ORIGINAL ARTICLE. Experience With Excision and Botulinum Toxin Injection. relatively uncommon, difficult-to-treat

ORIGINAL ARTICLE

Recurrent Contact Granuloma

Experience With Excision and Botulinum Toxin Injection

Importance:Contact granuloma is a difficult-to-treat laryngeal disorder associated with vocal abuse, habitual throat clearing, and laryngopharyngeal reflux. It has a high propensity for persistence and recurrence despite many treatment alternatives.

Objective:To present our experience with recurrent con-tact granuloma treated with microlaryngoscopic exci-sion and botulinum toxin injection.

Design:Case series. The follow-up period had a mean (range) of 41 (11-88) months.

Setting:Tertiary referral university clinic.

Participants:Twenty patients with recurrent, grade 3 and grade 4 contact granuloma whose lesion was excised at least once after failure of conservative treatments. Interventions: Microlaryngoscopic excision and-botulinum toxin type A injection into the region of

the bilateral thyroarytenoid and lateral cricoarytenoid muscles.

Main Outcomes and Measures:Disappearance of con-tact granuloma.

Results:Seventeen patients were cured of their contact granuloma. Three patients experienced recurrences: 2 re-ceived botulinum toxin injection only as outpatients and recovered. The other patient required reexcision and re-injection under general anesthesia. These 3 patients were free of granuloma at their last follow-up.

Conclusions and Relevance:After failed conserva-tive treatment, microlaryngoscopic excision and botuli-num toxin type A injection is successful in the treat-ment of recurrent contact granuloma. Removing recurrent granulomas can result in a low recurrence rate if botu-linum toxin type A is added at the time of removal. JAMA Otolaryngol Head Neck Surg. 2013;139(6):579-583

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relatively uncommon, dif-ficult-to-treat laryngeal disorder with multifacto-rial causes. It arises from the vocal process of the arytenoid carti-lage, and less commonly from the body of the arytenoid cartilage. This is why it is also called arytenoid granuloma. It is most com-monly associated with vocal abuse, ha-bitual throat clearing, and laryngopharyn-geal reflux. It has a high propensity for persistence and recurrence despite many treatment alternatives.1,2

Intubation trauma associated with granuloma was once thought an impor-tant etiological factor; however, this le-sion is called intubation granuloma and is a different disease entity from contact granuloma. Intubation granuloma is ob-served equally or more commonly in fe-male patients than in fe-male patients. It has a high rate of spontaneous resolution. If

it does not resolve spontaneously, its sur-gical excision yields a low recurrence rate, in contrast to contact granuloma.1,2

Perichondritis of the arytenoid carti-lage, infection, allergy, and psychoso-matic disorders are suspected to be in-volved in the etiology of contact granuloma. Individual susceptibility is also men-tioned as a possible etiological factor.1

In this article, we present our experi-ence with patients with recurrent contact granuloma who received several differ-ent types of conservative treatmdiffer-ents and underwent surgical excision elsewhere be-fore being treated in our department.

METHODS

Participants consisted of 20 patients with re-current contact granuloma whose contact granuloma was excised at least once after fail-ure of conservative treatments. Eighteen pa-tients were male and 2 were female, yielding a

Author Aff Departmen Otolaryngo Surgery, Ha Faculty of M Turkey. Author Affiliations: Department of

Otolaryngology–Head & Neck Surgery, Hacettepe University Faculty of Medicine, Ankara, Turkey.

male to female ratio of 9:1. Their mean (range) age was 47 (35-69) years. On first examination, 13 cases were graded as grade 3 and 7 cases as grade 4. All patients had experienced at least 1 surgical excision and recurrence: 11 underwent 1 excision, 4 underwent 2 excisions, 2 had 3 excisions, and 3 had 4 exci-sions before visiting our department.

Our treatment protocol for any contact granuloma started with a 3-month regimen of 8 to 12 sessions of voice therapy, double-dose proton pump inhibitors, and lifestyle changes de-signed to prevent reflux. For patients with grade 1 or 2 lesions that did not respond to the aforementioned regimen, we ad-vised botulinum toxin type A (BTA) injection (2⫻1.25 U to 2⫻5 U) into the region of the bilateral thyroarytenoid muscles as an office procedure through thyrohyoid injection; for the non-responding grade 3 and 4 lesions, we applied microlaryngo-scopic excision and BTA injection (2⫻1.25 U to 2⫻5 U) into the region of the bilateral thyroarytenoid and lateral cricoary-tenoid muscles. The operation was performed using general an-esthesia with endotracheal intubation or jet ventilation. An ap-propriately sized surgical laryngoscope was inserted into the larynx to expose the contact granuloma and suspended from the anterior chest wall. The granuloma was grasped with for-ceps close to its neck and drawn to the opposite side. This ma-neuver makes its base more visible. With the aid of microscis-sors, the granuloma was cut at its base superficial to the perichondrium of the arytenoid cartilage and totally removed. Preserving the perichondrium is crucial because it will reepi-thelialize easily in a short time; however, if the perichondrium is removed, bare cartilage is difficult to epithelialize and may become infected and undergo necrosis as a result of a decrease in the blood supply that was provided by the perichondrium. Under these circumstances, inflammatory granulation tissue will try to cover the bare cartilage; hence, granuloma will recur. Af-ter the granuloma was removed, BTA injections were per-formed. No corticosteroids were administered, neither oral, nor inhaled, nor injected around the base of the lesion.

The BTA injection sites are shown inFigure 1. For the thy-roarytenoid route, the injection needle is aimed lateral to the vocal ligament of the midmembranous vocal fold at the floor of the laryngeal ventricle. For the lateral cricoarytenoid route,

the lateral cricoid lamina is palpated laterally and deep into the vocal process of the arytenoid. After palpation of the cricoid, the BTA is injected just lateral to the cricoid lamina. For the interarytenoid muscle, the injection is performed deep into the mucosa right between both arytenoids. For the aryepiglottic muscle, the injection is performed deep into the mucosa in the middle of the aryepiglottic fold.

RESULTS

The follow-up period had a mean (range) of 41 (11-88) months. Treatment of contact granuloma was success-ful for 17 patients. However, 3 patients experienced re-currences; 2 received another BTA injection as an out-patient procedure and recovered. The other out-patient required reexcision and reinjection under general anes-thesia. These 3 patients were free of granuloma at their last follow-up appointment. Detailed information on pa-tients is given in theTable.

Patient 4 had a right-sided grade 4 lesion (Figure 2A). He has been free of granuloma for more than 7 years (Figure 2B).

Patient 14’s lesion did not respond to office BTA in-jection, so she underwent reoperation; because her le-sion was located superiorly on the body of the aryte-noid, we injected 2⫻5 U BTA into the region of the bilateral aryepiglottic muscle and interarytenoid muscle to relax the supraglottic sphincter.

DISCUSSION

Contact granuloma results from continued hammering of 1 vocal process against the other during phonation, re-ferred to as “hammer and anvil.” This is especially true for loud phonations and hard glottal attacks. Treatment strategy should be aimed at decreasing this hammering ac-tion by teaching the patient to speak with softer phona-tion and without hard glottal attack. This is the aim of the voice therapy. However, voice therapy is not always suc-cessful in alleviating granuloma because some patients can-not follow the recommendations of a voice therapist and are unable to diminish hard glottal attacks.

Contact granuloma has been observed 10 to 20 times more commonly in men than in women. In our series, it is 9 times more common in men than in women. The question of how women are protected against contact granuloma is answered by noting the presence of a pos-terior chink at their vocal process during phonation.

Contact granuloma is usually seen in people older than 30 years. The patients characteristically abuse their voice and habitually clear their throat. The lesions are mostly uni-lateral; however, bilateral cases are also seen. Seventy-five percent of contact granulomas are located at the medial face of the vocal process of the arytenoid, and the other 25% are seen posterosuperiorly on the body of the arytenoid.

The voice characteristics of patients with contact granu-loma include intensity above 80 dB and low pitch. They frequently perform hard glottal attacks during phona-tion. Their mean flow rate is low and range is narrow. Their voice is usually strained, pressed, and loud. They demonstrate excess vocal fry.1

A

B D

C

Figure 1.Botulinum toxin A injection sites within the larynx. A, Thyroarytenoid muscle; B, lateral cricoarytenoid muscle; C, interarytenoid muscle; D, aryepiglottic muscle.

Diagnosis of contact granuloma is simple to perform by means of clinical examination alone, because of its char-acteristic location and peculiar appearance. No other tests are necessary. Biopsy is performed rarely—only if ma-lignancy is suspected.

Despite its name, contact granuloma is not a granu-loma in the pathological sense. On a specimen of con-tact granuloma, under light microscopy we may ob-serve focal ulceration, epithelial hyperplasia, necrotic tissue with desquamating epithelium, acute and/or chronic inflammation, capillary proliferation, fibrosis, and par-tially necrotic arytenoid cartilage.2

Farwell et al3_{have proposed a grading system for} con-tact granuloma based on its endoscopic appearance. A grade 1 lesion is limited to the vocal process, there is no ulceration, and the lesion is sessile. A grade 2 lesion is limited to the vocal process and is ulcerated or

pedun-culated. A grade 3 lesion extends beyond the vocal pro-cess but does not cross the midline of the fully abducted vocal fold. A grade 4 lesion extends beyond the vocal pro-cess and crosses over the midline of the fully abducted vocal fold. Unilateral cases are designated as “A” and bi-lateral ones as “B.”

There are many treatment options available for con-tact granuloma. Such a high number of alternatives in-dicates lack of satisfaction from a single therapy modal-ity. Furthermore, physicians are in search of better options. Wang et al4_{claim that observation alone yields an 81%} remission rate within a mean of 30.6 weeks (approxi-mately 7 months). According to our experience, a high spontaneous remission rate is a characteristic of intuba-tion granuloma, whereas contact granulomas rarely dis-appear without treatment. Contact granuloma is a be-nign lesion and does not have to removed. However, all Table. Characteristics of Patients With Recurrent Contact Granuloma

Patient No. PEs, No. Lesion Grade VTSs, No. Preop Symptoms Recurrences, No.

Additional Treatment, No.

Postop Symptoms Follow-up, mo BTA Surgery 1 4 4 8 Dysphonia, dyspnea, throat irritation 0 0 0 Throat irritation 36 2 2 3 9 Dysphonia 0 0 0 None 11 3 1 3 8 Dysphonia, throat irritation 0 0 0 None 18 4 3 4 10 Dysphonia, dyspnea, lump in throat 1 1 0 None 88 5 1 3 10 Dysphonia 0 0 0 None 24 6 1 3 12 Dysphonia, throat irritation 0 0 0 Throat irritation 48 7 4 4 12 Dysphonia, dyspnea, lump in throat 0 0 0 None 56 8 3 4 11 Dysphonia, dyspnea, lump in throat 0 0 0 None 52 9 2 3 9 Dysphonia, throat irritation 0 0 0 None 40 10 4 3 12 Dysphonia, lump in throat 2 2 0 None 16 11 2 4 12 Dysphonia, dyspnea, lump in throat 0 0 0 None 60 12 1 3 8 Dysphonia 0 0 0 None 76 13 1 3 9 Dysphonia, throat irritation 0 0 0 Throat irritation 32

14 1 4 10 Lump in throat 1 2 1 None 11

15 1 3 12 Dysphonia 0 0 0 None 44 16 1 3 11 Dysphonia, throat irritation 0 0 0 None 54 17 2 4 12 Dysphonia, dyspnea, lump in throat, throat irritation 0 0 0 Throat irritation 18 18 1 3 10 Dysphonia, lump in throat, throat irritation 0 0 0 None 32 19 1 3 12 Dysphonia 0 0 0 None 38 20 1 3 8 Dysphonia, lump in throat, throat irritation 0 0 0 Throat irritation 58

of our patients complained of a change in their voice and feeling a lump in their throat. Patients with grade 4 le-sions also reported dyspnea on exertion. Throat irrita-tion, which is more commonly observed in patients with chronic pharyngitis, may persist after the granuloma has disappeared. These symptoms are given in the Table. Fur-thermore, once our patients see the mass on a video moni-tor, no matter what we say they want get rid of it one way or another. Although the prior pathology report in-dicates that it is benign, they still ask, “Why doesn’t it disappear?” or “Why does it come back again and again?” This attitude may be peculiar to our patients. Many years ago when endoscopic camera facilities were unavailable or underdeveloped, patients were unable to see their le-sion and more readily followed their physician’s advice to treat it more conservatively. Today, however, having seen it with their own eyes, they are afraid of the mass and want it to go away, especially if it is a grade 3 or 4 granuloma. They seem to suspect cancer despite being informed of the benign results of pathologic analysis.

Voice therapy comprises the first step in treating a pa-tient with contact granuloma because the lesion devel-ops as a result of hard glottal attack and voice misuse.5 Because laryngopharyngeal reflux is thought to be a fac-tor in causing contact granuloma, it is also treated with antireflux medication and lifestyle modifications, such

as changing the diet, avoiding reflux-provoking foods and beverages, eating small volume meals, avoiding recum-bency after meals, and elevating the head of the bed dur-ing sleep. Antireflux medications include sdur-ingle-dose or double-dose proton pump inhibitors with or without H2 receptor blockers administered before bedtime, alginic acid, and prokinetics. However, the rarity of contact granu-loma and frequency of laryngopharyngeal reflux makes us think that such an association, if it ever exists, is vague. Botulinum toxin was suggested for the first time as a form of treatment for patients with contact granuloma by Nasri et al6_{in 1995. Damrose and Damrose}7_claimed that percutaneous injection of BTA is a safe and effec-tive therapy in resolving vocal process granulomas in pa-tients whose disease was refractory to traditional therapy. It is used in total doses ranging from 2.5 to 30 U. It is injected into the region of the thyroarytenoid and lat-eral cricoarytenoid muscles to relax their adducting ac-tion on the arytenoid vocal process to decrease trauma of 1 vocal process to the other one. This injection re-laxes the glottic sphincter. It can be used as a sole treat-ment or combined with microlaryngoscopic excision. In-jections of BTA can be performed as an office procedure via the oral cavity, via the thyrohyoid membrane, via the thyroid cartilage, via the cricothyroid membrane, or using general anesthesia. The resultant temporary paresis of the vocal folds allows for a window of time during which the vocal process can heal and the granulomas can re-solve without being exposed to ongoing intermittent con-tact and friction with the opposing arytenoid.8_Our pa-tients with recurrent contact granuloma responded well to our treatment protocol. Three of 20 patients had con-tinued recurrence; however, their recurring lesions were also successfully managed with the same protocol. In a case resistant to regular BTA injection, injection into the region of the aryepiglottic muscle and interarytenoid muscle to relax the supraglottic sphincter may be an al-ternative method. This was successfully used for 1 of our patients.

The use of antibiotics against chondritis of the aryte-noid andHelicobacter pylori–induced reflux may be ben-eficial in some patients with contact granuloma. Corti-costeroids have been administered as topical spray, intralesional injection, and systemically to prevent in-flammation in contact granuloma. However, inflamma-tion is secondary to mucosal trauma and ulcerainflamma-tion on the vocal process, and without acting on the primary cause, that is, mucosal trauma, corticosteroids are not likely to cure contact granuloma. Hillel et al9_{treated 54} patients with granuloma with proton pump inhibitors and inhaled triamcinolone acetonide; 20 of their patients (37%) had intubation granuloma. They found a 69% com-plete response rate with a mean (range) follow-up of 21 (5.9-84.6) weeks. The main drawback of their study is the inclusion of patients with intubation granuloma in the study sample.

Vitamin and mineral supplementation has been tried to treat patients with contact granuloma. Recently, Sun et al10_{claimed that zinc sulfate (ZnSO}

4) supplementa-tion was successful in contact granuloma treatment, either as an initial or compensatory treatment. However, zinc supplementation can cure vocal process granuloma only A

B

Figure 2.Images of patient 4. A, Right-sided grade 4 lesion; B, after follow-up of more than 7 years.

in the presence of a zinc deficiency. If the patients have normal blood and tissue levels of zinc, zinc supplemen-tation, even in large doses (the authors gave 22 times the daily requirement), is not expected to solve the prob-lem.11_{Microlaryngoscopic excision with or without} la-ser, cryotherapy, and electrocautery are other alterna-tives for contact granuloma treatment. Mucosal graft was used to cover the mucosal defect after surgical excision to prevent granuloma recurrence. Low-dose radio-therapy has been suggested for cases resistant to other forms of treatment.12

Surgery alone should not be used as a first-line and sole treatment of contact granuloma because this leads to a mean of 3 removals per patient. Surgery alone yielded a 90% recurrence rate for contact granuloma.1_{Some claim} that surgery has no role in the treatment of this condi-tion and should be used only for histologic diagnosis in case malignancy is suspected. However, Hirano et al13 pro-posed fiberoptic laryngeal surgery as an office proce-dure to facilitate repeated surgical removals.

If there is glottal insufficiency due to paresis and pa-ralysis, contact granuloma develops as a result of the com-pensatory stronger action of the healthy vocal process on the paretic one. In such cases, vocal fold augmentation in the form of injection laryngoplasty may alleviate the granuloma. Halum et al14_{pointed out the association of} vocal process granulomas with unilateral superior laryn-geal nerve paresis, potentially related to altered contact points between the vocal processes of the arytenoids.

Removing a part of the arytenoid cartilage, usually the vocal process, to stop trauma to the other side has been suggested; however, we believe that this is an unethical and unacceptable form of treatment for a benign disor-der because it will lead to permanent dysphonia.

First-line therapy for contact granuloma is conserva-tive, taking the form of voice therapy together with an-tireflux therapy. The recommended duration of this treat-ment, 3, 6, 9, or 12 months or longer, has not yet been determined. We have used this conservative treatment for 3 months and, if unsuccessful, have switched to BTA injection for grade 3 and 4 lesions. Thus far, we have been successful with this treatment regimen for recurrent or nonresponsive contact granuloma. In a case resistant to regular BTA injection to the thyroarytenoid and lateral cricoarytenoid muscles, injection to the aryepiglottic muscle and interarytenoid muscle to relax the supraglot-tic sphincter may be an alternative method.

In conclusion, removing recurrent granulomas can result in a low recurrence rate if BTA is added at the time of removal.

Submitted for Publication:January 7, 2013; final revi-sion received February 21, 2013; accepted March 17, 2013.

Correspondence:Taner Yılmaz, MD, Department of Oto-laryngology,HacettepeUniversityFacultyofMedicine,06100 Sıhhiye, Ankara, Turkey ([email protected]).

Author Contributions:All authors had full access to all the data in the study and take responsibility for the in-tegrity of the data and the accuracy of the data analysis. Study concept and design:Yılmaz.Acquisition of data:All authors.Analysis and interpretation of data:Yılmaz, Atay, O¨zer, Gu¨naydın, and Bajin.Drafting of the manuscript:All authors.Critical revision of the manuscript for important intellectual content:Yılmaz and Bajin.Administrative, tech-nical, and material support:All authors.Study supervi-sion:Yılmaz.

Conflict of Interest Disclosures:None reported.

Previous Presentation:This study was presented at the Fall Voice Conference; October 5, 2012; New York, New York.

Additional Contributions:We thank Ebru Oralli for cre-ating Figure 1 for us.

REFERENCES

1. Ylitalo R, Hammarberg B. Voice characteristics, effects of voice therapy, and long-term follow-up of contact granuloma patients.J Voice. 2000;14(4):557-566. 2. Devaney KO, Rinaldo A, Ferlito A. Vocal process granuloma of the larynx—

recognition, differential diagnosis and treatment.Oral Oncol. 2005;41(7):666-669.

3. Farwell DG, Belafsky PC, Rees CJ. An endoscopic grading system for vocal pro-cess granuloma.J Laryngol Otol. 2008;122(10):1092-1095.

4. Wang CP, Ko JY, Wang YH, Hu YL, Hsiao TY. Vocal process granuloma—a re-sult of long-term observation in 53 patients.Oral Oncol. 2009;45(9):821-825. 5. Leonard R, Kendall K. Effects of voice therapy on vocal process granuloma: a

phonoscopic approach.Am J Otolaryngol. 2005;26(2):101-107.

6. Nasri S, Sercarz JA, McAlpin T, Berke GS. Treatment of vocal fold granuloma using botulinum toxin type A.Laryngoscope. 1995;105(6):585-588. 7. Damrose EJ, Damrose JF. Botulinum toxin as adjunctive therapy in refractory

laryngeal granuloma.J Laryngol Otol. 2008;122(8):824-828.

8. Orloff LA, Goldman SN. Vocal fold granuloma: successful treatment with botu-linum toxin.Otolaryngol Head Neck Surg. 1999;121(4):410-413.

9. Hillel AT, Lin LM, Samlan R, Starmer H, Leahy K, Flint PW. Inhaled triamcino-lone with proton pump inhibitor for treatment of vocal process granulomas: a series of 67 granulomas.Ann Otol Rhinol Laryngol. 2010;119(5):325-330. 10. Sun GB, Sun N, Tang HH, Zhu QB, Wen W, Zheng HL. Zinc sulfate therapy of

vocal process granuloma.Eur Arch Otorhinolaryngol. 2012;269(9):2087-2090. 11. Yılmaz T. Zinc sulfate treatment of vocal process granuloma.Eur Arch

Otorhinolaryngol. 2013;270(3):1175.

12. Song Y, Shi L, Zhao Y, Zhao D, Shi M, Deng Z. Surgical removal followed by radiotherapy for refractory vocal process granuloma.J Voice. 2012;26(5):e1-e5, e15.

13. Hirano S, Kojima H, Tateya I, Ito J. Fiberoptic laryngeal surgery for vocal pro-cess granuloma.Ann Otol Rhinol Laryngol. 2002;111(9):789-793.

14. Halum SL, Miller P, Early K. Laryngeal granulomas associated with superior la-ryngeal nerve paresis.J Voice. 2010;24(4):490-493.