Office-based treatment of laryngeal papillomatosis withpercutaneous injection of cidofovirDINESH K. CHHETRI, MD, JOEL H. BLUMIN, MD, NINA L. SHAPIRO, MD, and GERALD S. BERKE, MD, Los Angeles, California

OBJECTIVE: Our aim was to report our experiencewith office-based treatment of severe laryngealpapillomatosis with percutaneous injection of cldo-fovir in a case series of 5 patients.STUDY DESIGN AND SETTING: We conducted a ret-rospective review of a case series in a tertiary ac-ademic care voice disorders clinic. Adult patientswith papillomas of the vocal cords and anteriorcommissure received percutaneous injection usinga point-touch technique. Clinical improvement orremission of the papillomatosis was noted.RESULTS: Before initiation of office treatments, pa-tients required direct laryngoscopy and CO2 laserablation of papillomas on average every 2.8months. There were no complications related to theinjection technique. During a treatment period of 7to 16 months (mean 12 months), a significant re-duction in the volume of papillomatosis wasachieved in all patients. One patient received 2treatments and another received 1 treatment in theoperating room for final clearance of papillomas.CONCLUSION: Office-based treatment of adult pa-tients with anterior laryngeal papillomatosis usingpercutaneous injection of cidofovir reduces theneed for repeated direct laryngoscopy and laserablation under general anesthesia.SIGNIFICANCE: Percutaneous injection treatmentwith cidofovir is a useful adjunct to direct laryngos-copy and laser ablation in the treatment of laryn-geal papillomatosis. (Otolaryngol Head Neck Surg2002; 126:642-648.)

Percutaneous injection of the larynx is a usefultechnique in the armamentarium of skills of an

From the Division of Head and Neck Surgery, UCLA School ofMedicine.

Presented at the Annual Meeting of the American Academyof Otolaryngology Head and Neck Surgery, Denver, CO,September 9-12, 200 I.

Reprint requests: Gerald S. Berke, MD, Division of Head andNeck Surgery, UCLA School of Medicine, 10833 Le ConteAve, ChS 62-132, Los Angeles, CA 90095; e-mail,dchhetri@ucla.edu.

Copyright © 2002 by the American Academy of Otolaryn-gology-Head and Neck Surgery Foundation, Inc.

0194-599812002/$35.00 + 0 23/1/125604doi: 10.1067/mhn.2002.125604

642

otolaryngologist. The technique is quick and safeand can be performed in the office setting. Greenet al ' described a "point-touch technique" for theinjection of botulinum toxin for the treatment ofspasmodic dysphonia. The senior author (G.S.B.)routinely uses this technique for botulinum toxinand collagen injections. Knowledge of laryngealanatomy based on external landmarks is an essen-tial component in this technique to properly directthe needle. A flexible nasopharyngoscope con-nected to a video monitor is also necessary toimprove the precision of the placement of laryn-geal augmentation agents.

Recurrent respiratory papillomatosis is the mostcommon benign neoplasm of the larynx. It occursin both juvenile and adult forms. The standardtreatment for this disease consists of repeated mi-crosuspension direct laryngoscopy and CO 2 laserablation of papillomatous growths under generalanesthesia. Numerous publications have recentlyreported the efficacy of intralesional injection ofthe antiviral drug cidofovir (Gilead Sciences, Fos-ter City, CA) in the treatment of laryngeal papil-lomas.>> Cidofovir is a cytosine nucleotide analogthat is approved for treatment of cytomegalovirus(CMV) retinitis in human immunodeficiency vi-rus infected patients. It is administered parenter-ally in these patients. It suppresses CMV throughselective inhibition of viral DNA synthesis. Afterentry into a cell, the drug undergoes phosphoryla-tion and its active metabolite, cidofovir diphos-phate, selectively inhibits CMV DNA poly-merases. Incorporation of cidofovir into thegrowing DNA chain results in reduction in the rateof viral DNA synthesis. The long intracellularhalf-life of cidofovir and its metabolites allows forinfrequent dosing." Cidofovir has also been shownto be effective against a broad range of DNAviruses, including human papilloma virus. 2,8

Van Cutsem et aF first reported the successfultreatment of 1 adult with hypopharyngeal papillo-mas with intralesional cidofovir. Subsequently,Snoeck et aP reported successful treatment in 16

Otolaryngology-Head and Neck SurgeryVolume 126 Number 6

of 17 adults with laryngeal papillomas, and Wil-son et al- reported a phase I trial with successfultreatment of 3 adults with laryngeal papillomas. Inall of these studies, intralesional cidofovir injec-tion was the only modality of treatment and wasadministered under general anesthesia. Pransky eta15.6 successfully combined concurrent laser abla-tion and mechanical debulking with intralesionalcidofovir in treating children with severe recurrentlaryngeal papillomas. These reports demonstratedthat cidofovir was effective against respiratorypapillomas, but disease relapses should be antici-pated even with combined therapy. However, re-current lesions also respond to further treatmentswith cidofovir.

After reviewing the initial reports on the effi-cacy of cidofovir against respiratory papillomato-sis, we began offering office-based cidofovir treat-ments to select adult patients with aggressivelaryngeal papillomatosis. The purpose was to ap-ply the percutaneous laryngeal injection techniqueto treat laryngeal papillomatosis with cidofovir.This in tum could minimize the necessity andfrequency of operative laser laryngoscopy. Pa-tients were selected based on accessibility of thepapillomas to the percutaneous technique. Herewe report our experience to date with this tech-nique.

MATERIALS AND METHODSPatient Selection

Adult patients with laryngeal papillomatosis were selected

based on the severity of disease and accessibility of papillo-

mas to the percutaneous technique. Cidofovir treatment was

offered if the frequency of operative laser ablation of papil-

lomas was approaching every 2 to 3 months. Only those

patients with symptomatic papillomas of the vocal cords andanterior commissure were offered percutaneous injection be-

cause injection of other areas of the larynx is difficult with

this technique. The drug, injection method, and potential

serious risks were carefully discussed with each patient, and

fully informed consent was obtained. A baseline serum cr~atinine level was checked to establish normal renal status m

all patients before treatment. All patients were otherwise

healthy nonsmokers without comorbidities.

Injection Techniqueib d . 1 19The injection method has been descn e previous y..

The patient is seated in an eXaminati~n ~hair..The nose andpharynx are topically anesthetized WIth lidocaine 2% spray.

CHHETRI et 01 643

Fig 1. Needle placement in the transcartilaginous ap-proach for percutaneous injection.

The neck is palpated to identify the outline of the larynx. Thesuperior and inferior borders of the thyroid cartilage and thecricoid cartilage can be marked on the neck skin using asurgical marking pen. A flexible nasopharyngoscope (P3;Olympus, Los Angeles, CA) is passed through the anesthe-

tized nasal cavity into the hypopharynx until the larynx isvisualized. The image is viewed on a video monitor.

The cutaneous needle injection site is prepared with alco-hol swabs. The injection is administered with a I-mL syringe

and a 1'/4-inch 27-gauge needle. Transcartilaginous injectionis performed unless the laryngeal cartilage is ossified, inwhich case the injection is performed through the cricothy-roid membrane. The location of the anterior commissure is

estimated as midway between the thyroid notch and theinferior border of the thyroid cartilage. For transcartilaginous

approach, the needle is inserted 5 mm lateral and 5 mminferior to this point (Fig 1). Passage of the needle through the

cartilage can be felt as a slight give or "loss of resistance" asthe needle passes through the inner thyroid perichondrium.

Proper needle positioning is achieved by pointing and ad-

vancing the needle submucosally toward the papillomas andconfirming the position through the nasopharyngoscope be-

fore injection. For transmembrane injection, the needle is

placed just under the edge of the thyroid cartilage, approxi-

mately 1.5 em from the midline, and on going through the

membrane, the needle is bent 45° to 70° and then directedsuperiorly and medially toward the lesiogs (Fig 2).

The needle tip should be directed submucosally toward the

papillomatous areas and can be visualized on the monitor

when the vocal fold epithelium "tents up" with pressure from

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*OR Frequency indicates how often patients require surgical inter-vention (microsuspension direct laryngoscopy and CO2 laser abla-tion) for laryngeal papillomatosis before initiation of percutaneoustreatment.

ing 5 male patients had an average age of 44.4years and required an operative microsuspen-sion direct laryngoscopy/Ctj, ablation of laryn-geal papillomas an average of every 2.8 months(Table 1). All had symptomatic papillomas ofthe true vocal cords or the anterior commissure.During a mean treatment period of 12 months(range 7-16 months), an average of 7.2 injec-tions (range 2-12) were administered (Table 2).The average dose of cidofovir was 47 mg (range38-57 mg). No patient received> I mg/kg ofcidofovir per dose. All injections were giveninitially 2 to 4 weeks apart and then at longerintervals according to the response of papillo-mas. All patients reported a mild stinging sen-sation as the medication was administered.There were no other complications related to theinjection.

Percutaneous treatment with cidofovir did notcompletely clear papillomatous lesions in all pa-tients, although the volume of papillomas recededby at least 90% in all patients. Two patients (pa-tients I and 2) required surgical treatment forcomplete clearance of papillomas. The illustrativecase of patient I is discussed here. Patient 2, whorequired a return to the operating room, had whatappeared to be complete response of the papillo-mas to the injections. However, a small anteriorweb was uncovered after the papillomas receded,and 8 months after starting cidofovir injections, hewas taken to the operating room to divide the web.In the operating room, subglottic papillomas werediscovered, and therefore he instead received CO

2laser ablation of the residual papillomas. At 4months after this surgical intervention, he had not

Table 1. Patient demographics

Every 2 moEvery 3 moEvery 4 moEvery 3 moEvery 2 moEvery 2.8 mo

OR frequency*

216262492844.4

Age (y)

I2345

Average

Patient

\Fig 2. Needle placement in the transcricothyroid ap-proach for percutaneous injection.

the needle tip or a small amount of injection. Once thelocation of the tip is visualized, it can be redirected toward thebase of the papillomas. The drug is then injected at this time.Proper depth of injection is confirmed by distention of theepithelium at the base of the lesion. The procedure generallytakes

Otolaryngology-Head and Neck SurgeryVolume 126 Number 6 CHHETRI et al 645

Table 2. Treatment and follow-up

Total To OR on Larynx atno. of Average Follow-up OR treatment Reason for trip latest

Patient injections mg/injection (mo) intervention month to OR" follow-up

I 10 51 16 No NA NA AC lesion2 12 57 16 Yes II Injection of residual Clear

lesions3 5 38 9 No NA NA Clear4 8 53 12 Yes 8 AC web Clear5 2 38 7 No NA NA Clear

Average 7.2 47 12

NA. Not applicable; AC. anterior commissure. *Reason for trip to the operating room is discussed in the text.

received any more treatments and his laryngo-scopic examination was clear of papillomas.

Patient 1A 21-year-old man presented with hoarseness

and a recent history of vocal cord "polyp" re-movaL On examination, a papillomatous lesionarising from the anterior larynx was evident (Fig3A). Microsuspension direct laryngoscopy re-vealed a papillomatous growth arising from theanterior commissure and the right true vocal fold.The papillomas were mechanically debulked andCO2 laser ablated. Recurrence was noted within 2months (Fig 3B). After 6 CO2 laser treatments inthe ensuing 9 months, he was referred to a hema-tology oncology consultation, and interferon-atreatments were started. He responded minimallyto the interferon therapy and required 10 addi-tional CO2 laser ablations in the next 22 months.He was then offered percutaneous cidofovir treat-ments. He received 10 percutaneous treatmentswith cidofovir at an average dose of 51 mg overthe next 16 months. Figure 3C is a laryngoscopicview of his larynx 2 months after the last laserablation and at the office visit for the secondinjection treatment. At his latest visit at 16months, his voice was stable and his larynx wasclear of papillomas except for a small stable lesionat the anterior commissure (Fig 3D). He has notrequired operative intervention under general anes-thesia since starting percutaneous treatments with

cidofovir.

Patient 2A 62-year-old man presented with a 20-year

history of laryngeal papillomatosis (Fig 4A). He

required laser ablation of his papillomas approxi-mately every 3 months. He had tried a prolongedcourse of acyclovir and indole-3-carbinol therapywithout success. He expressed a desire for analternative treatment modality and was offeredpercutaneous treatments with cidofovir. He re-ceived 12 percutaneous treatments with cidofovirat an average dose of 57 mg over the next 16months. At 11 months after initiation of percuta-neous treatments, recurrence of a papillomatouslesion was observed in the left aryepiglottic fold(Fig 4B). Because this area is not easily accessibleby percutaneous injection, he was brought to theoperating room for cidofovir injection undermonitored anesthesia care. Cidofovir was in-jected in the true vocal folds as well as thearyepiglottic fold percutaneously under moni-tored anesthesia care. Despite overall excellentresponse of papillomas to percutaneous treatment,some myxoid tissue persisted in the anterior third ofboth vocal folds (Fig 4C). At 14 months after initi-ation of office therapy, the patient received mechan-ical debulking of these residual lesions and cidofovirinjection under general anesthesia. Histopathologicexamination of the lesions revealed benign squa-mous papilloma with no evidence of dysplasia. Athis latest follow-up visit 2 months later, the vocalcords were clear of papillomas and he has not re-ceived further treatments (Fig 4D).

DISCUSSIONOur experience in a small group of 5 adults with

severe laryngeal papillomatosis shows a positiveresponse of the papillomas to office-based percu-taneous intralesional injection therapy with cido-fovir. All patients received laser ablation of pap-

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Fig 3. Laryngoscopic examination of patient 1 at initial presentation (A), typical recurrence after microsuspension directlaryngoscopy/C02 ablation (B), at the second injection (C), and at latest follow-up 16 months (D) after initiation ofpercutaneous treatments with cidofovir. The patient did not require return to the operating room after initiation ofoffice-based therapy.

illomas at the onset of percutaneous treatments.The goal was to eliminate the need for laser abla-tion under general anesthesia. This was not borneout in all patients. Although some lesions com-pletely responded to the therapy, others recededremarkably but did not completely disappear (Fig4). The lesions at the anterior commissure wereparticularly difficult to eradicate despite the easyaccess of this area to percutaneous injection (Fig3). This may be related to the relatively thin win-dow of soft tissuebetween cartilage and mucosa atthis location, which may limit the amount of drugthat can be deposited. Persistent lesions eventuallyrequired removal via operative intervention undergeneral anesthesia (Fig 4). Both patients who re-quired removal of residual papillomas under gen-

eral anesthesia were free of papillomas at the latestfollow-up visit and no cidofovir was injected (at 2-and 4-month postoperative visits, respectively).

Candidacy for percutaneous cidofovir injectionsremains in question. We believe it is a usefuladjunct to laser therapy in patients with severedisease requiring laser ablation every 2 to 3months. The morbidity of general anesthesia andthe risks and complications of laser treatment areavoided with percutaneous treatment. Complica-tions of laser therapy include injury to normalmucosa, laser-induced fire, and the developmentof webs and scars. Percutaneous treatment is per-formed in the office and is quick. However, cido-fovir cannot yet be considered the standard of carein the treatment of respiratory papillomas because

Oto laryngology-Head and Neck SurgeryVolume 126 Number 6 CHHETRI et a l 647

Fig 4. laryngoscopic examination of patient 2 at initial presentation (A) and 11 months (B), 14months (C), and 16months(D) after initiation of percutaneous treatments with cidofovir. B, Papillomatous lesions can be seen in the left aryepiglotticfold, which was treated with percutaneous injection of cidofovir under monitored anesthesia care. C, Myxoid persistentlesions can be seen in both vocal folds, which were treated with mechanical debulking. D, The patient's vocal cords areclear of papillomas at the latest follow-up visit.

its role remains to be studied in a well-designedprospective trial. Percutaneous treatment is alsolimited technically to adults with papillomas in-volving the vocal cords and anterior commissure.Supraglottic and subglottic sites are not easilyaccessible with this technique, nor would this befeasible in children, who constitute the majority ofaffected individuals.

There have been some discussions about poten-tial carcinogenicity of cidofovir, although no casesof malignancy attributed to laryngeal injection ofcidofovir have been reported.e" There was noevidence of dysplasia in the pathologic specimensof either patient in our study who required surgicalintervention to eradicate residual disease. The bi-

opsies were performed 8 and 14 months afterinitiation of percutaneous treatments and after cu-mulative doses of 420 and 685 mg of cidofovir,respectively. At the present time, we believe theintralesional injection of cidofovir for papilloma-tosis is a viable option for patients requiring fre-quent operative laser procedures. However, long-term follow-up is necessary regarding potentialsequelae from this treatment modality.

CONCLUSION

Recurrent laryngeal papillomatosis typicallyhas an extended, chronic course and can be frus-trating to treat. Office-based treatment with percu-taneous injection of cidofovir is a useful adjunct to

648 CHHETRI et 01

the treatment of this disease and reduces the needfor frequent repeated laser ablations under generalanesthesia.

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7. Hitchcock MJM, Jaffe HS, Martin JC, et al. Cidofovir, anew agent with potent anti-herpesvirus activity. AntiviralChern Chemother 1996;7:115-27.

8. Safrin S, Cherrington J, Jaffe HS. Clinical uses of cidofo-vir. Rev Med Viral 1997;7:145-56.

9. Berke GS, Gerratt B, Kreiman J, et al. Treatment ofParkinson hypophonia with percutaneous collagen aug-mentation. Laryngoscope 1999;109:1295-9.