The Cellular Origins of Breast Implant–Associated Anaplastic Large Cell Lymphoma (BIA-ALCL): Implications for Immunogenesis

Abstract

The exact cellular origins of most malignancies are unknown, largely because of the complex nature of malignancies, and because the potential vast number of pathways towards transformation are difficult to discern from established growths. This is compounded by the fact that cancer cells have evolved rather than being the consequence of a design process, with most data collected from (sometimes epidemiological) studies of large numbers of related malignancies. In the case of breast implant–associated anaplastic large cell lymphoma (BIA-ALCL), the relative rarity of this disease, coupled with limited insight into its biological basis, have hampered progress. The known facts that are holding up as our knowledge increases with rising incidences are that most cases have been reported in the context of textured breast implants, although not all women with these implants develop BIA-ALCL, and cure for early-stage disease (accounting for the majority of patients) can be achieved via complete capsulectomy and implant removal. However, some theories can be gleaned from the limited biological studies conducted to date whereby a T-helper cell derivation is implicated, with its specific and apparent subset of origin dependent on, and shaped by, a number of factors, including the inflammatory microenvironment (the presence of other inflammatory cell types), the driving antigen (bacterial and/or synthetic), the acquisition of driving oncogenic events, and the inherent genetics/health status of the patient.

The association of cancers with foreign bodies, including bacteria and implants, is not new, but has garnered heightened interest in the plastic surgery community since reports of an increase in the incidence of breast implant–associated anaplastic large cell lymphoma (BIA-ALCL).^1-6 Although there has been much speculation on the pathophysiology and etiology of this disease, the low incidence of cases, resulting in a lack of studies with significant power, has failed to yield any definitive answers, and certainly none of the published studies provide sufficient evidence to rule out any one theory. However, if one focusses on the facts and what is known about the more widely studied systemic and cutaneous forms of ALCL and related malignancies, as well as the physiological functions of the immune system, it is possible to generate some viable theories on which to build.

Fact vs “Fiction” (or Unverified Opinions)

The clearest fact to emerge so far is that most patients diagnosed with BIA-ALCL have at some point in their clinical history received a textured implant; this common underlying denominator suggests that some aspect of these implants must play a role in disease development.⁶ Immediately, this points towards the composition of such implants, their interaction with the host, and possibly unique mechanical factors associated with their presence in the breast. After all, if the implant type played no role in disease pathogenesis, BIA-ALCL would undoubtedly be observed following any procedure involving the implantation of foreign bodies. However, one cannot discount the effects of the location of the implants, in which case smooth implants would also lead to BIA-ALCL if this were alone essential for tumor development. The other fact is that not all women given textured breast implants develop BIA-ALCL, suggestive of host factors contributing to this process. Whether these host factors are inherent, such as genetic predisposition, or the result of unique individual circumstances, such as pre-existing allergies and/or autoimmunities, or a specific microbiome, remains to be determined. In support of a genetic association, there has to date been only one case reported in a woman of an Asian background, and there are case reports of BIA-ALCL occurring in women with Li-Fraumeni syndrome.^7-10 Moreover, as with most human diseases, and with cancer in particular, a host of “just right” factors must converge to lead to disease pathology; after all, these aberrant cells have evolved rather than having arisen by design.

Another important fact associated with BIA-ALCL is that most cases can be cured by surgical intervention alone: complete capsulectomy and implant removal can lead to apparent cure.¹¹ This is specifically the case when the disease is diagnosed at a presumed early stage—when existing as a seroma contained within the capsule, having not spread to the breast parenchyma, axillary lymph nodes, or underlying bone and other tissue. In these latter cases, chemotherapy and/or radiotherapy is required, with anecdotal evidence suggestive of superior outcomes with brentuximab vedotin over the standard T-cell lymphoma CHOP regimen.^12-14 As such, although it has been proposed that BIA-ALCL merely represents a lymphoproliferation, the fact that it can become aggressive, and lead to death, ultimately places it as a malignancy. Indeed, a spectrum of disease, if not at least 2 clinical entities, has been proposed.⁵ In concert with the facts presented above, this further adds fuel to the likelihood of the implants themselves playing a significant role in disease pathogenesis. Hence, BIA-ALCL is associated with textured implants, which must play a role in disease pathology, whether that be due to a specific feature of the textured surface, a host factor, and/or providing an environment conducive to disease-promoting factors.

Determining Disease Pathogenesis from the Identity of the Cell of Origin

For many human malignancies, much information can be garnered from knowing the cell of origin; working backwards from the features of the presenting cell, the processes leading to the malignant state can be deduced.¹⁵ In the case of BIA-ALCL, the tumor cells are clearly lymphoid in nature, and furthermore of T lineage as determined by the presence of T-cell receptor (TCR) gene rearrangements at the molecular level.^16,17 This is also the case for systemic ALCL where tumor cells share the histopathological presentation with common expression of CD30 and the presence of so-called “hallmark cells,” both being distinguishing features observed in other non-Hodgkin lymphomas.¹⁸ This common histological appearance may be indicative of a shared cell of origin and/or a common pathway towards disease development. The presence of TCR rearrangements and sporadic expression of one of a panel of T-cell–defining antigens, most commonly CD4, together with production of perforin and/or granzyme B, has led to the supposition that ALCL derives from cytotoxic T cells.¹⁹ However, at least for sporadic anaplastic lymphoma kinase–positive (ALK⁺) ALCL, the production of cytotoxic proteins has been attributed to oncogene expression rather than cell of origin, and studies have demonstrated expression of a plethora of Th cell proteins.^20,21 Indeed, a thymic origin has been suggested for systemic ALK⁺ ALCL, due to the presence of aberrant molecular TCR rearrangements, and an enriched gene expression and methylation profile consistent with an early thymic progenitor.^22-24 However, whereas systemic ALK⁺ ALCL is associated with an early age group, largely a pediatric one, systemic ALK^– ALCL, cutaneous ALCL, and BIA-ALCL are more often malignancies of adulthood, particularly in regards to the latter classification.²⁵ Whether the age of diagnosis is reflective of differing disease pathogenesis is unclear, but the contrasting prognoses with systemic ALK^– ALCL having the far worse outcome of the 4 disease entities is perhaps more suggestive of disease mechanisms. Regardless of when and where incipient tumor cells arose, the common histopathology of the established tumor cells provides some evidence towards disease pathogenesis.

Mature, Circulating T-Helper Cells Are Derivatives of an Inflammatory Response

Gene expression profiling has suggested a T-helper 17 (Th17) cell or analogous innate lymphoid cell type 3 (ILC3) cellular phenotype for systemic ALCL.^26,27 This is further precipitated by the production of cytokines and transcription factors by ALCL tumor cell lines and patient material (including BIA-ALCL) associated with Th17 functions, including retinoic acid–related orphan receptor γ (RORγ), interleukin 17 (IL-17), and IL-26 (Figure 1).^16,17,21,27 IL-26, a member of the IL-10 family of cytokines, is produced by a few cell types, but among Th cells is unique to Th1 and Th17, where it is linked to direct and indirect antiviral and antimicrobial activity.²⁸ However, expression of other Th cell cytokines and transcription factors are seen in BIA-ALCL, particularly those relating to a Th1 or a regulatory T-cell (Treg) phenotype including T-bet and FOXP3, respectively.¹⁷ This is not, however, surprising considering the plasticity of Th cell subsets coupled with the instability of malignant cells.^29,30 In the former regard, the ultimate functions and phenotype of Th cells are driven by the collective expression profile and relative expression levels of identifying transcription factors; in the latter regard, oncogenic driver mutations could modulate the expression profile of a cell. Indeed, mutations in JAK/STAT3 have been detected in a small number of cases of BIA-ALCL as has been observed in a larger series of systemic ALK^– ALCL.^31-33 The JAK/STAT pathways are central mediators of inflammation coordinating the production of cytokines, with STAT3 playing a particular role in the differentiation towards a Th17 or T follicular helper cell (Tfh) phenotype (Table 1).³⁰ In addition, 3 BIA-ALCL cell lines, TLBR1–3, variably produce IL-6, IL-10, transforming growth factor β (TGFβ), interferon γ (IFNγ), IL-2, IL-17A, and vascular endothelial growth factor (VEGF), cytokines usually produced by Th1, Treg, and/or Th17 cells (Table 2).^17,21 These data present a trichotomy as to the real identity of the BIA-ALCL cell of origin, and suggest a dynamic microenvironment within the tumor may alter the ultimate identity of the tumor cell, which may well vary from patient to patient, and with different driving oncogenic events (Figure 2).

Figure 1.

Anaplastic large cell lymphoma (ALCL) cell lines produce transcripts for the aryl hydrocarbon receptor (AHR) and secrete interleukin 26 (IL-26) into cell culture supernatant. Unpublished data from our laboratory show that a variety of ALCL cell lines, including those derived from anaplastic lymphoma kinase–positive (ALK⁺) systemic ALCL (SUDHL-1, Karpas-299, SR-786, SUPM2), ALK^– systemic ALCL (FEPD), cutaneous ALCL (MAC2A), breast implant–associated (BIA)-ALCL (TLBR1), and human T cells transiently expressing nucleophosmin (NPM)-ALK (CD4NA1), secrete IL-26 protein into the cell culture media (A) and produce transcripts for the AHR (B). These data represent the means and standard deviations of biological triplicates for each of the indicated cell lines. Transcript levels were detected by quantitative reverse transcriptase-polymerase chain reaction using primers specific for AHR, and IL-26 protein was detected by enzyme-linked immunosorbent assay of cell culture supernatant.

Table 1.

The Identity of T Helper Cells Is Often Determined by the Expressed Transcription Factors and Cytokines Produced, Although These Factors Are Not Binary in Dictating Cell Fate

Th subset	STAT isoform driving differentiation	Cytokines inducing Th subset differentiation	Cytokines produced by differentiated cell	Defining transcription factor of differentiated cell
Th1	STAT1/4	IL-12, IFNγ	IFNγ, IL-26	T-bet
Th2	STAT6	IL-4	IL-4, IL-5, IL-13	GATA-3
Th17	STAT3	IL-6, IL-21, IL-23, TGFβ, IL-1β	IL-17A, IL-17F, IL-22, IL-26	RORγ, AHR
Treg	STAT5	TGFβ, IL-2	IL-10, TGFβ	FoxP3
Tfh	STAT3	IL-6, IL-21	IL-21	Bcl6
Th22	STAT3?	IL-6, TNF	IL-22	AHR
TR1	?	IL-10, IL-27	IL-10	AHR
Th9	STAT6	IL-4, TGFβ	IL-9	PU.1, IRF4

AHR, aryl hydrocarbon receptor; IFNγ, interferon γ; IL, interleukin; RORγ, retinoic acid–related orphan receptor γ; STAT, signal transducer and activator of transcription; Tfh, T follicular helper cell; TGFβ, transforming growth factor β; Th, helper T cell; TNF, tumor necrosis factor; Treg, regulatory T cell;

Table 2.

The Assignment of BIA-ALCL to a Specific Helper T Cell Subset Is Contentious and Likely Context Dependent: Evidence From Biological Studies of BIA-ALCL That Supports Assignment to Individual Th subsets

Th subset
Th17	Th1	Treg
RORγ, AHR	T-bet	FOXP3
STAT3 mutations
IL-17, IL-22, IL-26	IFNγ, IL-26	IL-10, TFGβ
IL-6/IL-6R

AHR, aryl hydrocarbon receptor; IFNγ, interferon γ; IL, interleukin; RORγ, retinoic acid–related orphan receptor γ; TGFβ, transforming growth factor β; Th, helper T cell;

Figure 2.

The identity of the cell of origin of breast implant–associated anaplastic large cell lymphoma (BIA-ALCL) is generally difficult to decipher because the presenting tumor cell phenotype is a consequence of a combination of factors. The capsule that forms around a breast implant largely consists of a fibrous meshwork with scattered inflammatory cells rich in lymphocytes [particularly regulatory T cells (Treg) and T-helper 17 (Th17) cells⁴⁵], macrophages and giant multinuclear cells, the latter often enveloping particles such as silicone derivatives.⁴⁶ The presence of these cell types would lead to the secretion of a variety of cytokines conducive to an inflammatory response, with the ultimate composition of cell types present reflective of the type of stimulus.⁴⁷ In the case of an allergic reaction or the presence of extracellular pathogens, one might expect a higher ratio of Th2 cells in the presence of eosinophils, basophils, and B lymphocytes; infection with intracellular pathogens would lead to an increase in a Th1 skew with the knock-on effect of inhibiting Th2 differentiation—in addition, dendritic cells and macrophages would prevail in the inflammatory microenvironment, whereas Th17 cells would perhaps prevail in patients with autoimmune conditions, and be associated with neutrophils and bacterial infections. In this latter regard, the plasticity between Th17 and immunsuppressive Treg cells is dependent on the availability of IL-6 in comparison to leukemia inhibitory factor (LIF).⁴⁸ Features of all of these scenarios have been detected in BIA-ALCL (highlighted in red), some in studies of cell lines which have perhaps lost features due to their removal from their environment, some in fixed tissue sections of capsules, and others in seroma fluid. It is not inconceivable that BIA-ALCL represents a range of “cells of origin” due to varying antigenic stimuli/intracellular proliferation drivers, host factors, and patient genetics, and these cells ultimately develop into a disease that is also shaped by the acquisition of genetic oncogenic drivers.

One might also consider a scenario whereby the prevalence of distinct Th subsets within individual patients might be dictated by their health status. Women with autoimmune conditions may have higher levels of circulating Th17 cells, and those with allergies more Th1/2 cells. As such, the chances of any particular subset becoming transformed may be related to its predominance within the patient. Indeed, BIA-ALCL has been proposed to have a Th2 origin, a cell type largely present as an allergic response, particularly when in the presence of eosinophils.³⁴ Hypersensitivity reactions to silicone and its particulates have occasionally been reported in patients with breast implants, although to my knowledge, no synthetic antigens have yet been implicated in the pathogenesis of lymphoma.³⁵ An alternative explanation for a preponderance of Th17 or Th1 cells may be related to their normal physiological roles of protecting against large extracellular pathogens, such as bacteria or intracellular pathogens, respectively. In the former regard, BIA-ALCL, in a limited sample of patients, demonstrated higher levels of Ralstonia sp. in the implant capsule.³⁶ Given that Ralstonia sp. is a common contaminant of DNA isolation kits, combined with the low level of significance of these data, it remains to be definitively determined whether this, or indeed any other species of bacteria, is involved in the pathogenesis of BIA-ALCL.³⁷

The Identity of the Transforming Stimulus in BIA-ALCL

As alluded to above, the microbiome has been implicated as a driving stimulus in a variety of cancer types, most notably Helicobacter pylori and mucosal-associated lymphoid tissue (MALT) lymphoma.³⁸ However, the mechanism of tumorigenesis here is indirect: Th cells stimulated by the bacteria activate autoreactive B cells that subsequently transform, in time becoming independent of the T cells and the bacterial stimulus through the generation of oncogenic events.³⁸ As such, chronic infection with H. pylori in the gut can lead to the generation of a B-cell lymphoma. In contrast, ALCL is a T-cell lymphoma and would presumably require a direct bacterial-derived stimulus if this were the responsible mechanism. Bacterial infections at the site of breast implants is not a new tumorigenic concept, and suggestions have been made that adhering to a strict 14-point plan during surgery will prevent many cases of BIA-ALCL, rendering it insignificant in the future, although this is debatable.^39,40 It is feasible that other antigens in addition to bacterially derived ones may be involved; indeed enteropathy-associated T cell lymphoma (EATL) develops in the context of refractory celiac disease whereby chronic exposure to a diet including gluten predisposes to EATL, particularly in patients with specific human leukocyte antigen genotypes.⁴¹ However, the question then arises as to the role of the textured implant so commonly associated with this disease. It has been proposed that the textured surface provides a “safe haven” for bacteria to colonize, although this has not been unequivocally demonstrated.⁴²

An alternative hypothesis is that a component of the textured implant, recognized as a foreign antigen by the immune system, acts as the trigger. In this regard, the chemical composition of breast implants is difficult to fathom: manufacturing methods often remain closely guarded secrets, and therefore the identity of any potential antigen is difficult to discern. However, it is not uncommon to see giant cell responses in implant capsules, suggestive of an ongoing response to a large extracellular pathogen. Indeed, the role of Th17 cells is to detect large extracellular pathogens, and in doing so, to recruit neutrophils, whereas Th1 cells enlist macrophages and dendritic cells to their localized battle. With regard to the cellular microenvironment, eosinophils and mast cells have been detected in the capsules of women with BIA-ALCL, a feature of allergic inflammation and more compatible with a Th2 phenotype.⁴³ In this latter regard, although GATA3 has been detected in some patient specimens, it is absent in BIA-ALCL cell lines, perhaps because its expression is heavily reliant on microenvironmental factors.^17,43 However, these data raise the intriguing possibility of a role for a chronic allergic response in disease pathogenesis, with the antigen remaining to be defined. The antigen may constitute a synthetic factor rather than a biological one, and as mentioned above, many allergies to synthetic materials exist. Alternatively, if the cell of origin is a Th17 cell, the aryl hydrocarbon receptor (AHR), a ligand-activated transcription factor expressed in many tissues, including the liver, and within the T cell compartment may be responsible for driving cellular proliferation.⁴⁴ The AHR, as the name suggests, binds to aryl hydrocarbons, and it is not inconceivable that textured implants are abundant in these chemical structures. It has been shown that skewing towards a Th17 cell type is mediated through exposure of Th cells to low-dose aryl hydrocarbons such as 5,11-dihydro-indolo[3,2-b]carbazole-6-carboxaldehyde and 6-formylindolo[3,2-b]carbazole, whereas high doses lead to Treg differentiation.⁴⁴ As such, low-dose, chronic exposure to aryl hydrocarbons might also elicit an inflammatory Th17 response, leading to the development of BIA-ALCL.

CONCLUSIONS

It has been established beyond doubt that BIA-ALCL is almost exclusively associated with textured implants, for the most part has an indolent course, and is of T-cell origin. Other aspects of this lymphoma are less clear, with varying cytokines, transcription factors, and other cellular phenotypes fluctuating from study to study—most of which, it should be noted, include only limited numbers of patients. As such, beyond the established facts, it is not possible to definitively exclude any of the theories proposed to explain the pathogenesis of this disease. Indeed, I suggest that it is very likely that a spectrum of mechanisms exists amongst patients, with allergy and autoimmunity providing conducive backgrounds for chronic stimuli whether of bacterial and/or synthetic origins. Ultimately, the chronic nature of the stimuli causes prolonged proliferation and initiates oncogenic genetic events, leading to clonal outgrowth and tumor development. Although explant and capsulectomy seemingly prevents this process from progressing, leading to cure for the majority of patients, it is clear that in some cases aggressive disease can ensue. Hence, although this lymphoma is considered largely indolent, it is conceivable that leaving the implant and capsule in place could lead to aggressive, metastatic disease with clear malignant progression.

Disclosures

The author has received grant funding from a GlaxoSmithKline Varsity Award (grant number: 3000029612) and Bloodwise (grant number: 12065).

Funding

This supplement is sponsored by Allergan plc (Dublin, Ireland), Aesthetic Surgery Education & Research Foundation (ASERF) (Garden Grove, CA), Establishment Labs (Alajuela, Costa Rica), Mentor Worldwide, LLC (Irvine, CA), Polytech Health & Aesthetics GmbH (Dieburg, Germany), and Sientra, Inc. (Santa Barbara, CA).