Effect of human acellular dermal matrix (Megaderm™) on infra-auricular depressed deformities, Frey’s syndrome, and first bite syndrome following parotidectomy: a multi-center prospective study

Introduction

Parotidectomy is the primary treatment for parotid gland tumors. However, parotidectomy can cause considerable complications including a prominent facial scar or infra-auricular depressed deformity, gustatory sweating, facial pain, numbness and paralysis (1). Most parotidectomy patients, especially young women, are concerned about postoperative changes in facial appearance, which can have adverse effects on patients’ mental status. Recently, the facial scar problem has been somewhat resolved with the modified facelift incision method (2). However, preventing an infra-auricular depressed deformity continues to be a challenge, particularly in total parotidectomy.

In addition, patients undergoing parotidectomy occasionally complain about flushing, sweating, or intense pain in the parotid region during food intake, which may be attributed to Frey’s syndrome (3). It results from aberrant regeneration of parasympathetic nerve fibers within the parotid gland to the overlying sweat glands of the skin (4). Rarely, patients with parotidectomy suffer acute facial pain at the first bite of each meal, which is aptly termed “First bite syndrome” (5). All of these complications have negative effects on patients’ quality of life.

Current surgical methods for preventing depressed deformities and Frey’s syndrome include dermo-fat graft, temporalis myofascial flap, and sternocleidomastoid muscle flap (6-10). However, these autologous tissue transplantations have problems such as additional surgical donor site trauma, increased operating time, and a limited donor quantity (11). Since the early 1990s, acellular dermal matrix (ADM) has been developed and utilized for various head and neck reconstructions (12). ADM is obtained from human cadaver skin by solvent, detergent, and freeze-drying processes to eliminate cellular components (13). It consists of an extracellular matrix and basement membrane which is sterile and non-immunogenic.

In parotid surgery, ADM has proven useful for the space-occupying effect and prevention of Frey’s syndrome (14,15). However, previous studies have shown insignificant results due to retrospective designs or small numbers of patients, and there have been no prospective and large-scale clinical trials for ADM use with parotid surgery. Therefore, we performed a multi-center prospective trial to evaluate the effectiveness of Megaderm™ ADM for the prevention of infra-auricular depressed deformities, Frey’s syndrome, and first bite syndrome following parotid tumor surgery.

We present the following article in accordance with the CONSORT reporting checklist (available at http://dx.doi.org/10.21037/gs-20-703).

Methods

Study protocol

This multi-center prospective clinical trial was carried out at 6 tertiary head and neck centers (Ajou University Hospital, Cheonan Soonchunhyang University Hospital, Gangnam Severance Hospital, Inha University Hospital, International St. Mary’s Hospital, and Severance Hospital).

The trial was conducted in accordance with the Declaration of Helsinki (as revised in 2013). The study was approved by the institutional review boards of Ajou University, Cheonan Soonchunhyang University, Gangnam Severance Hospital, Inha University, International St. Mary’s Hospital, Severance Hospital and informed consent was taken from all individual participants.

Patients

Between November 2015 and March 2018, patients with benign parotid tumors who underwent superficial or total parotidectomy by experienced head and neck surgeons were considered eligible. The exclusion criteria ruled out patients who were younger than 18 or older than 70 years, had a malignant tumor at final histology, a history of keloid scarring, a current pregnancy, recurrent parotid tumors, previous parotid surgery, or an uncontrolled medical illness.

Surgical procedure

A modified facelift incision method was used through the skin, subcutaneous tissue, and platysma in all patients. The skin flap was raised under the parotid fascia to the anterior border of the masseter muscle, and superficial or total parotidectomy was performed in all participating hospitals. In the case with implantation of Megaderm™ (L & C BIO Corp., Seongnam-si, Korea), a 5 cm × 8 cm sheet was used in single-layer grafts or folding grafts according to the surgeon’s decision (Figure 1). Megaderm™ was trimmed to the proper size and shape based on the size of the depression and inserted between the flap in the parotid bed and the residual parotid tissue. All patients had a Hemo-vac drain inserted during surgery and removed when the amount of drainage was less than 20 cc.

Figure 1 The implantation of ADM (acellular dermal matrix) following total parotidectomy. (A) Preoperative photo shows the modified facelift incision method that was used. (B) Intraoperative view shows the surgical field after total parotidectomy with preservation of the facial nerve. (C) The ADM is designed and inserted between the parotid bed flap and the residual parotid tissue.

Allocation

All of the participants were then allocated into two groups. Half of the enrolled patients underwent parotidectomy with implantation of Megaderm™ (L & C BIO Corp., Seongnam-si, Korea). The other patient group underwent parotidectomy alone without Megaderm™ implantation. The use of Megaderm™ was decided by choice of patients with the recommendation of the surgeon. The surgeon performed the implantation of Megaderm™ only on the agreed patients. The patients purely determined the use of Megaderm^TM because of the economic burden of the Megaderm™ and the fact that the external material is inserted into the patient’s body.

Outcome measures

Preoperative data including age, gender, body mass index (BMI), underlying disease, allergic history, and pathologic tumor type were collected. Follow-up examinations were carried out at 1 week, and 3, 6, and 12 months postoperatively. The evaluation of acute complications including infection, seroma, hematoma, skin necrosis, and acute parotid area pain was performed 1 week postoperatively. Grading of Frey’s syndrome was performed at 3, 6, and 12 months (Table 1). The iodine-starch test was performed at each follow-up visit. Objective evaluation of infra-auricular depressed deformities was performed by two independent, blinded physicians using a visual analog scale of contouring deformity based on facial photos taken from the anterior, head-elevating, lateral, and oblique views (1, undetectable deformity; 2, mild deformity; 3, moderate deformity; 4, severe deformity; 5, extremely severe deformity). At 3, 6, and 12 months, each patient also filled in a questionnaire that included a subjective satisfaction score of gross neck appearance (Score 1–5; 5 being the most satisfactory); quality of Frey’s syndrome (Scores 1–4: 1, hardly ever; 2, sometimes and tolerable; 3, regular and unpleasant; 4, often and annoying); and acute parotid area pain using a visual analog scale (scores 1–10; 10 being the most severe).

Table 1 Clinician evaluation of Frey’s syndrome
Full table

Statistical analysis

An unpaired t-test and chi-square test were used for descriptive analysis and Pearson’s chi-square test and Fisher’s exact test were used for qualitative variables. A P value less than 0.05 was considered statistically significant. Statistical analysis was performed using SPSS software, version 22.0 (IBM Corporation, USA).

Results

Patient characteristics

A total of 134 patients were enrolled, with 25 patients lost to follow-up, 109 patients (58 Megaderm™ group and 51 control group) completing all follow-up examinations. There were 59 males and 50 females with a mean age of 42.5±4.8 years (range, 21 to 67 years). There were no statistically significant differences in patient characteristics and pathologic distribution of the two groups (Table 2).

Table 2 Patient demographic and clinical characteristics by group
Full table

Acute postoperative complications

Complications were observed in 38/109 (34.8%) patients at 1 week postoperatively. The most common acute complication (20 patients, 18.3%) was seroma (Table 3). The rate of seroma complications at postoperative week 1 was significantly higher in the Megaderm™ group compared with the control group. However, there was no significant difference between the groups in the rate of any other complications.

Table 3 Surgical complications at 1 week postoperative
Full table

Effect on Infra-auricular depressed deformity

The appearance of the infra-auricular depressed deformity was assessed using a contouring deformity VAS and subjective satisfaction score at 3, 6, and 12 months after parotidectomy. The contouring deformity VAS of the Megaderm™ group compared with the control group was significantly lower at 3, 6, and 12 months. The subjective satisfaction scores of the Megaderm™ group were also significantly higher than in the control group at 3, 6, and 12 months after parotidectomy (Table 4).

Table 4 Visual analogue scale for the contouring deformity and subjective satisfaction scores for both patient groups
Full table

Effect on Frey’s syndrome

According to patients’ reported symptoms, 17 (15.5%), 16 (14.6%), and 12 (11%) of the 109 patients experienced Frey’s syndrome at 3, 6, and 12 months after parotidectomy, respectively. Significant decreases in the incidence and total clinician calculated Frey’s syndrome score at 3, 6, and 12 months after surgery were observed in the Megaderm™ group. However, there was no difference between groups in the patient reported Frey’s syndrome quality scores at 3, 6, and 12 months (Table 5).

Table 5 Patient evaluation of Frey’s syndrome in both groups
Full table

Effect on first bite syndrome

The Megaderm™ group reported significantly lower rates of acute pain during the past 3 months and pain VAS scores compared with those in the control group at 3, 6, and 12 months after parotidectomy (Table 6).

Table 6 Evaluation of First bite syndrome pain in parotidectomy patients in both groups
Full table

Discussion

Parotidectomy is commonly thought to be a burdensome surgery because of potential complications that adversely affect patients’ daily life. Common complications associated with parotidectomy are facial nerve injury, facial numbness, asymmetric facial contour, gustatory sweating, and postprandial facial pain (1).

Frey’s syndrome and an infra-auricular depressed deformity are two complications that may be prevented by similar methods. Frey’s syndrome occurs by the aberrant regeneration of sectioned parasympathetic fibers, which re-grow to the sympathetic nerve fibers that control the subcutaneous sweat glands and vessels. Based on the above pathophysiology, Frey’s syndrome is believed to be prevented by blocking aberrant innervations with a barrier between the skin flap and the remnant parotid tissue (6,7). Infra-auricular depressed deformity is almost always observed in total parotidectomy patients due to the loss of profuse parotid tissue. Over the years, various autologous tissue interposition methods have been reported to reduce the incidence of both Frey’s syndrome and depressed deformity (6-10). However, autologous tissue interposition has various drawbacks, such as the need for additional donor sites, increased operation time, limited donor sources, and the possibility of postoperative complications and resorption (11).

ADM was first used in full-thickness burns by Livesey et al. in 1995 (16). Since then, ADM implantation is gradually replacing autologous tissue interposition owing to the ease of trimming, variability in size and thickness, and avoidance of donor site morbidity in head and neck reconstruction (11,12). However, most studies of ADM in parotidectomy have been retrospective and observational in design. This study is significant as the first multi-center prospective trial to investigate the effect of ADM on chronic complications of parotidectomy.

In this study, the incidence and total Frey’s syndrome score following parotidectomy in the Megaderm™ group were significantly lower compared with those in the control group at 3, 6, and 12 months. Also, the objective and subjective evaluation of the facial contour showed a better outcome in the Megaderm™ implantation group compared with those in the control group at 3, 6, and 12 months.

ADM is derived from human cadaveric skin and consists of basement membrane and collagen-based connective tissue without cellular and immunogenic components (17). The main mechanisms of ADM implantation are based on fibroblast infiltration and neo-vascularization. In the application to fill dead space, it induces cellular infiltration by macrophages, finally leading to tissue generation and revascularization within the host (18). ADM has been used as an interposition barrier and tissue augmentation substitute in parotidectomy, and the type IV collagen in the dermal matrix serves to block the misconnected in-growth of the nerve fibers (19).

In this study, patients with Megaderm™ implants had less acute pain and a lesser pain VAS score during eating compared with those in the control group at 3, 6, and 12 months. One of the common complications of parotidectomy, First bite syndrome, presents as acute and sharp pain at the first mastication of a meal following parapharyngeal surgery or deep lobe parotid surgery. It is caused by loss of sympathetic innervations to the parotid gland and subsequent cross-stimulation of parasympathetic neurotransmitters released by mastication. There are several treatment options for first bite syndrome, such as medication, tympanic neurectomy, and botulinum toxin type A (BTA) injection. However, efficacy of these therapies has not been fully demonstrated. BTA intra-parotid injection has recently been introduced as the most safe and effective method for the management of first bite syndrome (20). The effectiveness is thought be due to a blockade of the neurotransmitters that induce intense myoepithelial contractions. Similarly, ADM can reduce the intensity and incidence of first bite syndrome by blockage of neurotransmitters.

Our study suggests that Megaderm™ implantation was associated with an increased rate of seroma at 1week postoperatively. The reason for this is uncertain. One hypothesis is that seroma results from a disturbance of saliva reabsorption caused by interactions with Megaderm™ and remnant parotid tissue (17). We suggest that Hemovac use is particularly important to prevent seroma with Megaderm™ implantation.

The primary limitation of this study is the low number of patients with total parotidectomy. Thus, a comparative analysis of superficial and total parotidectomy could not be performed. Moreover, the postoperative follow-up period in this study was 1 year, which may not be adequate to verify the long-term effects of Megaderm™ application and any long-term complications such as resorption and foreign body sensation. Many clinical studies have demonstrated the effectiveness of Megaderm™ for preventing infra-auricular depressed deformities and Frey’s syndrome after parotidectomy (11,12). However, this multi-center study is the first to prospectively investigate the usefulness of Megaderm™ in regard to various parotidectomy complications.

Megaderm™ implants are available in various sizes, avoid the problem of donor site morbidity, and lead to fewer complications than parotidectomy without ADM. Megaderm™ implantation in parotidectomy is a safe and effective method for preventing infra-auricular depressed deformity, Frey’s syndrome, and first bite syndrome. Megaderm™ implantation may be especially advantageous in complex parotidectomy with significant complications expected.

Acknowledgments

Funding: This study was supported by a faculty research grant of Yonsei University College of Medicine (6-2020-0144).

Footnote

Reporting Checklist: The authors have completed the CONSORT reporting checklist. Available at http://dx.doi.org/10.21037/gs-20-703

Data Sharing Statement: Available at http://dx.doi.org/10.21037/gs-20-703

Peer Review File: Available at http://dx.doi.org/10.21037/gs-20-703

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/gs-20-703). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The trial was conducted in accordance with the Declaration of Helsinki (as revised in 2013). The study was approved by the institutional review boards of Ajou University, Cheonan Soonchunhyang University, Gangnam Severance Hospital, Inha University, International St. Mary’s Hospital, Severance Hospital (No. 4-2014-0848) and informed consent was taken from all individual participants.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

References

1. Erkan AN, Yavuz H, Ozer C, et al. Quality of life after surgery for benign disease of the parotid gland. J Laryngol Otol 2008;122:397-402. [Crossref] [PubMed]
2. Grover N, D'Souza A. Facelift approach for parotidectomy: an evolving aesthetic technique. Otolaryngol Head Neck Surg 2013;148:548-56. [Crossref] [PubMed]
3. Fiacchini G, Cerchiai N, Tricò D, et al. Frey Syndrome, First Bite Syndrome, great auricular nerve morbidity, and quality of life following parotidectomy. Eur Arch Otorhinolaryngol 2018;275:1893-902. [Crossref] [PubMed]
4. Glaister DH, Hearnshaw JR, Heffron PF, et al. The mechanism of post-parotidectomy gustatory sweating (the auriculo-temporal syndrome). Br Med J 1958;2:942-6. [Crossref] [PubMed]
5. Linkov G, Morris LG, Shah JP, et al. First bite syndrome: incidence, risk factors, treatment, and outcomes. Laryngoscope 2012;122:1773-8. [Crossref] [PubMed]
6. Sanabria A, Kowalski LP, Bradley PJ, et al. Sternocleidomastoid muscle flap in preventing Frey's syndrome after parotidectomy: a systematic review. Head Neck 2012;34:589-98. [Crossref] [PubMed]
7. Clayman MA, Clayman SM, Seagle MB. A review of the surgical and medical treatment of Frey syndrome. Ann Plast Surg 2006;57:581-4. [Crossref] [PubMed]
8. Fasolis M, Zavattero E, Iaquinta C, et al. Dermofat graft after superficial parotidectomy to prevent Frey syndrome and depressed deformity. J Craniofac Surg 2013;24:1260-2. [Crossref] [PubMed]
9. Rubinstein RY, Rosen A, Leeman D. Frey syndrome: treatment with temporoparietal fascia flap interposition. Arch Otolaryngol Head Neck Surg 1999;125:808-11. [Crossref] [PubMed]
10. Liu DY, Tian XJ, Li C, et al. The sternocleidomastoid muscle flap for the prevention of Frey syndrome and cosmetic deformity following parotidectomy: A systematic review and meta-analysis. Oncol Lett 2013;5:1335-42. [Crossref] [PubMed]
11. Luo W, Zheng X, Chen L, et al. The use of human acellular dermal matrix in the prevention of infra-auricular depressed deformities and Frey's syndrome following total parotidectomy. Oral Surg Oral Med Oral Pathol Oral Radiol 2012;114:e9-13. [Crossref] [PubMed]
12. Shridharani SM, Tufaro AP. A systematic review of acelluar dermal matrices in head and neck reconstruction. Plast Reconstr Surg 2012;130:35S-43S. [Crossref] [PubMed]
13. Kim YS, Na YC, Yoon HS, et al. Short-term changes of human acellular dermal matrix (Megaderm) in a mouse model. Arch Craniofac Surg 2019;20:10-6. [Crossref] [PubMed]
14. Ye WM, Zhu HG, Zheng JW, et al. Use of allogenic acellular dermal matrix in prevention of Frey's syndrome after parotidectomy. Br J Oral Maxillofac Surg 2008;46:649-52. [Crossref] [PubMed]
15. Sachsman SM, Rice DH. Use of AlloDerm implant to improve cosmesis after parotidectomy. Ear Nose Throat J 2007;86:512-3. [Crossref] [PubMed]
16. Livesey SA, Herndon DN, Hollyoak MA, et al. Transplanted acellular allograft dermal matrix. Potential as a template for the reconstruction of viable dermis. Transplantation 1995;60:1-9. [Crossref] [PubMed]
17. Athavale SM, Phillips S, Mangus B, et al. Complications of alloderm and dermamatrix for parotidectomy reconstruction. Head Neck 2012;34:88-93. [Crossref] [PubMed]
18. Athavale SM, Rangarajan S, Dharamsi L, et al. AlloDerm and DermaMatrix implants for parotidectomy reconstruction: a histologic study in the rat model. Head Neck 2013;35:242-9. [Crossref] [PubMed]
19. May JS, McGuirt WF. Frey's syndrome: treatment with topical glycopyrrolate. Head Neck 1989;11:85-9. [Crossref] [PubMed]
20. Ghosh A, Mirza N. First bite syndrome: Our experience with intraparotid injections with botulinum toxin type A. Laryngoscope 2016;126:104-7. [Crossref] [PubMed]