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Journal of Pediatric Surgery (2007) 42, E9–E11

Topical application of mitomycin C in the treatmentof esophageal and tracheobronchial stricture:a report of 2 casesPaul Dahera,⁎, Edward Riachya, Beyrouthy Georgesa,Dabar Georgesb, Moukarzel Adiba

aDepartment of Pediatric Surgery, Hotel Dieu de France Hospital, Beirut, LebanonbDepartment of Pulmonology, Hotel Dieu de France Hospital, Beirut, Lebanon

0d

Index words:Mitomycin C;Esophagus;Mainstem bronchus,

stricture;Dilatation

Abstract We present 2 cases of successful treatment of recurrent anastomotic strictures using a topicalapplication of mitomycin C. In the first case, a 4-year-old boy had a cervical cyst excised, whichappeared to be an ectopic gastric mucosa. He consequently presented severe stenosis at the origin of thecervical esophagus that needed repeated balloon dilatations. The second case is about a 12-year-old girlwho presented a traumatic complete rupture of the right mainstem bronchus managed by primary repair,with subsequent anastomotic stricture. Both patients were successfully managed with topical applicationof mitomycin C (1 mg/mL), and needed no more dilatations.© 2007 Elsevier Inc. All rights reserved.

Mitomycin C (MMC) is an antineoplastic agent thatinhibits fibroblast proliferation, reduces collagen cross-linking, and has been proven to be effective in reducingscar formation [1]. It is increasingly being used for themanagement of esophageal stenosis with encouraging results[2-6]. We present our experience of using MMC in themanagement of 2 cases: a recurrent esophageal stricture in achild with ectopic gastric mucosa at the origin of theesophagus, and a tracheobronchial anastomotic stricture.

1. Case 1

A 4-year-old boy had an excision of a left cervical cysticlesion suspected to be a third branchial arch cyst. Because it

⁎ Corresponding author. Tel.: +961 3 324577; fax: +961 1 615300x7323.E-mail address: jmpaul@dm.net.lb (P. Daher).

022-3468/$ – see front matter © 2007 Elsevier Inc. All rights reserved.oi:10.1016/j.jpedsurg.2007.06.007

relapsed 2 weeks later, a cervical ultrasound was performedand showed a posterolateral fistula opening in the piriformsinus; a peroperative fistulography showed a posterolateralfistulous pathway with an internal orifice at the level of thepiriform sinus. Although the tissues were still inflamma-tory, the cyst and fistula were excised. The fistula was a redand fleshy mucosa that was excised until the piriform sinus.The operation was complicated by a breach with thehypopharynx that was managed conservatively, and healedspontaneously within a week. Three weeks later, the patientwas admitted for dysphagia for solids and drooling. Therewas no associated odynophagia, dysphonia, stridor, hema-temesis, or hemoptysis. Esophagoscopy revealed a severestenosis (1 mm in diameter, 10 mm in length) at the originof the cervical esophagus (ie, at the level of thetracheoesophageal bifurcation) that was dilated to 15 mmwith a balloon dilator. At that time the pathologicexamination of the fistulous mucosa came out, revealing

ig. 2 Bronchoscopy in case 2 revealing the recurrence of thenastomotic stricture at the level of the right mainstem bronchus). Mitomycin C application with soaked pledget performed undergid bronchoscopy (B).

E10 P. Daher et al.

that the cyst was composed of fundic gastric mucosa, withtypical parietal cells, consistent with the diagnosis ofectopic gastric mucosa. The patient was discharged with aprotein pump inhibitor for possible residual ectopic gastricmucosa, although further endoscopic esophageal biopsies atthe stenosis site ruled out a residual ectopic gastric mucosa.However, recurrent symptoms necessitated repeated balloondilatations on a further 3 occasions, with an interval of 2 to3 weeks between each procedure; the size of the balloonprogressively increased from 15 to 20 mm. As thesymptoms of esophageal stenosis relapsed, we discussedthe possibility of using topical MMC with the child'sparents, because it had been shown to be useful inesophageal stenosis. Before MMC application, endoscopicballoon dilation (20 mm) was performed under generalanesthesia (Fig. 1A). Then, using a rigid endoscope, weapplied MMC topically by a cotton pledget soaked insolution (1 mg/mL) for 2 minutes at each of the 4 quadrantsof the esophageal stricture. The pledget was held in a pairof forceps, and covered by the endoscope during itsintroduction, in a manner to be only uncovered when it wasexactly applied at the stricture site, and therefore preventingthe dissemination of MMC to surrounding normal tissue.The patient needed a second application 2 weeks later. Noprocedure-related complication was observed, and the childremained asymptomatic on a follow-up of 9 months. Arevision endoscopy performed 6 months after the proceduredemonstrated a widely patent esophagus that permitted easypassage of an adult endoscope (Fig. 1B).

2. Case 2

A 12-year-old girl had a car accident with thoracoab-dominal blunt injury. Because she had bilateral pneu-mothorax, pneumomediastinum, and massive subcutaneousemphysema despite adequate pleural drainage, a tracheo-bronchial injury was suspected, and a bronchoscopy wasconsequently performed, identifying a complete rupture ofthe right mainstem bronchus. A primary surgical repairthrough a posterolateral thoracotomy and selective ventila-

Fig. 1 Aspect of esophageal stenosis despite repeated balloondilatations (A). Revision endoscopy demonstrating a widely patentesophagus and easy passage of an adult endoscope (B).

Fa(Ari

tion was performed: the right mainstem bronchus wasreimplanted to the carina using semicircumferential absorb-able interrupted sutures, and a pericardial flap was placedover the suture line to prevent anastomotic stricture. Thepatient dramatically improved and was discharged home.However, she presented with wheezing 1 month later. Rigidbronchoscopy revealed a granulation tissue and an anasto-motic stricture at the level of the right mainstem bronchusthat were managed by argon laser. Three months later, thepatient's stenosis recurred (Fig. 2A). Because we alreadyhad a previous successful result in MMC, we obtained theparent's consent for its use. Under rigid bronchoscopy, anargon ion laser was used for excision and dilatation of thestricture, followed by a topical application of MMC by acotton pledget soaked in solution (1 mg/mL) for 2 minutes,as previously described (Fig. 2B). The patient experiencedno side effects, and remained symptom-free on follow-upof 6 months; a revision bronchoscopy was not found tobe necessary.

3. Discussion

Esophageal and tracheal strictures in children are usuallysecondary to contracture of a postsurgical anastomotic site orto injury such as caustic ingestion, usually requiringtreatment by repeated dilatations.

The efficacy of treatment by esophageal dilations variesfrom 76% to 96% [7,8]. The cause of recurrent stenosis isunknown, but intense fibrogenesis during healing and after atraumatic dilation procedure is possible. Repeated dilatationsare necessary but increase the risk of complications, and it hasbeen estimated that perforations occur in 5% to 8% ofdilations [9,10]. Laser, once thought of as a solution, hasprobably caused more fibrosis than other modalities. Theplacement of a silicone stent in the prevention of stenosis hasshown merely 50% of success rate, and a high rate ofcomplications including slippage and migration [11].

Therefore, conservative treatment (dilatation, bougie, …)is always preferable to surgical treatment, particularly inour first case where the location of the lesion is at theorigin of the esophagus (ie, at the level of the cricoid

E11Topical application of mitomycin C in the treatment of esophageal and tracheobronchial stricture

cartilage and the vocal cords), which makes a surgicalrepair virtually impossible.

Mitomycin C, an anthracyclin antibiotic isolated fromStreptomyces caespitosus (also used as an antineoplasticagent), has also an antiproliferative effect on fibroblasts: bybonding to DNA, it inhibits DNA-dependent RNA synthesisand reduces fibroblastic proliferation and collagen bonding.

It has been successfully used as an antifibrotic agent toprevent scar formation when treating lacrimal duct stenosis[12], choanal atresia [5], laryngeal and tracheal stenosis[5,13-19], as well as refractory esophageal stricturessecondary to congenital esophageal atresia reparation or asa complication of caustic ingestion or reflux esophagitis [1-6].

Complications including ulceration, necrosis, aplasia,alopecia, nausea, and vomiting are very rare [20], and maybe secondary to an overdosage or an inadvertent systemicinjection. This is why the application of MMCmust be strictlytopical and must consider the doses and concentrations.

No data exist that indicate the most effective concentra-tion, duration, or frequency of application of MMC. We useda solution of 1 mg/mL MMC, and applied this to the stenosisfor 2 minutes. This dosage was higher than that used by otherauthors, but was successfully used in another series [2]. Thisconcentration was effective and did not cause any complica-tions during follow-up.

4. Conclusion

Although conservative treatment such as dilatation ispreferable to surgical treatment in cases of esophageal ortracheal stenosis, it should be kept in mind that dilatationitself can lead to further stenosis. However, its associationwith a topical application of MMC seems to be safe, andoffers encouraging results with virtually no further needfor dilatation.

References

[1] Turkyilmaz Z, Sonmez K, Demirtola A, et al. Mitomycin C preventsstrictures in caustic esophageal burns in rats. J Surg Res 2005;123:182-7.

[2] Uhlen S, Fayoux P, Vachin F, et al. Mitomycin C: an alternativeconservative treatment for refractory esophageal stricture in children?Endoscopy 2006;38:404-7.

[3] Afzal NA, Albert D, Thomas AL, et al. A child with oesophagealstrictures. Lancet 2002;359:1032.

[4] Gillespie MB, Day TA, Sharma AK, et al. Role of mitomycin in upperdigestive tract stricture. Head Neck 2007;29:12-7.

[5] Rahbar R, Jones DT, Nuss RC, et al. The role of mitomycin in theprevention and treatment of scar formation in the pediatric aero-digestive tract: friend or foe? Arch Otolaryngol Head Neck Surg 2002;128:401-6.

[6] Kumar A, Bhatnagar V. Topical application of mitomycin-C incorrosive esophageal strictures. J Indian Assoc Pediatr Surg 2005;10:25-7.

[7] Huet F, Mougenot JF, Saleh T, et al. Esophageal dilatation inpediatrics: study of 33 patients. Arch Pediatr 1995;2:423-30.

[8] Tsai JY, Berkery L, Wesson DE, et al. Esophageal atresia andtracheoesophageal fistula: surgical experience over two decades. AnnThorac Surg 1997;64:778-83.

[9] Lan LC, Wong KK, Lin SC, et al. Endoscopic balloon dilatation ofesophageal strictures in infants and children: 17 years' experience anda literature review. J Pediatr Surg 2003;38:1712-5.

[10] Jayakrishnan VK, Wilkinson AG. Treatment of oesophageal stricturesin children: a comparison of fluoroscopically guided balloon dilatationwith surgical bouginage. Pediatr Radiol 2001;31:98-101.

[11] Broto J, Asensio M, Vernet JM. Results of a new technique in thetreatment of severe esophageal stenosis in children: poliflex stents. JPediatr Gastroenterol Nutr 2003;37:203-6.

[12] Kao SCS, Lia CL, Tseng JH, et al. Dacryocystorhinostomy withintraoperative mitomycin. Ophthalmology 1997;104:86-91.

[13] Penafiel A, Lee P, Hsu A, et al. Topical mitomycin-C for obstructingendobronchial granuloma. Ann Thorac Surg 2006;82:E22-3.

[14] Perepelitsyn I. Endoscopic treatment of laryngeal and tracheal stenosis—has mitomycin C improved the outcome? Otolaryngol Head NeckSurg 2004;131:16-20.

[15] Annino Jr DJ, Goguen LA. Mitomycin C for the treatment ofpharyngoesophageal stricture after total laryngopharyngectomy andmicrovascular free tissue reconstruction. Laryngoscope 2003;113:1499-502.

[16] Simpson CB, James JC. The efficacy of mitomycin-C in the treatmentof laryngotracheal stenosis. Laryngoscope 2006;116:1923-5.

[17] Ubell ML, Ettema SL, Toohill RJ, et al. Mitomycin-c application inairway stenosis surgery: analysis of safety and costs. Otolaryngol HeadNeck Surg 2006;134:403-6.

[18] Phillips PS, Amonoo-Kuofi K, Hore ID, et al. Successful treatment oflaryngeal stenosis in laryngo-onycho-cutaneous syndrome with topicalmitomycin C. Pediatr Dermatol 2006;23:75-7.

[19] Senders CW. Use of mitomycin C in the pediatric airway. Curr OpinOtolaryngol Head Neck Surg 2004;12:473-5.

[20] Hueman EM, Simpson CB. Airway complications from topicalmitomycin C. Otolaryngol Head Neck Surg 2005;133:831-5.