Recurrent PDL1 expression and PDL1 (CD274) copy number alterations in breast implant-associated anaplastic large cell...

Breast implant-associated anaplastic large cell lymphoma (BI-ALCL) is a variant of anaplastic large cell lymphoma arising within seroma effusion associated with breast implants. BI-ALCL is a rare disease, recently recognized as a new provisional entity by the 2017 revised World Health Organization classification. All BI-ALCLs tested so far showed a "triple-negative" genetic profile-negative for ALK, DUSP22, and TP63 rearrangements-and were characterized by mutational and gene expression profiles consistent with aberrant activation of the JAK/STAT pathway. The active form of STAT3 (pSTAT3) is constantly expressed in BI-ALCLs and may favor tumor immune escape by triggering the transcription of PDL1 (CD274), a gene encoding the immune-checkpoint molecule programmed cell death ligand 1 (PDL1); immunohistochemical positivity for PDL1 has been recently described in 3 BI-ALCL cases, and one of them also harbored PDL1 gene amplification. We evaluated PDL1 and pSTAT expression by immunohistochemistry and PDL1 copy number alterations (CNAs) at chromosome 9p24.1 by fluorescent in situ hybridization in a cohort of 9 BI-ALCL cases; we also investigated the presence of tumor-infiltrating programmed cell death 1 (PD1)+ T cells (tumor-infiltrating lymphocytes, or TILs) and PDL1+ tumor-associated macrophages (TAMs) in BI-ALCL microenvironment. Tumor cells expressed PDL1 in 5 (56%) of 9 cases and harbored PDL1 CNAs in 3 (33%) of 9 cases; immunohistochemistry for pSTAT3 was positive in all 6 cases tested (100%), indicative of active JAK/STAT signaling. We observed PDL1 CNAs only among PDL1-positive cases, whereas PD1+ TILs and PDL1+ TAMs were present at variable levels in both PDL1-positive and PDL1-negative BI-ALCLs. We report frequent PDL1 expression and recurrent PDL1 CNAs in BI-ALCLs: our data suggest that 9p24.1 alterations represent a common mechanism of PDL1 overexpression in this disease, likely acting in synergy with constitutive pSTAT3 signaling. In PDL1-positive cases without chromosomal aberration, PDL1 expression may be induced by JAK/STAT signaling alone and/or others alternative pathways. BI-ALCL microenvironment hosts variable amounts of PD1+ TILs and PDL1+ TAMs, suggesting the presence of an active PD1/PDL1 axis. These findings may be of therapeutic value in advanced-stage patients who may benefit from a PD1/PDL1 blocking treatment.