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Theories of Etiopathogenesis of Breast Implant–Associated Anaplastic Large Cell Lymphoma

Rastogi, Pratik, MBBS, GDAAD, MS; Riordan, Edward, MBBS; Moon, David, MBBS; Deva, Anand K., BSc(Med), MBBS, MS, FRACS

Plastic and Reconstructive Surgery: March 2019 - Volume 143 - Issue 3S - p 23S-29S
doi: 10.1097/PRS.0000000000005566
Original Articles

Summary: Breast implant–associated anaplastic large cell lymphoma is a malignancy of T lymphocytes that is associated with the use of textured breast implants in both esthetic and reconstructive surgeries. Patients typically present with a delayed seroma 8–10 years following implantation or—less commonly—with a capsular mass or systemic disease. Current theories on disease pathogenesis focus on the interplay among textured implants, Gram-negative bacteria, host genetics, and time. The possible roles of silicone leachables and particles have been less well substantiated. This review aims to synthesize the existing scientific evidence regarding breast implant–associated anaplastic large cell lymphoma etiopathogenesis.

Sydney; and Miranda, New South Wales, Australia

From the Department of Plastic, Reconstructive, and Maxillofacial Surgery, Macquarie University; and the Integrated Specialist Healthcare Education and Research Foundation.

Received for publication September 16, 2018; accepted December 11, 2018.

Disclosure:Drs. Rastogi, Riordan, and Moon have no affiliations or financial interests to disclose. Professor Anand K. Deva is a consultant, research coordinator, educator for Allergan, Mentor (Johnson & Johnson), Sientra, Motiva and Acelity (KCI). He has previously coordinated industry-sponsored research for these companies relating to both biofilms and breast prostheses.

Anand K. Deva, BSc(Med), MBBS, MS, FRACS, 2 Technology Place, Suite 301, Macquarie Park, NSW 2109, Australia,, Twitter: @saferimplants, Instagram: @ProfDeva

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The body of literature on breast implant–associated anaplastic large cell lymphoma (BIA-ALCL) has expanded significantly because it was first recognized as a disease entity by the Food and Drug Administration in 2011.1–4 BIA-ALCL is now understood to be a distinct T-cell–derived lymphoma within the non-Hodgkin’s lymphoma group that develops following exposure to textured implants. It appears to have a number of clinical phenotypes: a small subset of cases present with solid tumor mass and progressive disease, but the majority of cases present with a delayed-onset periprosthetic seroma 8–10 years following implantation, and follow an indolent course with a good prognosis.5,6 A number of diagnostic markers for disease have been identified, with BIA-ALCL T-cells known to exhibit CD30-positive and anaplastic lymphoma kinase (ALK)-negative expression patterns.7,8

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It has previously proven difficult to establish exact figures for BIA-ALCL incidence and locoregional distribution, largely due to issues with inaccurate implant exposure histories, duplicate case reports, missed and variable pathologic diagnoses, and a paucity of implant sales data. The establishment of comprehensive databases (eg, the Patient Registry and Outcomes for Breast Implants and Anaplastic Large Cell Lymphoma Etiology and Epidemiology, or PROFILE) has consolidated the available data; over 600 unique cases of BIA-ALCL have now been confirmed across 25 countries.5 To date, all confirmed cases of BIA-ALCL have involved exposure to a textured implant or expander, and the relative risk appears to increase in accordance with the surface area of the implant.4,9 A recent article4 using Australian and New Zealand data suggests an implant-specific risk of 1/3,817 for Biocell, 1/7,788 for polyurethane, and 1/60,631 for Siltex implants. A significant regional variance in disease incidence has also been noted, with European, Asian, and South-American countries demonstrating the lowest relative incidences, and Australia and New Zealand reporting the highest incidence.4 The United States has reported an incidence of 1 in 30,000 and close to 200 unique cases, although this is substantially lower than the figure of approximately 500 cases that would be expected based on extrapolation from Australian and New Zealand implant-specific incidence data.3,10 This figure, in addition to the finding that a greater proportion of cases within the United States is reported at a more advanced stage of disease, has raised concern about the possibility of underreporting and highlights the importance of accurate patient registries.6

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Diagnosis and Treatment

The first National Comprehensive Cancer Network consensus guidelines for the management of BIA-ALCL were developed in 2016, and represent the current standard of accepted practice.11 The National Comprehensive Cancer Network guidelines recommend that specimens undergo histology, flow cytometry, and immunohistochemistry, with specific advice for the pathologist regarding the need for CD30 markers. Following histologic confirmation and multidisciplinary input, current evidence suggests that disease localized to the capsule may be treated with surgery alone, with removal of implants and complete excision of the capsule and any suspicious lymph nodes.6,11

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Following its initial identification, the World Health Organization classified the disease now known as BIA-ALCL as an anaplastic lymphoma at all stages, and patients were staged using the Ann-Arbor system.12 Recent evidence indicates that the tumor-node-metastasis system for staging solid tumors may be more appropriate for prognostication, and that BIA-ALCL may incorporate 2 separate subtypes of disease; mass type and effusion limited. The most recent available data—from an Australian cohort—indicate that approximately 76% of cases appear to present with effusion-limited disease and subsequently follow a favorable clinical course, whereas those with mass-type malignancy demonstrate a pattern of capsular infiltration and locoregional spread, and a distinctly poorer prognosis.4,6

It has also been suggested that BIA-ALCL may potentially even represent a spectrum of disease, from a lymphoproliferative disorder to infiltrative mass-type malignancy.6 Although BIA-ALCL appears to be a distinct form of ALCL on the basis of genetic subtyping, it demonstrates a number of clinical and histologic similarities with primary cutaneous ALCL (pcALCL). Both BIA-ALCL and pcALCL show CD30+, ALK(−), HLA-DR+, and TIA-1+ patterns, and high levels of SOCS3 and STAT3 expression, and are associated with a relatively slow rate of progression and a correspondingly good prognosis.13 Of particular interest is the fact that pcALCL is known to be the malignant endpoint of spectrum of a lymphoproliferative disease that runs from lymphomatoid papulosis through to pcALCL.14 Lymphomatoid papulosis demonstrates occasional spontaneous lesion regression, and there is evidence to indicate that chronic inflammation is a possible causative factor in the development of these cutaneous T-cell lymphomas.15 It has been suggested that effusion-limited disease in BIA-ALCL may also represent a regression of sorts, given the likelihood that malignant cells were originally derived from the capsule, and a number of cases that are suspicious for spontaneous regression of BIA-ALCL effusion-limited disease have now been published.16,17 The similarities between the diseases, and the potential for a comparable inflammatory etiology, suggest that the developments in immunophenotyping and immunotherapy for pcALCL may inform future study of BIA-ALCL, and the possible reclassification of BIA-ALCL as a lymphoproliferative disease.

Central to clarifying the links between these varying patterns of disease is the need to identify the processes driving disease initiation and progression. Several diverse factors appear to play a role—including texturing of implants, chronic inflammation, the presence of Gram-negative bacteria, and genetic susceptibility to disease (Fig. 1). Current evidence suggests that a sustained inflammatory response to the greater bacterial antigen load around highly textured implants may at least partly mediate disease initiation.4,7,8 This review article will outline the relative strength of the current evidence that is available for each of the possible etiologies of BIA-ALCL, and the proposed directions of research that may be required to address the current gaps in the understanding of the disease.

Fig. 1.

Fig. 1.

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A brief overview of T-cell immunology is required before discussion of the possible factors involved in BIA-ALCL pathogenesis.

The adaptive immune system comprised of B and T lymphocytes and is activated by the cells of the innate immune system to produce a body of effector cells with specificity for a particular antigen; as well a number of memory cells to enable a rapid response in the event of future re-exposure.18 In broad terms, CD4+ and CD8+ T lymphocytes are stimulated by the interaction between T-cell receptors and antigens presented to them via major histocompatibility complexes, and costimulatory surface molecules and cytokines expressed by antigen-presenting cells. This produces a clonal expansion of antigen-specific T lymphocytes—CD8+ effector cells lyse cells expressing the antigen via class I major histocompatibility complex, and CD4+ cells interact with B cells and class II antigen-presenting cells to guide the production of high-affinity and antigen-specific antibodies and effector cytokines. Once activated, the CD4+ cells can further differentiate into a number of subsets including Th1 (intracellular viral and bacterial pathogens), Th2 (large extracellular pathogens and allergic response), Th9 (parasitic infections), Th17 (mucosal immunity and autoimmune disorders), Th22 (inflammatory skin disorders), TFH (follicular helper T cells regulate B cell activity), and Treg (inhibit proinflammatory T cells)18 (Fig. 2).

Fig. 2.

Fig. 2.

Chronic inflammation related to repeated antigenic stimulation has been shown to cause prolonged T-cell activation and recruitment, and it is associated with a number of T-cell malignancies including enteropathy-associated and cutaneous T-cell lymphomas.15,19 The mechanism of lymphomagenesis has not yet been fully elucidated but is potentially related to genetic instability in the inflammatory microenvironment favoring the emergence of malignant clonal T-cell populations, and a subsequent upregulation of tumor-promoting cytokines such as interleukin (IL)-6, IL-10, and IL-17.7,19–21 Kadin et al.7 confirmed a Th17/Th1 phenotype of BIA-ALCL tumor lymphocytes, supporting the potential role of antigenic stimulation and chronic inflammation in the initiation and promotion of BIA-ALCL.

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Implant Texturing and Biofilm

Several in vitro studies have reported higher rates of biofilm formation in textured implants compared with smooth implants.22–26 Hu et al.26 demonstrated a linear correlation between bacterial load in contaminated textured implants and the number of activated lymphocytes. This correlation was strongest for CD4+ T cells, the cell of origin for BIA-ALCL.26 Loch-Wilkinson et al.4 also demonstrated that high- and intermediate-surface area textured implants were 10 times more likely to be associated with BIA-ALCL relative to low-surface area textured implants. Recognizing the heterogeneity of implant texturing, Jones et al.27 have proposed a grading system for implant shell texture into 4 ordinal categories (high/intermediate/low/minimal) based on surface area and roughness measurements. This proposed grading system objectively categorizes implant texture morphology and is arguably superior to existing descriptive terms such as “macrotexture,” “microtexture,” and “nanotexture,” which are not well correlated with objective measurement or functional outcomes.27

The pathologic synergy between implant texturization and biofilm formation is well known. Following adhesion to the implant surface, bacterial proliferation and extracellular polysaccharide synthesis occur, forming highly structured microcolonies.28–30 The biofilm architecture confers host resistance and survival advantages.15,28–30 Despite the antigenic stimulus and incumbent T-cell proliferation within this environment, not all implant-associated biofilms and their capsules develop a malignant phenotype. Benign breast capsules are typically associated with Gram-positive microbiomes (eg, Staphylococcus epidermidis) that are representative of normal skin and endogenous breast microflora (Fig. 1). Hu et al.28 reported a Gram-negative shift in the BIA-ALCL microbiome, with clusters of Ralstonia spp. observed, which are not typical constituents of the endogenous breast microflora (Fig. 1). Ralstonia spp., which are nonfermenting Gram-negative bacilli found in soil and water, have been reported in nosocomial infections resulting from contamination of medical solutions.28,31 No other significant microbial cluster has been reported in BIA-ALCL cases to date. Despite the associations, the observation of Ralstonia spp. in the microbiome does not prove causation of BIA-ALCL. Critics suggest that the Ralstonia spp. predominance in BIA-ALCL samples may represent an “opportunistic” infection drawn into the peritumoral region by chemotaxis or complex signal transduction.32,33

Several hypotheses have been proposed to explain the correlation between bacterial antigens and BIA-ALCL tumorigenesis. The lipopolysaccharide coat of Gram-negative bacteria, which is linked to other infectious and autoimmune diseases, has been proposed as a potential malignant trigger.34 Bacterial superantigens may also theoretically play a role in tumorigenesis, through a massive induction of cytokine release and T-cell differentiation.8,35 Despite this argument, no such antigen has been identified for Ralstonia spp. or other organisms to date. The synergism between host–bacterial interaction and implant texturization needs to be further investigated to verify a unifying hypothesis for BIA-ALCL etiology.

No scientific studies have been reported to define the exact timing of implant contamination in BIA-ALCL cases. Although bacterial inoculation during implant insertion is logically the most probable route of contamination, the use of contaminated irrigation solutions, bacterial translocation, and seeding of the device from transient bacteremia are other hypothetical avenues of contamination. Nonetheless, with the increasing recognition of biofilm formation as a potential trigger for both capsular contracture formation and BIA-ALCL, intraoperative procedures have been scrutinized to reduce the risk of prosthetic contamination. Deva et al.36 proposed a 14-point checklist, which ultimately focuses on aseptic surgical technique to arguably reduce the risk of bacterial contamination. The checklist has not been specifically evaluated in patients who went on to develop BIA-ALCL. The clinical latency between implant insertion and disease presentation means that representative longitudinal studies are inherently challenging. With specific reference to implant sleeves and funnels, Moyer et al.37 demonstrated reduced skin contact, and bacterial contamination risk with their use. A recent survey of American surgeons reported that 42%–80% use an insertion funnel for either all or most of their breast augmentation procedures.38 The authors recognize that several of the 14 points are emblematic of good surgical practice, and are not intended to represent blind surgical dogma.

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Genetics and Proliferative Signals

With the growing understanding of the interplay among chronic inflammation, biofilm, implant texturing, and BIA-ALCL, recent reports have investigated the genetic mutations associated with the disease process.7,25,39–44 Somatic mutations in JAK–STAT signaling, which is implicated in cell proliferation, differentiation, and apoptosis, are the most commonly reported genetic aberrancies in BIA-ALCL cases.7,39,42,43 Gain of function mutations in STAT3 has also been reported in 18% of systemic ALK-negative ALCL and 5% of cutaneous ALCL cases.41 Other reported somatic mutations involve SOCS proteins (negative regulators of the JAK–STAT pathway), JunB (transcription factor regulating gene activity and primary growth factor responses),7 SATB1 (thymocyte precursor promoting CD30+ T-cell proliferation through repression of cell cycle inhibitor p21),7 Notch1 (cell signaling),40 TP53,39,42 MYC,39,42 and deoxyribonucleic acid methyltransferase 3A39,42. Germline mutations have also been recognized in patients with BIA-ALCL including activating mutations of TP53—with and without classic Li-Fraumeni syndrome.45,46 Many of the aforementioned somatic and germline mutations are insufficient to cause BIA-ALCL in isolation, however, with a “second-hit” required for disease activation (Kadin et al.7).

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Silicone Leachables/Particles

Recognizing the role of chronic inflammation in the pathogenesis of BIA-ALCL, silicone leachables have also been theorized as a potential etiologic trigger for disease. Silicone gel–filled implants have been widely adopted due to their superior cosmetic results relative to earlier implant types, exhibiting less wrinkling, a more natural feel, and a lower risk of volume loss in the event of rupture with cohesive gels.47 These benefits, coupled with the theorized inert biologic profile, heralded the potential panacea for breast augmentation and reconstruction. The tissue biocompatibility of silicone has been intermittently questioned in the literature and by regulatory bodies, however, due to concerns raised in published case reports regarding possible associations between silicone-containing devices and neoplasms. Pacemakers, joint prostheses, and intraocular and extraocular silicone gel or tubes have all been associated with peri-implant neoplasms, including lymphomas.48,49 Associations with autoimmune disorders and silicone granulomatous reactions have also been reported,50 and silicone has been noted to “bleed” through the breast implant envelope with a silicone gel diffusion rate of up to 300 mg/y.51 Despite this, recent in vitro studies have suggested that silicone breast implant shell surfaces did not induce T-cell proliferation,52 nor did the shell extensively alter the proportion of T-cell subsets.53 The observed clustering and locoregional distribution of BIA-ALCL also does not readily support silicone leachables as a defining etiologic trigger.

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The etiopathogenesis of BIA-ALCL is likely to be multifactorial, with current evidence-based theories recognizing the combination of chronic infection (skewed toward Gram-negative organisms), biofilm formation, implant texturization, chronic inflammation, and time in tumorigenesis. Although silicone bleeds and particles can theoretically provide the antigenic stimulus for chronic inflammation and potential malignant transformation, this premise has yet to be scientifically proven. Additional research is required to establish a unifying theory for the etiology of BIA-ALCL. Future directions for research should include the identification of specific bacterial antigens or other antigenic stimuli, differential studies of benign and malignant seromas (cytokines, inflammatory, and CD30+ count), and additional genetic sequencing studies in BIA-ALCL cases. Current thinking will continue to evolve as more robust scientific evidence accrues, potentially facilitating better surveillance and treatment.

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