Laryngologic Seminar
Mitomycin can reduce granuloma formation
2002-8-28 R3 KST
Granuloma:
mucosa injury release of plasma protein, blood cells, PLTs + TFs
fibrin-fibronectin matrix, migration of capillaries, fibroblasts, inflammatory cells,
fibroblast proliferation, formation of collagen & GAGs & fibronectin
granulation tissues (about 1 week)
collagen maturation, myofibroblast contraction (about 2 weeks)
scar formation [6]
Previous Mx: limited effects
1. Avoid mucosal injury/ cricothyroidectomy/ high tracheostomy
2. Avoid tube-free self retaining tracheostomy
3. Soft pliable, biocompatible stent /stoma tubes
4. antibiotics, anti-reflux agents
5. steroid (local, systemic)
6. cold humidification
7. penicillamine, beta-aminoproprionitrile, 5-FU, N-acetyl-L-cysteine:
inhibit cross-linking of collagen/ scar formation
Mitomycin:
1. An aminoglycoside from fungus Streptomyces caespitosus
2. alkylating antineoplastic agents: ssDNA breakage /C-G cross linking
 inhibit RNA and protein synthesis at higher dose (cytocidal)
3. Systemic form side effects:
delayed bronchospasm/lung fibrosis, HUS, GI upset, HF, BM suppression etc.
Mitomycin's effects on fibroblasts:
1. increased Fas-expression, small increase in Bax, Bcl-2, bcl-x, but increased apoptosis
of fibroblast is not inhibited by Fas receptor blocker
some Fas receptor signaling-independent pathway [1]
2. Inhibition of fibroblast proliferation, migration, ECM production, collagen formation
by single exposure: but still some growth factors of fibroblast expression, ECM / some
scar formation
Animal model (dogs in UADT stenosis, rabbits in antrostomy/choanal atresia)
1. Vocal fold healing/ function:
Negative consequences of topical MMC on vocal fold function: fewer fibroblasts
and less collagen in Reinke’s spaces diminished mucosal wave [8]
Microflap excision of mucosa + MMC, LVS before, 2 4 wks, manual adduction, air
compressor air flow:
1
2. Laryngeal injury/stenosis:
CO2 laser expose cartilage near CA joint1 + 1 % MMC: improved CAJ mobility,
decreased granulation tissue, no 2nd vocal granuloma, No Cx [9]
Suture arytenoid adduction, mobility by tensiometry
3. Subglottic/glottic stenosis:
a. CO2 laser + MMC [10, 15]: decreased submucosal collagen,
b. Suction of seretion reduce stenosis
c. Repeat MMC days later: no further improvement of stenosis: Single topical use
4. Sinus antrostomies patency:
a. Dose-related delayed closure of antrostomy and nasal mucosa healing.
b. Ciliary function: initially impaired, normalized within 2 week after MMC,
c. No Cx/ permanent microscopic changes, decrease posto stenosis. [11, 13]
Clinical practice of mitomycin in reducing granuloma formation:
1. Clinical use: Dose and time-dependent inhibitory effects
2. Most clinical single topical use/studies:
0.1-0.4 mg/ml for 1-5 mins in Grade 0-2 laryngotracheal stenosis
3. Higher dose (e.g.1 mg/ml): cytocidal effect on fibroblast
In Ophthalmology:
1. Pterygium: 1st use by Kunitomo and Mori, decrease recurrence: 88% to 2~3%
2. trabecular patency: in glaucoma surgery
3. NLD patency: after DCR
4. Optic nerve sheath fenestration
5. Strasbismus
Reported complications:
1. 2nd glaucoma/cataract, scleral/corneal ulceration, scleromalacia, symblepharon,
calcification, iritis, ocular hypotonia, decreased wound healing infections,
2. Most single topical use is safe:
0.02 % (0.2 mg/ml) for 5 mins, 0.04% for 3 mins: No significant different effects of
fibroblast inhibition.
In ENT fields:
1. myringotomy: longer patency
2. Glottic, subglottic, tracheal, hypopharyngeal stenosis +/- LTR or CTR:
Endoscopic CO2 laser radial incision+ dilatation+ topical MMC
(93%): 14/15 improvement of airway and preoperative symptoms, no complication,
e.g. Wegner’s granulomatosis [3]
[4, 1st use] [5] [6]
2
Against [12]
Subglottic or upper tracheal stenosis s/p LTR:
topical MMC at the time of extubation or stent removal,
No difference in MMC (+) or N/S groups in stenosis distribution
3. Esophageal stenosis:
dilatation+ MMC: minor improvement [6]
4. Choanal atresia: (e.g. CHARGE, VACTERL syndrome)
s/p endoscopic drillout, transnasal: unilateral+ some bilateral, some transpalatal, +/postoperative stenting:
Msot open decrease need for stenting, dilatations, revision
surgery [6, 14]
In surgery:
1. Abdominal adhesionalysis:
bush cecum and peritoneum induce + laparoscpic MMC 10 days later [2]
2. bilateral bronchial necrosis:
a. Restenosis despite Argon-laser, stentin, dilatation many times in cystic fibrosis s/p
bilateral lung transplantation
b. Open after endoscopic dilatation and stenting + MMC [7]
Ischemia induced donor lung infection, bronchomalacia, granuloma
Possible applications: (before possible granuloma formation or after removal)
1. In prolonged intubation,
tracheostomy,
airway trauma at surgery.
2. Before airway stent, while changed,
3. Following dilatation/ laser surgery for UADT stenosis
4. Autoimmune/Granulomatous diseases: Wegner’s granulomatosis, sarcoidosis etc.
5. ? slow-release form over stenting
6. No data indicating what conc., duration, frequency of application of MMC is
more efficacious, e.g. in UADT stenosis
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References:
1. Crowston JG, Chang LH, Constable PH, et al. Apoptosis gene expression and death receptor
signaling in mitomycin-C-treated human tenon capsule fibroblasts. Invest Ophthalmol Vis Sci
2002;43:692-9
2. Cubukcu A, Alponat A, Gonullu NN, et al. An experimental study evaluating the effect of
Mitomycin C on the prevention of postoperative intraabdominal adhesions. J Surg Res
2001;96:163-6
3. Rahbar R, Shapshay SM, Healy GB, et al. Mitomycin: effects on laryngeal and tracheal stenosis,
benefits, and complications. Ann ORL 2001;110:1-6
4. Rahbar R, Valdez TA, Shapshay SM, et al. Preliminary results of intraoperative mitomycin-C in
the treatment and prevention of glottic and subglottic stenosis. J Voice 2000;14:282-6
5. Ward RF, April MM. Mitomycin-C in the treatment of tracheal cicatrix after tracheal
reconstruction Int J Ped Otorhinolaryngol 1998;44:221-6
6. Rahbar R, Jones DT, Nuss RC, et al. The role of mitomycin in the prevention and treatment of scar
formation in the pediatric aerodigestive tract: friend or foe? Arch Otolaryngol Head Neck Surg
2002;128:401-6
7. Erard AC, Monnier P, Spiliopoulos A, et al. Mitomycin C for control of recurrent bronchial
stenosis: a case report. Chest. 2001;120:2103-5
8. Garrett CG, Soto J, Riddick J, et al. Effect of mitomycin-C on vocal fold healing in a canine model
Ann ORL 2001;110:25-30
9. Spector JE, Werkhaven JA, Spector NC, et al. Preservation of function and histologic appearance
in the injured glottis with topical mitomycin-C. Laryngoscope. 1999;109:1125-9
10. Correa AJ, Reinisch L, Sanders DL, et al. Inhibition of subglottic stenosis with mitomycin-C in
the canine model. Ann ORL 1999;108:1053-60
11. Rahal A, Peloquin L, Ahmarani C. Mitomycin C in sinus surgery: preliminary results in a rabbit
model. J Otolaryngol 2001;30(1):1-5
12. Hartnick CJ, Hartley BE, Lacy PD, et al. Topical mitomycin application after laryngotracheal
reconstruction: a randomized, double-blind, placebo-controlled trial. Arch Otolaryngol Head Neck
Surg 2001;127:1260-4
13. Ingrams DR, Volk MS, Biesman BS, et al. Sinus surgery: does mitomycin C reduce stenosis?
Laryngoscope 1998;108:883-6
14. Prasad M, Ward RF, April MM, et al. Topical mitomycin as an adjunct to chanal atresia repair.
Arch Otolaryngol Head Neck Surg 2002;128:398-400
15. Elishar R, Eliachar I, Esclamado R, et al. Can topical mitomycin prevent laryngotracheal
stenosis ? laryngoscope. 1999;109:1594-1600
16. Occleston NL, Daniels JT, Tarnuzzer RW, et al. Single exposure to antiproliferatives: long-term
effects on ocular fibroblast wound-healing behavior. Invest Opthalmol Vis Sci. 1997;10:1998-2007
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