Journal Logo


How to Diagnose and Treat Breast Implant–Associated Anaplastic Large Cell Lymphoma

Clemens, Mark W. M.D.; Brody, Garry S. M.D.; Mahabir, Raman C. M.D.; Miranda, Roberto N. M.D.

Author Information
Plastic and Reconstructive Surgery: April 2018 - Volume 141 - Issue 4 - p 586e-599e
doi: 10.1097/PRS.0000000000004262


I am first and foremost a surgeon with my primary responsibilities to my patients, my profession, and to intellectual honesty, which is critical to our role as surgeons.

—Scott L. Spear, M.D., addressing U.S. Food and Drug Administration hearings on silicone breast implant safety, 2006

Fulfilling our commitment to patient safety requires awareness of adverse events, vigilance, and adherence to best-evidence treatment guidelines. Breast implant–associated (BIA) anaplastic large cell lymphoma (ALCL) is a rare T-cell lymphoma that can present as a delayed fluid collection around a textured implant or surrounding scar capsule.1–5 Despite case reports dating back two decades, BIA-ALCL came to limited national attention only after a U.S. Food and Drug Administration safety communication in 2011.1 Awareness has grown exponentially following advisory statements by the World Health Organization,6,7 the National Cancer Institute,8 the U.S. Food and Drug Administration in 2016 and 2017,9 numerous government agencies worldwide,10–12 and media coverage.13 Research efforts have focused on several theories of lymphomagenesis, with most in agreement regarding an inciting multifactorial chronic inflammatory stimulus leading to T-cell dysplasia in a genetically susceptible patient.14–21 Although the exact mechanism of pathogenesis remains elusive, clear data have now been reported on the histopathology,22–30 epidemiology,31–35 imaging,36,37 treatment outcomes,38,39 and practice guidance.40 This article reviews the diagnosis and treatment of BIA-ALCL, with specific focus on established consensus guidelines, published outcomes, and experience following over 500 unique confirmed cases worldwide.


In 2016, the National Comprehensive Cancer Network established widely accepted consensus guidelines for the diagnosis and management of BIA-ALCL within their clinical practice guidelines for non-Hodgkin lymphomas, now adopted by the American Society of Plastic Surgeons and the American Society for Aesthetic Plastic Surgery.41,42 National Comprehensive Cancer Network guidelines represent the authoritative oncology standards used worldwide, and are also important in coverage justification by insurance providers. Copyright agreement prevents publishing images of the algorithm, but the guidelines are available for free from, and the essential elements are summarized in Figure 1. Although the National Comprehensive Cancer Network guidelines represent the most up-to-date evidence-based approach to this disease, many treating physicians may never have encountered the variable disease stages, and therefore individual treatment plans are best formulated in a multidisciplinary fashion.

Fig. 1.:
Diagnosis and treatment follows the National Comprehensive Cancer Network guidelines, which are available for free download from The essential elements are summarized in the algorithm. BIA, breast implant–associated; MRI, magnetic resonance imaging; IHC, immunohistochemistry; PROFILE, Patient Registry and Outcomes For breast Implants and anaplastic large cell Lymphoma etiology and Epidemiology; PET, positron emission tomography; CT, computed tomography; US, ultrasound; Tx, therapy; CHOP, cyclophosphamide, vincristine, doxorubicin, and prednisone. (Modified with permission from Clemens MW, Butler CE. ASPS/PSF efforts on BIA-ALCL. Plast Surg News 2015;26:8.)


Delayed seromas greater than 1 year after implantation occur in approximately 0.1 to 0.2 percent of patients following implantation of textured implants. Of note, and discussed below, smooth implants are likely not associated with BIA-ALCL.43 In prospective studies, BIA-ALCL has been estimated to occur in 9 to 13 percent of delayed seroma presentations.44 Any seroma occurring greater than 1 year after implantation not readily explainable by infection or trauma should be considered suspicious for disease. An otherwise postoperative seroma or seroma occurring less than 1 year after the first implant seroma is not part of the disease spectrum of BIA-ALCL. Patients most commonly present with the rapid onset of a spontaneous fluid collection (60-90 percent) or capsular mass (10 to 40 percent) at an average of 8 to 10 years after implantation with a textured breast implant, and are distributed roughly equally between cosmetic and reconstructive indications.38 All reported cases to date where a detailed implant history was available involved a textured surface breast implant.39 Other more rarely described symptoms have included skin rash,45 capsular contracture,46 and lymphadenopathy.38 However, capsular contracture in isolation as the only disease manifestation has not been described; therefore, its reliability as a symptom of the disease is questionable and may be coincidental. Disease is not confined to female patients, as three transsexual patients with textured implants have been confirmed.47 Following the National Comprehensive Cancer Network guidelines, initial workup of an enlarged breast should include ultrasound evaluation specifically for a fluid collection, a breast mass, or enlarged regional lymph nodes (axillary, supraclavicular, and internal mammary). For cases where ultrasound is indeterminate or requires further confirmation, physicians may also use magnetic resonance imaging. Adrada and colleagues reviewed 44 BIA-ALCL patients with imaging studies and reported on the sensitivity and specificity for detecting an effusion using ultrasound (84 percent and 75 percent), computed tomography (55 percent and 83 percent), magnetic resonance imaging (82 percent and 33 percent), and positron emission tomography/computed tomography (38 percent and 83 percent).36 In addition, the sensitivity and specificity to detect a mass were reported for ultrasound (46 percent and 100 percent), computed tomography (50 percent and 100 percent), magnetic resonance imaging (82 percent and 33 percent), and positron emission tomography/computed tomography (64 percent and 88 percent). The sensitivity of mammography was found to be inferior for both effusion and mass and therefore is not considered an acceptable imaging modality for BIA-ALCL. Based on these findings, ultrasound evaluation is used as a screening tool, whereas positron emission tomography/computed tomography is used after an established diagnosis for oncologic workup before surgery (Fig. 2).

Fig. 2.:
A patient with effusion-limited (stage IA) left BIA-ALCL is shown on an axial 18F-fluorodeoxyglucose positron emission tomography (PET)/computed tomographic image with increased metabolic activity of the left capsule. (Above, left) Note that a paratracheal lymph node with small cell lung cancer was incidentally found as a second primary cancer. Both diseases were treated and the patient achieved complete remission. Positron emission tomographic/computed tomographic images of invasive BIA-ALCL masses stage IIA (above, right and below, left), seen grossly at time of explantation with a mass growing radially out from the surface of a textured implant. (below, right).

Periprosthetic fluid collections should undergo fine needle aspiration. At the time of aspiration, ultrasound guidance may aid in implant protection and displacement, and can be performed either in a clinic setting or by interventional radiology (Fig. 3). A suspicious mass requires tissue biopsy and evaluation by an oncologist to rule out breast cancer. Specimens should be sent for cell block cytology and CD30 immunohistochemistry. Pathologists will require a clinical history and directions to rule out BIA-ALCL. Fluid specimens do not require storage in any specialized media, and should be transported to a pathology laboratory within a reasonable amount of time (<48 hours). Although cells may lyse if left for a prolonged period, diagnostic protein markers in neoplastic cells do not degrade and diagnosis is possible on fixed cell blocks years later. Fluid collections may be centrifuged down to a supernatant to concentrate cells for pathologic evaluation. If after evaluation diagnosis of lymphoma is indeterminate, secondary hematopathology consultation is recommended at a tertiary cancer center with disease experience. Surgeons investigating a suspicious seroma must supply a pathologist with an adequate volume (minimum, 20 to 50 ml; ideally, >100 ml) to thoroughly evaluate and perform further tests such as flow cytometry and molecular studies, which may be necessary for diagnosis.

Fig. 3.:
Disease diagnosis should be made prior to any surgical intervention to allow for an adequate preoperative oncologic work up and staging. (Above) In a clinical setting, a periprosthetic fluid collection is aspirated under ultrasound guidance and facilitated by implant displacement. (Image with permission and courtesy of Olaya Sanchez Crespo, M.D.) (Below) A BIA-ALCL effusion aspirate is shown and may appear serous, viscous, and/or bloody. Fluid specimens should be sent in entirety, at least 50ml, to facilitate an accurate diagnosis.


BIA-ALCL is a monoclonal T-cell expansion of large anaplastic (Reed Sternberg-like) cells that express CD30 within a periprosthetic effusion or mass aggregate5,48 (Fig. 4). CD30 is a cell membrane protein that serves as a lymphoma tumor marker, although CD30 can occur normally on activated T- or B-cell lymphocytes (Fig. 5). A background of CD30+ T cells is estimated to constitute 0.1 to 5 percent of circulating T cells, and a higher concentration may exist in inflammatory states. Increased CD30 expression can be induced on both T cells and B cells as a result of viral infection.49 CD30+ lymphocytes have been described temporarily increasing from a background of 0.1 percent to as high as 95 percent transiently.49 Immunoblastic proliferation that occurs in infectious mononucleosis can develop Reed-Sternberg–like cells, temporarily making differentiation from Hodgkin lymphoma difficult. BIA-ALCL, and the entire family of ALCLs, display diffuse CD30 expression on their cell surface. Morphologic evaluation by a pathologist and determination of clonal expansion on flow cytometry are critical to diagnosis (Fig. 4). If the pathologic evaluation is negative for ALCL, the patient can be referred to a plastic surgeon for management of a benign seroma. In accordance with the U.S. Food and Drug Administration’s recommendation, histologic confirmation of BIA-ALCL should be reported to the American Society of Plastic Surgeons BIA-ALCL PROFILE (Patient Registry and Outcomes For breast Implants and anaplastic large cell Lymphoma etiology and Epidemiology) registry ( The purpose of this important registry is to increase scientific data on BIA-ALCL in women with breast implants and to support research to characterize the disease. As of February 2018, 518 unique cases of BIA-ALCL across 25 countries have been reported which includes 194 unique US cases to the PROFILE BIA-ALCL patient registry.50

Fig. 4.:
A malignant effusion in a BIA-ALCL patient demonstrates large pleomorphic cells with prominent horseshoe-shaped nuclei, and nuclear folding and strong diffuse CD30 reactivity by immunohistochemistry (CD30 immunohistochemistry with hematoxylin counterstain, original magnification, × 1000). Inset demonstrates a single T-cell population on flow cytometry. Positive cytology and a diffuse expression of CD30 are required for diagnosis.
Fig. 5.:
CD30 immunohistochemistry of a benign late seroma demonstrates a normal mixture of small lymphocytes, histiocytes, and rare eosinophils. Histiocytes display abundant clear cytoplasm with nuclei of variable size. Note that most lymphocytes and all histiocytes are negative for CD30 except for rare isolated morphologically normal lymphocytes (CD30 immunohistochemistry with hematoxylin counterstain, original magnification, × 1000).


After confirmation of BIA-ALCL diagnosis, preoperative consultation with a lymphoma oncologist and consideration of a surgical oncologist are recommended. Oncologic workup should proceed before any operative intervention. A bone marrow biopsy may be indicated but is only performed in rare select cases at the oncologist’s discretion to differentiate from other peripheral T-cell lymphomas. Testing for anaplastic lymphoma kinase translocation status also differentiates from anaplastic lymphoma kinase–positive systemic ALCL, a much more aggressive disease. Note that BIA-ALCL is always anaplastic lymphoma kinase–negative, and therefore anaplastic lymphoma kinase is not a screening tool but a descriptive tool for established disease. For confirmed cases, a positron emission tomographic/computed tomographic scan is beneficial for demonstrating associated capsular masses, chest wall involvement, regional lymphadenopathy, and/or distant organ metastasis.8 A positron emission tomographic scan can act as a roadmap for surgical planning, resection strategy, and timing of surgery. For instance, unresectable chest wall invasion may become resectable following neoadjuvant chemotherapy.


BIA-ALCL was formally staged as a liquid tumor; however, tumor biology has preferentially supported staging as a solid tumor. The Lugano revision to the Ann Arbor Staging System is a liquid tumor staging, with stage IE disease limited to breast involvement only and stage IIE disease limited to the breast and ipsilateral axillary lymph nodes.51 Using this system, nearly all BIA-ALCL patients have low-stage disease, either stage 1E (83 to 96 percent) or stage IIE (3.6 to 18.8 percent)38 (Table 1). An M. D. Anderson tumor, node, metastasis staging system is modeled after the American Joint Committee on Cancer tumor, node, metastasis system (Figs. 6 and 7 and Table 2). Using this system, BIA-ALCL is a spectrum of disease consisting of stages IA (35.6 percent), IB (11.5 percent), IC (13.8 percent), IIA (25.3 percent), IIB (4.6 percent), III (9.2 percent), and IV (0 to 9 percent)5 (Table 1). The World Health Organization currently classifies BIA-ALCL as a lymphoma at all stages.6 Clinical observation of effusion-limited (IA) disease demonstrates a typically indolent course, and therefore this stage may be more akin to a lymphoproliferative disorder. However, BIA-ALCL can become an invasive lymphoma and metastasize at more advanced stages. Other malignant lymphoproliferative disorders include lymphomatoid papulosis and primary cutaneous ALCL. Both can regress spontaneously and have an observed progression rate to invasive lymphoma of 5.6 to 9 percent and 10 to 27 percent, respectively.52,53 It is not yet possible to determine the progression rate of effusion-only (IA) BIA-ALCL to invasive lymphoma, as the staging requires pathologic examination of the resected capsule (in essence, treating the disease). Therefore, how indolent the disease is or quantifying what amount of delay in treatment will lead to progression of disease is not yet possible. It is important to note that all of these designations and nomenclatures are still referring to a cancer. Patients with BIA-ALCL can have progression of their disease, lymph node involvement, and death as a result of disease, particularly with significant delay in diagnosis or suboptimal treatment.54 These patients are described as having local or regional extension of their disease or very rare distant organ metastasis, which is more similar to solid tumors. This emphasizes the solid tumor classification and that this is a distinct entity that progresses locally.

Table 1.:
Reported Stages of BIA-ALCL
Table 2.:
BIA-ALCL Tumor, Node, Metastasis Staging*†
Fig. 6.:
Clinical and pathologic staging of BIA-ALCL follows the M. D. Anderson Solid Tumor Staging System modeled after the American Joint Committee on Cancer tumor, node, metastasis stages. (Reprinted with permission from Clemens MW, Medeiros LJ, Butler CE, et al. Complete surgical excision is essential for patients with breast implant-associated anaplastic large cell lymphoma. J Clin Oncol. 2016;34:160–168.)
Fig. 7.:
Pathologic T staging. (Above) Stage T1: lymphoma cells confined to the effusion or a layer on the luminal side of the capsule. (Second row) Stage T2: lymphoma cells superficially infiltrate the luminal side of the capsule. (Third row) Stage T3: clusters or sheets of lymphoma cells infiltrate into the thickness of the capsule. (Below) Stage T4: lymphoma cells infiltrating beyond the capsule, into the adjacent soft tissue or breast parenchyma. (Left, hematoxylin and eosin stain; right, CD30 immunohistochemistry; original magnification, × 3100.)


Timely diagnosis and complete surgical excision of disease, implants, and the surrounding fibrous capsule is the optimal approach for the management of BIA-ALCL in the majority of patients. Disease localized to the capsule (Lugano stage IE, M. D. Anderson stage IA to IIA) may be treated with surgery alone in the majority of cases (Fig. 8). Surgical goals are a total capsulectomy with removal of the breast implant, excision of any associated capsular mass, and excisional biopsy of suspicious lymph node(s). In retropectoral or dual-plane implants, adherence to the ribcage may make resection difficult, and tumescence of the anatomical plane can facilitate capsulectomy55 (Fig. 9). Care should be taken when dissecting capsule off of intercostal muscles to avoid a pneumothorax. It remains unclear what effect inadvertent spillage of the seroma during capsulectomy has on local seeding of disease; however, clinically, this has not been observed to influence recurrence rates. Complete mass excision with negative margins is essential, as retained disease likely will subject the patient to otherwise unnecessary adjuvant chemotherapy. At present, there is no role for radical mastectomy, sentinel lymph node biopsy, or full axillary dissection. According to the National Comprehensive Cancer Network guidelines, surgeons may consider removal of the contralateral implant, as approximately 4.6 percent of cases to date have demonstrated incidental ALCL in the contralateral breast implant.5 Consultation with a surgical oncologist may be beneficial for plastic surgeons unaccustomed to oncologic ablation and lymph node excisional biopsies.

Fig. 8.:
A 77-year-old woman underwent postmastectomy prosthetic reconstruction for breast cancer. Eleven years after implantation, she developed rapid swelling of the right breast manifested as marked breast asymmetry. (Left) BIA-ALCL was diagnosed on fine needle aspiration. (Right) The patient then underwent a total capsulectomy and implant removal.
Fig. 9.:
Treatment of BIA-ALCL includes total capsulectomy with excision of any associated masses, as residual disease left on the chest wall may continue to progress and require further treatment such as chemotherapy. With subpectoral implants, elevation of the posterior capsular wall off of the rib cage may be difficult, but is still essential. Pictured is standard tumescence being infiltrated by Angiocath (Becton, Dickinson Co., Franklin Lakes, N.J.) into the posterior capsule of a BIA-ALCL patient to facilitate complete removal of the capsule. An inframammary approach was used to allow for immediate reconstruction.

Pathologic evaluation of both the periprosthetic fluid and the capsule are important for staging of the disease (Figs. 10 and 11). Evaluation of the capsule may be performed by either widely sampling the internal lining; alternatively, the capsule may be opened and set out flat and sampled after fixation. Timing and type of reconstruction remain controversial and are currently being prospectively studied with institutional review board oversight. Replacement with smooth implants can be done depending on patient's preferences, but replacement with textured implants should be avoided because of likely genetic predisposition and demonstrated susceptibility.

Fig. 10.:
Implant capsule and implant interface are shown, demonstrating mass pebbling of the luminal capsule surface. (Left) The capsule thickness may be thin or thick. Also demonstrated is a 7-cm mass adjacent to the capsule that required excision. (Right) Note minimal vascularity of the mass, which can grossly appear similar to scar tissue or fat necrosis but is dense tumor under pathologic evaluation. Mass aggregate portends a statistically worse prognosis and represents disease progression.
Fig. 11.:
(Left) Scanning electron microscopic photograph of the textured surface implant and scar capsule interface in a BIA-ALCL patient (original magnification, × 40). Note the shark-tooth impression of the luminal capsule surface that mirrors the implant surface. (Right) Scanning electron microscopic photograph of a textured shell surface with clusters of ALCL cells growing on the surface of the implant (original magnification, × 300).


Adjuvant chemotherapy will frequently be warranted in patients with advanced disease (2 to 18 percent) such as lymph node metastasis (Lugano stage II to IV; M. D. Anderson stage IIB to IV) (Table 1). Systemic ALCL is treated with an anthracycline-based regimen (cyclophosphamide, vincristine, doxorubicin, and prednisone) for first-line therapy. Anthracycline-based multiagent chemotherapy with or without radiation therapy followed by autologous stem cell rescue is the standard approach for most patients with newly diagnosed systemic T-cell lymphomas.56 However, National Comprehensive Cancer Network guidelines allow physicians to consider following either a systemic ALCL chemotherapy regimen (cyclophosphamide, vincristine, doxorubicin, and prednisone) or alternatively with brentuximab vedotin as a first-line agent. Brentuximab vedotin is a toxin-antibody conjugate to CD30. Pro and colleagues reported 4-year survival data from an ongoing Phase II study of brentuximab vedotin in patients with refractory systemic ALCL that demonstrated an objective response rate of 83 percent and a complete remission rate of 62 percent.57,58 A randomized Phase III study is evaluating brentuximab vedotin in combination with cyclophosphamide, doxorubicin, and prednisone for frontline treatment of CD30+ mature T-cell lymphomas, including systemic ALCL. Outcomes of chemotherapeutic regimens in BIA-ALCL are from case reports; however, complete remissions have been achieved in patients with organ metastasis when treated with brentuximab vedotin.59 The drug may also have a role as a neoadjuvant targeted agent for downgrading chest wall invasion.60,61 Stem cell transplant and external beam radiation therapy are reserved only for unresectable disease in a salvage setting.


Patients are best followed by an oncologist that may monitor for disease recurrence and evaluate for adjunctive therapy. Treated patients with no evidence of disease are evaluated every 3 to 6 months for 2 years, and then as clinically indicated. Physicians may include computed tomographic or positron emission tomographic/computed tomographic scans every 6 months for 2 years and then only as clinically indicated. Relevant surgical codes for diagnosis and management of BIA-ALCL are listed in Table 3. Most insurance companies do not specify whether treatment for BIA-ALCL is a covered benefit; however, Blue Cross Blue Shield and Aetna have recently guaranteed coverage for implant and capsule removal with a confirmed diagnosis of BIA-ALCL in both cosmetic and reconstructive implant patients.

Table 3.:
Relevant International Classification of Diseases, Tenth Revision, and Current Procedural Terminology Codes for Suspected and Confirmed BIA-ALCL Cases


BIA-ALCL generally appears to be a biologically indolent disease with an excellent prognosis when confined to the capsule and treated with complete surgical resection. To date, we have not confirmed a case of BIA-ALCL with spontaneous resolution of disease without any treatment intervention. Regression and healing can rarely occur with other malignancies such as melanoma, but we have not confirmed a case of regression with BIA-ALCL to date.62 Note that gradually lower concentrations of anaplastic cells have been observed after serial aspirations, making diagnosis more difficult after a previous seroma drainage. This may represent dilution of the tumor burden rather than regression, and should still be addressed with surgical resection. Statistically worse prognosis has been identified in patients with mass formation and extracapsular extension.22 Miranda and colleagues reported on the long-term outcomes of 60 patients and found that more patients without a mass achieved complete remission compared with those with a mass (93 percent of 42 patients compared with 72 percent of 18 patients).22 The median overall survival for patients with a discrete breast mass was 12 years, whereas the median overall survival had not been reached for patients who did not have a discrete breast mass. It remains unclear whether the worse prognosis associated with a mass is attributable to a more aggressive variant or more progressed disease, or perhaps is a consequence of inadequate surgical ablation of tumor infiltration.

Clemens et al. reported on the outcomes of 87 patients treated with surgery alone (40 percent); surgery and radiation (9 percent); surgery and chemotherapy (19 percent); surgery, chemotherapy, and radiation therapy (30 percent); or chemotherapy alone (2 percent).38 Both the presence of a mass at the time of diagnosis and extracapsular disease extension were associated with an increased risk for recurrence and patient death. At a median follow-up of 45 months, 28 percent had recurrent disease, of whom 73 percent were treated with salvage chemotherapy. Complete surgical excision of the disease had the lowest recurrence rate of 4 percent at 1, 3, and 5 years. Kaplan-Meier survival curves by treatment modality are displayed in Figure 12. At present, a total of 16 patients have been reported dead from BIA-ALCL disease in Australia, Brazil, France, United Kingdom, The Netherlands, New Zealand, Sweden, and the United States.10–12,34,53,63,64 A recurring theme in these tragic outcomes is significant delay in diagnosis, and/or chemotherapeutic treatment of the disease with limited or no surgical resection.

Fig. 12.:
Survival curves according to treatment approaches (above) and tumor, node, metastasis solid tumor staging (below). Event-free survival (left), overall survival (right). (Reprinted with permission from 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. J Clin Oncol. 2016;34:160–168.)


BIA-ALCL was first described over 20 years ago65 but has only recently led to a wave of concern among the public, media, and physicians. BIA-ALCL appears to begin as an indolent disease with excellent prognosis in the majority of patients. Early stages are similar to a lymphoproliferative disorder arising in an effusion around a textured breast implant, and can progress to an invasive lymphoma with infiltration of the fibrous capsule, mass formation, and regional metastasis. Diagnosis requires large anaplastic cells on cell block cytology, CD30 immunohistochemistry expression, and surrogate markers for T-cell clonality by flow cytometry. National Comprehensive Cancer Network consensus guidelines have been established and widely adopted for the diagnosis and management of BIA-ALCL. Surgical ablation with explantation and capsulectomy is frequently curative with disease confined to the capsule. Novel targeted chemotherapy agents have demonstrated early success and may be the preferred treatment in advanced disease. Understanding and implementation of a standardized approach is critical to prevent delays in diagnosis, disease progression, and avoidable adverse sequelae. Patient safety is our first and foremost responsibility.


1. U.S. Food and Drug Administration. Anaplastic large cell lymphoma (ALCL): Preliminary FDA findings and analyses. Available at: Accessed March 20, 2017.
2. Clemens MW, Miranda RNComing of age: Breast implant-associated anaplastic large cell lymphoma after 18 years of investigation. Clin Plast Surg. 2015;42:605613.
3. Ramos-Gallardo G, Cuenca-Pardo J, Rodríguez-Olivares E, et al.Breast implant and anaplastic large cell lymphoma meta-analysis. J Invest Surg. 2016;18:110.
4. Gidengil CA, Predmore Z, Mattke S, van Busum K, Kim BBreast implant-associated anaplastic large cell lymphoma: A systematic review. Plast Reconstr Surg. 2015;135:713720.
5. Clemens MW, Nava MB, Rocco N, Miranda RNUnderstanding rare adverse sequelae of breast implants: Anaplastic large-cell lymphoma, late seromas, and double capsules. Gland Surg. 2017;6:169184.
6. Swerdlow SH, Campo E, Pileri SA, et al.The 2016 revision of the World Health Organization classification of lymphoid neoplasms. Blood 2016;127:23752390.
7. World Health Organization International Agency for Research on Cancer. IARC monographs on the evaluation of carcinogenic risks to humans: Report of the advisory group to recommend priorities for IARC monographs during 2015–2019. Available at: ENG/Publications/internrep/14-002.pdf. Accessed August 1, 2017.
8. U.S. National Cancer Institute. Treatment for health professionals. Available at: Accessed August 1, 2017.
9. U.S. Food and Drug Administration. Anaplastic large cell lymphoma (ALCL) in women with breast implants: Medical device reports of breast implants in women with ALCL. Available at: Accessed January 17, 2018.
10. Institut National du Cancer. Breast implant associated anaplastic large cell lymphoma: An expert’s opinion. Available at: Breast%20implants-associated%20anaplastic%20large%20cell%20lymphomas.pdf. Accessed February 1, 2017.
11. Australian Therapeutic Goods Administration. Breast implants: Update on TGA monitoring of anaplastic large cell lymphoma. Available at: Accessed December 20, 2016.
12. Medicines and Healthcare Products Regulatory Agency. Breast implants and anaplastic large cell lymphoma (ALCL). Available at: Accessed July 26, 2017.
13. Grady DA shocking diagnosis: Breast implants ‘gave me cancer’. The New York Times. May 14, 2017:12.
14. Hu H, Jacombs A, Vickery K, Merten SL, Pennington DG, Deva AKChronic biofilm infection in breast implants is associated with an increased T-cell lymphocytic infiltrate: Implications for breast implant-associated lymphoma. Plast Reconstr Surg. 2015;135:319329.
15. 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;133:471e480e.
16. Hammond DCReply: Chronic biofilm infection in breast implants is associated with an increased T-cell lymphocytic infiltrate: Implications for breast implant–associated lymphoma. Plast Reconstr Surg. 2015;135:1057e1059e.
17. Prince HM, Johnstone RCommentary on: Biomarkers provide clues to early events in the pathogenesis of breast implant-associated anaplastic large cell lymphoma. Aesthet Surg J. 2016;36:782783.
18. Kadin ME, Deva A, Xu H, et al.Biomarkers provide clues to early events in the pathogenesis of breast implant-associated anaplastic large cell lymphoma. Aesthet Surg J. 2016;36:773781.
19. Brody GSThe case against biofilm as the primary initiator of breast implant-associated anaplastic large cell lymphoma. Plast Reconstr Surg. 2016;137:766e767e.
20. Bizjak M, Selmi C, Praprotnik S, et al.Silicone implants and lymphoma: The role of inflammation. J Autoimmun. 2015;65:6473.
21. Orciani M, Sorgentoni G, Torresetti M, Di Primio R, Di Benedetto GMSCs and inflammation: New insights into the potential association between ALCL and breast implants. Breast Cancer Res Treat. 2016;156:6572.
22. 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;32:114120.
23. Lechner MG, Megiel C, Church CH, et al.Survival signals and targets for therapy in breast implant-associated ALK–anaplastic large cell lymphoma. Clin Cancer Res. 2012;18:45494559.
24. Montgomery-Goecker C, Fuda F, Krueger JE, Chen WImmunophenotypic characteristics of breast implant-associated anaplastic large-cell lymphoma by flow cytometry. Cytometry B Clin Cytom. 2015;88:291293.
25. Kuehlmann B, Prantl LBreast implants and possible association with ALCL: A retrospective study including a histological analysis of 296 explanted breast tissues and current literature. Clin Hemorheol Microcirc. 2016;63:439449.
26. Taylor CR, Siddiqi IN, Brody GSAnaplastic large cell lymphoma occurring in association with breast implants: Review of pathologic and immunohistochemical features in 103 cases. Appl Immunohistochem Mol Morphol. 2013;21:1320.
27. Xu J, Wei SBreast implant-associated anaplastic large cell lymphoma: Review of a distinct clinicopathologic entity. Arch Pathol Lab Med. 2014;138:842846.
28. Miranda RN, Lin L, Talwalkar SS, Manning JT, Medeiros LJAnaplastic large cell lymphoma involving the breast: A clinicopathologic study of 6 cases and review of the literature. Arch Pathol Lab Med. 2009;133:13831390.
29. Aladily TN, Medeiros LJ, Alayed K, Miranda RNBreast implant-associated anaplastic large cell lymphoma: A newly recognized entity that needs further refinement of its definition. Leuk Lymphoma 2012;53:749750.
30. 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;36:10001008.
31. de Jong D, Vasmel WL, de Boer JP, et al.Anaplastic large-cell lymphoma in women with breast implants. JAMA 2008;300:20302035.
32. Doren EL, Miranda RN, Selber JC, et al.U.S. epidemiology of breast implant-associated anaplastic large cell lymphoma. Plast Reconstr Surg. 2017;139:10421050.
33. 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;139:10291039.
34. Loch-Wilkinson A, Beath K, Knight RJW, et al.Breast implant associated anaplastic large cell lymphoma in Australia and New Zealand: High surface area textured implants are associated with increased risk. Plast Reconstr Surg. 2017;140:10291039.
35. Campanale A, Boldrini R, Marletta M22 Cases of breast implant-associated ALCL: Awareness and outcome Tracking from the Italian ministry of health. Plast Reconstr Surg. 2018;141:11e–19e.
36. Adrada BE, Miranda RN, Rauch GM, et al.Breast implant-associated anaplastic large cell lymphoma: Sensitivity, specificity, and findings of imaging studies in 44 patients. Breast Cancer Res Treat. 2014;147:114.
37. Acevedo-Báñez I, García-Gomez FJ, Jiménez-Granero P, Carrillo-Cruz E, Perez-Lopez O, Borrego-Dorado I18F-FDG-PET/CT in implant-associated anaplastic large cell lymphoma of the breast. Br J Haematol. 2015;169:1.
38. 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. J Clin Oncol. 2016;34:160168.
39. 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;135:695705.
40. Clemens MW, Miranda RN, Butler CEBreast implant informed consent should include the risk of anaplastic large cell lymphoma. Plast Reconstr Surg. 2016;137:11171122.
41. Clemens MW, Horwitz SMNCCN Consensus guidelines for the diagnosis and management of breast implant-associated anaplastic large cell lymphoma. Aesthet Surg J. 2017;37:285289.
42. National Comprehensive Cancer Network. About NCCN. Available at: Accessed February 10, 2018.
43. McGuire P, Reisman NR, Murphy DKRisk factor analysis for capsular contracture, malposition, and late seroma in subjects receiving Natrelle 410 form-stable silicone breast implants. Plast Reconstr Surg. 2017;139:19.
44. Di Napoli A, Pepe G, Giarnieri E, et al.Cytological diagnostic features of late breast implant seromas: From reactive to anaplastic large cell lymphoma. PLoS One 2017;12:e0181097.
45. Alcalá R, Llombart B, Lavernia J, Traves V, Guillén C, Sanmartín OSkin involvement as the first manifestation of breast implant-associated anaplastic large cell lymphoma. J Cutan Pathol. 2016;43:602608.
46. Lazzeri D, Zhang YX, Huemer GM, Larcher L, Agostini TCapsular contracture as a further presenting symptom of implant-related anaplastic large cell lymphoma. Am J Surg Pathol. 2012;36:17351736; author reply 17361738.
47. de Boer M, van Leeuwen FE, Hauptmann M, et al.Breast implants and the risk of anaplastic large-cell lymphoma in the breast. JAMA Oncol. 2018. [e-pub ahead of print].
48. Clemens MW, Miranda RNCommentary on: Lymphomas associated with breast implants: A review of the literature. Aesthet Surg J. 2015;35:545547.
49. Falini B, Pileri S, Pizzolo G, et al.CD30 (Ki-1) molecule: A new cytokine receptor of the tumor necrosis factor receptor superfamily as a tool for diagnosis and immunotherapy. Blood 1995;85:114.
50. PSF PROFILE Registry Statistics. Available at: Accessed August February 23, 2018.
51. Cheson BD, Fisher RI, Barrington SF, et alAlliance, Australasian Leukaemia and Lymphoma Group; Eastern Cooperative Oncology Group; European Mantle Cell Lymphoma Consortium; Italian Lymphoma Foundation; European Organisation for Research; Treatment of Cancer/Dutch Hemato-Oncology Group; Grupo Español de Médula Ósea; German High-Grade Lymphoma Study Group; German Hodgkin’s Study Group; Japanese Lymphorra Study Group; Lymphoma Study Association; NCIC Clinical Trials Group; Nordic Lymphoma Study Group; Southwest Oncology Group; United Kingdom National Cancer Research Institute. Recommendations for initial evaluation, staging, and response assessment of Hodgkin and non-Hodgkin lymphoma: The Lugano classification. J Clin Oncol. 2014;32:30593068.
52. Paulli M, Berti E, Rosso R, et al.CD30/Ki-1-positive lymphoproliferative disorders of the skin: Clinicopathologic correlation and statistical analysis of 86 cases. A multicentric study from the European Organization for Research and Treatment of Cancer Cutaneous Lymphoma Project Group. J Clin Oncol. 1995;13:13431354.
53. Wieser I, Wohlmuth C, Nunez CA, Duvic MLymphomatoid papulosis in children and adolescents: A systematic review. Am J Clin Dermatol. 2016;17:319327.
54. Clemens MW, Collins MS, Butler CE, et al.Characteristics and treatment of patients with breast implant-associated anaplastic large cell lymphoma presenting with aggressive features. Plast Reconstr Surg. 2015;136(Suppl):119120.
55. Brody GSBrief recommendations for dealing with a new case of anaplastic large T-cell lymphoma. Plast Reconstr Surg. 2012;129:871e872e.
56. Horwitz SM, Zelenetz AD, Gordon LI, et al.NCCN guidelines insights: Non-Hodgkin’s lymphomas, version 3.2016. J Natl Compr Canc Netw. 2016;14:10671079.
57. Pro B, Advani R, Brice P, et al.Four-year survival data from an ongoing pivotal phase 2 study of brentuximab vedotin in patients with relapsed or refractory systemic anaplastic large cell lymphoma. Blood 2014;124:3095.
58. Pro B, Advani R, Brice P, et al.Brentuximab vedotin (SGN-35) in patients with relapsed or refractory systemic anaplastic large-cell lymphoma: Results of a phase II study. J Clin Oncol. 2012;30:21902196.
59. Zimmerman A, Locke FL, Emole J, et al.Recurrent systemic anaplastic lymphoma kinase-negative anaplastic large cell lymphoma presenting as a breast implant-associated lesion. Cancer Control 2015;22:369373.
60. Johnson L, O’Donoghue J, Stark H, et al.Breast implant associated anaplastic large cell lymphoma (BIA-ALCL): The UK experience and first reported case of neoadjuvant brentuximab. Cancer Res. 2017;77(Suppl):Abstract P50302.
    61. Richardson K, Alrifai T, Grant-Szymanski K, et al.Breast implant-associated anaplastic large-cell lymphoma and the role of brentuximab vedotin (SGN-35) therapy: A case report and review of the literature. Molecular and Clinical Oncology. 2017;6(4):539542.
    62. Khosravi H, Akabane AL, Alloo A, Nazarian RM, Boland GMMetastatic melanoma with spontaneous complete regression of a thick primary lesion. JAAD Case Reports. 2016;2(6):439441.
    63. 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;128:112e118e.
    64. Ivaldi C, Perchenet AS, Jallut Y, Casanova DTwo cases of lymphoma in an implant capsule: A difficult diagnosis, an unknown pathology (in French). Ann Chir Plast Esthet. 2013;58:688693.
    65. Keech JA Jr, Creech BJAnaplastic T-cell lymphoma in proximity to a saline-filled breast implant. Plast Reconstr Surg. 1997;100:554555.
    Copyright © 2018 by the American Society of Plastic Surgeons