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The Role of Mitomycin in the Prevention and Treatment of Scar Formation in the Pediatric Aerodigestive Tract
Friend or Foe?
Reza Rahbar, DMD, MD;
Dwight T. Jones, MD;
Roger C. Nuss, MD;
David W. Roberson, MD;
Margaret A. Kenna, MD;
Trevor J. McGill, MD;
Gerald B. Healy, MD
Arch Otolaryngol Head Neck Surg. 2002;128:401-406.
ABSTRACT
Objective To evaluate the role of mitomycin in the prevention and treatment of
scar formation in the pediatric aerodigestive tract.
Design Prospective study; institutional review board–approved clinical
trial.
Setting Tertiary care pediatric medical center.
Patients Fifteen patients; choanal atresia in 5 patients, airway stenosis in
8 patients, hypopharyngeal stenosis in 1 patient, and esophageal stenosis
in 1 patient.
Outcome The efficacy and safety of mitomycin in the prevention of scar formation.
Intervention All patients underwent surgical repair of the stenotic area, followed
by topical application of mitomycin (1 mL of 0.4 mg/mL) for 4 minutes.
Results Ten patients (67%) showed major improvement, 4 patients (27%) showed
minor improvement, and 1 patient (7%) showed no improvement.
Conclusion Topical application of mitomycin can play an effective role in the prevention
and treatment of scar formation in the aerodigestive tract.
INTRODUCTION
SCAR FORMATION and restenosis continue to be the main cause of failure
in surgical management of the choana, oropharynx, esophagus, and laryngotracheal
complex. Mucosal injury appears to be the inciting event, causing fibroblast
proliferation and collagen formation, which are key steps in the initiation
of scar formation. Modulation of wound healing and minimization of scar formation
can be effective in increasing the success rate of surgery in these areas
of the aerodigestive tract.
In the past decade, there has been a surge of interest in using pharmacological
agents for altering wound healing to prevent scar formation.1-3
Mitomycin has gained wide acceptance in the field of ophthalmology as an agent
to reduce scar formation and restenosis in conditions such as glaucoma, dacryocystorhinostomy,
and pterygium surgery.4-5
Favorable clinical responses to the topical application of mitomycin
in reducing scar formation in the larynx and trachea have been described in
previous reports.6-7 In 1998,
an institutional review board–approved prospective clinical study was
undertaken at Children's Hospital Boston to evaluate the safety and efficacy
of the topical application of mitomycin in the prevention and treatment of
scar formation in the pediatric aerodigestive tract. Three patients in this
study were described earlier7 and are herein
reviewed again with a longer follow-up.
PATIENTS AND METHODS
Fifteen patients were enrolled in an institutional review board–approved
clinical trial at Children's Hospital Boston between July 1, 1998, and December
30, 2000. Five patients presented with choanal atresia, and 10 patients presented
with stenosis in other areas of the aerodigestive tract (3 glottic, 4 subglottic,
1 trachea, 1 hypopharynx, and 1 esophagus). Informed consent was obtained
from all patients or their parents. All patients received topical application
of mitomycin at the completion of surgical repair of the stenotic area. A
10-mm neurosurgical cottonoid sponge was soaked with mitomycin (1 mL of 0.4
mg/mL) and applied to the area of repair for 4 minutes. Thereafter, the area
was irrigated with 30 mL of isotonic sodium chloride solution and suctioned
thoroughly.
RESULTS
CHOANAL ATRESIA
Five patients presented with unilateral mixed bony membranous choanal
atresia (4 on the left side and 1 on the right) (mean age, 3.4 years; range,
2-5 years). Two had undergone failed surgical repair before enrollment in
the study: patient 2 had 2 prior endoscopic transnasal approaches and patient
3 had 1. Ten procedures were performed on the 5 patients (mean, 2 per patient).
Patients 1, 2, and 3 had 2 procedures each, patient 4 had 1, and patient 5
had 3. The method of repair (transnasal vs transpalatal, with or without stenting)
was at the discretion of the primary surgeon.
Patients 1, 2, 4, and 5 underwent endoscopic transnasal repair with
topical application of mitomycin (Figure 1). Patient 3, who also had a history of CHARGE syndrome and history
of a failed transnasal approach, underwent transpalatal repair with application
of mitomycin. Stents were used in patients 1, 2, 3, and 5 for a mean duration
of 4.3 weeks (range, 2-6 weeks). These patients underwent a second procedure
for stent removal and nasal endoscopy under general anesthesia. All 4 patients
showed patent choanae without scar tissue or need for dilation. Patient 5
presented with minimal scarring 1 month after the second look, which required
dilation once. Patient 4, who had transnasal repair without stenting, underwent
nasopharyngoscopy in the office, which revealed a patent choana without scar
tissue formation. The mean follow-up for the 5 patients was 20 months (range,
11-32 months).
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Figure 1. A, Choanal atresia. B, Endoscopic
repair.
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GLOTTIC STENOSIS
Three patients presented with glottic stenosis (mean age, 7 years; range,
5-10 years). Patients 6 and 8 presented with posterior glottic stenosis. Patient
6 was born at 31 weeks' gestation and had a history of prolonged intubation
and bilateral vocal cord paralysis. She had originally undergone laryngotracheal
reconstruction (LTR) for subglottic stenosis and left arytenoidopexy for vocal
cord paralysis. This patient was tracheostomy dependent and did not tolerate
capping of the tracheostomy tube. Patient 8 had a history of prolonged intubation
because of prematurity and had undergone LTR. He re-presented with posterior
glottic stenosis, causing shortness of breath at rest. Patient 7 presented
with shortness of breath and vocal fatigue and was diagnosed as having an
anterior glottic web (Figure 2).
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Figure 2. A, Glottic web. B, Laser excision.
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All 3 patients underwent microlaryngoscopy and bronchoscopy. Patients
6 and 8 had moderate scarring at the level of the left arytenoid and interarytenoid
areas. Both underwent suspension microlaryngoscopy and partial excision of
the scarred area using a carbon dioxide laser, followed by application of
mitomycin. Because of the degree and location of stenosis, it was not possible
to completely excise the scarred areas. They have shown improvement of the
airway on follow-up endoscopy. Patient 6 continues to be tracheostomy dependent,
although she is tolerating capping of the tracheostomy tube. Patient 8 has
mild shortness of breath on exertion.
Patient 7 had a 60% anterior glottic web of 4-mm thickness. A carbon
dioxide laser was used for excision of the web, followed by application of
mitomycin (Figure 2). Follow-up
evaluation revealed a much improved glottic inlet, with only a 10% persistence
of scar in the anterior commissure. At 9 months' follow-up, there is complete
resolution of her preoperative symptoms.
SUBGLOTTIC STENOSIS
Patients 9, 10, 11, and 12 presented with shortness of breath and stridor
due to subglottic stenosis (mean age, 7 years; range, 1-15 years). All had
a history of prolonged intubation. Patients 10, 11, and 12 had a history of
LTR for subglottic stenosis. All patients underwent suspension microlaryngoscopy
and bronchoscopy. The airway size and length of stenosis were measured with
a ventilating bronchoscope or an endotracheal tube through a laryngoscope.
The preoperative subglottic stenoses were circumferential in all 4 patients
and ranged from 50% to 80% (mean, 66%), with a thickness of 4 to 8 mm (mean,
6 mm). A carbon dioxide laser was used to excise the subglottic stenosis via
radial incision and dilation, followed by topical application of mitomycin
(Figure 3).8
All patients underwent a subsequent airway endoscopy at 6 weeks and 4 months
(within 3 weeks), which showed a postoperative stenosis that ranged from 20%
to 60% (mean, 32%), with a thickness of 3 to 8 mm (mean, 5.5 mm).
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Figure 3. A, Subglottic stenosis. B, Laser
excision. C, Topical application of mitomycin. D, After surgery.
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Patients 10 and 12 had history of prolonged intubation and had undergone
LTR. Both presented with restenosis and were tracheostomy dependent before
our evaluation. Although both have shown improvement of their airways on follow-up
endoscopy, they remain tracheostomy dependent. Patient 11, with a history
of prolonged intubation and subglottic stenosis, underwent LTR and presented
with restenosis of the subglottic area. He had previously undergone 3 bronchoscopy
and dilation procedures without any improvement. He underwent carbon dioxide
laser excision of the stenotic area and mitomycin application. He responded
well and at 12 months' follow-up is asymptomatic. Patient 9 presented with
a 50% subglottic stenosis of 5-mm thickness. He responded well to carbon dioxide
laser excision and mitomycin application. Subsequently, he underwent multiple
procedures because of congenital cardiac anomalies and required a prolonged
course of intubation because of cardiac and pulmonary conditions. He is now
tracheostomy dependent due to recurrence of subglottic stenosis.
TRACHEAL STENOSIS
Patient 13, with a history of prolonged intubation because of prematurity
(26 weeks' gestation) had a 99% subglottic stenosis, for which she underwent
LTR. She presented with stridor and shortness of breath. Microlaryngoscopy
and bronchoscopy revealed a 70% tracheal circumferential stenosis of 4-mm
thickness. She underwent suspension microlaryngoscopy, and a carbon dioxide
laser was used for radial excision and dilation of the stenotic area, followed
by application of mitomycin. Follow-up endoscopy revealed a much improved
airway, with a 10% circumferential narrowing of the trachea. At 23 months'
follow-up, she has remained asymptomatic without any shortness of breath,
with or without exertion.
HYPOPHARYNGEAL STENOSIS
Patient 14 presented with hypopharyngeal stenosis. Her history was significant
for necrotizing fasciitis of the hypopharynx following a routine tonsillectomy
and adenoidectomy for obstructive sleep disorder at age 2 at another institution.
She was tracheostomy dependent and required a gastrostomy tube for nutritional
support. Following decannulation, she presented with moderate obstructive
sleep disorder due to worsening of the pharyngeal stenosis, documented by
a sleep study. She underwent carbon dioxide laser excision of the pharyngeal
scar and topical application of mitomycin. A postoperative sleep study has
shown resolution of the preoperative obstructive sleep disorder. At 19 months'
follow-up, she is doing well, with improvement of her preoperative symptoms
of snoring, restlessness of sleep, and apnea.
ESOPHAGEAL STENOSIS
Patient 15 presented with esophageal stenosis. His history was significant
for stage III rhabdomyosarcoma of the neck and base of the skull, treated
with chemotherapy and radiation. He presented with inability to swallow and
recurrent aspiration. Microlaryngoscopy and esophagoscopy revealed a 99% stenosis
of the esophagus below the cricopharyngeal level, with a 10-mm extension to
the cervical esophagus. He underwent routine dilation without any success.
Subsequently, he underwent dilation and application of mitomycin (Figure 4). He is doing well and is tolerating
liquids without difficulty. A postoperative modified barium swallow showed
normal swallowing of liquids, without aspiration.
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Figure 4. A, Near-total esophageal stenosis.
B, Retrograde dilation using a balloon dilator.
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ANALYSIS
For further analysis of our results, we used a grading classification
to describe the degree of clinical response to our protocol: "major," "minor,"
or "none." We defined success as: (1) clinical improvement on follow-up endoscopy
and (2) resolution of preoperative symptoms. If both were present, the response
was described as major; partial improvement, minor; and no improvement, none.
Analysis of our data (Table 1, Table 2, and Table 3) shows that 10 patients (67%) had major improvement; 4 patients
(27%), minor improvement; and 1 patient (7%), no improvement.
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Table 1. Characteristics of Patients With Choanal Atresia
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Table 2. Characteristics of Patients With Glottic, Subglottic, Tracheal,
Hypopharyngeal, and Esophageal Stenosis*
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Table 3. Analysis of Results
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However, it is important to point out that patients 6, 10, and 12 were
tracheostomy dependent before our evaluation. All 3 have had a complicated
medical and surgical history of their airways. Although all 3 have shown improvement
on subsequent endoscopy, we have not been able to decannulate them. Patient
6 is now tolerating capping of the tracheostomy tube.
Further analysis of our results reveals that we were able to excise
the areas of stenosis and obtain major clinical improvement in 9 patients
(patients 1, 2, 3, 4, 5, 7, 11, 13, and 14). In patients 6, 8, 10, and 12,
in whom total excision was not possible because of the degree or location
of stenosis (subglottic or posterior glottic stenosis), partial excision and
dilation were not as effective and resulted in minor improvement. Simple dilation
without excision of the area of stenosis showed major improvement only in
patient 15, who had esophageal stenosis.
COMMENT
Treatment of aerodigestive stenosis in the pediatric population remains
one of the most difficult challenges in the area of pediatric otolaryngology.
In the past decade, there has been a surge of interest in using pharmacological
agents or different surgical approaches to reduce the degree of scar formation
and increase the success rate of these surgeries.
An understanding of the basic steps of scar formation is essential in
the modulation of wound healing. Inciting events, such as mucosal injury (intubation,
trauma, and surgery), cause release of plasma proteins, blood cells, and platelets,
which react with tissue factors to form a fibrin-fibronectin clot.9 This serves as a matrix for the migration of capillaries,
fibroblasts, and inflammatory cells. Fibroblasts synthesize collagen, glycosaminoglycans,
and fibronectin to form granulation tissue. Over time, there is collagen maturation,
capillary resorption, and myofibroblast contraction, causing scar formation.9 Different agents have been used to affect wound healing
at different stages. One of the most commonly used agents is corticosteroid,
which can cause inhibition of the inflammatory response and fibroblast proliferation.
Agents such as penicillamine and beta-aminoproprionitrile have also been tried
with some success owing to their ability to inhibit cross-linking of collagen,
therefore reducing scar formation.10 In the
past decade, mitomycin has gained wide attention in the prevention of scar
formation because of its potent inhibition of fibroblast proliferation.
Mitomycin is an antibiotic produced by Streptomyces
caespitosus. It was first isolated by Wakaki and associates in 1958.11 It has antineoplastic and antiproliferative properties.
Mitomycin's antineoplastic activity is similar to that of the alkylating agents,
causing single-band breakage and cross-linking of DNA at the adenosine and
guanine molecules, therefore inhibiting RNA and protein synthesis. As an antiproliferative
agent, it can inhibit fibroblast proliferation and decrease scar formation.
In 1963, Kunitomo and Mori12 presented
the first clinical application of mitomycin for the treatment of pterygium.
Mitomycin's antiproliferative properties on fibroblasts have been shown in
vivo and in vitro.13-14 Since
the 1980s, mitomycin has gained wide acceptance as an antiscarring agent in
the field of ophthalmology and has been successfully used as an adjunct treatment
in glaucoma surgery, dacryocystorhinostomy, and optic nerve sheath fenestration.4, 15-16 Ward and April17 have shown that mitomycin can be effective in the
reduction of tracheal cicatrix and granulation tissue. Correa18
and Eliashar19 and their colleagues have shown
the efficacy of mitomycin in the prevention of subglottic stenosis in a canine
model. Rahbar and colleagues6-7
reported the first clinical use of topical application of mitomycin as an
adjuvant treatment to endoscopic carbon dioxide laser management of laryngeal
and tracheal stenosis in the pediatric and adult populations.
The exact mechanism by which mitomycin exerts an antifibroblast activity
is unknown. Studies4-7,17
have shown beneficial results using different concentrations of mitomycin
and durations of exposure. To our knowledge, there are no data indicating
what concentration, duration, or frequency of application of mitomycin is
more efficacious. In this study, we used mitomycin as an adjuvant treatment
in the surgical management of 15 patients with stenosis in different areas
of the aerodigestive tract. The dosage (1 mL of 0.4 mg/mL) and duration of
exposure (4 minutes) were chosen based on previous reports6-7
that ensured efficacy and safety, in conformity with the guidelines of the
institutional review board committee at our institution. There are certain
limitations to our study, including the lack of a control group, small number
of patients in each group, different primary surgeons, and use or lack of
use of stenting in the choana. However, this study, along with previous reports,6-7 confirms that topical application of
mitomycin can be effective in the treatment and prevention of scar formation
in the aerodigestive tract.
When considering use of mitomycin as an antiscarring agent, it is essential
to recognize its limited effect on fibroblast activity. It is clear that fibroblasts
are key players in the scarring process. Fibroblasts not only undergo proliferation
during wound healing but also cause extracellular matrix production, migration,
and contraction. Occleston and colleagues20
have shown that a single exposure to mitomycin can arrest growth and proliferation
of fibroblasts. However, they note that fibroblasts appear to continue to
express growth factors, form extracellular matrix molecules, and migrate.
This could explain why there is some scar formation and restenosis, despite
topical application of mitomycin. Also, it is imperative to consider the long-term
safety of mitomycin. There have been reports in the ophthalmology literature
of complications, such as secondary glaucoma, corneal perforation, secondary
cataract, and infection.21-22
A possible higher rate of postoperative infection is attributed to weakness
of the wound-healing phase. Although there have not been any complications
seen in our patient population at a mean follow-up of 18 months, the risk-benefit
ratio must be considered with respect to possible long-term complications.
It appears that mitomycin will be an increasingly important component
of the therapeutic armamentarium in different areas of otolaryngology. Future
work should be directed toward gaining a better understanding of its mechanism
of action and long-term safety.
AUTHOR INFORMATION
Accepted for publication September 20, 2001.
This study was presented at the American Society of Pediatric Otolaryngology,
Combined Otolaryngology Spring Meetings, Scottsdale, Ariz, May 9-12, 2001.
Corresponding author and reprints: Reza Rahbar, DMD, MD, Department
of Otolaryngology and Communication Disorders, Children's Hospital Boston,
300 Longwood Ave, Boston, MA 02115 (e-mail: reza.rahbar{at}tch.harvard.edu).
From the Department of Otolaryngology and Communication Disorders,
Children's Hospital Boston, and Department of Otology and Laryngology, Harvard
Medical School, Boston, Mass.
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