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Mast Cells in the Breast Peri-Prosthetic Capsule: Initiators of the Fibrogenic Response
Stephanie Malliaris, MD1, Jacqueline Brazin, PhD2, Kadria Derrick, MD2, David Otterburn, MD2, Babak Mehrara, MD3, David Hidalgo, MD2, Randi Silver, PhD2, Jason A. Spector, MD2.
1New York Presbyterian Hospital, New York, NY, USA, 2Weill Cornell Medical College, New York, NY, USA, 3Memorial Sloan Kettering Cancer Center, New York, NY, USA.
BACKGROUND: Capsular contracture remains a significant source of morbidity associated with breast prosthetic devices. An increasing body of data points to mast cells being crucial mediators of the fibrotic response in a variety of tissues, including lung and kidney. In these tissues it has been shown that mast cell degranulation and release of renin, histamine and TGF-β acts via a paracrine pathway to activate neighboring fibroblasts, resulting in an increase in collagen lattice contraction. Considering the fibrotic nature of capsular contracture, we hypothesized that mast cells may be a crucial mediator of peri-prosthetic capsular contracture as well. Towards this end we analyzed the mast cell and fibroblast populations in breast capsule tissue from patients undergoing capsule excision.
METHODS: Capsular tissue was collected from patients undergoing routine exchange of tissue expanders for permanent implants, revision of reconstruction or revision augmentation. The anterior and posterior sides of the capsule were sampled separately. Capsule tissue was fixed and embedded for histology and immunohistochemistry of mast cells and fibroblasts. Fresh capsule tissue was used to isolate mast cells and fibroblasts, and for collagen analysis. Lysates from mast cells were analyzed for fibrogenic mediators. Isolated fibroblasts were analyzed for receptor expression of those same fibrogenic mediators.
RESULTS: In breast capsule tissue, the average number of mast cells and fibroblasts were 9±1/mm2 and 33±10/mm2, respectively. There were significantly more mast cells on the posterior side compared to the anterior side of capsule tissue (12±2 vs 6±1/mm2, p<0.01). Baker Grade IV capsules had an increased number of fibroblasts compared to Baker Grade I capsules (93±9 vs 40±19/mm2, p<0.001), whereas the number of mast cells showed no significant difference in relation to Baker grade. Mast cells residing within breast capsule tissue were found to contain renin, histamine and TGF-β. The renin within these mast cells was active (measured by angiotensin I (AT1)-forming activity, which depends on renin for activation), and was significantly increased in lysates from the posterior capsule when compared to the anterior capsule. Histamine levels showed no difference between anterior and posterior capsule samples, and collagen density was similar as well. The respective receptors for these mast cell mediators, AT1R, H1R, and TGF-βRI were expressed by neighboring fibroblasts in the breast capsule.
CONCLUSIONS: Although mast cells have been shown previously in breast peri-prosthetic capsule tissue, our work demonstrates for the first time that mast cells contain the profibrotic mediators that can activate neighboring fibroblasts within the capsule, thus identifying a novel potential mechanism of capsular contracture. Further understanding of the role of mast cells in pathologic peri-prosthetic breast capsule formation may lead to novel therapies to prevent and treat capsular contracture.
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