(Chest. 2001;120:2103-2105.)
© 2001
American College of Chest Physicians
Mitomycin C for Control of Recurrent Bronchial Stenosis*
A Case Report
Anne-Catherine Erard, MD;
Philippe Monnier, MD;
Anastase Spiliopoulos, MD and
Laurent Nicod, MD
*
From the Divisions of Pneumology (Drs. Erard and Nicod) and Thoracic Surgery (Dr. Spiliopoulos), University Hospital of Geneva, Geneva, Switzerland; and the Division of Otolaryngology (Dr. Monnier), University Hospital of Vaud, Lausanne, Switzerland.
Correspondence to: Laurent Nicod, MD, Division of Pneumology, University Hospital, 1211 Geneva, Switzerland; e-mail: Laurent.Nicod{at}hcuge.ch
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Abstract
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A 27-year-old patient with cystic fibrosis underwent a bilateral
lung transplantation despite the presence of multiresistant
Burkholderia cepacia. Postoperatively, the patient
presented with bilateral bronchial necrosis. During the 14th week, his
FEV1 dropped to 2.5 L from a baseline level of 3.4 L. A
subtotal occlusion of the right mainstem bronchus below the suture was
noted. Using argon electrocoagulation, the right upper lobe bronchus,
the intermediate bronchus, and the right middle lobe bronchus were
reopened. During the period between weeks 20 and 42
post-transplantation, a recurrent stenosis required eight endoscopic
interventions combining dilatation and stenting. During the 42nd week,
dilatation followed by mitomycin C application stabilized the right
lung function. This case report is the first to describe the
effectiveness of the local application of mitomycin C to stop recurring
extensive bronchial stenosis following bronchial necrosis secondary to
lung transplantation.
Key Words: airway complications • granulation tissue • lung transplantation • mitomycin C • stent
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Introduction
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Ischemia
-related bronchial dehiscence or strictures of the bronchi in the donor
lung have been described as complications after lung transplantation.
Following ischemia, airway obstruction may occur because of granulation
tissue, infection, or bronchomalacia, and this represents a significant
source of morbidity.1
Airway stenosis at the bronchial
anastomosis may lead to increased morbidity. Depending on the nature of
the strictures, specific therapies may be required.2
The
most challenging stenoses are those related to extended necrosis with
severe cartilage damage, followed by intraluminal granulation tissue,
because of their high rate of recurrence.
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Case Report
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In July 1998, a 27-year-old patient with cystic fibrosis
underwent a bilateral lung transplantation despite bronchial
colonization with multiresistant Burkholderia cepacia.
Postoperatively, the patient developed bilateral necrosis of the
bronchial mucosa without strictures but with B cepacia
colonization. Antimicrobial therapy was started and continued for 3
months. Tacrolimus, mycophenolate mofetil, and prednisone were used for
immunosuppression. At 14 weeks post-transplantation, the patient
complained of exertional dyspnea and his FEV1
dropped by 26% from 3.4 L (75% of predicted) to 2.5 L (56% of
predicted). Bronchoscopy revealed strictures of the right upper lobar
bronchus (90%), the intermediate bronchus (80%), and the left main
bronchus (40%) that were related to granulation tissue (Fig 1
, left, A).
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Figure 1.. Left, A: 14 weeks
post-transplantation, the right upper lobar bronchus (arrow) and the
intermediate bronchus (arrowhead) are shown with 90% and 80%
strictures, respectively. Middle, B: 42
weeks post-transplantation, the right upper lobar bronchus with stent
(arrow) and a subocclusion of the intermediate bronchus (arrowhead) are
shown. Right, C: 96 weeks
post-transplantation, after mitomycin C therapy, the upper lobar
bronchus (arrow) with a Wallstent and the intermediate bronchus
(arrowhead) are shown with residual 30% strictures.
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Electrocoagulation with an argon laser (Deltamed, AG; Winterthur,
Germany) reopened the strictures of the right lung. The left main
bronchus was not treated. Following a concurrent A2 rejection,
treatment with thymoglobulin (Merieux; Lyon, France) was
initiated and immunosuppression was intensified. Antimicrobial therapy
was continued. Between the 20th and the 42nd weeks
post-transplantation, the strictures recurred, always associated with
exertional dyspnea, and they required eight endoscopic interventions
(ie, dilatation and stenting). Variable decreases of the
FEV1 were noted each time, with the lowest
FEV1 value at 2.07 L. Ultimately, a Wallstent
(diameter, 9 mm; length, 10 mm) [Boston Scientific, Natick, MA] and a
Palmaz stent (diameter, 9 mm; length, 15 mm) [Corning/Johnson and
Johnson; Warren, NJ] were placed in the right upper lobar bronchus, a
Nitiniol stent (diameter, 10 mm; length, 15 mm) [Microvasire, Boston
Scientific; Natick, MA] was placed in the intermediate bronchus, and a
Wallstent (diameter, 12 mm; length, 20 mm) was placed between the
intermediate and main bronchi (Fig 2
). All stents were uncoated. The middle lobar bronchus, which had
previously been reopened with an argon laser, was definitively
occluded. At 42 weeks post-transplantation, despite the various stents,
the FEV1 dropped from 3.62 L (81% of predicted)
to 3.08 L (69% of predicted). Bronchoscopy showed that the right upper
lobar and intermediate bronchi once again were suboccluded by the
proliferation of granulation tissue through the stents with a residual
lumen just large enough to introduce dilators of 1 to 2 mm (Fig 1
,
middle, B). No infection or colonization was
present.
A last attempt to save the function of the right lung using a topical
application of mitomycin C, a drug known to inhibit fibroblast
proliferation, was attempted following dilatation. A cotton swab
soaked in a solution of 2 mg/mL mitomycin C was applied topically on
the granulation tissue of the upper and intermediate bronchi for 2 min.
Following this procedure, the FEV1 increased to
4.18 L (95% of predicted) on the 48th week, and the patient’s
symptoms resolved. Six months later (ie, at 77 weeks
post-transplantation), the patient was still symptom-free and his
FEV1 level was stable. However, a 40% residual
stricture of the intermediate bronchus that was visualized during an
elective bronchoscopy was once again dilated and treated with mitomycin
C to prevent restenosis. Furthermore, a concurrent rejection was
treated with thymoglobulin (Merieux), and a Pseudomonas
aeruginosa colonization was treated with antimicrobial therapy. At
96 weeks post-transplantation, the spirometric values remained stable
(FEV1, 4.11 L [94% of predicted]), and a
control bronchoscopy showed a favorable result without any progression
of the strictures of the intermediate and right upper lobar bronchi
(Fig 1
, right, C).
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Discussion
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Among the bronchial complications described after lung
transplantation, disruption or stricture both have been attributed to
ischemia of the donor bronchus. Indeed, the bronchial artery
circulation is not reestablished during transplantation, and the
viability of the donor bronchus is dependent on retrograde reflux from
the pulmonary arteries.2
Bronchial anastomotic strictures
related to bronchomalacia, infection, or granulation tissue occur as a
consequence of the necrosis of the mucosa and, occasionally, also of
the cartilage. Airways stenoses at the bronchial anastomosis also are
observed. Based on the etiology, the following different types of
management are possible: dilatation and, if necessary, stent placement
for surgical stenosis; stent placement alone for bronchomalacia;
debridement and antimicrobial therapy for infection; and a combination
of laser debridement, dilatation, and stenting for strictures due to
granulation tissue.2
This last category is the most
challenging, because the recurrence rate is high. In several
reports,3
4
5
the conventional dilatation/stenting has been
associated with newer methods (ie, cryotherapy,
growth factor, and brachytherapy) in an attempt to reduce the
proliferation of granulation tissue. From this perspective, we have
described a promising new treatment with topical mitomycin C, an
antineoplastic agent that is known for its capacity to inhibit the
proliferation of fibroblasts in vitro and in
vivo. This drug is already used in ophthalmology for the treatment
of refractory glaucoma or pterygioums. In otorhinolaryngology,
mitomycin C has been shown to be useful in preventing or reducing
laryngotracheal stenosis in several animal studies.6
7
8
9
It
also has been used with success in a study of adult
patients10
and in a pediatric study11
for the
treatment and prevention of recurrent subglottic stenosis. The present
case report describes the first successful topical application of
mitomycin C to control recurrent bronchial subocclusion secondary to
granulation tissue proliferation after lung transplantation. Early
application of mitomycin C in such cases may reduce the incidence of
recurrent strictures due to granulation tissue and, thus, may preserve
lung function.
Received for publication December 5, 2000.
Accepted for publication May 24, 2001.
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References
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Davis, RD, Pasque, MK (1995) Pulmonary transplantation. Ann Surg 221,14-28[ISI][Medline]
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Kshettry, VR, Kroshus, TJ, Hertz, MI, et al (1997) Early and late airway complications after lung transplantation: incidence and management. Ann Thorac Surg 63,1576-1583[Abstract/Free Full Text]
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Hertz, MI, Harmon, KR, Knighton, DR, et al (1991) Combined laser phototherapy and growth factor treatment of bronchial obstruction after lung transplantation. Chest 100,1717-1719[Abstract/Free Full Text]
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Kennedy, AS, Sonett, JR, Orens, JB, et al (2000) High dose rate brachytherapy to prevent recurrent benign hyperplasia in lung transplant bronchi: theoretical and clinical considerations. J Heart Lung Transplant 19,155-159[CrossRef][ISI][Medline]
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Maiwand, MO, Zehr, KJ, Dyke, CM, et al (1997) The role of cryotherapy for airway complications after lung and heart-lung transplantation. Eur J Cardiothorac Surg 12,549-554[Abstract]
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Coppit, G, Perkins, J, Munaretto, J, et al (2000) The effects of mitomycin-C and stenting on airway wound healing after laryngotracheal reconstruction in a pig model. Int J Pediatr Otorhinolaryngol 53,125-135[CrossRef][ISI][Medline]
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Correa, AJ, Reinisch, L, Sanders, DL, et al (1999) Inhibition of subglottic stenosis with mitomycin C in the canine model. Ann Otol Rhinol Laryngol 108,1053-1060[ISI][Medline]
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Eliashar, R, Eliachar, I, Esclamado, R, et al (1999) Can topical mitomycin prevent laryngotracheal stenosis? Laryngoscope 109,1594-1600[CrossRef][ISI][Medline]
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Spector, JE, Werkhaven, JA, Spector, NC, et al (1999) Preservation of function and histologic appearance in the injured glottis with topical mitomycin-C. Laryngoscope 109,1125-1129[CrossRef][ISI][Medline]
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Rahbar, R, Valdez, TA, Shapshay, SM (2000) Preliminary results of intraoperative mitomycin-C in the treatment and prevention of glottic and subglottic stenosis. J Voice 14,282-286[CrossRef][ISI][Medline]
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Ward, RF, April, MM (1998) Mitomycin-C in the treatment of tracheal cicatrix after tracheal reconstruction. Int J Pediatr Otorhinolaryngol 44,221-226[CrossRef][ISI][Medline]
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Abstract
Introduction
