The Laryngoscope VC 2010 The American Laryngological, Rhinological and Otological Society, Inc.

Case Report

Spray Cryotherapy for the Treatment of Glottic and Subglottic Stenosis

William S. Krimsky, MD; Michael P. Rodrigues, MD; Navara Malayaman, MD; Saiyad Sarkar, MD

to manage despite a variety of surgical and endoluminal Objectives/Hypothesis: Functional partial occlu- approaches. Surgical interventions, such as resection or sion of the glottic and subglottic areas by stenosis and tracheostomy, and endoluminal interventions, such as di- strictures is challenging to manage despite a variety of surgical and endoluminal approaches that are prone to lation, stenting, and ablation, are often combined with complications and inconsistent outcomes. We report one another with variable and inconsistent results. here the first three human cases of glottic and subglottic Given the potential complications and inconsistent out- narrowing treated with spray cryotherapy alone or in comes of surgery, alternative approaches to managing combination with balloon dilation. glottic and subglottic stenoses are needed. Although Study Design: Institutional review board- prior work with cryoprobes in the aerodigestive tract approved clinical human trial. demonstrated some normalization of the mucosa and a Methods: A 42-year-old female with idiopathic more controlled wound response, there remained issues subglottic strictures, a 74-year-old female with glottic with mechanical injury and the degree to which the tem- strictures and vocal cord stenosis following neck radi- perature of the target tissue could be reduced.1 ation, and a 33-year-old female with strictures from a previous tracheal stent were treated by four cycles of Noncontact spray cryotherapy is a novel modality a 5-second cryotherapy spray alone or with balloon di- that has been used extensively in the gastrointestinal (GI) lation. The effects of treatment were observed up to 6 tract. Studies in the GI tract have demonstrated eradica- months, 12 weeks, and 9 months, respectively. tion of intramucosal carcinoma,1 effective treatment of Results: In all cases, patency of the stenosed human papillomavirus infection,2 and hemostasis3 provid- areas was achieved with minimal bleeding and at ing for a submucosal injury without the potential for least some degree of normalization of the glottic and mechanical injury and normalization of the mucosa with a subglottic mucosa. Airway patency and laryngeal controlled wound response. Additionally, cryotherapy has functions were restored without complications. also been used as adjuvant therapy in patients undergoing Conclusions: The use of spray cryotherapy transoral resection of early glottic cancers and has been alone or in conjunction with balloon dilation is a 4 promising and effective therapeutic approach to treat- shown to improve voice quality in these patients. These ing glottic and subglottic narrowing. findings, combined with the breadth of evidence regarding Key Words: Spray cryotherapy, glottic stenosis, cryotherapy in dermatology and other fields, suggest that subglottic stenosis, balloon dilation. treatment with spray cryotherapy may be an appropriate Laryngoscope, 120:473–477, 2010 modality for primary or adjunctive treatment of glottic and subglottic stenosis to modify the wound response, and INTRODUCTION when appropriate, combined with balloon dilation. Herein, Narrowing of the glottic and subglottic areas from we present the first three cases in the treatment of glottic either congenital or acquired stenosis remains difficult and subglottic stenosis accompanied by granulation tissue with spray cryotherapy.

From the Department of Pulmonary and Critical Care (W.S.K., S.S.), the Department of Otolaryngology (M.P.R.), and the Department of Internal Medicine (N.M.), Franklin Square Hospital, Baltimore, Maryland, U.S.A. MATERIALS AND METHODS Editor’s Note: This Manuscript was accepted for publication Spray cryotherapy was performed with the CryoSpray October 28, 2009. Ablation System (CSA System, Model CC2-NAM; CSA Medical, William S. Krimsky, MD is a consultant for CSA Medical. Inc., Baltimore, MD), which has 510(k) clearance by the US Send correspondence to William S. Krimsky, MD, 9103 Franklin Food and Drug Administration and European Conformity/CE Square Drive, Suite 300, Baltimore, MD 21237. E-mail: wkrimsky@ mark for use in Europe (as a cryosurgical tool in the field of gmail.com general surgery, specifically for endoscopic applications). The DOI: 10.1002/lary.20794 CSA System, a noncontact method of cryotherapy, was used to

Laryngoscope 120: March 2010 Krimsky et al.: Spray Cryotherapy for Stenosis Treatment 473 TABLE I. Patient Treatments.

Initial Dose Pneumatic Dilation Subsequent Dose Total Time, min Patient 1, 43-year-old 4 cycles 5 sec Sequential dilation with 8-9-10–mm 2 cycles 5 sec 28 Caucasian female CRE balloon, followed by dilation with 12-13.5-15–mm CRE balloon Patient 2, 74-year-old 4 cycles 5 sec Sequential dilation with 8-9-10–mm 2 cycles 5 sec 37 Caucasian female CRE balloon, followed by dilation with 12-13.5-15–mm CRE balloon Patient 3, 33-year-old 4 cycles 5 sec No dilation performed None 35 Caucasian female

The treatment cycle begins when the targeted area is covered with a visual ice field. Cycle is complete after 5 seconds. Subsequent cycles begin after visual thaw (i.e., loss of ice field) has been achieved. This takes approx 30 to 40 seconds. CRE ¼ controlled radial expansion.

apply medical-grade liquid nitrogen (196C), directly to the balloon and repeat dilation with a 12-13.5-15–mm CRE balloon. tissue via a low-pressure, disposable 7-French cryocatheter Spray cryotherapy was then delivered to the dilated wound but introduced through the vocal cords through the working chan- with two cycles of 5-second sprays in an attempt to modify the nel of a therapeutic flexible bronchoscope (Olympus BF-X1T160 injury response. The patient tolerated the procedure well, and or BF-X1T180; Olympus America Inc., Center Valley, PA). A no adverse events occurred. This treatment led to complete waiver was obtained from the Medstar Institutional Review remission of the patient’s hoarseness and profound improve- Board (Hyattsville, MD) such that the data might be reviewed. ment in her breathlessness within 7 days. Follow-up at 1, 3, Patients initially received four cycles of 5-second spray and 6 months post-treatment confirmed the patient had near cryotherapy with a complete thaw of the treated area between complete luminal patency of the airway without evidence of each application (Table I). If needed, balloon dilation followed restricturing or granulation tissue. She remains symptom free using appropriately sized balloons (controlled radial expansion and no longer requires use of corticosteroids. [CRE] balloon; Boston Scientific, Natick, MA) with subsequent Glottic stricture and vocal cord stenosis following delivery of an additional two cycles of 5-second spray cryother- radiation. A 74-year-old Caucasian female with a 53-year his- apy after the mechanical injury. The balloon dilation was either tory of smoking and gastroesophageal reflux disease had performed after the patients were suspended using a Lindholm recently completed 28 of 33 sessions of radiation therapy for a laryngoscope or through a laryngeal mask airway. recent diagnosis of squamous cell carcinoma of the right vocal Freeze and thaw techniques were monitored by direct vis- cord. Over the preceding month, she had developed progressive ualization. The duration and extent of the cryogen spray to the severe dyspnea, stridor, and hoarseness. selected site was at all times under the control of the physician. A month prior to presentation, when the symptoms began, All cases were performed in the operating room under general she had received a Solu-Medrol taper for her shortness of breath anesthesia. along with a ventilation/perfusion scan that was negative for pul- monary embolism. Four weeks later, evaluation with fiberoptic laryngoscopy by speech, language, and pathology revealed a web- Case Presentations like circumferential occlusion of the glottic opening with a 4- to Three cases of glottic and subglottic stenosis, one of which 5-mm aperture likely a consequence of her radiation therapy. A was accompanied by granulation tissue, are presented here. All bronchoscopy and suspension microlaryngoscopy confirmed laryn- three patients were treated with low-pressure spray cryother- geal stenosis secondary to web formation from the midcord to the apy either alone or in combination with balloon dilation. anterior commissure. (Fig. 2) The patient was treated with four Tracheal stenosis of unclear etiology. A 43-year-old cycles of 5-seconds of spray cryotherapy. This was followed by di- Caucasian woman with a history of gastroesophageal reflux, lation with an 8-9-10–mm CRE balloon, then further dilation chronic allergic rhinitis, and no history of smoking presented with with a 12-13.5-15–mm CRE balloon. A subsequent two cycles of stridor, hoarseness, and trouble breathing. The dyspnea and stri- 5-second spray cryotherapy was delivered. Airway patency was dor had progressively worsened over the preceding 24 months. She achieved with an increased postprocedure lumen to approxi- received a speech, language, and pathology evaluation after she mately 12 to 15 mm in diameter. developed hoarseness and a change in voice quality. She had car- At 12 weeks postprocedure, repeat speech, language, and ried the questionable diagnosis of severe asthma, which was pathology evaluation along with flexible laryngoscopy demon- diagnosed roughly 2 to 3 years prior to the development of her strated a normal appearance of her vocal cords and larynx hoarseness and was treated with increasing amounts of oral corti- without any return of her previous symptoms. In addition, pul- costeroids with marginal control of her symptoms. monary function tests demonstrated an increase in her peak Flexible laryngoscopy was performed and revealed a sub- flow rates of nearly 180% (1.82 L/min–5.03 L/min). glottic stricture beginning at the distal end of the thyroid Tracheobronchomalacia with partial obstruction of cartilage and extending down to the second tracheal ring. The previous tracheostomy tube. A 33-year-old Caucasian female lumen of the proximal trachea measured 5 to 6 mm in diameter with a 20-year history of smoking and asthma since childhood (Fig. 1). Work-up for the etiology of the subglottic stricture was presented with progressive dyspnea on exertion, recent exacer- unrevealing. The patient was treated with four cycles of 5-sec- bations of chronic breathlessness, and an occasional cough that ond spray cryotherapy, with a complete interim thaw of the was negative for hemoptysis. Computed tomography scan dem- treated tissue, lasting approximately 30 to 40 seconds between onstrated the congenital absence of the left lobe of the thyroid sprays. This was followed by dilation with an 8-9-10–mm CRE and a prominent right lobe. Bronchoscopy revealed significant

Laryngoscope 120: March 2010 Krimsky et al.: Spray Cryotherapy for Stenosis Treatment 474 Fig. 1. Endoscopic view demonstrating tracheal stenosis in a 43-year-old female. (A) Pretreatment with tracheal lumen is 5 to 6 mm. (B) Ten days post-treatment. (C) Four weeks post-treatment with complete tracheal lumen patency restored. tracheobronchomalacia involving the lateral and posterior wall induced injury also can result in stricturing with some extending from the trachea to the proximal left mainstem bron- degree of frequency as well.5 Treatment of subglottic ste- chus, which further work-up deemed to be idiopathic in nature nosis has been challenging, and the literature reviewing (Fig. 3). Because of her worsening dyspnea, tracheal stenting the success of treatment is conflicting at best. Surgical with a silicone stent was attempted. Although initially tolerated resection of the stenosed area may be considered, but is well, roughly 9 months later she was found to have developed often ruled out because the length of the stenosis is too extensive granulation tissue at both the proximal and distal ends of the stent resulting in obstruction and dyspnea. This long or the patient is not an appropriate surgical candi- was removed and temporized with a metal hybrid stent that date. There is also the associated difficulty with scarring ultimately fractured and migrated. and restricturing at the surgical site. Although advances Following removal of the stent, the patient underwent a have been made to improve surgical options for airway tracheostomy followed by T-tube placement to increase airway patency in these patients, long-term laryngeal function patency. Six months later she developed a stricture and granu- for voice production is not well understood.6 lation tissue in the subglottic region and at the distal end of the Idiopathic stenosis of the trachea (ITS) is often T-tube in the midtrachea. The patient then underwent treat- categorized by fibrous tightening of the proximal ment with spray cryotherapy and received four cycles of 5- trachea without a causative event, such as infection, seconds of spray cryotherapy at both the sites and at the ostomy inflammation, gastroesophageal reflux disease, trauma, site, which also had developed granulation tissue. Follow-up was conducted regularly, and now at 9 months post-treatment, inhalational injury, or intubation. ITS primarily affects airway examination confirmed no recurrence of the stricture women and typically involves the subglottic larynx and and no granulation tissue with the T-tube remaining in place. the proximal 2 to 4 cm of the trachea circumferentially. Stent placement has begun to gain favor in the treatment of benign stenosis; however, stent placement is also asso- DISCUSSION ciated with significant problems such as stent migration, Laryngotracheal stenosis may result from congeni- recurrence of stenosis due to tissue hyperplasia, stent tal causes, such as subglottic membranous or fracture, and the difficulty of stent removal.7 Balloon dila- cartilaginous narrowing, or acquired causes, often as a tion has become an accepted treatment for benign result of trauma due to prolonged endotracheal intuba- tracheobronchial strictures.8 However, successful treat- tion or laryngotracheal injury. Additionally, radiation ment of fibrotic strictures has been unproven, with

Fig. 2. Endoscopic view demonstrating glottic stricture and vocal cord stenosis in a 74-year-old female. (A) Pretreatment with glottic open- ing of 4 to 5mm. (B) During spray cryotherapy treatment. (C) Six weeks post-treatment with complete lumen patency.

Laryngoscope 120: March 2010 Krimsky et al.: Spray Cryotherapy for Stenosis Treatment 475 Fig. 3. Endoscopic view demonstrating tracheobronchomalacia in a 33-year-old female. (A) Pretreatment. (B) Six months post-treatment. resultant reports of low primary and secondary patency cal time and an emergent reintubation or a rates (24% and 20%, respectively) after balloon dilation tracheostomy may become necessary. Preoperatively, all alone.8 patients are made aware of the risk of airway obstruc- In 1977, Rodgers et al. reported the successful use tion and are consented for a possible tracheostomy. of endotracheal cryotherapy in the treatment of experi- There were no cases of aspiration pneumonia, sloughing mental tracheal strictures. In their technique, the tip of of tissue, or damage to the glottis. Notably, these are a nitrous oxide cryoprobe was applied directly to the complications that may occur with any endoscopic air- stricture, and upon removal of the cryoprobe, forceps way procedure. were used to resect the frozen tissue. In a follow-up report by the same authors, it was found that cryother- apy successfully relieved the airway strictures in 20 of CONCLUSION the 24 lesions in which treatment was completed.9 This case series represents the first use of low-pres- Strome et al. have shown that adjuvant cryotherapy sure spray cryotherapy to treat glottic and subglottic improved glottic wound healing after endoscopic laser stenosis in three patients in whom standard surgical cordectomy in a canine model. Videostroboscopy per- and endoluminal treatment modalities either previously formed after treatment revealed a return of mucosal failed or were not suitable. waves. Histological evaluation showed improved wound Spray cryotherapy with or without balloon dilation healing compared to controls including improved colla- allows for immediate removal of membranous and/or gen organization and decreased keratinization.4 Strome fibrotic strictures and granulation tissue both immedi- et al. also performed a retrospective study to evaluate ately and at 9 months of follow-up. Bleeding is vocal outcomes in patients treated with adjuvant cryo- minimized, and there is at least partial restoration of therapy after a laser resection of early glottic carcinoma. normal mucosa on follow-up examinations. Our patients Patients showed improvement in post-treatment voice all achieved improvement in their airway patency and quality even in those who had resection of the entire restoration of other laryngeal functions such as phona- vocalis muscle.10 tion. Aside from minimal bleeding, no complications After demonstrating safety and feasibility in animal were seen immediately postoperatively or at 9 months of trials, a study in the airway of humans was conducted follow-up. These cases suggest that spray cryotherapy using surgically resected specimens to determine safety has a role in management and treatment of subglottic and histological effect.11 This study demonstrated con- stenosis regardless of the etiology. These cases also sug- siderable cellular injury to the treated tissue, whereas gest that spray cryotherapy can be effective as an the supporting connective matrix was left intact. Long- adjunctive therapy when following surgical resection or term pathology findings (>100 days post-treatment) as a temporizing measure when standard surgical or reveal a complete lack of scarring or stricture. Notably, endoluminal approaches have either failed or are not spray cryotherapy is an alternative method that has feasible. Further studies are needed to evaluate longer- been successfully used in the gastrointestinal tract to term outcomes. treat Barrett’s esophagus, dysplastic lesions of the Many procedures have been studied to mechanically esophagus, and esophageal cancers.12 dilate the lumen of the trachea. Often, patients with With any manipulation of the airway, it is possible low-grade stenosis improve with dilation alone, either to produce more mucosal injury and worsen the degree rigid or pneumatic. There is a known rate of restenosis of stenosis. This did not occur in our limited study. In in this patient population despite the modality used. It patients with a high-grade stenosis, it is possible to is difficult or impossible to discern if the patients in this cause edema resulting in acute airway obstruction. The study would have improved with dilation alone. How- entire team needs to be aware that extubation is a criti- ever, there is evidence that cryotherapy improves

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