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 Table of Contents  
ORIGINAL ARTICLE
Year : 2020  |  Volume : 4  |  Issue : 2  |  Page : 262-268

Effect of topical application of mitomycin-c as an adjuvant treatment of laryngotracheal stenosis


1 Department of Otorhinolaryngology, Faculty of Medicine, Al-azhar University, Cairo, Egypt
2 Department of Lecturer of Otorhinolaryngology, Faculty of Medicine, Al-azhar University, Cairo, Egypt
3 Department of Radiology, Faculty of Medicine, Al-Azahar University, Cairo, Egypt

Date of Submission28-Feb-2020
Date of Decision23-Mar-2020
Date of Acceptance29-Mar-2020
Date of Web Publication29-Jun-2020

Correspondence Address:
Mohamed K Al Awady
Lecturer of Deprtament of Otorhinolaryngology, Faculty of Medicine, Al-Azahar University, El Moktom, Cairo
Egypt
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/sjamf.sjamf_32_20

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  Abstract 


Background Laryngotracheal stenosis (LTS) has become more frequent because of prolonged endotracheal intubation (PEI). The endoscopic treatment of LTS is often associated with high recurrence rate owing to excessive fibrosis. Mitomycin-c (MMC) inhibits fibroblast proliferation, so it is used at the time of endoscopic dilation to improve outcomes.
Objective The aim was to assess the effect of application of topical MMC in the treatment of LTS to prevent recurrence of stenosis.
Patients and methods A prospective study was carried out on 20 patients with LTS subjected to endoscopic dilatation. All patients were divided to two groups: group A (case group) included 10 patients with LTS who were subjected to endoscopic dilatation with topical application of MMC (0.5 mg/ml), and group B (control group) included 10 patients with LTS who were subjected to endoscopic dilatation without topical application of MMC. A neck computed tomography scan was done for all patients to detect the site and length of stenotic area.
Results In group A, LTS was due to PEI in six (30%) patients, due to laryngoscleroma in three (30%) patients, and due to Wegener’s granulomatosis in one (10%) patients, whereas in group B, it was due to PEI in four (40%) patients, due to rhinoscleroma in four (40%) patients, and due to Wegener’s granulomatosis in two (2%) patients. The most common site of stenosis was subglottic and trachea in both groups. Most of the patients in case group ended up with grade 2 dyspnea (mild dyspnea with no limitation to daily activities), whereas three patients in control group achieved this outcome, with a statistically significant difference (P=0.043). None of the patients in the case group developed postoperative stridor 6 months after surgery, compared with four patients in the control group.
Conclusion Topical application of MMC as an adjuvant treatment for endoscopic management of LTS has shown good results, low recurrence rate, and high success rate.

Keywords: endoscopic dilation, laryngotracheal stenosis, mitomycin-c (MMC) application


How to cite this article:
Al Awady MK, El-Morsy MA, Refaat OM, Tawfik MH. Effect of topical application of mitomycin-c as an adjuvant treatment of laryngotracheal stenosis. Sci J Al-Azhar Med Fac Girls 2020;4:262-8

How to cite this URL:
Al Awady MK, El-Morsy MA, Refaat OM, Tawfik MH. Effect of topical application of mitomycin-c as an adjuvant treatment of laryngotracheal stenosis. Sci J Al-Azhar Med Fac Girls [serial online] 2020 [cited 2020 Oct 26];4:262-8. Available from: http://www.sjamf.eg.net/text.asp?2020/4/2/262/288276




  Introduction Top


Laryngotracheal stenosis (LTS) has become more frequent because of the prolonged endotracheal intubation (PEI) associated with mechanical ventilation and the development of reanimation measures in intensive care units [1]. The stenosis process begins with mucosal edema and ulceration, which are often associated with local infection. Afterward, the infection of the cartilage can damage tracheal cartilage, and increased fibroblastic activity generates retractile fibrous tissue that causes stenosis and airway obstruction [2].

LTS due to granulomatous disease of the upper respiratory tract such as by laryngoscleroma and Wegener’s granulomatosis usually affects the subglottic region and upper trachea, resulting in various degrees of stenosis. Patients with LTS may present with stridor, shortness of breath, or exercise intolerance and may be tracheostomy dependent [3],[4].

Tracheal reconstruction requires major surgery, with a mortality rate of ∼3%. Rigid bronchoscopy with tracheal dilatation and stenting has been described as some of the treatment methods for less serious lesions [5],[6].

The endoscopic treatment of LTS by rigid dilatation, despite short-term improvement, is often associated with long-term relapse. Recurrence is common because of excessive granulation tissue formation and an insidious process of scar [7],[8].

Mitomycin is an antimitotic drug that inhibits in-vitro fibroblast proliferation and can prevent the formation of scars and fibrosis in humans [9]. Mitomycin-c (MMC) inhibits fibroblast proliferation and synthesis of extracellular matrix proteins, and thereby modulates wound healing and scarring. MMC application at the time of endoscopic dilation has been suggested to improve outcomes [10],[11].


  Objective Top


The objective was to assess the effect of application of topical MMC in the treatment of LTS to prevent recurrence of stenosis.


  Patients and methods Top


A prospective study was carried out on 20 patients with LTS undergoing an endoscopic rigid dilation or laser dilation procedures with or without topical application of MMC (0.5 mg/ml) to the airway stenosis at Al-Azhar University Hospitals and others ENT hospitals in period between august 2016 to march 2018. This study was approved by Medical Ethical Committee. All patients were informed, and a written consent was obtained from all patients. This study included 20 cases, comprising five (25%) female and 15 (75%) male, ranging in age from 10 to 60 years, with a mean of 35 years.

Inclusion criteria

The following were the inclusion criteria:
  1. LTS due to PEI.
  2. LTS due to laryngoscleroma, Wegener’s granulomatosis, or autoimmune diseases.
  3. LTS not associated with cartilage damage and less than 3 cm in length (thickness).


Exclusion criteria

The following were the inclusion criteria:
  1. LTS associated with cartilage damage or greater than 3 cm in length (thickness).
  2. Supraglottic stenosis or congenital laryngeal stenosis.


All patients were divided to two groups:

Group A (case group) included 10 patients with LTS who were subjected to endoscopic rigid dilatation with topical application of MMC (0.5 mg/ml) to the stenotic segment after dilatation. Group B (control group) included 10 patients who were subjected to an endoscopic rigid dilatation without topical application of MMC (0.5 mg/ml) to the stenotic segment.

Preoperative evaluations

Complete laryngeal history regarding changes of voice, shocking, aspiration, and degree of dyspnea according to dyspnea symptom scale ([Table 1]) was comparable in both groups.
  1. Neck computed tomography scan was done for all patients to detect the site and length of stenotic area and grade of airway stenosis and to confirm the presence of a short-segment tracheal stenosis less than 3 cm ([Figure 1] and [Figure 2]).
    Figure 1 Sagittal and coronal cut of neck computed tomography scan showing subglottic stenosis of granulomatous stage of laryngoscleroma.

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    Figure 2 Neck computed tomography scan showing of laryngotracheal stenosis owing to prolonged endotracheal intubation of patient having tracheostomy.

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  2. Videostroboscopy or fiber-optic endoscopic laryngeal examination was done to assess the vocal cord mobility and detect the site of stenosis and exclude other laryngeal lesions ([Figure 3] and [Figure 4]).
    Figure 3 Endoscopic view of subglottic stenosis owing to laryngoscleroma shows granulation tissue.

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    Figure 4 Endoscopic view subglottic stenosis owing to prolonged endotracheal shows web-like stenosis.

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Table 1 Dyspnea symptom scale [4]

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Operative technique

Under general anesthesia, at first, the airway was examined with a magnifying 0 telescope to detect the site of stenosis ([Figure 5]), and then an endoscopic rigid dilation was done. Pledgets soaked with diluted MMC (concentration 0.5 mg/ml) were prepared and were ready to be used after dilatation ([Figure 6]).
Figure 5 Direct laryngoscopic under general anesthesia showing the airway was examined with magnifying before dilatation.

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Figure 6 Pledgets soaked with diluted mitomycin C (concentration 0.5 mg/ml).

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Rigid forceps were used to remove the necrotic tissues if present and then different sizes of Bougie dilators were used to dilate the stenotic area in incremental size to a final size of 1 cm ([Figure 7]). In the case group, pledgets soaked with diluted MMC (concentration 0.5 mg/ml) were introduced using rigid forceps through the rigid laryngoscope to the raw surface of the mucosa, and direct pressure was applied via the rigid forceps ([Figure 8]). Pressure was applied for 2 min until blanching of the mucosa was seen. The procedure was repeated circumferentially until all mucosa was treated. Hemostasis was then secured with pledgets soaked with adrenaline.
Figure 7 Endoscopic rigid dilatation of subglottic stenosis by different sizes of Bougie dilators.

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Figure 8 Pledget soaked with mitomycin C applied via rigid forceps to the stenotic area.

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Some patients were subjected to another sitting of endoscopic rigid dilatation procedures over 1-month or 2-month interval. Two factors were used to determine the need for further treatment and another sitting of dilatation: endoscopic office-based laryngotracheal appearance of the airway and patient’s subjective airway symptoms.

Follow-up and assessment

All patients were followed up every 2 months for up to 1 year by endoscopic office-based laryngotracheal appearance of the airway for relapse of airway stenosis with clinical symptoms sufficient to require another sitting or subsequent procedure.

Office laryngoscopy was carried out regularly for the assessment of the laryngeal airway and documenting laryngeal healing. The presence of any granulation, laryngeal scarring, or restenosis was recorded.


  Results Top


Group A (case group) included 10 patients with LTS, comprising seven (70%) males and three (30%) females, whereas in group B (control group), there were 10 patients, including eight (80%) males and two (20%) females. The age of patients ranging from 10 to 60 years. There were no statistically significant differences between both groups regarding age and sex.

In this study, regarding the etiology of LTS, in group A, it was owing to PEI in six (60%) patients, owing to laryngoscleroma in three (30%) patients, and owing to Wegener’s granulomatosis in one (10%) patients, whereas in group B, it was owing to PEI in four (40%) patients, owing to laryngoscleroma in four (40%) patients, and owing to Wegener’s granulomatosis in two (20%) patients ([Table 2]).
Table 2 Etiology of laryngotracheal stenosis in both groups

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In this study, regarding the site of stenotic segment, in group A, the site of stenosis was in the glottic region in four (40%) patients, in subglottic (SG) region alone in two (30%) patients, and SG and tracheal in four (40%) patients, whereas in group B, the site of stenosis was in glottic region in three (30%) patients, in subglottic (SG) region alone in two (20%) patients, and in SG and tracheal in five (50%) patients. We found the most common site of LTS is both subglottic and tracheal in each group, with statistically significant differences between SG alone and both sites (SG and tracheal) (P<0.05 and χ2=5.401, [Table 3]).
Table 3 Site of stenotic segment in both groups

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Preoperative dyspnea symptom scale

The severity of dyspnea was evaluated in the preoperative and postoperative periods by means of a five-level symptom scale, reflecting the limitation in daily activity ([Table 1]).

All patients were evaluated regarding degree of dyspnea according to dyspnea symptom scale ([Table 1]). Preoperative dyspnea and postoperative improvement was comparable in both groups.

Regarding preoperative dyspnea symptom scales, in group A, five patients had a previous tracheotomy, and the remaining five patients had less dyspnea and managed their everyday activities without tracheotomy. However, in group B, four patients had a previous tracheotomy, and the remaining six patients had less dyspnea and managed their everyday activities without tracheotomy. There was no statistically significant difference between both groups in preoperative dyspnea symptom scale (χ2=23.98 and P=0.0895) ([Table 4]).
Table 4 Preoperative dyspnea symptom scale in case and control groups

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Postoperative dyspnea and decannulation

Regarding postoperative dyspnea symptom scales, most patients in the MMC group ended up with grade 2 dyspnea (mild dyspnea with no limitation to normal everyday activities) (6 of 10 patients), whereas only a third of the control group achieved this outcome (3 of 10 patients), with a statistically significant difference in postoperative symptom dyspnea scale of the study and control groups (χ2=6.21, P=0.043) ([Table 5]).
Table 5 Postoperative dyspnea symptom scale in case and control groups

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None of the patients in case group developed postoperative stridor 6 months after the surgery, compared with two patients in the control group. Two patients from the control group needed tracheotomy in the postoperative period because of the development of granulation, scarring, and restenosis.

Of the 10 patients in case group, five patients had a previous tracheotomy. All five patients were successfully decannulated within 16 weeks (median, 5 weeks). Of the remaining five patients, one had a revision surgery for restenosis and none required tracheotomy. On the contrary, of the 10 patients in the control group, four patients had a previous tracheotomy, whereas six patients had no preoperative tracheotomy. Decannulation failed in one patient despite revision surgery. Two patients required temporary postoperative tracheotomy. There were no postoperative complications in either group ([Table 5]).

All patients were followed every 2 month for up to 2 years for relapse of airway stenosis with clinical symptoms sufficient to require another sitting or subsequent procedure. We found that in group A, after 2 months, six (60%) patients improved after one sitting of MMC applications, whereas four (40%) patients developed dyspnea and stridor 3–6 months postoperatively owing to the recurrence of airway stenosis and subjected to a second endoscopic dilation with application of MMC. These patients improved after the second sitting. However, in group B, after 1 or 2 months, nine (90%) patients developed dyspnea and stridor owing to recurrence of airway stenosis. All of them were subjected to endoscopic second dilation. Five of them (50%) improved after second sitting, whereas other four (40%) patients did not improve, so these four patients were subjected to a third sitting of endoscopic dilation procedure 2 months later with MMC application ([Table 6]).
Table 6 Airway improvement after surgical sitting

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  Discussion Top


The optimal treatment of LTS remains undefined. Traditionally, LTS has been managed by thoracic and otorhinolaryngology surgeons. Endoscopic procedures are usually performed as a bridge to definitive surgical intervention. With the development of surgical intervention in the last 20 years, definitive management of LTS using minimally invasive endoscopic methods became a possibility [12].

One of the main drawbacks of endoscopic treatment and surgery is the risk of recurrence of trachea stenosis owing to granulation and fibrotic tissue. Studies have shown that most of the recurrence of tracheal stenosis occurs within 1–3 months after the procedure [13].

In this study, we have found that MMC is beneficial in preventing excessive scarring after endoscopic rigid dilatation.

This is similar to Spector et al. [14], who used topical MMC to decrease granulation tissue formation after endoscopic CO2 laser dilatation PEI and prevention of subsequent restenosis and scar formation in the larynx. Moreover, Laccourreye and colleagues reported a 92% decannulation rate of tracheostomy tube with the use of topical MMC after endoscopic CO2 laser dilatation in 25 patients having LTS owing to PEI.

In this study, the most common site of LTS is both subglottic and tracheal in each group, with statistically differences between SG alone and both sites (SG and tracheal) (P<0.05 and χ2=5.401).

This is similar to the results of Simpson et al. [15], who applied endoscopic dilatation to LTS involving many lesions of the larynx and trachea and found the most common site of postintubation stenosis is both subglottic and trachea. They demonstrated successful management of subglottic and tracheal stenosis using endoscopic dilation.

Moreover, Duncavage et al. [16], have three studies were retrospective studies comparing the different treatment modalities done at different times. These included CO2 laser and dilation alone, CO2 laser dilation and steroid injection, and CO2 laser dilation and MMC application. A study of 47 patients included various combinations of laryngeal and LTS. ‘Success’ was defined as the absence of symptom recurrence after surgical treatment, although no time interval definition was mentioned. Some patients required ‘fine-tuning’ procedures and were included as a ‘success.’ Three of the 20 patients treated by CO2 laser alone, 2 of 11 with laser and steroid, and 12 of 16 with laser and MMC were ‘success.’ The average follow-up was 25.2 months, with some as low as 5 months. This may not be a sufficient time interval to adequately assess the outcomes of these procedures.

Moreover, Perepelitsyn and colleagues and Simpson and colleagues, conducted their retrospective study on 36 patients. Patients were divided into endoscopic treatment alone and endoscopic treatment plus MMC. Overall, nine patients had endoscopic treatment plus MMC. Of the 29 patients treated with laser/dilation and 0.4 mg/ml MMC, 20 were symptom free after one treatment during a follow-up period. In the tracheostomy patients, four of seven (57%) were decannulated after one treatment [17].

In this study, recurrence rate after one applications of mitomycin is 40% and no recurrence after second applications in the short-term follow-up. This is similar to the results of Marshall and colleagues who stated that long-term recurrence rates are consistent with reported rates of 40–70%. Their study demonstrated that using the protocol of two applications of MMC reduces the rate of symptomatic airway restenosis over the first several years compared with one application [18].

These results emphasize the importance of long-term assessment of these patients. 1- or 2-year outcomes do not sufficiently describe the results of treatment of LTS, given the known natural history of this disease process. These results suggest a beneficial effect of reapplication of MMC after the 3-week interval at which the first application of MMC has worn off. The effect of MMC on fibroblast activity lasts for about 3 weeks. The suppression of fibroblast activity allows additional time for epithelialization in an effort to reduce contracture. MMC delays the wound-healing response but does not entirely suppress it [19]


  Conclusion Top


The endoscopic management of LTS is appropriate as a first-line treatment. MMC application at the time of endoscopic dilation has been approved to reduces granulation tissue formation and fibrosis and improve outcomes. The use of MMC in reducing the need or frequency of airway dilation procedures is effective. Moreover, topical application of MMC as an adjuvant treatment for endoscopic management of stenosis has shown good results, low recurrence rate, and high success rate.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

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Spector JE, Werkhaven JA, Spector NC, Huang S, Page RN, Baranowski B et al. Preservation of function and histologic appearance in injured glottis with topical mitomycin-C. Laryngoscope 1999; 109(7 Pt 1):1125–1129.  Back to cited text no. 14
    
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Simpson GT, Strong MS, Healy GB, Shapshay SM, Vaughan CW. Predictive factors of success or failure in the endoscopic management of laryngeal and tracheal stenosis. Ann Otol Rhinol Laryngol 2006; 91:384–388.  Back to cited text no. 15
    
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    Figures

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

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



 

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