Substance P staining can be observed only at high magnification (arrowheads in inset, Grade +1; arrowheads and inset, Grade +2). Smooth muscle cells in vessel walls stained with α-SMA are indicated by arrows (Grade 0), myofibroblasts stained with α-SMA are present as strong as staining of the vessels (Grade +1), and high levels of α-SMA are indicated by strong staining of many myofibroblasts (Grade +2). Grade 0 = negative, Grade +1 = low intensity or weak positive, and Grade +2 = high intensity or strong positive. Original magnification: ×400 (top row) and ×200 (bottom row).
Surgery-induced injury activates mast cells and fibroblasts by neuropeptide signaling. In at-risk patients, persistent noxious and mechanical stimuli caused by the presence of a silicone prosthesis results in continued neuropeptide synthesis and chronic activation of myofibroblasts. Over time, collagen hyperplasia and extracellular matrix (ECM) contraction result in nasal contracture. α-SMA indicates alpha-smooth muscle actin; PDGF, platelet-derived growth factor; and TGF-β1, transforming growth factor-beta 1.
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Sunwoo W, Jung H, Kim DW, Jin HR. Immunohistochemical Analysis of Capsular Contracture in Silicone Implant Rhinoplasty. JAMA Facial Plast Surg. 2017;19(5):436–437. doi:10.1001/jamafacial.2017.0207
Contracted nose is common in patients who have undergone rhinoplasty with a silicone implant.1,2 Commonly, patients who develop a contracted nose have histories of multiple rhinoplasties. Repeated injuries to the nasal tissue, infection, absence of dorsal volume following silicone removal, and overaggressive resection of normal cartilage are presumed to contribute to the development of nasal contracture. However, nasal contracture develops even with silicone in situ and without manipulation of the nasal tip. Although it is not the sole cause of contracted nose, silicone implant–related capsular contracture is presumed to play an important role in the development of this condition, especially in patients for whom the development of contracture cannot be otherwise explained.
From January 1, 2014, to September 30, 2016, capsules were obtained from 12 patients (3 men and 9 women; median age, 27.5 years [range, 21-46 years]) whose silicone implants were removed during revision rhinoplasty performed because of unsatisfactory aesthetic results or complications. The study protocol was approved by Seoul National University Boramae Medical Center Institutional Review Board. All patients provided written informed consent.
Considering anthropometric results from preoperative and current facial photographs, present nasal status, previous surgical histories, and surgical findings, capsules from 3 patients were assigned to the capsular contracture (CC) group. Each patient in the CC group underwent a single operation for silicone implantation and showed no evidence of cartilage or soft tissue resection during the procedure. Capsules from 9 patients were assigned to the non–capsular contracture (NCC) group.
Immunohistochemical staining was performed. We used antibodies directed against substance P (SP), tryptase, and chymase for mast cell counts; myeloperoxidase heavy chain for neutrophil counts; and alpha-smooth muscle actin for myofibroblast staining. A 3-point grading scale was used to analyze alpha-smooth muscle actin and SP staining (Figure 1).
Among the 12 patients in the study, the median number of previous surgeries was 1 (range, 1-7), and the median duration of implantation was 3.5 years (range, 2-25 years). No significant differences between the groups were found in the baseline data.
The CC group showed a higher level of SP than did the NCC group did. All capsules in the CC group showed positive SP staining to various degrees (2 of grade +2 and 1 of grade +1; P < .01, linear by linear association). Two of 9 capsules in the NCC group showed low-intensity SP staining (grade +1) and the other 7 showed negative findings. However, mast cell and neutrophil counts and staining grades of the myofibroblasts were not significantly different between the 2 groups.
In this study, SP immunoreactive staining was stronger in the CC group than in the NCC group. Similarly, elevated levels of SP have been observed in various fibrotic conditions.3 Mast cells and fibroblasts are exposed to activating signals during a surgery-induced injury. Under normal conditions, numbers of fibroblasts, myofibroblasts, and mast cells diminish as healing progresses. However, persistent mechanical stimuli caused by the silicone prosthesis can result in persistent neuropeptide synthesis and chronic fibroblast and mast cell activation. Although significant associations were not found between SP and numbers of mast cells in our study, SP has been called a mast cell secretagogue.4 Substance P also stimulates fibroblast proliferation and impairs proapoptotic signaling in myofibroblasts.5 Mast cell–derived histamine causes the release of SP from type-C unmyelinated nerve fibers.6 Substance P, in turn, potentiates histamine release. Thus, fibroproliferative stimuli persist and escape regulatory control. As mast cells and fibroblasts are activated, a cycle is engaged. These events create an environment of sustained myofibroblast hyperplasia, resulting in disorganized collagen deposition (Figure 2).
Owing to its small sample size, our report must be considered preliminary. Although our evidence supports a neuroinflammatory axis as the mechanism underlying capsular contracture, further studies with additional biomarkers and larger groups of patients may reveal more information about the pathogenesis of capsular contracture.
Accepted for Publication: February 4, 2017.
Corresponding Author: Hong Ryul Jin, MD, PhD, Department of Otorhinolaryngology–Head and Neck Surgery, Seoul National University Boramae Medical Center, Seoul National University College of Medicine, 20 Boramae-ro 5-gil, Dongjak-gu, 156-707, Seoul, Korea (firstname.lastname@example.org).
Published Online: July 13, 2017. doi:10.1001/jamafacial.2017.0207
Author Contributions: Drs Sunwoo and Jin had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.
Study concept and design: Sunwoo, Kim, Jin.
Acquisition, analysis, or interpretation of data: All authors.
Drafting of the manuscript: Sunwoo, Jung, Kim.
Critical revision of the manuscript for important intellectual content: Sunwoo, Kim, Jin.
Statistical analysis: Sunwoo, Jung, Kim.
Administrative, technical, or material support: Jung.
Study supervision: Jin.
Conflict of Interest Disclosures: None reported.
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