Commentary on: Biomarkers Provide Clues to Early Events in the Pathogenesis of Breast Implant-Associated Anaplastic Large Cell Lymphoma

Breast implant-associated anaplastic large cell lymphoma (BIA-ALCL) is a rare form of T-cell non-Hodgkin lymphoma (NHL) and is being increasingly recognized as a complication of breast implants.1 There has now been close to 200 cases reported in the literature although the actual number of cases is likely to be higher; in the United States alone, the FDA have received 258 medical device reports which include confirmed and unconfirmed reports. The true incidence is likely underestimated due to both lack of awareness of this condition (and hence not submitting seroma fluid for detailed pathological analysis) and under-reporting. Collaborative efforts are underway to determine the true incidence, the relative risk, and etiological factors that may predispose to this lymphoma. For a recent perspective from the FDA, we refer the reader to their website.2 For the non-oncologist, it is important to gain a perspective where this disease fits into other types of lymphoma. Firstly, this is the one of the least common forms of lymphoma involving the breast; 90% are actually B-cell lymphomas comprising the subtypes of marginal zone lymphoma, follicular lymphoma, and diffuse large B-cell lymphoma. Only 9% of breast lymphoma are of T-cell type. T-cell NHL is a rare type of NHL in itself and peripheral T-cell lymphoma (PTCL) is the most common subtype − of which anaplastic large cell lymphoma (ALCL) makes up approximately 15% of all PTCL. The classic type of ALCL is typically a systemic disease which pathologically contains anaplastic appearing large cells that almost universally express the CD30 antigen on their surface. Systemic ALCL is further subcategorized according to the expression or absence of the ALK protein; ALK-expressing lymphomas have a superior outcome over ALK-negative lesions. Another important type of ALCL is the cutaneous type; this lesion is considered part of a spectrum of cutaneous lymphoproliferative disorders (LPD) that express CD30 and range from the indolent relapsing/regressing lesions of lymphomatoid papulosis (LyP) to the potentially more aggressive primary cutaneous ALCL (pcALCL). The latter, although at the aggressive end of the cutaneous CD30+ LPD spectrum, has a much better outcome over its systemic counterparts. Of note, the pcALCL lesions (like BIA-ALCL) virtually never express the ALK protein. As the cases of BIA-ALCL have been accumulated it has become clear that most behave in an indolent fashion. The archetypal indolent lesion is one that presents some years after implantation of a textured implant and presents with moderately rapid onset of unilateral breast swelling. When the lesion is sampled it contains numerous anaplastic CD30 positive cells. On removal of the entire capsule there is no evidence of tumor invasion into the capsule with the malignant cells restricted to the seroma±seroma lining. Treatment is removal alone. Survival is excellent approaching 100%. Conversely, if the BIA-ALCL invades the surrounding tissue (variously labelled “infiltrative” or “mass-associated”) the prognosis is substantially poorer. Spread is usually loco-regional, akin to cutaneous ALCL and another CD30+ condition − Hodgkin lymphoma (unlike many other lymphomas that spread hematogenously). Systemic therapy is usually required involving chemotherapy±radiotherapy. It is still to be determined if the non-invasive and invasive subtypes are derived from the same biological processes and if the former, if left untreated, will always progress to the latter invasive form. Needless to say, BIA-ALCL has been a controversial entity since it was first recognized in the mid-2000s. Some initially claimed it was an inflammatory lesion only, but now it can confidently be considered a true malignancy with clonality confirmed by consistently positive T-cell receptor (TCR) gene rearrangement studies, and the reporting of chromosomal abnormalities and cell lines established with xenograft murine models established.3 In this edition of the Journal4 we are provided with more evidence of the pathobiology of BIA-ALCL. In this study gene expression array analysis/profiling (GEP), flow cytometry, and immunohistochemistry (IHC) were used to compare cell lines of pcALCL and BIA-ALCL. Clinical samples from patients with LyP, pcALCL, BIA-ALCL, and “control” capsular contracture samples were also studied to examine and compare transcription factor and cytokine profiles of both tumor cells and surrounding lymphocytes. GEP of the cell lines demonstrated considerable similarities between BIA-ALCL and pcALCL. Although there were variations across the different lines representing these two entities, there was high gene expression of IFN gamma, the Th17 cytokine IL-17F, and IL-17A and SOCS3 and SOCS2. One deficiency of this report is that it would have been very interesting to compare the BIA-ALCL directly to systemic ALCL cell lines; nonetheless, as the investigators point out, both ALK positive and ALK negative systemic ALCL are recognized to highly express SOCS3. Flow cytometry data of the cell lines demonstrated that they produce IFN-gamma and IL-17F. The IHC of the BIA-ALCL clinical samples demonstrated cytoplasmic IFN-gamma, SOCS3, and (albeit weaker) IL-17F. Of some interest, although preliminary, some samples showed junB expression (transcription factor) and SATB1. This data contributes three important pieces to the puzzle of BIA-ALCL. Firstly, the comparative GEP data supports the currently held belief that this condition is more akin to the relatively indolent cutaneous form of ALCL. Secondly, the GEP and IHC data demonstrate that key pathways recognized to be important in other T cell NHL (ie, SOCS3 and JunB) are aberrant in BIA-ALCL. This lends further support that this is true malignancy. Finally, the Th17 phenotype supports the contention that BIA-ALCL may arise from a chronic inflammatory process. Indeed, chronic bacterial stimulation has recently been implicated in the pathogenesis of BIA-ALCL.5 Fortunately, BIA-ALCL remains relatively rare and most often behaves in an indolent fashion. However, heightened awareness of this entity is required to recognize it early and ensure early removal of the implant. Such studies provide insights into the biology of this disease − likely due to chronic antigen stimulation. To date, the two most frequently implicated aetiological contributors appear to be use of textured implants and chronic bacterial stimulation. Factors that predispose individuals may in the future be gleaned from registry data, HLA profiling, and germline gene variation/mutation profiling. Already such studies are building an awareness that modifications of practice may be required in the foreseeable future (eg, implant choice, bacterial decontamination). However, we still are no clearer as to why some patient present with the more aggressive “infiltrative/mass-associated” form of BIA-ALCL. More studies with larger patient numbers and a wider spectrum of disease presentations will be required. The authors declared no potential conflicts of interest with respect to the research, authorship, and publication of this article. The authors received no financial support for the research, authorship, and publication of this article.