Oncogenic Drivers of Breast Implant-Associated Anaplastic Large Cell Lymphoma

It is with great pleasure that we read the article “Molecular Drivers of Breast Implant-Associated Anaplastic Large Cell Lymphoma” (BIA-ALCL) by Blombery et al.¹ Appearing in the Plastic and Reconstructive Surgery BIA-ALCL supplement, ² the article concisely reviews the current literature surrounding the molecular mechanisms implicated in the pathogenesis of this rare malignancy. The authors are to be commended for their continued work in this important area. Of particular interest to us was the author’s focus on the genetic drivers of the disease and the role of the JAK/STAT3 pathway in the pathogenesis of BIA-ALCL.

The understanding of BIA-ALCL has evolved immensely over the past two decades as a result of significant works from laboratories around the world that have continued to push knowledge of the disease forward. Despite these efforts, elucidating the molecular mechanisms responsible for BIA-ALCL tumorigenesis and progression remains a challenge. The lack of an animal model has limited hypothesis testing and remains a barrier to progress in the field. While tumor cell lines provided early insight into pathogenicity, demanding growth requirements and difficulties with heterotransplantation led to their discontinuation. As a result, clinical specimens have become an invaluable but finite resource for mechanistic investigations of the disease.

A number of hypotheses attempting to explain the pathogenesis of BIA-ALCL have been put forth.³ While limited scientific evidence has precluded development of a unifying theory, ⁴ inciting events such as repetitive trauma to the breast pocket, macrophage phagocytosis of particulate matter (e.g. silicone from the implant), bacterial inoculation, viral pathogens and an allergen-driven etiology have been postulated. In combination with one or more of these postulates, aberrant gene expression is also thought to play a critical role in the oncogenic transformation of BIA-ALCL as it progresses from a chronic inflammatory state to a full-blown malignancy.

The recent utilization of next-generation sequencing has yielded unprecedented molecular data which has provided insight into the pathogenesis of BIA-ALCL. To date, novel, oncogenic mutations in the JAK/STAT3 pathway, as well as point mutations in TP53 and DNMT3A have been described.⁵ Importantly, immunohistochemical studies have shown STAT3 activation in 100% of tested BIA-ALCL tumor specimens. In addition, administration of a STAT3 inhibitor has been shown to induce tumor cell death in heterotransplanted immunodeficient mice. Collectively, these data suggest that persistent JAK/STAT3 activation is a main driver of BIA-ALCL. This is significant, as aberrant STAT3 signaling is known to be the mechanistic link between chronic inflammation and malignant transformation in other cancers.

Although oncogenomic research continues to provide important clues regarding the molecular mechanisms of BIA-ALCL, a better understanding of JAK/STAT3 signaling as it relates to malignant transformation and progression of BIA-ALCL is needed. As such, future investigations should focus on the comprehensive analysis of the genome (including the epigenome) as well as the transcriptome and should include the use of corresponding healthy control tissue. While the interrogation of tumor specimens continues to provide important molecular data, the development of an animal model may prove instrumental in elucidating the oncogenic drivers of this disease.