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The Laryngoscope © 2021 The American Laryngological, Rhinological and Otological Society, Inc.

Different Surgical Strategies in the Prevention of Frey Syndrome: A Systematic Review and Meta-analysis Armando De Virgilio, MD, PhD ; Andrea Costantino, MD ; Elena Russo, MD; Fabio Ferreli, MD ; Raul Pellini, MD; Gerardo Petruzzi, MD ; Jacopo Zocchi, MD ; Giuseppe Spriano, MD; Giuseppe Mercante, MD Objective/Hypothesis: To de fi ne the best surgical technique able to reduce Frey syndrome (FS) incidence after parotidectomy. Study Design: Systematic review and network meta-analysis. Methods: An arm-based network analysis was conducted using a Bayesian hierarchical model. The primary and second ary outcomes were the incidence of subjective (clinical) and objective (positive starch-iodine test result) FS, respectively. Results: A total of 3830 patients with a median age of 50.35 years (n = 2323; IQR 44.25 – 54.18) were included for six interventions [temporoparietal fascia (TPFF), free fat graft (FFG), acellular dermal matrix (ADM), sternocleidomastoid muscle (SCM) fl ap, and super fi cial musculoaponeurotic system (SMAS) fl ap]. If compared to no treatment, the greatest reduction of subjective (clinical) FS incidence was measured for the TPFF (OR: 0.07, CI: 0.004 – 0.57), the ADM (OR: 0.09, CI: 0.02 – 0.35), and the FFG (OR: 0.11, CI: 0.03 – 0.42) techniques. However, a signi fi cant difference was measured also for the SCM fl ap (OR: 0.38, CI: 0.18 – 0.73) and for the SMAS fl ap (OR: 0.42, CI: 0.19 – 0.97). All treatments showed a signi fi cant reduction of the objective FS incidence if compared to no treatment (FFG, OR: 0.06, CI: 0.002 – 0.62; TPFF, OR: 0.07, CI: 0.01 – 0.33; ADM, OR: 0.11, CI: 0.03 – 0.44; SMAS, OR: 0.36, CI: 0.17 – 0.71; SCM, OR: 0.40, CI: 0.19 – 0.74). Conclusions: TPFF, ADM, and FFG seem to be the best treatment strategies to prevent FS after parotidectomy. Further randomized controlled trials comparing these techniques should be conducted to de fi ne speci fi c indications. Key Words: Parotidectomy, free fat graft, temporoparietal fascia, acellular dermal matrix. Laryngoscope , 131:1761 – 1768, 2021

cells of the parotid acini. 3,4 The reported incidence of FS after parotidectomy vary between 12.5% and 62% based on the presence of symptoms, and up to 98% when a Minor ’ s starch iodine test is performed. 5 – 7 The timing of its development ranged from 20 days to 22 months with a median of 11 months. 8 FS often leads to a signi fi cant degree of patient dis satisfaction, and several papers showed that it represents the most serious self-perceived sequelae, along with cos metic dis fi gurement, with signi fi cant potential negative social and psychological implications. 9 – 12 Although the primary aim of a parotidectomy is to completely remove the tumor preserving the facial nerve branches, the possi bility to prevent the occurrence of FS should not be underestimated. Many surgical techniques aiming to prevent this complication have been described. 7,13 – 17 A previous meta analysis performed by Curry et al. 18 demonstrated that the use of these techniques decreases the likelihood of FS symptoms and/or a positive starch-iodine test result. However, the analysis performed by the authors does not allow to de fi ne the best surgical treatment. Some random ized clinical trials 6,19 – 24 and meta-analysis 25 – 28 compared speci fi c techniques with no treatment con fi rming that the prevention of the FS is recommended. Nevertheless, these data are not able to suggest, which technique should be used, and the choice of a speci fi c treatment is nowadays based on the surgeons ’ preference and experience.

INTRODUCTION Frey syndrome (FS), also known as gustatory sweat ing or auriculotemporal nerve syndrome, is characterized by abnormal fl ushing, sweating, and burning sensation of the skin in the preauricular region, induced by mastica tion and salivatory stimulation. 1 This phenomenon was fi rst described by Duphenix in 1757, 2 while the role of the auriculotemporal nerve in the pathogenesis of this condi tion was fi rst reported by Frey in 1923. 1 FS is considered caused by an aberrant nervous regeneration of parasym pathetic fi bers after the disruption of the parotid bed. The fi bers reinnervate sweat glands and the subcutaneous vascular plexus, instead of connecting the secretomotor From the Department of Biomedical Sciences ( A . D . V ., A . C ., E . R ., F . F ., G . S ., G . M .), Humanitas University, Via Rita Levi Montalcini 4, Pieve Emanuele – Milan, Italy; Otorhinolaryngology Unit ( A . D . V ., A . C ., E . R ., G . S ., G . M .), IRCCS Humanitas Research Hospital, Via Manzoni 56, Rozzano – Milan, Italy; and the Department of Otolaryngology Head and Neck Surgery ( R . P ., G . P ., J . Z .), Regina Elena National Cancer Institute, IRCCS, Rome, Italy. Additional supporting information may be found in the online version of this article. Editor ’ s Note: This Manuscript was accepted for publication on January 12, 2021. G . S . and G . M . contributed equally to this work. The authors have no funding, fi nancial relationships, or con fl icts of interest to disclose. Send correspondence to Andrea Costantino, MD, Otorhinolaryngol ogy Unit, IRCCS Humanitas Clinical and Research Center, Via Manzoni 56, 20089 Rozzano, MI, Italy. E-mail: andrea.costantino94@gmail.com

DOI: 10.1002/lary.29414

Laryngoscope 131: August 2021

De Virgilio et al.: Surgical prevention of Frey syndrome 1761