Anaplastic large cell lymphomas associated with breast implants: from diagnosis to molecular sequencing

Breast implant-associated anaplastic large-cell lymphoma (BI-ALCL) is a new entity recently recognized in the updated WHO classification of Haematologic neoplasms in 2017. Following its first description in 1997, the prevalence of BI-ALCL is estimated at 0.1 or 5 to 100,000 women with breast implants. The diagnosis of BI-ALCL is based on the pathological examination of the capsule or peri-prosthetic effusion showing a proliferation of large cytotoxic tumor T cells expressing CD30 and EMA. In 2016, the first French series of BIALCL patients has described for the first time two BI-ALCL histological subtypes that correlated with the two main clinical presentations: in situ BI-ALCL found in patients with seroma, characterized by lymphoma cells lining the capsule border and/or suspended in a serous/fibrinoid material, which is associated to an excellent outcome; ii) tumor-type BI-ALCL mostly found in patients with tumor mass, characterized by capsule invasion and having the worse prognosis. The therapeutic management and prognosis of BI-ALCL depend on tumor extend evaluated by a recent proposed TNM staging system. BI-ALCL has an excellent prognosis with overall survival at 3 years and 5 years at 93 % and 89 %, respectively. Whereas in situ BI-ALCL (80%) are efficiently treated with capsulectomy alone, BI-ALCL with tumor mass (20% of BI-ALCL) are more aggressive and require a more intensive therapeutic approach. The pathogenesis of BI-ALCL could be explained by multiple intrinsic and extrinsic factors such as chronic antigenic stimulation by the implant immunogenicity or microbiome, host genetic susceptibility and acquired genetic alterations. Several distinct steps likely result in the transformation of a reactive cytotoxic T cell, to a polyclonal T-cell proliferation then, to BI-ALCL clonal lymphoma. In 2020, the genomic characterization of a large series of BI-ALCL using whole-exome sequencing has confirmed the key role of the JAK/STAT pathway, but also highlighted the importance of epigenetic dysregulation in BI-ALCL pathogenesis. Although BI-ALCL is a rare disease, its incidence has doubled in 7 years in France leading to the recall from the French market of macro-textured and polyurethane implants by the National Agency for the Safety of Medicines (ANSM). Since 2018, in France, a BIA-ALCL registry sponsored by the LYSA/LYSARC collects all clinical and biological data of BIALCL patients via a national multidisciplinary tumor board meeting and Lymphopath network funded by French National Cancer Institute (INCa) that will provide new therapeutic guidelines for improving therapeutic management of BI-ALCL patients and delineate the genetic and environmental risk factors of this disease.