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Year : 2014  |  Volume : 27  |  Issue : 1  |  Page : 16-22

Assessment of fibroproliferative healing after functional endoscopic sinus surgery

1 Department of Otorhinolaryngology, Faculty of Medicine, Menoufia University Hospital, Shebin El-Kom, Egypt
2 Department of Pathology, Faculty of Medicine, Menoufia University Hospital, Shebin El-Kom, Egypt

Date of Submission16-Jul-2013
Date of Acceptance13-Oct-2013
Date of Web Publication20-May-2014

Correspondence Address:
Ahmed Ragab
Department of Otorhinolaryngology, Faculty of Medicine, Menoufia University, Shebin El-Kom, 32155
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/1110-2098.132296

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The aim of the present study was to assess fibroproliferative healing after endoscopic sinus surgery (ESS) by endoscopic, histopathological, and immunohistochemical (IHC) examination. The secondary objectives were to assess the correlation between fibroproliferative tissue formation and the evaluated clinical parameters.
Fibrous tissue formation is an inevitable process during wound healing after ESS that results in the formation of sinus adhesions and synechia and is reflected on patient's comfort and recovery from sinus diseases.
Materials and methods
Twenty chronic rhinosinusitis patients (12 with and eight without nasal polyposis) subjected to ESS were enrolled in the study. Patients were subjected to computed tomography and preoperative endoscopic staging of sinus disease. Patients were assessed at 2, 4, and 12 weeks postoperatively through endoscopic and tissue (histopathological and IHC) evaluation.
There is a significant increase in the degree of fibroproliferation along the three visits in the form of fibroblast and myofibroblast proliferation (H&E stain) (P = 0.001 and P < 0.001, respectively) and presence of collagen fibers (using Masson Trichrome stain) (P = 0.008), and there was a significant increase in the ͍-smooth muscle IHC score (P < 0.001). There were no associated increases in the rate of middle meatal synechia formation or middle meatal antrostomy closure during the three follow-up periods (P > 0.05).
Wound healing after functional ESS along 12 weeks is associated with microscopic fibroproliferative healing, not apparent at macroscopic levels, and is proportional to preoperative computed tomography and endoscopic and operative technique staging.

Keywords: Fibroproliferative healing, functional endoscopic sinus surgery, middle meatal synechia, wound healing

How to cite this article:
Ragab A, El-Rasheedy AL, Samaka RM, Hola NS, Hamdan A. Assessment of fibroproliferative healing after functional endoscopic sinus surgery. Menoufia Med J 2014;27:16-22

How to cite this URL:
Ragab A, El-Rasheedy AL, Samaka RM, Hola NS, Hamdan A. Assessment of fibroproliferative healing after functional endoscopic sinus surgery. Menoufia Med J [serial online] 2014 [cited 2021 Mar 3];27:16-22. Available from: http://www.mmj.eg.net/text.asp?2014/27/1/16/132296

  Introduction Top

Endoscopic sinus surgery (ESS) has become the standard treatment for the management of medically refractory chronic rhinosinusitis (CRS) with and without nasal polyposis. Wound healing and repair after such surgery is a complex overlapping multistage process by which there is tryout for favorable healing and restoration of anatomic integrity and function after injury [1]. Sometimes the healing process fails and the reparative mechanism produces pathological conditions that are commonly termed fibrosis or fibroproliferative healing (FPH). Healing with scarring can lead to restoration of integrity of tissue with some intrinsic structural differences with/without recovery of the function of sinonasal passages. In extensive scarring process with excessive FPH, impairment of structural and functional recovery can take place [2]. Hence, recognition of the scarring in disturbed wound healing in the paranasal sinuses after surgical removal of their mucosa is of particular importance with respect to the sequelae of such surgery. In addition, recognition of such abnormal healing will affect the type and time of postoperative care.

Adhesions, synechiae, and fibrosis are the classical expressions of fibroproliferative evolution of wound repair. In skin, keloid and hypertrophic scars are two disorders of FPH. In sinus mucosa, postoperative synechiae in the middle meatus are the most common apparent complications of FPH after ESS, with incidence ranging from 1 to 36% [3]. An in-depth evaluation of the troubled wound-healing focusing on the scarring process at tissue level after ESS in vivo has been almost unattainable in the literature. Such scarring process in the middle meatus can block the normal mucociliary drainage pathway of the sinuses and lead to disease recurrence and surgical failure. A better understanding of the FPH microenvironment will almost certainly lead to the development of novel interventions that can prevent, reduce, or even reverse FPH and its progression.

Hence, the aim of the present study was to assess the degree and manner of FPH after ESS: at macroscopic level by endoscopic examination and at microscopic levels by histopathological and immunohistochemical (IHC) assessments. The secondary objectives were to assess the correlation between fibroproliferative tissue formation at one hand and computed tomography (CT) scan, endoscopic staging of paranasal sinus disease, and operative technique at the other hand.

  Materials and methods Top

Twenty patients with CRS (with and without nasal polyposis) refractory to medical treatment and subjected for ESS were recruited in the present study. Patients with history of previous sinus surgery were excluded for standardization of the sinus mucosal condition. Patients with primary ciliary dyskinesia, cystic fibrosis, or underlying immunosuppressive disorders (e.g. insulin-dependent diabetes mellitus or HIV) were excluded. Patients were enrolled in the study after failure of medical treatment for 3 months. The study was approved by the ethical committee of the hospital and the patients gave informed consent.

All patients were assessed preoperatively by the Lund-Mackay CT staging of the nose and paranasal sinus [4] and by the Lund-Kennedy endoscopic score [5]. All patients underwent bilateral ESS using a mucosal sparing technique through cutting instruments while preserving the middle turbinate bilaterally. Operative technique was assessed by the Lund-Kennedy score [5].

Postoperatively, the patients were continued on antibiotics (amoxacillin-clavulanic acid) for 10 days. They were instructed for regular saline irrigation of the nasal cavities. Regular nasal suctioning and debridement were performed for all patients under local anesthesia.

Follow-up of the patients was performed at 2, 4, and 12-week intervals postoperatively. At each visit, endoscopic evaluation of the paranasal sinuses was performed using a 0° endoscopic lens with 4 mm diameter under local anesthesia (lidocaine 10%) and vasoconstrictors (xylometazoline hydrochloride 0.1%). Two parameters had a strong relationship with the extent of fibrosis; closure of middle meatus synechia and middle meatus antrostomy (MMA) was graded using the modified Lund-Mackay endoscopic score [5],[6]. Middle meatus synechia was graded for each nasal cavity as 0 = no synechia, 1 = nonobstructing synechia, and 2 = obstructing synechia. MMA closure was graded as 0 = patent MMA, 1 = partially closed MMA, and 2 = completely closed MMA.

Tissue samples were taken at each visit from inside the cavity of the anterior ethmoid. The biopsy was performed using a nasal forceps (Blakesley-Wilde nasal forceps, 45° upturned). The specimens were subjected to routine tissue processing at Pathology Department, Faculty of Medicine, Menoufia University that ended with paraffin-embedded tissues ready for sectioning for the following:

  1. Hematoxylin and Eosin (H&E)-stained slides for routine histopathological assessment of the degrees of proliferation of fibroblast and myofibroblast subjectively as mild, moderate, or severe.
  2. Masson Trichrome (MT) stain to assess the degree of fibrosis, density of collagen fibers, and orientation.
  3. Alpha smooth muscle A SMA (͍-SMA) (Clone 1A4) (Dako, Glostrup, Denmark) concentrated mouse monoclonal antibody, with a dilution of 1 : 50. ͍-SMA was used for the identification of myofibroblast. The positive control was the blood vessels.

Technique of immunohistochemical staining

Multiple 5-μm-thick sections were cut from the paraffin-embedded block, with subsequent steps of deparaffinization and dehydration in xylene and in a graded series of alcohol, respectively. Antigen retrieval was performed by boiling in 10 mmol/l citrate buffer (pH 6.0) for 20 min, followed by cooling at room temperature. The slides were incubated overnight in humidity chamber at room temperature with ͍-SMA (Clone 1A4) (Dako) concentrated mouse monoclonal antibody, with a dilution of 1 : 50. ͍-SMA was used for the identification of myofibroblast. The positive control was the blood vessels.

The Envision 1 (Dako) method was used for detection of antibodies binding. The reaction was visualized by an appropriate substrate/chromogen (diaminobenzidine) reagent with Mayer's hematoxylin as a counterstain.

Interpretation of IHC staining

For ͍-SMA scoring, we used Histoscore (H-score). According to Bilalovic et al. [7], H-score considered both the intensity and percentage of cell staining at each intensity. The score was calculated as follows:

H-score = (%3 + cells × 3) + (%2 + cells × 2) + (%1 + cells × 1)

Statistical methods

Data were collected, tabulated, and statistically analyzed using statistical package for the social science program for windows, version 17 (SPSS Inc., Chicago, Illinois, USA). To test whether these variables differed according to clinicopathological parameters and biological markers, the Pearson χ2 -test, the Wilcoxon test, and the McNemar test were performed. The Spearman correlation coefficients were used for correlation between numeric variables on an ordinal ranked scale. The correlation was expressed on a scale of 0-1, where 0.9 indicates strong correlation, 0.8 fairly strong correlation, 0.7 moderate correlation, and 0.6 indicates fairly weak correlation. All P-values were two sided; P-values of less than 0.05 were considered statistically significant and of less than 0.01 were considered highly significant.

  Results Top

Twenty patients were included in the present study: 12 male patients (60%) and eight female patients (40%) with age ranging from 22 to 43 years and mean age of 31.7 years ± 5.57 SD. The study included 12 CRS patients with nasal polyposis and eight CRS patients without nasal polyposis. Preoperative Lund-Mackay score for CT scanning had a mean of 12.35 ± 3.33 SD. The Lund-Kennedy endoscopic score for sinus disease had a mean of 7.7 ± 1.26 SD. Intraoperative Lund-Kennedy score for operative technique had a mean of 9.7 ± 1.34 SD [Table 1].
Table 1: Preoperative and operative assessment of the studied group

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On endoscopic assessment with the specified postoperative care along 12 weeks postoperative, there was a significant decrease in the rate of synechia development from 2 to 12 weeks (P = 0.014) [Table 2]. MMA closure did not show any differences between 2 and 12 weeks postoperatively [Figure 1].

On histopathological assessment using H&E staining, there were significant increases in the grade of fibroblast and myofibroblast proliferations from 2 to 12 weeks (P = 0.001 and P < 0.001, respectively) [Figure 2],[Figure 3],[Figure 4] and [Figure 5] and [Table 3]. Using Masson Trichrome staining, there was a significant increase in the presence of collagen fibers from 2 to 12 weeks (P = 0.008) [Table 4]. There were no differences in the orientation of collagen fibers between the three visits [Figure 6] and [Figure 7]. On ͍-SMA staining, there was a significant increase in ͍-SMA H-score from 2 to 12 weeks (P < 0.001) [Figure 8],[Figure 9] and [Figure 10] and [Table 5].
Figure 1:

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Figure 2;

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Figure 3:

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Figure 5:

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Figure 7:

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Figure 8:

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Figure 9:

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Figure 10:

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Table 2: Comparison between middle turbinate synechia, middle meatal antrostomy closure, and total POSE score at 2, 4, and 12 weeks postoperatively

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Table 3: Comparison between fibroblast and myofibroblast proliferations as detected by H&E staining at 2, 4, and 12 weeks postoperatively

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Table 4: Comparison between collagen fibers status at 2, 4, and 12 weeks postoperatively by MT staining

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Table 5: Comparison between á-SMA H-score at 2, 4, and 12 weeks postoperatively

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Table 6: Correlation between preoperative and operative factors and á-SMA H-score at 12 weeks postoperatively

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On analyzing the correlation between preoperative CT, the endoscopic staging systems and operative factors, and the ͍-SMA H-score at 12 weeks, there was strong positive correlation between the Lund-Mackay CT score and ͍-SMA H-score at 12 weeks (R = 0.99). In addition, preoperative Lund-Kennedy score of sinus disease and operative Lund-Kennedy score for operative technique had strong positive correlation with ͍-SMA H-score at 12 weeks (R = 0.94 and 0.89, respectively) [Table 6].{Table 6}

  Discussion Top

Wound healing is a highly organized process, involving inflammation, cell proliferation, matrix deposition, and remodeling, and it is regulated by a wide variety of growth factors [2]. Any derangement in the process of healing may result in the formation of hypertrophic scar or impaired tissue differentiation, thus reducing the functioning capacity of the organ involved. Healing defects of the respiratory mucosa regularly lead to development of synechia, infection, or obstructing scar formation, making revision surgery necessary [8].

In the current study, both middle turbinate synechia and MMA closure showed a significant increase in healing during the first month but both showed decreased healing during the next 2 months along with normal re-epithelialization. Xu et al. [9] observed the morphological characteristics of sinus cavity mucosa after functional endoscopic sinus surgery (FESS). In their study [9], over 90% of the nasal and sinus cavities were cleaned within 1-2 weeks, over 80% of the operative cavities experienced a reaction to mucosa removal or regenerative diseases within 3-10 weeks, such as mucosal edema, vesicles, granulation tissue, mini polyps, fibrous hyperplasia, and adhesion, which competed against the mucosa epithelialization process [9]. In the same study after careful treatment, 90% of the nasal and sinus cavities finished epithelialization, and 60% of them completed epithelialization within 11-14 weeks after operation [9].

In the current study, an increase in the degree of fibroproliferation was detected histologically by the presence of fibroblasts and myofibroblasts (H&E stain), collagen fibers (Masson Trichrome stain), and more accurate detection of myofibroblast (IHC of ͍-SMA) that upraised during the first 3 months after FESS. Sinonasal mucosal wound-healing patterns following surgery were studied by Benninger et al. [10] in rabbits, 10 weeks after maxillary sinus mucosa removal. An increase in inflammation, scarring, fibrous bands, and mucous viscosity was noted after mucosal stripping, and these findings were confirmed histologically. A similar study [11] also showed a decrease in the size of the operated maxillary sinus owing to increased scarring, fibrosis, and bone degradation. Epithelialization was noted 2 weeks after mucosal injury; however, the lamina propria was far from healing.

Watelet et al. [12] studied histopathological changes in six controls and 14 patients with CRS with or without nasal polyposis before and after functional ESS. They found a significant decrease in fibrosis at the first month (H&E stain). In addition, fibrosis appeared to be increased in months 2 and 6 when compared with month 1. A stabilization in the fibrosis formation was observed between month 2 and month 6. ͍-SMA was found to be increased between month 1 and month 2. The amount of ͍-SMA-positive cells remained stable between month 2 and month 6, and the same difference was observed between month 1 and month 6.

Several studies tried to evaluate the impact of preoperative and operative factors on the postoperative outcomes of FESS. In the present study, the authors found a significant relationship between CT, endoscopic and operative scores, and the degree of fibrosis 3 months postoperatively as represented by ͍-SMA H-score. These results can be explained on clinical background as evidenced with a significant relationship between the clinical (CT and endoscopic) extent of CRS and the surgical outcome [13]. In addition, Sharp et al. [14] identified that the results of ESS in patients with CRS were related to the Lund-Mackay CT score system.

The present results reveal the need for introduction of the anti-FPH maneuvers to decrease the rate of postoperative fibrosis in patients with CRS with or without nasal polyposis (after ESS), whether or not it is associated with synechia and/or sinus ostium closure. These maneuvers may include mucosal sparing techniques, the application of nasal packing and stenting, the administration of topical fibrinolytic agents such as mitomcin C, and the use of intranasal corticosteroids. This eventually needs further study and investigation.

  Conclusion Top

Wound healing after functional ESS along 12 weeks is associated with microscopic FPH, not apparent at macroscopic levels, which is proportional to preoperative CT and endoscopic and operative technique staging.

  Acknowledgements Top

Conflicts of interest

None declared.

  References Top

1.Sun X, Wang D, Yu H, Hu L. Serial cytokine levels during wound healing in rabbit maxillary sinus mucosa. Acta Otolaryngol 2010; 130:607-613.  Back to cited text no. 1
2.Watelet J, Bachert C, Gevaert P, Van Cauwenberge P. Wound healing of the nasal and paranasal mucosa: a review. Am J Rhinol 2002; 16:77-84.  Back to cited text no. 2
3.Numthavaj P, Tanjararak K, Roongpuvapaht B, McEvoy M, Attia J, Thakkinstian A. Efficacy of mitomycin C for postoperative endoscopic sinus surgery: a systematic review and meta-analysis. Clin Otolaryngol 2013; 38:198-207.  Back to cited text no. 3
4.Lund VJ, Mackay IS. Staging in rhinosinusitus. Rhinology 1993; 31:183-184.  Back to cited text no. 4
5.Lund VJ, Kennedy DW. Quantification for staging sinusitis. The staging and therapy group. Ann Otol Rhinol Laryngol Suppl 1995; 167:17-21.  Back to cited text no. 5
6.Fishman JM, Sood S, Chaudhari M, Martinez-Devesa P, Orr L, Gupta D. Prospective, randomised controlled trial comparing intense endoscopic cleaning versus minimal intervention in the early post-operative period following functional endoscopic sinus surgery. J Laryngol Otol 2011; 125:585-589.  Back to cited text no. 6
7.Bilalovic N, Sandstad B, Golouh R, Nesland JM, Selak I, Torlakovic EE. CD10 protein expression in tumor and stromal cells of malignant melanoma is associated with tumor progression. Mod Pathol 2004; 17:1251-1258.  Back to cited text no. 7
8.Pajiæ-Penaviæ I. Endoscopic monitoring of postoperative sinonasal mucosa wounds healing. In: Cornel I Advances in endoscopic surgery. Rijeka: InTech Open Access publisher 2011; 419-436.  Back to cited text no. 8
9.Xu G, Jiang H, Li H, Shi J, Chen H. Stages of nasal mucosal transitional course after functional endoscopic sinus surgery and their clinical indications. J Otorhinolaryngol Relat Spec 2008; 70:118-123.  Back to cited text no. 9
10.Benninger MS, Schmidt JL, Crissman JD, Gottlieb C, et al. Mucociliary function following sinus mucosal regeneration. Otolaryngol Head Neck Surg 1991; 105:641-648.  Back to cited text no. 10
11.1Forsgren K, Stierna P, Kumlien J, Carlsoo B. Regeneration of maxillary sinus mucosa following surgical removal. Annals of Otology, Rhinology and Laringology 1993; 102:459-466.  Back to cited text no. 11
12.1Watelet JB, Demetter P, Claeys C, Cauwenberge P, Cuvelier C, Bachert C. Wound healing after paranasal sinus surgery: neutrophilic inflammation influences the outcome. Histopathology 2006; 48:174-181.  Back to cited text no. 12
13.1Kennedy DW. Prognostic factors, outcomes and staging in ethmoid sinus surgery. Laryngoscope 1992; 102:1-18.  Back to cited text no. 13
14.1Sharp HR, Rowe-Jones JM, Mackay IS. The outcome of endoscopic sinus surgery: correlation with computerized tomography score and systemic disease. Clin Otolaryngol 1999; 24:39-42.  Back to cited text no. 14


  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6], [Figure 7], [Figure 8], [Figure 9], [Figure 10]

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6]


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