associated anaplastic large cell lymphoma (BIA-ALCL) have been recognized by the US Food and Drug Administration
and widely advocated by national specialty societies. Consensus guidelines have helped create a treatment standardization for BIA-ALCL at all stages of disease.
NCCN guidelines are evidence-based where possible and utilize expert consensus opinion to fill in gaps that may exist. NCCN undergoes annual panel review by
multidisciplinary faculty members, and this article represents the most up-to-date 2019 guidelines. Recommendations focus on parameters for achieving reliable
diagnosis and disease management and emphasize the critical role for complete surgical ablation. Suggestions for adjunct treatments and chemotherapy regimens
are included for advanced BIA-ALCL with lymph node involvement. BIA-ALCL recurrence and management of unresectable disease, and organ metastasis are
addressed. Adherence to recognized BIA-ALCL guidelines ensures patients receive the most current efficacious treatment available.
Editorial Decision date: December 13, 2018.
In 2016, the World Health Organization provisionally clas- agents, radiation therapy, and stem cell transplant depend-
sified breast implant-associated anaplastic large cell lym- ing on pathology, stage of disease, and disease recurrence.6,7
phoma (BIA-ALCL) as a novel lymphoma.1 In the same year, This article will summarize the 2019 update of the NCCN
the National Comprehensive Cancer Network (NCCN) estab- Consensus guidelines on BIA-ALCL and highlight recom-
lished evidence-based consensus guidelines for the diagno- mendations pertinent to a plastic surgery audience.
sis and treatment of the disease, which was highlighted in
this journal.2,3 NCCN guidelines on BIA-ALCL were subse-
quently recognized by the US Food and Drug Administration Dr Clemens is an Associate Professor, Department of Plastic Surgery,
(FDA) as well as national plastic surgery societies to help MD Anderson Cancer Center, Houston, TX; and is Breast Surgery
physicians understand the disease and provide reliable diag- Section Co-editor for Aesthetic Surgery Journal. Dr Jacobsen is an
nosis and treatment.4,5 A multidisciplinary team approach is Assistant Professor, Hematologic Oncology, Dana Farber Cancer
Center, Brigham & Women’s Hospital, Harvard Medical School,
essential for the management of this uncommon malignancy. Boston, MA. Dr Horwitz is a Lymphoma Oncologist, Department of
BIA-ALCL is generally an indolent and localized disease with Hematology, Memorial Sloan Kettering Cancer Center, New York, NY.
excellent prognosis when patients receive surgical excision.
It remains unclear whether timely diagnosis can mitigate Corresponding Author:
Dr Mark W. Clemens, Department of Plastic Surgery, 1400 Pressler
invasive disease or whether biologic variability of the tumor Street, Unit 1488, MD Anderson Cancer Center, Houston, TX
exists that affects prognosis. Advanced disease BIA-ALCL 77030, USA.
may require adjuvant treatments such as chemotherapeutic E-mail: [email protected]; Twitter: @clemensmd
S4 Aesthetic Surgery Journal 39(S1)
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Figure 1. Breast implant-associated anaplastic large cell lymphoma disease algorithm. Current evidence-based algorithm
for achieving diagnosis followed by treatment by stage of disease. Bx, biopsy; CBC, complete blood count; CHOP,
cyclophosphamide doxorubicin vincristine prednisolone; CMP, complete metabolic profile; daE, dose adjusted etoposide; FNA,
fine needle aspiration; LDH, lactate dehydrogenase; MRI, magnetic resonance imaging; PET/CT, positron emission tomography
computed tomography; RT, radiation therapy.
For over 25 years, NCCN has created evidence-based NCCN guidelines on BIA-ALCL focus on the diagno-
algorithms to improve the quality of cancer care in the sis and management throughout the stages of disease
United States. 8 The NCCN Clinical Practice Guidelines based on the most current data available and expert
are based on the consensus of 27 member cancer consensus. BIA-ALCL guidelines undergo annual
centers and focuses on achieving optimal outcomes panel review among multidisciplinary faculty. The
through prevention, accurate diagnosis, treatment, 2019 updated BIA-ALCL guidelines were achieved by a
and provision of supportive services. Over 1200 cli- consensus of lymphoma oncologists, plastic surgeons,
nician volunteers comprise the member committees radiation oncologists, and surgical oncologists from
for NCCN guidelines and are disease-specific sub- the NCCN member institutions.
specialists who have extensive experience in treating
respective diseases. NCCN gives recommendations
after evaluating the best evidence available at this Diagnosis and Workup of a Suspected
time supplemented with expert consensus opinion to
Patient
help fill gaps in evidence. As new data are published
on BIA-ALCL, NCCN regularly updates recommenda- NCCN guidelines on BIA-ALCL are organized by the
tions to reflect new findings, current research, and recommended approach for evaluating and treating a
clinical information that may change current standard patient, specifically, symptoms, imaging, pathology and
of care. NCCN guidelines are the recognized standard disease workup, surgery, staging, adjuvant treatments, and
in cancer care, and recommendations on BIA-ALCL surveillance (Figure 1). The most common presentation
have been adopted worldwide by government author- of BIA-ALCL is a large spontaneous periprosthetic
ities and specialty societies. In addition to physician fluid collection occurring at least 1 year and on aver-
providers, NCCN guidelines also inform insurance age 7 to 10 years following cosmetic or reconstructive
providers to ensure needed patient care is indicated implantation with a textured surface breast implant.
and approved. All NCCN guideline algorithms can be To date, there have been no confirmed cases of a BIA-
found at www.nccn.org, and this article represents a ALCL in a patient with only smooth devices.9,10 In the
summary by NCCN lymphoma committee members. last safety advisory on BIA-ALCL in March 2018, the FDA
Clemens et alS5
A B
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Figure 2. Imaging in suspected breast implant-associated anaplastic large cell lymphoma patients. Patients presenting with
an enlargement of the breast more than 1 year after implantation should be evaluated with ultrasound. (A) Ultrasound should
include implant, chest wall, regional lymph node basins, and contralateral breast implant. (B) Computed tomography scan
or (C) magnetic resonance imaging may aid in diagnosis for soft tissue masses when ultrasound is indeterminate. Red arrows
indicate periprosthetic fluid collections. Mammography is a poor imaging modality for breast implant-associated anaplastic
large cell lymphoma and is less sensitive for effusions and/or masses that do not display calcifications. (D) Red arrow
indicates a periprosthetic mass.
acknowledged receiving 414 adverse event reports on fevers, and capsular contracture. Patients with a large
BIA-ALCL, of which 30 occurred in patients who received fluid collection may have fluid levels around an implant
a smooth implant.5 Importantly, the FDA noted that in all and consequently may be misdiagnosed with an implant
cases diagnosed in patients with smooth implants, the rupture. As a general rule, implant ruptures do not
patients either had a mixed implant history of smooth increase the overall volume of a breast. Other common
and textured devices or no clinical history supplied to etiologies for a delayed seroma are infection and recent
review. In addition to large fluid collections and delayed trauma to the chest wall, which should be investigated
seromas, 8% to 24% of patients will present with an and excluded.12 Every implant will likely have a scant or
associated palpable mass and 4% to 12% with lymphade minimal amount (5-10 mL) of surrounding fluid, and this
nopathy.3,7,8,11 Less commonly described (<5% of cases) incidental finding in an otherwise asymptomatic patient
are local and systemic symptoms including skin rash, does not require biopsy or further investigation. Initial
S6 Aesthetic Surgery Journal 39(S1)
Table 1. TNM Stage Classification of BIA-ALCLa
TNM classification TNM stage
T: Tumor extent IA T1 N0 M0
T1 Confined to effusion or a layer on luminal side of capsule IB T2 N0 M0
T2 Early capsule infiltration IC T3 N0 M0
T3 Cell aggregates or sheets infiltrating the capsule IIA T4 N0 M0
T4 Lymphoma infiltrates beyond the capsule IIB T1-3 N1 M0
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N: Lymph node III T4 N1-2 M0
N0 No lymph node involvement IV Tany Nany M1
N1 One regional lymph node (+)
N2 Multiple regional lymph nodes (+)
M: Metastasis
M0 No distant spread
Figure 3. Imaging in pathology confirmed breast implant-
associated anaplastic large cell lymphoma patients. After M1 Spread to other organs/distant sites
diagnosis of breast implant-associated anaplastic large cell
lymphoma, oncologic workup should include imaging with a BIA-ALCL, breast implant-associated anaplastic large cell lymphoma; NCCN, National
trunk positron emission tomography computed tomography Comprehensive Cancer Network; TNM, tumor, lymph node, metastasis. aA solid tumor TNM
scan to determine any associated capsular masses staging of disease based on clinical and pathological evaluation was first proposed in 2016 by
MD Anderson Cancer Center and is now included in the 2019 update of the NCCN guidelines.
lymphadenopathy or any organ metastasis. The patient
demonstrates infiltrative disease with 2 capsular masses,
indicated by red arrows. positron emission tomography
computed tomography scan can act as a surgical roadmap to
guide surgical planning and resection.
workup of an enlarged breast should include ultrasound cells within the specimen. CD30 immunohistochemistry
evaluation for fluid collection, breast masses, and is a fundamental part of the diagnostic tests for BIA-ALCL,
enlarged regional lymph nodes (Figure 2). Axillary (93%) but is not, by itself, pathognomonic because CD30 expres-
lymph node involvement is most commonly followed sion is nonspecific and CD30 can be expressed on benign
by internal mammary and supraclavicular metastases, inflammatory cells. Scant or rare CD30 positive lympho-
whereas involvement of nonregional lymph nodes is very cytes with normal morphology is considered a normal
uncommon.13 Adrada and colleagues investigated the finding and does not require further investigation.15,16 The
diagnostic imaging findings of BIA-ALCL patients and diagnosis of BIA-ALCL requires careful clinicopathologic
reported the sensitivity and specificity of ultrasound for correlation, and physicians should include a relevant clin-
detecting an effusion (84% and 75%) or a mass (46% ical history and directions to the pathologist to exclude
and 100%). In cases where ultrasound is equivocal, BIA-ALCL.
magnetic resonance imaging is recommended for further Quesada recently performed an in-depth pathology
characterization.14 review of the stages of BIA-ALCL and emphasized the
Fine needle aspiration, in the clinic or by interventional importance of excluding other malignancies or benign pro-
radiology, is the optimal method to sample a periprosthetic cesses that may mimic BIA-ALCL.17 Additional biomark-
fluid collection. At the time of aspiration, ultrasound may ers that may be required to establish the diagnosis and
aid in implant displacement and protection. As much fluid exclude other malignancies include CD2, CD3, CD4, CD5,
as possible should be collected (minimum 50 mL) to aid CD7, CD8, CD45, and anaplastic lymphoma kinase (ALK)
in the diagnosis of disease. Fine needle aspiration (FNA) expression. BIA-ALCL is always ALK negative; however,
evaluation after previous serial drainages may artificially because other systemic and cutaneous forms of ALCL are
lower tumor burden, thus making diagnosis difficult. frequently ALK negative, this finding alone does not estab-
A suspicious mass requires tissue biopsy and evaluation. lish a diagnosis of BIA-ALCL.
Specimens should be sent for cell morphology by cytol- Hematopathology consultation at a tertiary cancer cen-
ogy, CD30 immunohistochemistry, and flow cytometry ter is strongly encouraged to establish or exclude a diagno-
for evaluation, quantification, and characterization of T sis of BIA-ALCL. Following exclusion of BIA-ALCL, benign
Clemens et alS7
A B
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C D
Figure 4. Breast implant-associated anaplastic large cell lymphoma case example. (A) This 32-year-old woman presented
with rapid onset of a right periprosthetic effusion approximately 6 years following cosmetic augmentation mastopexy with a
Silimed Polyurethane textured surface implant. Breast implant-associated anaplastic large cell lymphoma was diagnosed by
fine needle aspiration. (B) Demonstration of large anaplastic morphology consistent with breast implant-associated anaplastic
large cell lymphoma (red arrows). Preoperative oncologic workup with positron emission tomography computed tomography
scan demonstrated disease confined to the capsule with no signs of metastasis. She received surgical ablation with an en bloc
resection of her implant and capsule and a contralateral explantation with capsulectomy. (C) Demonstration of a complete
elevation of the implant capsule off the rib cage. (D) Demonstration of a specimen with pathology orientation sutures in place.
(E) Demonstration of pathology evaluation of the capsule with removal of the malignant effusion, which is typically straw-
colored, turbid, and viscous in nature (F) but may be clear, bloody, or absent. Patient’s polyurethane implant was grossly
normal appearing with some adhesions to the surrounding capsule. Capsule was negative for evidence of disease invasion. (G)
Patient was staged 1A and received no further treatment. She elected for no further reconstruction.
seromas may be managed as appropriate by a plastic sur- Preoperative Workup in Confirmed
geon. The FDA recommends that all patients meeting the BIA-ALCL
pathologic criteria for BIA-ALCL should be reported to
the PROFILE registry of the American Society of Plastic Once the diagnosis of BIA-ALCL has been established,
Surgery (www.thepsf.org/PROFILE).18 As of December 1, physicians are strongly encouraged to consult with a
2018, the PROFILE registry had received reports of over multidisciplinary team including oncologists, pathologists,
250 unique cases of BIA-ALCL, and the American Society surgical oncologists, and plastic surgeons. Suggested
of Plastic Surgery had tracked a total of over 650 unique laboratory testing includes a complete blood count with
cases in 33 countries worldwide. differential, comprehensive metabolic panel, lactate
S8 Aesthetic Surgery Journal 39(S1)
E F
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G
Figure 4. Continued
dehydrogenase, and hepatitis B testing (if adjuvant chemo- to or involvement of local lymph nodes.19 Employing this
therapy is being considered). We suggest a bone marrow system, nearly all BIA-ALCL patients have early-stage
biopsy for patients for whom there is a high suspicion disease, either stage 1E (83-84%) or stage IIE (10-16%)
of systemic ALCL such as patients with aggressive local vs stage IV disease (0-7%).4,7 Due to the limited appli-
invasion or lymph node metastasis. For any confirmed cability of the Ann Arbor staging system for BIA-ALCL,
cases of BIA-ALCL, a preoperative positron emission which does not account for capsular invasion or penetra-
tomography computed tomography (PET/CT) scan is tion, NCCN guidelines now include the recently proposed
optimal for demonstrating associated capsular masses and tumor, lymph node, metastasis (TNM) solid tumor staging
chest wall involvement and will serve as a “roadmap” for system modeled after the American Joint Committee on
surgical excision (Figure 3).9 Due to significant surgery- Cancer TNM (Table 1). Early manuscripts suggested that
induced inflammation, PET/CT scans are not reliable for BIA-ALCL presentation is binary, either effusion limited
evaluating local disease if performed within 2 to 3 months or an invasive mass.20 However, the TNM classification
after surgery. describes BIA-ALCL as a spectrum of disease from IA (35-
Non-Hodgkin lymphoma is traditionally staged utiliz- 70%, effusion only), IB (3-11%), IC (8-13%), IIA (8-25%),
ing the Lugano modification of the Ann Arbor staging sys- IIB (3-5%), and III (3-9%) to stage IV (1-2%).7,14,21 Note
tem. Stage IE disease is limited to a single extranodal (E) that BIA-ALCL is classified as a lymphoma at all stages
site such as the breast or implant capsule, whereas stage and presentations. Although indolent early on, BIA-ALCL
IIE disease is defined as extranodal disease with spread is a malignancy and not considered benign at any stage.
Clemens et alS9
A B
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D
Figure 5. Breast implant-associated anaplastic large cell lymphoma lymph node metastasis. (A) This 57-year-old woman
demonstrates a right supraclavicular lymph node metastasis as part of an advanced case of breast implant-associated
anaplastic large cell lymphoma. In addition to surgical resection, the patient received chemotherapy. (B) A separate 46 year
old female with multiple axillary lymph node metastasis is shown receiving a full axillary dissection in addition to an en bloc
resection. (C) Pathology specimen ultimately demonstrated 16 positive lymph nodes for breast implant-associated anaplastic
large cell lymphoma, and the patient was also recommended chemotherapy. (D) Histology from the 46 year old patient
demonstrates characteristic sinusoidal pattern of lymph node infiltration of breast implant-associated anaplastic large cell
lymphoma metastasis.
In a study of 87 BIA-ALCL patients, Clemens et al reported Surgical Treatment With en Bloc
an overall survival rate of 94% and 91% at 3 and 5 years, Explantation
respectively. Within this study, solid tumor TNM stag-
ing predicted survival and recurrence for BIA-ALCL more Essential to the treatment of BIA-ALCL is timely diagno-
accurately than Ann Arbor staging (P = 0.01).7 sis and complete surgical excision.7 The goals of surgery
S10 Aesthetic Surgery Journal 39(S1)
A B
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C
Figure 6. Surgical ablation of breast implant-associated anaplastic large cell lymphoma. (A) This 38-year-old woman
presented with an outside misdiagnosis of left breast implant rupture and spontaneous capsular contracture. She had a
periprosthetic effusion around an intact implant by ultrasound evaluation and was diagnosed with BIA-ALCL following fine
needle aspiration. (B) Surgical en bloc resection was performed through her inframammary fold incision. (C) The implant is
shown with double capsule formation and capsular adhesions. Disease was invasive into but not beyond the capsule, and she
was a stage 1C and required no further treatment.
should be to remove the implant with the surrounding Complete resection of disease is associated with excel-
fibrous capsule and any associated capsule mass lent, long-term, disease-free survival (Figure 6). Disease
(Figure 4). Complete surgical excision prolongs overall localized to the capsule (Lugano IE, MD Anderson
survival (P = 0.001) and event-free survival (P = 0.001) Cancer Center [MDA] IA-IIA) may be treated with sur-
compared with all other therapeutic interventions. gery alone in most cases if complete surgical excision is
Surgical specimens should be oriented and inked to possible, though a slightly higher rate of recurrence is
allow for the anatomic location of the diseases. This is noted with invasive disease. The rate of disease events
important for tumor site surveillance and in cases of and recurrence is 2.6-fold higher for stage II disease and
recurrence requiring reexcision. At present, there is no 2.7-fold higher for stage III disease compared with stage
clear role for radical mastectomy or sentinel lymph node I disease.7 The rate of disease events following com-
biopsy. Full axillary dissection has been used rarely for plete surgical excision is 14.3% for patients with T4 dis-
gross involvement of multiple lymph nodes (Figure 5). ease compared with 0% for patients with T1-T3 disease
An estimated 2% to 4% of patients develop bilateral dis- (P = 0.001).7 Local recurrence is most common following
ease, and therefore surgeons may consider removal of the incomplete resections or partial capsulectomies (Figure
contralateral implant and capsule.8 A surgical oncology 7). Radioactive seed localization can facilitate surgical
consultation is not compulsory, but may be beneficial resection. All attempts should be made to gain complete
for plastic surgeons unaccustomed to optimal surgical surgical resection because retained or unresectable dis-
resection of a malignancy. ease likely indicates the need for adjuvant treatments.
Clemens et alS11
A B
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C D
Figure 7. Management of breast implant-associated anaplastic large cell lymphoma with local disease recurrence. A 52-year-
old woman developed a left delayed seroma of the right breast 9 years following cosmetic augmentation with Biocell textured
surface implants. After repeated aspirations, she elected for explantation and received a partial anterior strip capsulectomy
during implant removal. Pathology from the case demonstrated BIA-ALCL with capsule invasion, however no further treatment
was performed at this time. Eleven months following surgery, the patient developed a 2cm medial breast mass adjacent to her
previous capsule, which is shown on (A, red arrow) positron emission tomography computed tomography scan and (B, red
arrow) magnetic resonance imaging. (C, Red arrow) Ultrasound-guided radioactive seed placement was performed to aid in
surgical localization, and preoperative seeds (D, red arrow) within the mass are shown in a mammogram. (E) Radiograph was
performed intraoperatively to confirm complete excision of the mass and radioactive seeds which defined the boundaries of
the mass (red arrows), with adequate surrounding margins. The patient remains disease-free after 2 years.
S12 Aesthetic Surgery Journal 39(S1)
Adjuvant Treatments Acknowledgments
There are no prospective trials to guide the management The authors gratefully acknowledge the NCCN and the
of patients with disseminated disease, and treatment Non-Hodgkin Lymphoma NCCN Guideline panel members
paradigms are generally extrapolated from the treatment for their contribution in the development of the 2019 BIA-
experience of primary cutaneous and systemic ALCL. ALCL recommendations.
Local or involved site radiation therapy with 24 to 36 Gray
Disclosures
(Gy) is suggested for patients with local residual disease,
positive margins, or unresectable disease with chest wall The authors serve as non-Hodgkin lymphoma panel members
for NCCN and declared no potential conflicts of interest with
invasion. Systemic therapy is warranted in patients with
respect to the research, authorship, and publication of this
Lugano stage II-IV or MDA stage IIB-IV disease. Oncologists
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article. Dr. Clemens was a clinical investigator for the Athena
can consider either a standard approach for systemic ALCL Trial by Mentor Corporation), is a clinical investigator for the
(NCCN guidelines for first-line therapy of a peripheral FDA US Safety Trials by Establishment Labs), and received
T-cell lymphoma) such as combination anthracycline- travel expenses from Allergan Corporation for speaking on
based chemotherapy or, alternatively, a combination with ALCL at an educational meeting.
brentuximab vedotin. Case reports have demonstrated
favorable activity of brentuximab vedotin in BIA-ALCL, Funding
and the combination of anthracycline-based chemotherapy This supplement is sponsored by Allergan plc (Dublin, Ireland),
and brentuximab vedotin demonstrated an overall survival Aesthetic Surgery Education & Research Foundation (ASERF)
advantage compared with chemotherapy alone in the (Garden Grove, CA), Establishment Labs (Alajuela, Costa
first-line treatment of CD30 expressing peripheral T-cell Rica), Mentor Worldwide, LLC (Irvine, CA), Polytech Health &
lymphomas in the ECHELON II trial.22-27 Based on the results Aesthetics GmbH (Dieburg, Germany), and Sientra, Inc. (Santa
of the ECHELON II trial, the addition of brentuximab is Barbara, CA).
now considered "preferred" first line therapy for peripheral
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