INTRODUCTION — Breast implant-associated anaplastic large cell lymphoma (BIA-ALCL) is an uncommon and still emerging peripheral T cell lymphoma caused by and arising around textured-surface breast implants placed for either reconstructive or cosmetic indications. The association of breast implants with a cancer of the immune system has created understandable concern among patients, plastic surgeons, and oncologists.
Initial studies suggest that BIA-ALCL follows a relatively indolent course in most patients and those with early stage disease have an excellent prognosis. However, reports of disseminated cancer and deaths attributed to the disease emphasize the importance of appropriate surveillance, timely diagnosis, and adequate treatment.
BIA-ALCL is rarely seen at most medical centers, and thus a diagnosis of BIA-ALCL can become delayed, often not being suspected and only diagnosed at the time of implant revision surgery performed for a persistent seroma. Thus, clinicians must maintain a high index of suspicion. BIA-ALCL usually presents as localized disease with either a seroma or, less commonly, a discrete breast mass adjacent to the implant. Most cases present approximately one decade after implant placement, although earlier or later presentations can be seen.
The clinical features, diagnosis, treatment, and prognosis of BIA-ALCL are reviewed here. The diagnosis and management of systemic ALCL (anaplastic lymphoma kinase [ALK]-positive and ALK-negative) and primary cutaneous ALCL are presented separately. (See "Clinical manifestations, pathologic features, and diagnosis of systemic anaplastic large cell lymphoma (sALCL)" and "Primary cutaneous anaplastic large cell lymphoma" and "Initial treatment of systemic anaplastic large cell lymphoma (sALCL)".)
CLASSIFICATION — Lymphoma is the most common hematologic malignancy and is a cancer of the immune system developing from B or T lymphocytes [1]. The peripheral T cell lymphomas are a heterogeneous group that are derived from cells that normally develop into T lymphocytes (cytotoxic T lymphocytes, helper T lymphocytes, or regulatory T lymphocytes). Peripheral T cell lymphomas constitute <15 percent of all lymphomas in adults. (See "Classification of hematopoietic neoplasms", section on 'Lymphoid neoplasms'.)
Anaplastic large cell lymphoma (ALCL), T/null cell type is the second or third most common peripheral T cell lymphoma histology depending on the series analyzed and accounts for <2 percent of lymphomas in adults. The World Health Organization (WHO) classification of lymphoid neoplasms recognizes four distinct forms of ALCL based on clinical features and molecular characterization, including expression of anaplastic lymphoma kinase (ALK) [2]:
●Primary systemic ALCL, ALK positive (ALK-positive ALCL)
●Primary systemic ALCL, ALK negative (ALK-negative ALCL)
●Primary cutaneous ALCL (PC-ALCL)
●Breast implant-associated ALCL (BIA-ALCL)
Neither PC-ALCL nor BIA-ALCL expresses ALK. In contrast, primary systemic ALCLs are subclassified according to ALK expression (ie, ALK-positive ALCL versus ALK-negative ALCL). ALK expression is most commonly a result of the t(2;5) translocation involving the 2p23 and the 5q35 chromosomes that create an oncogenic fusion protein of the ALK gene and the nucleophosmin (NPM) gene [3]. (See "Clinical manifestations, pathologic features, and diagnosis of systemic anaplastic large cell lymphoma (sALCL)", section on 'Molecular genetics'.)
While ALCL has been historically considered a clinically aggressive lymphoma, the clinical course varies considerably among subtypes. Without treatment, systemic ALCL often pursues an aggressive clinical course with widespread involvement and rapid progression. Among those with systemic ALCL, ALK expression is associated with better outcomes. By contrast, PC-ALCL is usually more indolent with excellent survival rates at five years (>90 to 95 percent) [4]. Clinically, BIA-ALCL generally behaves more like PC-ALCL, or a solid tumor acting locally and regionally, rather than the more aggressive systemic forms of ALCL. (See "Clinical manifestations, pathologic features, and diagnosis of systemic anaplastic large cell lymphoma (sALCL)" and "Initial treatment of systemic anaplastic large cell lymphoma (sALCL)" and "Primary cutaneous anaplastic large cell lymphoma".)
PATHOGENESIS AND IMPLANT CHARACTERISTICS — Available evidence suggests that BIA-ALCL develops in the setting of textured surface implant-induced chronic inflammation [5-7]. Chronic immune stimulation in some patients has been reported [8,9]. One proposed mechanism implicates chronic T cell stimulation with local antigenic drive in the development of lymphoma [10]. The immune system’s response to chronic inflammation surrounding the breast implant may lead to degeneration and dysplasia in a genetically susceptible patient [6,11]. Activation of the JAK/STAT3 signaling pathway and/or activating mutations in JAK1 and STAT3 are common in BIA-ALCL [12-15]. Whole exome sequencing or targeted deep sequencing of 54 cases of BIA-ALCL (15 tumors, 19 in situ cases) also identified mutations of epigenetic modifiers in three-quarters of cases [16].
Several etiologic factors have been proposed as the cause of chronic immune stimulation. This includes macrophage perpetual exhaustive phagocytosis of particulate from textured implants or increasing mutational genetic burden [17], but these observations have not been confirmed in formal epidemiological studies [18]. Further research is required to identify modifiable risk factors, susceptible populations, and optimal screening and surveillance modalities. Additional theories of pathogenesis have been postulated. Macrophage digestion of shell particulate may release inflammatory cytokines that lead to lymphomagenesis in genetically susceptible individuals [19-21]. Another study that reported a summary of 79 published patients and 94 previously unreported cases reported that all patients had a history of at least one textured device [22]. All cases to date that have been reported have included a textured surface device when clinical history was known. Due to a predominance of textured cases and concerns of textured biocompatibility, the French National Agency for Medicines and Health Product Safety (ANSM) instituted a black box warning of a clearly established link between breast implants and lymphoma [23]. The US Food and Drug Administration (FDA) has also provided a black box warning for breast implants in the United States in 2020 and use of a standardized informed consent. In 2021, the Scientific Committee on Health, Emerging and Environmental Risks (SCHEER) from the European Commission on Health (DGSANTE) released a white paper analysis denoting a "moderate" and sufficient level of evidence for a causal relationship between all textured breast implants and BIA-ALCL [24].
Laboratory studies suggest that texturing of the surface of the implant may induce BIA-ALCL. In an Australian study, the capsules of textured and smooth implants in pigs were compared; textured implants showed increased numbers of lymphocytes with a predominance of T cells compared with smooth breast implants [25,26]. All clinical case reports and case series have demonstrated a clinical history of textured-surface implants. An animal model demonstrated localized immune suppression with higher levels of immunosuppressive FOXP3+ regulatory T cells surrounding textured-surface implants in comparison with smooth surface implants and confirmed in human explantation specimens [27]. Among breast implant adverse events and ALCL reported to the FDA as of April 1, 2022, where surface characteristics were known, 95.6 percent of cases occurred with textured devices [28,29]. Among the reported events and ALCL, some cases were reported with smooth surface devices, though the FDA warned that these either had a clinical history of a prior textured device or no clinical history was available for review, and that they could not confirm any pure smooth device clinical history of BIA-ALCL. This safety communication indicated awareness of 1130 unique pathologically confirmed cases of ALCL worldwide, which included 59 deaths attributable to the disease [30]. Of the 1130 unique cases of BIA-ALCL, 953 were attributable to Allergan BIOCELL textured implants. Based upon a disproportionately higher manufacturer disease risk, the FDA requested a Class I device recall from Allergan Corporation for BIOCELL textured implants in 2019, which was immediately followed by a worldwide voluntary recall of Allergan BIOCELL tissue expanders and implants by the manufacturer. This followed a prior mandatory recall in 38 countries. (See "Implant-based breast reconstruction and augmentation", section on 'Types of implants' and "Implant-based breast reconstruction and augmentation", section on 'Concerns over breast implants'.)
EPIDEMIOLOGY — BIA-ALCL is an uncommon but increasingly well-described entity, and the exact incidence is not known. Most cases present approximately one decade after implant placement, although earlier or later presentations can be seen. This corresponds to a median age of onset of approximately 50 years of age [31,32].
Among women with breast implants, the absolute risk of developing ALCL is low, although this entity occurs much more frequently in the textured implant population when compared with the general population (ie, high relative risk). This was illustrated in a population-based case-control study from the Netherlands (approximately 9 million women) which reported an 18-fold higher rate of ALCL arising in the breast among women with breast implants compared with women who did not have implants (odds ratio 18.2, 95% CI 2.1-156.8) [33]. At the time of the study, the Netherlands was nearly a complete textured implant market, but has subsequently increased smooth implant use due to concerns over BIA-ALCL. While a number of prior studies failed to show an association between breast implants and lymphoma, these studies were limited by small sample sizes and/or short follow-up time [34-37]. These studies illustrate the difficulty of determining the incidence and prevalence of an uncommon and emerging clinical entity.
Reliable epidemiologic data for the incidence and prevalence of BIA-ALCL has been estimated for the 20 to 30 million women with breast implants worldwide in several studies [37]. As examples:
●Between 1997 and 2016, approximately 134 cases were reported either in individual reports or within literature reviews on BIA-ALCL [5,7,8,20,31,38-71]. The number of cases published annually has increased with the formal recognition of BIA-ALCL as an entity and wider physician education about BIA-ALCL (figure 1).
●In the Netherlands database study, the estimated number of textured implants needed to cause one breast implant ALCL case before age 75 years was approximately 6920 [72]. Importantly, this represents the average risk for textured implants among all breast implants used in the Netherlands.
●A 2017 study estimated the average lifetime prevalence of BIA-ALCL by comparing pathologically confirmed cases in the United States (US) with US textured implant sales to be 1 per 30,000 patients with textured breast implants, which is 67.6 times higher than that of primary ALCL of the breast in the general population [73]. Within this study, the rate for BIA-ACL for Allergan BIOCELL was approximately six times that of Mentor Siltex implants (1:6600 versus 1:53,300).
●In the largest prospective series of a specific type of textured implant, which included 17,656 women receiving 31,985 salt-loss textured (BIOCELL) implants, eight cases of BIA-ALCL cases occurred for an overall risk for Allergan BIOCELL implants of one in 2207 (95% CI 1120-5112) [74-76].
●The 26-year cumulative incidence of BIA-ALCL was estimated to be 1 in 355 for an Allergan BIOCELL implant and a patient-specific incidence rate was estimated at 0.311 cases per 1000 person-years (95% CI 0.018-0503) [77].
The reason for implant placement (cosmetic versus reconstructive) may influence the absolute risk of lymphoma [22]. The number of BIA-ALCL cases reported following primary breast augmentation compared with reconstruction for breast cancer or for prophylaxis are nearly equivalent; however, the number of women receiving augmentation implants outnumbers by double those women receiving reconstructive implants. This suggests an overall higher risk for BIA-ALCL in breast reconstruction compared with augmentation. Animal studies have suggested an increased risk with textured implants, but there does not appear to be any clinical association between the filling or inside of the implant (silicone versus saline) and the subsequent risk of BIA-ALCL [70].
There is no consistent finding of ALCL associated with other implanted medical devices other than breast implants. Lymphomas have also been described in the context of implanted orthopedic devices, but these are typically B cell lymphomas [78,79]. Individual case reports describe a very similar localized ALK-negative ALCL T cell lymphoma in association with a dental implant, a tibial implant, and a silicone chemotherapy infusion port [78,80,81].
While BIA-ALCL was the first described implant-associated malignancy, the US Food and Drug Administration released a safety communication on September 8, 2022 warning of case reports of several more inflammatory mediated tumors arising around implants, specifically B cell lymphomas (BCL) and squamous cell carcinoma (SCC) [82-84]. These case reports are limited, and not nearly as numerous as those for BIA-ALCL, with only approximately 20 cases of SCC and 30 cases of various BCLs. The largest series of BCLs arising around breast implants reported that all cases involved an active infection of Epstein-Barr virus (EBV), a known driver of B-cell lymphotropism and oncoviral properties. Therefore, EBV is a likely key component to pathogenesis within implant-associated BCLs. (See "Implant-based breast reconstruction and augmentation", section on 'Concerns over breast implants'.)
COUNSELING WOMEN WITH IMPLANTS — The safety communications from the US Food and Drug Administration (FDA) have cautioned women with breast implants about BIA-ALCL, and included information regarding clinical presentation, prognosis, and treatment options, which increased public and physician awareness of this entity [85]. In July 2019, the FDA called for a Class I device recall of Allergan BIOCELL Textured-surface implants and expanders out of concern for a disproportionately higher rate of BIA-ALCL with these devices [30]. The FDA classifies recalls by a numerical designation (I, II, or III) indicating the relative degree of health hazard, with class I as the most serious, signifying "a reasonable probability that the use of, or exposure to, a violative product will cause serious adverse health consequences or death." However, because the risk of developing BIA-ALCL is low, the FDA had no recommendation on prophylactic removal of textured implants. Further, no additional screening or monitoring was recommended for asymptomatic patients with textured implants who chose to keep their implants.
The FDA reported in 2020 that among cases when the device was known, Allergan BIOCELL was involved in the majority of worldwide cases and the risk with this device was at least six times higher compared with the next available textured breast implant in the United States [73]. In 2022, the FDA reported 59 known disease-related deaths. The US recall followed a prior 38 country restriction of sale on Allergan BIOCELL and ultimately resulted in a worldwide voluntary recall by the manufacturer. (See "Implant-based breast reconstruction and augmentation", section on 'Concerns over breast implants'.)
Based on the available data, the FDA recommends the following for counseling women with implants [86]:
●Although BIA-ALCL is uncommon, women with breast implants have a small but increased risk of developing BIA-ALCL in the capsule adjacent to a textured-surface breast implant.
●When BIA-ALCL occurs, it is most frequently identified in patients undergoing implant revision operations for late onset, persistent seroma. However, in some cases, patients present with capsular contracture or masses adjacent to the breast implant. (See 'Clinical and pathologic features' below.)
●Women with breast implants should perform regular self-breast exams and contact their health care provider promptly if they notice any changes.
●While there are no screening recommendations for asymptomatic patients specific to BIA-ALCL, the FDA recommends surveillance with ultrasound or magnetic resonance imaging for all those with breast implants at five years after implantation and then every three years thereafter.
●The FDA has no recommendation on prophylactic removal of textured breast implants. Textured implant removal or replacement to smooth implants has been shown to decrease the future onset of BIA-ALCL [87]. Surgeons may discuss the risks and benefits of explantation, with or without replacement of a smooth device, to help the patient choose the best option for them.
CLINICAL AND PATHOLOGIC FEATURES
History and physical — Most cases of BIA-ALCL arise in the scar capsule adjacent to a silicone or saline-filled textured-surface breast implant approximately 7 to 10 years after implantation on average [88]; however, cases have been reported within two years of implantation and as late as 32 years after implantation (figure 2) [59,89-91]. A systematic review reported one occurrence two months after exchange of an implant [88]. While most cases are unilateral, bilateral breast involvement has been reported in a minority of patients with bilateral breast implants [61,88,92].
Approximately 60 percent of patients present with a malignant effusion associated with the fibrous capsule surrounding a breast implant [7,89]. The seroma may be associated with breast swelling, asymmetry, or pain. A minority present with a discrete mass adjacent to the implant (17 percent) or both a mass and an effusion (20 percent). Rare cases present with capsular contracture; however, this is not specific, as capsular contracture is relatively common, occurring in approximately 10 percent following implant placement. There have also been reports describing the presence of associated skin lesions (eg, papules) [93,94].
Physical examination demonstrates a fluid collection in approximately 70 percent and a mass in 30 percent [95]. Ipsilateral regional lymphadenopathy is present in up to 17 percent of cases [95,96]. In one retrospective review of 60 patients with BIA-ALCL, 42 patients presented with a seroma only, while 18 presented with a discrete mass with a median diameter of 2 cm [70]. Ten patients had axillary adenopathy, though tumor was present in only 60 percent of the clinically or radiographically abnormal nodes.
Laboratory studies and biomarkers of early disease — Routine laboratory studies in patients found to have BIA-ALCL are largely normal; however, one case report described marked eosinophilia at initial presentation [94].
The use of biomarkers to identify early disease is largely investigational. Preliminary studies suggest that BIA-ALCL cells may be derived from Th1/Th17 cells in capsular tissues and surrounding seromas. Studies are aimed at determining whether select biomarkers such as JunB and SATB1 can identify nonmalignant precursors to BIA-ALCL [97].
Pathologic features — On pathologic examination, BIA-ALCL may appear as individual cells, cell clusters in aggregates, or as coherent sheets [98]. On excised specimens, the tumor involves the luminal surface of the fibrous capsule surrounding the implant and may show varying degrees of infiltration of the capsule, the surrounding soft tissue, or the breast parenchyma.
Morphologically the tumor is comprised of large cells, pleomorphic cells with abundant cytoplasm, and horseshoe-shaped or "embryoid" nuclei with prominent nucleoli [2,99]. On immunohistochemistry, BIA-ALCL demonstrates strong and uniform membranous expression of CD30 and lacks anaplastic lymphoma kinase (ALK) expression. Other T cell antigens are expressed variably, with the most common being CD4 (80 to 84 percent), CD43 (80 to 88 percent), CD3 (30 to 46 percent), CD45 (36 percent), and CD2 (30 percent) [100]. Expression of CD5, CD7, CD8, or CD15 is rare. (See "Clinical manifestations, pathologic features, and diagnosis of systemic anaplastic large cell lymphoma (sALCL)".)
While the diagnosis is based upon the presence of positive CD30 staining on immunohistochemical analysis of the fluid surrounding the capsule, CD30+ cells can often occur in the context of normal inflammation, and this finding must be in addition to large anaplastic morphology on cytology, a single T cell clone, and correlated to the patient's presentation before a final diagnosis is made with a combination of immunohistochemical analysis and clinical judgment [101].
There are no rearrangements involving the ALK gene on chromosome 2p23 in BIA-ALCL.
DIAGNOSIS
Evaluation of suspected cases — Clinicians should maintain a high index of suspicion to allow for early diagnosis and management of BIA-ALCL. Standardized diagnosis and management guidelines on BIA-ALCL have been established by the National Comprehensive Cancer Network (NCCN) [101-103]. BIA-ALCL should be suspected and tested for in patients who develop seroma more than one year after placement of a breast implant. Suspicious fluid collections should be aspirated and screened for BIA-ALCL by CD30 immunohistochemistry. Confirmation of diagnosis is performed with cell block cytology demonstrating anaplastic large cells as well as flow cytometry demonstrating a T cell clonal population [104]. A minority of BIA-ALCL patients will present with a mass adjacent to the breast implant. A suspicious mass, lymphadenopathy, or a confirmed case of BIA-ALCL may be referred to a surgical oncologist or an ablative surgeon familiar with the disease for evaluation.
The following describes our general evaluation of the patient with suspected BIA-ALCL (algorithm 1):
●The breast examination includes inspection and palpation of the neck, chest wall, both breasts, and axillae.
●Ultrasound is performed to define the extent of any seroma, identify any associated capsule masses, and guide seroma aspiration. Seroma volumes can range from 50 to 1000 mL and the fluid may be viscous from a high cellularity and protein content. Note that all implants will have a minute amount of periprosthetic fluid, which is normal and does not necessarily warrant investigation for BIA-ALCL. Draining the fluid is for diagnostic purposes, and the intent is not necessarily to drain the entire seroma; however, some patients with significant discomfort from a large fluid collection will benefit from therapeutic drainage.
●We collect fresh seroma fluid and representative portions of the capsule to send for culture and pathology tests specifically with the intent to "rule out BIA-ALCL." Fine needle aspiration (FNA) is performed under ultrasound guidance typically by an interventional radiologist. In an office-based setting, clinicians may alternatively use a blunt-tipped lipofilling cannula to avoid damage to the implant [105].
●Examination by an experienced hematopathologist should include cytological examination of seroma fluid with cytology (Wright Giemsa stained smears) (picture 1), cell block, flow cytometry [106,107], and immunohistochemistry (including studies of anaplastic lymphoma kinase [ALK] expression) [108,109]. For BIA-ALCL, CD30 will be positive, and ALK will be negative. (See 'Pathologic features' above.)
Ultrasound is the imaging modality of choice for those with suspected BIA-ALCL. In this population, the sensitivity and specificity of ultrasound for detecting an effusion (84 and 75 percent) or a mass (46 and 100 percent) are similar or better than those obtained with computed tomography or magnetic resonance imaging [110]. On ultrasound, the capsule surrounding the implant may be thickened and fibrous or may be deceptively normal in appearance, consistent with the under-appreciation of BIA-ALCL. If a mass is present, it can protrude into the implant creating a mass effect distortion on imaging, or the mass may protrude outward into the soft tissue.
Mammography is less sensitive than ultrasound for detecting an effusion or mass in the setting of BIA-ALCL [110]. For confirmed cases, positron emission tomography (PET) can be used to identify distant disease, and for subsequent surveillance [111].
Diagnosis and differential diagnosis — BIA-ALCL is a clinicopathologic diagnosis based upon characteristic morphologic features and immunohistochemical patterns found on biopsy specimens in conjunction with the clinical features found on presentation. (See 'Clinical and pathologic features' above.)
A diagnosis of BIA-ALCL requires the following [44]:
●A tumor with adequate pathological specimen for analysis, either lining a breast implant capsule (picture 2) or involving an effusion surrounding a breast implant
●Neoplasm with large anaplastic lymphoid cells with abundant cytoplasm and pleomorphic nuclei
●Tumor demonstrates T cell markers with uniform expression of CD30 by immunohistochemistry and a clonal expanded T cell population on flow cytometry
●Negative for anaplastic lymphoma kinase (ALK) protein or translocations involving the ALK gene at chromosome 2q23
BIA-ALCL must be differentiated from primary breast lymphoma, systemic ALCL, primary cutaneous ALCL, nodal ALCL with breast involvement, primary or recurrent breast cancer, and nonmalignant complications of breast implants including breast infection. Based on histologic features, BIA-ALCL with its pleomorphic large cells can be differentiated from primary or recurrent breast cancer, which is a carcinoma arising from epithelial components. (See "Pathology of breast cancer".)
●Nodal ALCL with breast involvement – Although ALCL in the breast has been reported in the absence of breast implants, in this scenario the ALCL is usually either a diffuse infiltrative process throughout the breast parenchyma or it occurs in conjunction with systemic disease [38,112,113], whereas BIA-ALCL always occurs in proximity to the implant and capsule and disseminated disease at presentation is uncommon. BIA-ALCL is ALK-negative, whereas systemic ALCL can be either ALK-negative or ALK-positive. (See "Clinical manifestations, pathologic features, and diagnosis of systemic anaplastic large cell lymphoma (sALCL)".)
●Primary cutaneous ALCL (PC-ALCL) – Both BIA-ALCL and PC-ALCL are ALK-negative. Rare cases of BIA-ALCL have skin involvement [93]; however, unlike BIA-ALCL, PC-ALCL is confined to the skin and does not involve the fibrous capsule surrounding breast implants. (See "Primary cutaneous anaplastic large cell lymphoma".)
●Primary breast lymphoma – Primary breast lymphoma is a disease of the breast parenchyma and is predominantly a B cell lymphoma (65 to 90 percent) [114,115], while BIA-ALCL is purely a T cell lymphoma arising either in an effusion surrounding the implant or in scar capsule surrounding a breast implant [8,44]. A B cell lymphoma associated with a breast implant (ie, growing on the implant) has not been described. Patients with B cell lymphoma may happen to have breast implants but the lymphoma is not in continuity with the implant or capsule [116].
Differentiation of a seroma due to BIA-ALCL from a benign seroma may not be possible on imaging alone. However, BIA-ALCL related seroma will demonstrate characteristic staining of cells on CD30 immunohistochemistry whereas a benign seroma is a relatively acellular serum will not stain for CD30. Complications of breast implants are discussed in more detail separately. (See "Complications of reconstructive and aesthetic breast surgery".)
STAGING — Staging of BIA-ALCL is undertaken largely to distinguish localized BIA-ALCL confined to the capsule from more disseminated disease. The stage can usually be determined based on the pathologic findings at the time of complete surgical resection in conjunction with findings on imaging (ie, positron emission tomography/computed tomography [PET/CT] scan). Disseminated disease suggested on imaging should be confirmed pathologically.
There are two main staging systems that may be used for BIA-ALCL: the traditional Lugano modification of the Ann Arbor staging system (table 1) and the BIA-ALCL tumor-node-metastasis (TNM) staging system (table 2). While early reports used the Ann Arbor staging system, many experts and the National Comprehensive Cancer Network (NCCN) are now using the TNM staging system, although the American Joint Committee on Cancer has yet to make formal staging recommendations.
Patients with any type of lymphoma are traditionally staged according to the Lugano revisions to the Ann Arbor staging system (table 1) [117,118]. Using this system, stage IE disease is limited to breast involvement only, and stage IIE disease is limited to the breast and ipsilateral axillary lymph nodes. Using this system, nearly all BIA-ALCL patients have low-stage disease. In one study, patients were either stage IE (84 percent) or stage IIE (16 percent) (figure 3) [89]. In another report, 83 percent of patients had stage I disease, 10 percent had stage II, and 7 percent of patients presented with stage IV disease [70]. (See "Pretreatment evaluation and staging of non-Hodgkin lymphomas", section on 'Staging'.)
However, patients with BIA-ALCL who have progression of their disease, lymph node involvement, or who have died, are described as having local or regional extension of their disease or very rare distant organ metastasis, which is more similar to solid tumors than non-Hodgkin lymphomas, suggesting BIA-ALCL is a distinct entity that progresses locally like a solid tumor and not like a liquid tumor similar to other lymphomas. This pattern of disease spread is better suited to a clinical and pathologic staging system modeled after the American Joint Committee on Cancer (AJCC) TNM system for staging solid tumors [119]. A BIA-ALCL TNM staging system has been proposed at MD Anderson Cancer Center (United States) and may be more applicable for predicting prognosis and for evaluating treatment regimens in patients with BIA-ALCL (table 2) [89].
TREATMENT
Selection of therapy — Treatment of BIA-ALCL follows established standardized guidelines by the National Comprehensive Cancer Network (NCCN) [101-103]. Data regarding the treatment of BIA-ALCL come from case series and case reports. Due to the rarity and recent identification of the condition, prospective registries are actively recruiting. The FDA suggests reporting of all confirmed cases to the Patient Registry and Outcomes For breast Implants and anaplastic large cell Lymphoma etiology and Epidemiology (PROFILE) registry and MedWatch website [120,121]. As such, patients should be referred for evaluation by a multidisciplinary care team familiar with this entity, whenever possible. (See 'Reporting of cases and future research' below.)
Expert consensus recommendations have been developed by a multidisciplinary expert review panel [109], the NCCN [101,122], and the French National Cancer Institute (Agence Nationale de Sécurité du Médicament [ANSM]) [123]. Our approach is generally consistent with these recommendations.
●For all patients with BIA-ALCL, we recommend complete surgical resection of the implant, the capsule, and any associated mass.
●For patients with localized disease (presenting as malignant effusion or mass) that can be completely excised by surgical removal of the breast implant and capsule (Ann Arbor stage IE, MD Anderson TNM Stage 1A to 2A), we suggest no adjunctive therapy (chemotherapy, radiotherapy).
●For patients with unresectable chest wall invasion or regional lymph node involvement (stage IIE, Stage 2B through 4 MD Anderson), we suggest adjunctive chemotherapy per NCCN Guidelines with multidisciplinary team input from a lymphoma oncologist. NCCN guidelines allow for either an anthracycline-based regimen (ie, EPOCH: etoposide, prednisone, vincristine [Oncovin], cyclophosphamide and doxorubicin hydrochloride; CHOP: cyclophosphamide, doxorubicin, vincristine, and prednisone), or brentuximab vedotin for first-line therapy in advanced BIA-ALCL. Early experience with the treatment of patients with advanced ALCL demonstrates efficacy of targeted therapy with brentuximab vedotin [124]. (See 'Adjuvant therapy for advanced disease' below.)
●We obtain biopsies to confirm residual, disseminated, or recurrent disease suspected on imaging. For patients with proven disseminated disease or patients who fail surgical therapy alone, we follow an approach identical to the management of de novo ALK-negative systemic ALCL. (See "Initial treatment of systemic anaplastic large cell lymphoma (sALCL)".)
Support for this approach is described in the following sections.
Complete surgical resection — For all patients with BIA-ALCL, we recommend complete surgical resection, which includes [89]:
●Removal of the implant
●Removal of any disease mass with negative margins
●Total capsulectomy
An incomplete resection or inadequate local surgical control may subject the patient to adjunctive treatments (ie, chemotherapy or radiation therapy), whereas complete resection provides definitive therapy and cure in the majority of cases [89]. Surgery should be performed with strict oncologic technique, including the use of specimen orientation sutures, placement of surgical clips within the tumor bed, and use of new instruments for the removal of a contralateral implant.
Because an implant capsule can drain to multiple regional lymph node basins, there appears to be no role for sentinel lymph node biopsy. Rather, excisional biopsies should be performed for axillary lymph nodes found to be enlarged on clinical exam or imaging studies. Approximately 60 percent of enlarged axillary nodes are pathologically involved [70]; fine needle aspiration is avoided, as it can yield false-negative results.
For patients with bilateral implants, we remove the contralateral uninvolved implant and capsule to avoid the risk of a contralateral occurrence or second contralateral lymphoma.
Capsule-confined BIA-ALCL most commonly follows an indolent course following adequate surgical treatment, without the need for adjunctive therapy (chemotherapy, radiotherapy) [9,70,89]. This was best illustrated in the following studies:
●In a retrospective analysis of 87 patients with BIA-ALCL followed for a median of 30 months, the estimated median overall survival was 13 years with three- and five-year survival rates of 93 and 89 percent, respectively [89]. The event-free survival (EFS) rate at one year was higher in those undergoing complete surgical excision (96 percent) when compared with those treated with more limited surgery (40 percent), radiation therapy (82 percent), or chemotherapy (76 percent).
●A retrospective series described the outcomes of 55 patients undergoing surgery for BIA-ALCL followed by either chemotherapy (39 patients), watchful waiting (12 patients), or radiation therapy (4 patients) [70]. The overall and progression-free survival rates were high and were similar regardless of whether the patients received chemotherapy. When compared with those presenting with seroma-only disease, the 18 patients presenting with a mass were less likely to achieve a complete remission (72 versus 93 percent) and had inferior survival rates at three (82 versus 100 percent) and five (75 versus 100 percent) years. However, when the ability to completely excise the mass was taken into account, recurrence rates and prognosis were similar. Thus, the worse prognosis was likely due to inadequate control of local disease spread.
Adjuvant therapy for advanced disease — The optimal management of patients with stage II or greater disease, patients with localized disease that recurs after complete surgical resection, or patients who do not achieve a complete remission with complete surgical resection is unclear [40]. While disseminated, persistent, or recurrent disease can be suggested by imaging studies, persistent residual inflammation can result in false-positive imaging. As such, biopsy is necessary for pathologic confirmation in these settings.
For patients with proven disseminated disease or patients who fail surgical therapy alone, we suggest an approach identical to the management of de novo ALK-negative systemic ALCL (algorithm 2). An anthracycline-based chemotherapy regimen (CHOP: cyclophosphamide, doxorubicin, vincristine, and prednisone) with or without etoposide is the basis of treatment. While early studies have demonstrated responses following targeted immunotherapy with brentuximab vedotin (an anti-CD30 antibody-drug conjugate) as a primary treatment, further studies are needed to better clarify its role in this disease [10,124-126]. Additional trials are underway (NCT01703949, NCT01805037). (See "Initial treatment of systemic anaplastic large cell lymphoma (sALCL)".)
The role of radiation therapy in the treatment of BIA-ALCL is unclear. While radiation therapy is central to the treatment of primary cutaneous ALCL, we do not routinely offer it to patients with BIA-ALCL. Patients who have received radiation treatments do not appear to have significant benefit compared with surgery alone. In one review of the treatment of 60 patients, the authors concluded that there was insufficient evidence to routinely recommend radiation if the patient achieves a complete remission with implant removal and capsulectomy; however, the number of patients receiving radiotherapy alone after implant removal and capsulectomy was small [70]. However, radiation therapy has been used in more locoregionally advanced cases for unresectable chest wall invasion (eg, stage IIE) [127].
FOLLOW-UP — Following the completion of therapy, patients are seen at periodic intervals to monitor for treatment complications and assess for possible relapse. The frequency and extent of these visits depends upon the comfort of both the patient and physician. There have been no trials comparing various schedules of follow-up. Our approach is largely consistent with that suggested by multidisciplinary consensus reports [109,128].
We schedule patient visits at least every six months for two years. In addition, we perform annual breast ultrasound for at least two years.
Breast reconstruction or repeat augmentation after definitive treatment for BIA-ALCL should reflect shared decision-making between the patient and surgeon. We suggest not performing replacement with a textured implant. The optimal timing of implant replacement (immediate versus delayed) is not known for certain. The National Comprehensive Cancer Network (NCCN) guidelines on BIA-ALCL state: "physicians may consider immediate (early stage) or delayed (advanced stage) breast reconstruction with autologous tissue or smooth surface breast implants." A retrospective multi-institution study reported outcomes among 66 women who underwent surgical resection with implant removal and complete capsulectomy, followed by reconstruction using smooth implants or autologous tissues [129]. With median follow-up of 42 months, there were no surgical complications reported and no local recurrence of BIA-ALCL, but one patient developed widespread bone metastases. There was general satisfaction among women who underwent repeat surgical reconstruction.
PROGNOSIS — There is a paucity of data regarding the prognosis of patients with BIA-ALCL. Available studies are limited by a small number of cases and short duration of follow-up. BIA-ALCL generally appears to be a biologically indolent disease with a good prognosis with complete surgical resection provided there is no extension beyond the implant capsule (figure 4). (See 'Complete surgical resection' above.)
Studies have suggested that the following features are associated with a worse prognosis:
●Mass lesion
●Extracapsular extension
●Bilateral disease
Although the presence of a mass lesion is associated with a worse prognosis, it is unclear if this indicates a more aggressive variant, more progressed disease, or perhaps a consequence of inadequate surgical ablation of tumor infiltration (figure 5).
In a retrospective review of 60 patients, 93 percent of patients underwent capsulectomy and implant removal [70]. 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). 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.
A review included 87 BIA-ALCL patients treated with surgery alone (40 percent); surgery and radiation (9 percent); surgery and chemotherapy (19 percent); surgery, chemotherapy, and radiation (30 percent); or with chemotherapy alone (2 percent) [89]. 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 one, three, and five years.
The presence of bilateral disease is a putative risk factor for a poor prognosis, but the small number of cases reported precludes a definitive assessment of this potentially negative risk factor [92].
MEDICOLEGAL CONSIDERATIONS
Informed consent prior to implant placement — Following recommendations made by the US Food and Drug Administration (FDA) in 2011, breast implant manufacturers in the United States and Canada added a package insert warning regarding the existence of BIA-ALCL [130]. The American Society of Plastic Surgeons (ASPS) produced breast implant informed consent examples that include the risk of BIA-ALCL; these are available for download from plasticsurgery.org [131].
Risk disclosure should meet at least these three basic objectives [132] (see "Implant-based breast reconstruction and augmentation", section on 'Informed consent'):
●Make patients aware of the existence of this rare disease. Prior to implantation, provide educational materials, and ensure that the patient is aware of the benefits and risks of the different types of implants. The FDA and the American College of Surgeons recommend the retroactive notification of the Class I recall to patients who have had Allergan BIOCELL textured implants.
●At the time of breast implant placement, provide the patient with the breast implant manufacturer's labeling, including the patient-specific labeling.
●Make patients understand common presenting symptoms such as a breast mass or delayed-presentation seroma or effusion.
●Compel patients to take action and follow up with a physician should these symptoms occur.
The legal threshold for inclusion of a specific risk in informed consent is vague, and therefore the decision to include BIA-ALCL in informed consent for breast implant placement should ideally be by self-obligation, not mandate. The FDA recommends that patients receive informative booklets on breast implants supplied by manufacturers, that surgeons follow a standardized checklist during the preoperative informed consent process, and that a black box warning be applied to all breast implants warning of BIA-ALCL. Procedure-specific informational pamphlets at an initial consultation are useful to help patients understand surgical details, and engender more effective recall [132]. (See "Informed procedural consent" and "Disclosure of errors in surgical procedures".)
Potential insurance issues — The United States still faces potential difficulties in providing insurance coverage for BIA-ALCL in patients with a prior history of cosmetic augmentation [133]. One study examined how United States insurance companies cover BIA-ALCL and reported that only 30 percent of the surveyed companies had a policy on it [134]. Of the companies that had a policy, 100 percent provided coverage for implant removal of the breast diagnosed with BIA-ALCL. In this study, two-thirds of companies covered medically necessary contralateral implant removal, while 43 percent covered contralateral removal for cosmetic augmentations. Most companies covered implant reinsertion, but it was typically only in cases of breast reconstruction, with only 17 percent covering implant reinsertion for cosmetic augmentations. In addition, some policies may explicitly deny coverage for any cancer therapy of BIA-ALCL if the patient has a history of cosmetic augmentation. As of October 1, 2022, the 2023 edition of the ICD-10-CM recognizes BIA-ALCL by diagnosis code C84.7A BIA-ALCL as anaplastic large cell lymphoma, anaplastic lymphoma kinase-negative breast when combined with an additional code, Z98.82, to identify breast implant status. Policy exclusions for BIA-ALCL in a previous cosmetic augmentation may result in patients being financially responsible for all medical care costs out of pocket. To address this coverage gap, the American Medical Association (AMA) approved Resolution 812, calling for the insurance support of diagnosis, staging, and treatment of implant-associated malignancies regardless of prior indication for implant placement [135].
Similar barriers are seen with breast implant rupture screening. The FDA recommends that all women with silicone breast implants undergo evaluation for breast implant failure at five to six years post-implantation, and every three years thereafter with ultrasound or magnetic resonance imaging, and removal of the implant if rupture is identified.
Fortunately, compliance with recommendations for BIA-ALCL appears to be better. In patients with clinical signs of the development of a periprosthetic fluid collection, the physician should not hesitate to evaluate for the presence a seroma, and if there is a reasonable clinical suspicion of BIA-ALCL, should also not hesitate to recommend to their patients appropriate pathologic review of the effusion, importantly with CD30 immunohistochemistry (which is not typically performed on routine specimen evaluation). (See 'Evaluation of suspected cases' above.)
Reporting of cases and future research — The Plastic Surgery Foundation, American Society of Plastic Surgeons, and FDA have worked together to create the PROFILE (Patient Registry and Outcomes For breast Implants and anaplastic large cell Lymphoma etiology and Epidemiology) registry, which is a prospective registry and repository for data on BIA-ALCL. The PROFILE website, which can be found at Profile: Investigating Breast Implant ALCL, also provides plastic surgeons, oncologists, and patients with information they need about breast implants and treatment of BIA-ALCL.
The FDA specifically recommends reporting of confirmed cases to the PROFILE registry and to the MedWatch website [120]. Treating physicians are encouraged to report confirmed cases to the PROFILE website [136]. Confirmed cases in the registry are available for research studies to better characterize BIA-ALCL. Further research is needed to determine the exact role of breast implants in the etiology of the disease, to determine whether some women have a predisposition to the development of the disease, and to determine if there are any patient or implant modifiable risk factors.
The establishment and characterization of a BIA-ALCL model cell line (TLBR-1) as well as heterotransplantation of the disease into immune-compromised mice has been reported [57]. Establishment of cell lines from effusion or excisional biopsies will be important to completely characterize the disease and identify potential molecular targets. Future research into the development of primary cell lines and biologic models will be important to fully elucidate the exact etiology and pathogenesis of BIA-ALCL.
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Breast cancer" and "Society guideline links: Breast surgery".)
SUMMARY AND RECOMMENDATIONS
●Breast implant-associated anaplastic large cell lymphoma – Breast implant-associated anaplastic large cell lymphoma (BIA-ALCL) is an uncommon CD30-positive peripheral T cell lymphoma arising around textured-surface breast implants placed for either reconstructive or cosmetic indications. Among those with breast implants, the absolute risk of developing BIA-ALCL is low, and screening or prophylactic implant removal is not recommended. (See 'Epidemiology' above and 'Counseling women with implants' above.)
●Clinical features and diagnosis
•Presentation – Most cases present approximately one decade after implant placement with either a seroma or, less commonly, a discrete breast mass adjacent to the implant. While most cases are unilateral, bilateral breast involvement has been reported in a minority of patients with bilateral breast implants. (See 'Clinical and pathologic features' above.)
•Clinical evaluation – The evaluation of suspected cases includes a bilateral breast examination, ultrasound of the involved breast, aspiration of the effusion (seroma), and biopsy of the capsule. The seroma fluid is sent for culture and specific pathology tests such as CD30 immunohistochemistry. (See 'Evaluation of suspected cases' above.)
●Diagnosis – BIA-ALCL is a clinicopathologic diagnosis based upon characteristic morphologic features and immunohistochemical patterns found on biopsy specimens in conjunction with the clinical features on presentation. BIA-ALCL involves the luminal surface of the fibrous capsule surrounding the implant and may show varying degrees of infiltration of the capsule, the surrounding soft tissue, or the breast parenchyma. The CD30-positive tumor cells morphologically resemble those of systemic ALCL. Unlike systemic ALCL, BIA-ALCL lacks expression of anaplastic lymphoma kinase (ALK) and does not have gene rearrangements involving the ALK gene on chromosome 2p23. BIA-ALCL must be differentiated from primary breast lymphoma, primary cutaneous ALCL, nodal ALCL with breast involvement, primary breast cancer, nonmalignant complications of breast implants, and breast infection. (See 'Diagnosis and differential diagnosis' above and 'Pathologic features' above.)
●Staging – Disease stage can usually be determined based on the pathologic findings at the time of complete surgical resection in conjunction with findings on imaging (ie, positron emission tomography/computed tomography [PET/CT] scan). Disseminated disease suggested on imaging should be confirmed pathologically. (See 'Staging' above.)
●Treatment – Data regarding the treatment of BIA-ALCL come from case series and case reports. Our approach is generally consistent with expert consensus recommendations. (See 'Selection of therapy' above.)
•For all patients with BIA-ALCL, we recommend complete surgical resection of the implant, the capsule, and any associated mass (Grade 1B). This recommendation is in accordance with National Comprehensive Cancer Network (NCCN) BIA-ALCL guidelines. (See 'Complete surgical resection' above.)
•For patients with localized disease (presenting as malignant effusion or mass) that can be completely excised by surgical removal of the breast implant and capsule (Ann Arbor stage IE, MD Anderson TNM Stage 1A to 2A), we suggest no adjunctive therapy (chemotherapy, radiotherapy) (Grade 2C).
•For patients with pathologically confirmed disseminated disease or patients who fail surgical therapy alone, we follow NCCN guidelines with either an anthracycline-based regimen (ie. CHOP) or brentuximab vedotin for first-line therapy (algorithm 2). (See 'Adjuvant therapy for advanced disease' above.)
●Monitoring – Following the completion of therapy, patients are seen at periodic intervals to monitor for treatment complications and assess for possible relapse. BIA-ALCL generally appears to be a biologically indolent disease with a good prognosis with complete surgical resection provided there is no extension beyond the implant capsule. (See 'Follow-up' above and 'Prognosis' above.)
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