Surgical Treatment of Persistent Macrocheilia in Patients with Melkersson-Rosenthal Syndrome and Cheilitis Granulomatosa

STUDY Surgical Treatment of Persistent Macrocheilia in Patients With Melkersson-Rosenthal Syndrome and Cheilitis Granulomatosa

Birgit Kruse-Lösler, MD, DMD; Dagmar Presser, MD; Dieter Metze, MD; Ulrich Joos, MD, DMD

Background: Various conservative methods for treat- cheiloplasty at our hospital between January 1, 1987, and ment of labial swelling in patients with cheilitis granu- December 31, 2002. Preoperative and postoperative medi- lomatosa have been attempted, often with only moder- cal histories were obtained, and criteria for the success ate success and sometimes with persistent disfiguring lip of surgical treatment were evaluated by clinical exami- swelling. Severe macrocheilia can produce an unaes- nation. Different techniques of reduction cheiloplasty are thetic facial deformity associated with functional distur- described and demonstrated in representative cases of se- bances. In patients with persistent macrocheilia, reduc- vere macrocheilia. tion cheiloplasty with excision of excess tissue may be indicated when conservative treatment has proven inef- Results: Surgical treatment in all 7 patients showed sat- fective in reducing swelling but may have been success- isfying aesthetic and functional outcomes that persisted ful in stabilizing disease. throughout follow-up (median follow-up, 6.5 years).

Objective: To evaluate long-term results after reduc- Conclusions: Reduction cheiloplasty is an effective tion cheiloplasty in patients with macrocheilia caused method to correct persistent macrocheilia and improve by Melkersson-Rosenthal syndrome or cheilitis granu- lip aesthetics in patients with Melkersson-Rosenthal syn- lomatosa. drome or granulomatous cheilitis in the persistent state of disease. With careful planning, proper sequencing of Design: Follow-up study in 7 patients with severe per- treatment, and proficiency in the various surgical tech- sisting macrocheilia, including 3 patients with Melkersson- niques, optimal results can be achieved. Rosenthal syndrome and 4 patients with cheilitis granulomatosa in a stable state of disease, treated by reduction Arch Dermatol. 2005;141:1085-1091

ELKERSSON-ROSEN- reditary disposition to disturbances of the thal syndrome (MRS) autonomic nervous system. The granulo- is characterized by re- matous reaction in the edematous tissue current or persistent may be due to an allergic response to dif- orofacial swellings, in- ferent agents. Macrocheilia can affect the termittent peripheral facial nerve paraly- upper or lower lip, with variable asym- M 1 sis, and a fissured tongue. Reports on the metric deformity. Typically, the lips ex- mucocutaneous and neurologic manifes- hibit nontender swelling that fluctuates tations of this disorder have been pub- and eventually is persistent because of fi- lished.1-3 One variant, cheilitis granulo- brosing lymphedema. Aesthetic defor- matosa of Miescher (CG), is generally mity is caused by the increase in lip vol- accepted as a monosymptomatic form of ume and eversion of the labial mucosa. MRS.4 Characteristic histologic findings are Functional deficiency may include labial edema and noncaseating epithelioid cell incompetence with resultant interfer- granulomas, variably containing multi- ence in speaking, drinking, salivary con- nucleated giant cells and paravascular and trol, and mastication, which may become perivascular mononuclear inflammatory intolerable for many patients. infiltrates.1 In the early pathologic pro- Author Affiliations: cess, there may only be lymphocytic in- Departments of See also page 1080 Cranio-Maxillofacial Surgery filtrates. The etiology and pathogenesis are (Drs Kruse-Lösler and Joos) still uncertain, but parainfectious, auto- Various methods of treating labial swell- and Dermatology (Drs Presser immune, and genetic causes have been ing have been established, often result- and Metze), University of proposed. Hornstein1 suggests that the dis- ing in moderate success1,5; these include Münster, Münster, Germany. order is a multicausal syndrome with a he- salazosulfapyridine, antihistamines, anti-

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Patient No./ Clinical Findings Clinical Findings Relapse-Free Sex/Age Diagnosis/Age at First at Latest Previous Period Before Surgical Method at Onset, y at Surgery, y Examination Follow-up Therapy Surgery, mo (Outcome/Cosmetic Result) 1/F/55 CG/61 Severe MC (LL Normal LL, minimal Intralesional and 10 UL: Conway and UL) MC in UL at 5 y systemic LL: Conway, wedge resection corticosteroids (remission/good) 2/M/20 CG/49 Gigantic MC (LL) Minimal edema NA NA LL: Conway, wedge resection, in LL at 6 y Z-plasty (remission/good) 3/M/15 CG/20 Severe MC (LL) Normal LL at 5 y Intralesional 8 LL: Conway (remission/good) corticosteroids, tetracyclines 4/M/30 MRS/36 Severe MC (UL Moderate edema Intralesional 12 UL: Conway, Mouly and LL), gingival in UL, gingival corticosteroids LL: Conway, wedge resection hyperplasia hyperplasia at 9 y (partial recurrence/moderate) 5/M/18 MRS/23 Severe MC (LL), Normal LL, fissured Intralesional and 9 LL: Conway (remission/good) fissured tongue tongue at 15 y systemic corticosteroids 6/M/38 CG/43 and 44 Severe MC (LL Normal lips at 6½ y Intralesional 11 UL and LL: Conway and UL) corticosteroids (remission/good) 7/M/32 MRS/32 and 36 Severe MC (LL), Normal LL, facial Intralesional 10 LL: Conway, wedge resection, facial palsy palsy at 10½ y corticosteroids, Z-plasty (remission/good) tetracyclines

Abbreviations: CG, cheilitis granulomatosa of Miescher; LL, lower lip; MC, macrocheilia; MRS, Melkersson-Rosenthal syndrome; NA, not available; UL, upper lip.

biotics, and irradiation.6 Most commonly used are cor- tients to treat severe and persistent swelling of the upper or lower ticosteroids administered intralesionally or systemi- lip when the lip volume reached at least twice the normal lip cally,1 as well as systemic treatment with clofazimine7 in size. At the time of surgical intervention, the patients were in the acute edematous phase, often resulting in only tem- a stable state of disease with a relapse-free period of 8 months porary relief. Whether elimination of infective sources, or longer. The patients were reexamined in 2002. The age at onset of disease, symptoms, surgical treatment, and preopera- such as dental foci or other inflammatory processes, might 8 tive and postoperative medical histories were also updated. A reverse the labial swelling in CG is controversial. Nev- clinical examination was performed to evaluate criteria for the ertheless, any inflammatory sources should be elimi- success of surgical treatment, including frontal and profile aes- nated in these patients. Potential allergens also should thetics and soft tissue thickness. Factors representing a good be identified by patch testing and eliminated. In pa- outcome were symmetry of the lip, normal anterior projec- tients with unsuccessful conservative treatment and per- tion, dimensional harmony between the upper and lower lips, sistent macrocheilia, reduction cheiloplasty with exci- inconspicuous cicatrices, oral continence, and normal lip sen- sion of excess tissue may be indicated.9 Reduction sation, interlabial distance, and lip thickness. With the lips re- cheiloplasty is most effective if performed when the swell- laxed, the normal interlabial distance is up to 3 mm. The ing is in the noninflammatory phase.8 Some surgeons and mean±SD normal lip thickness is approximately 12±2 mm in white subjects and 15±2 mm in black subjects.10 The surgical dermatologists are hesitant to recommend surgery, fear- outcome was regarded as moderate if one of these factors was ing that a postsurgical relapse might well be more se- not fulfilled. A poor result was indicated in the absence of 2 or vere than the primary constellation. more of the criteria. Our study was performed to determine whether there is risk of recidivism or worsened deformity from surgi- HISTORY cal lip correction in patients with CG. We evaluated long- term results after reduction cheiloplasty in patients with There were 3 patients with MRS and 4 with CG. All patients (6 persistent swelling of the lip associated with MRS and males and 1 female) were referred to our institution because CG and describe different surgical methods for reduc- of cosmetic or functional discomfort due to persistent labial tion cheiloplasty. Representative cases with severe mac- swelling. The median follow-up was 6.5 years (range, 5-15 years). rocheilia are discussed in detail to illustrate the avail- All patients had had symptoms for a minimum of 16 months able surgical options. before their diagnosis. The median age at the time of surgical resection was 36 years (range, 20-61 years). The Table gives the medical histories, medical treatment, surgical methods, and METHODS long-term results. Previous conservative treatment included mainly intralesional corticosteroid injections or systemic treat- PATIENTS ment with corticosteroids and tetracyclines.

The study included 7 patients with MRS or CG who under- PREOPERATIVE CLINICAL FINDINGS went surgical treatment at the Department of Cranio- Maxillofacial Surgery between January 1, 1987, and Decem- All 7 patients had severe persistent macrocheilia, with a lip vol- ber 31, 2002. The diagnosis was confirmed by biopsy in all ume more than twice the normal size. Facial palsy was ob- patients. Excision and reconstruction were performed in all pa- served in 1 patient with MRS, another patient with MRS had

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Seromucocutaneous Border

1.5 cm

Vermillion Border

E F G H

I J

Figure 1. Surgical methods. A and B, Conway procedure with transverse sickle-shaped mucosal excision. C and D, Conway procedure in sagittal projection, with excision of mucosal and submucosal tissue. E and F, Central wedge excision. G and H, Z-plasty after wedge resection. I and J, Mouly procedure.

a fissured tongue, and the third patient with MRS had gingival had to be excised. In 4 patients with severe lower lip macro- hyperplasia not related to any of its common causes. In addi- cheilia, the procedure was supplemented with the excision of tion to the cosmetic problems, some patients had difficulties in a central wedge. In 2 patients with severe and gigantic macro- speaking and drinking, depending on the degree of lip swelling, cheilia, the lip reduction was performed by combining the ba- hardening of the soft labial tissue, and relapsing fissures of the sic Conway procedure with a central sagittal excision of a labial surface. Macrocheilia was found concomitantly in the up- large wedge, followed by reconstruction of the lower lip with per lip and the lower lip in 3 patients. The ratio between upper a Z-plasty. In 1 patient with severe macrocheilia of the upper and lower lip involvement was 3:7. Labial lesions were gener- lip, a widely pronounced anterior projection of the lip was ally manifested as diffuse, pasty, nontender edema, with pro- corrected with a combination of a sickle-shaped mucosal in- nounced anterior projection of the lip. Some lesions were more cision and a procedure described by Mouly.12 The method, solid, with bleaching of the vermillion border. All lip swellings which includes the excision of 2 sagittal triangular wedges at were bilateral and almost symmetric at the time of surgery. the lateral eminences of the philtrum, enables the natural pro- trusion of the eminences and the normal central depression of SURGICAL TREATMENT the upper lip to be preserved. The undermining of the wound edges should be limited to that needed for appropriate tissue In the normal lip, the seromucocutaneous line is coincident apposition. Closure of the resection defects is usually per- with the crest of the lip. In the presence of macrocheilia, the formed in 2 layers, and sutures are removed 7 to 10 days after lip shows a pronounced anterior projection with eversion of surgery. The type of resection in each patient and the time be- the seromucocutaneous line and the vermillion border. All tween last disease activity and surgery are listed in the Table. 7 patients had these clinical features, and reduction cheilo- Patient 6 was treated by resection of the lower and upper lips, plasty was performed using different techniques (Figure 1). with a 1-year interval between procedures. In patients 1 and 4, The basic surgical procedure was the Conway11 method, in- reduction cheiloplasty of the upper and lower lips was per- cluding a transverse sickle-shaped mucosal incision between formed in 1 surgical session. 1 and 1½ cm dorsal to the vermillion border. Posteriorly, the incision was extended bilaterally into the cheek about 1 to HISTOLOGIC FINDINGS 2 cm distal to the commissure to prevent scarring in the im- mediate vicinity of the angle. Depending on the degree of lip In all resection specimens of the 7 patients, histologic exami- swelling, the excision was usually deepened to include a nation showed typical features of the late phase of MRS and wedge of mucosa and various amounts of submucosal glandu- CG, namely, fibrosis, dilated lymph vessels, and scattered non- lar tissue. In some cases, affected orbicularis oris muscle layer caseating epithelioid cell granulomas and paravascular lym-

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©2005 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/27/2021 fied the long-term result of this patient as moderate be- A cause of persistent solid swelling and anterior projection of the upper lip. The clinical results in the other 6 patients were good, with no signs of lip swelling. Post- operative evaluation of the cicatrices in all patients revealed an inconspicuous outcome with soft scarring. In all patients, skin sensitivity was preserved. Figure 3 (patient 1) and Figure 4 (patient 2) show preoperative findings of severe and gigantic macrocheilia, respec- tively, and the postoperative results after follow-up.

COMMENT

The therapeutic regimen in patients with CG favors con- B servative treatment such as systemic application of corticosteroids, sulfones, and salazosulfapyridine; local corticosteroid injections; and removal of underlying allergies, infections, or inflammatory foci. However, such treatment varies in success rates.1,8,9 In cases of persistent and disfiguring lip swelling, surgical treatment is often essential. In recurrent lip swelling, the mucocutaneous soft tissues show a diffuse persistent edema with solid reorganization and long- term fissures because of fibrosing lymphedema. Severe macrocheilia may result in conspicuous facial deformity, sometimes associated with salivary and labial incompetence. Figure 2. Histologic findings in cheilitis granulomatosa. A, Persistent fibrotic The timing of surgical treatment in macrocheilia is state of disease (hematoxylin-eosin, original magnification ϫ40). B, Active inflammatory disease, with typical epithelioid cell granulomas and based on the underlying disease process. The method paravascular inflammatory infiltrates (hematoxylin-eosin, original used for reduction cheiloplasty demands careful and magnification ϫ100). critical assessment of lip swelling to avoid stimulation of the granulomatous inflammatory process, which might induce a more severe pathologic process. Surgi- phocytic infiltrates (Figure 2A). By contrast, diagnostic bi- cal treatment should be deferred until the patient has opsy specimens in the early inflammatory phase of disease lacked been free of disease activity for about 1 year.9 Each of fibrosing lymphedema (Figure 2B). our 7 patients had had a minimum relapse-free preoperative period of 8 months. Ellitsgaard et al13 reported RESULTS that disease persisted in 6 of their 13 patients operated on, but swelling never surpassed the preoperative de- POSTOPERATIVE FINDINGS gree, nor was it permanent. They did not recommend deferring resection until patients had remained relapse- The patients received no systemic application or local in- free for a longer period. Our patients differed from jection of corticosteroids or any other conservative treat- those of Ellitsgaard et al in that they were treated by re- ment in the postoperative period. Temporary minimal duction cheiloplasty only during the nonactive period recurrences of lip swelling 1 to 6 months after reduc- of the disease. In accord with Vistnes and Kernahan,9 tion cheiloplasty occurred in 3 of the 7 patients. Patient we recommend surgical treatment of persistent macro- 3 developed minimal swelling of the resected lip 1 month cheilia in patients with MRS and CG after a relapse-free after surgery, without further recurrence. In the other period of about 8 to 12 months, regardless of patient sex 2 patients (patients 1 and 4), the duration and severity or age. Important factors are the anatomic condition of the exacerbations were minimal. The Table gives the and lip volume, including functional and aesthetic dis- postoperative courses of the patients. orders and histologic proof of the persistent fibrosing state of the disease. LONG-TERM RESULTS It is important that excision of hypertrophic fibro- AFTER SURGICAL TREATMENT glandular tissue be as extensive as possible; this will en- sure a postoperative outcome with normal lip dimen- At the time of the last examination in 2002, the 7 pa- sions by keeping the mass of the orbicularis oris muscle tients were satisfied with the functional and cosmetic re- largely intact.9 In our study, the transverse lip length, sults of their corrected lips. Only patient 4 showed mod- including the central part of the orbicularis oris muscle, erate swelling of the upper lip, with a minimally had to be shortened in 4 patients with pronounced mac- pronounced anterior projection, which did not surpass rocheilia by excising a median sagittal wedge. In 2 of the previously recorded degree of swelling. We classi- these patients, Z-plasty on the lower lip was necessary

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C D

Figure 3. Severe macrocheilia of upper and lower lips in a patient with cheilitis granulomatosa (patient 1 in the Table). A and C, Preoperative findings. B and D, Postoperative findings 5 years after Conway procedure on upper and lower lips and wedge resection on lower lip.

to achieve a stable vertical median lip dimension. The riod. Only 1 of our patients showed less than a good re- pathophysiologic process following reduction cheilo- sult, with middle-grade swelling of the upper lip at the plasty is not completely understood, especially in terms latest follow-up. of how surgically induced alteration may lead to im- General treatment principles for surgical correction provement even when disease still appears to be exacer- of macrocheilia involve the following important as- bating. One reason may be that partial excision of the pects. Lip resection should be conservative, resulting in persistently altered and swollen tissue reduces the harmonious upper and lower lip balance, symmetry, and amount of tissue available for swelling. Reduction chei- appropriate anterior projection. Furthermore, the sur- loplasty might also reduce local vasomotor distur- gical procedure should preserve oral continence, which bances and rectify defective lymphatic drainage by cre- is achieved through the interplay of lip sensation, strength ating lymphaticovenous anastomoses.14 In contrast to of the orbicularis muscle, and height of the lip curtain. the multimodal therapeutic regimen of Glickman et In their study of oral continence, Stranc and Fogel16 found al,15 our patients received no systemic application or lo- the most important factor to be preservation of normal cal injections of corticosteroids in the postoperative pe- lip sensation. In patients presenting with severe macro-

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C D

Figure 4. Gigantic macrocheilia of lower lip in a patient with cheilitis granulomatosa (patient 2 in the Table). A and C, Preoperative findings. B and D, Postoperative findings 6 years after Conway procedure, wedge resection, and Z-plasty.

cheilia with the pathologic process extending into the is important. Conservative treatment to bring the initial cheek and sulcus region, use of the Conway11 procedure inflammatory phase of the disease under control should must preserve near-maximal mental sensory function. For first be exhausted. Reduction cheiloplasty should be con- optimal results, an attempt should be made to establish fined to patients in a stable condition but showing per- a harmonious balance between the upper and lower lips sisting disfigurement of the lips. instead of reducing the lips to a norm. The results of our follow-up study, with no recidi- Accepted for Publication: November 15, 2004. vism of lip swelling after surgical correction, indicate that Correspondence: Birgit Kruse-Lösler, MD, DMD, De- reduction cheiloplasty may be performed in patients with partment of Cranio-Maxillofacial Surgery, University of disfiguring CG, not only to provide functional gain but Münster, Waldeyerstrasse 30, D-48129 Münster, Ger- also to achieve aesthetic remodeling of the lip and to as- many ([email protected]). sist in social reintegration in some cases. Although there Author Contributions: Study concept and design: Kruse- is little risk of failure or relapse with the surgical prin- Lösler. Acquisition of data: Kruse-Lösler, Presser, Metze, ciples described herein, the timing of surgical measures and Joos. Analysis and interpretation of data: Kruse-

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©2005 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/27/2021 Lösler. Drafting of the manuscript: Kruse-Lösler. Critical 6. Minor M, Fox R, Bukantz S, Lockey R. Melkersson-Rosenthal syndrome. JAl- revision of the manuscript for important intellectual con- lergy Clin Immunol. 1987;80:64-67. 7. Podmore P, Burrows D. Clofazimine: an effective treatment for Melkersson-Rosenthal tent: Kruse-Lösler, Presser, Metze, and Joos. Statistical syndrome or Miescher’s cheilitis. Clin Exp Dermatol. 1986;11:173-178. analysis: Kruse-Lösler. Obtained funding: Kruse-Lösler. Ad- 8. Worsaae N, Christensen KC, Schiodt M, Reibel J. Melkersson-Rosenthal syn- ministrative, technical, and material support: Kruse- drome and cheilitis granulomatosa: a clinicopathological study of thirty-three pa- Lösler and Metze. Study supervision: Joos. tients with special reference to their oral lesions. Oral Surg Oral Med Oral Pathol. Financial Disclosure: None. 1982;54:404-413. 9. Vistnes LM, Kernahan DA. The Melkersson-Rosenthal syndrome. Plast Recon- str Surg. 1971;48:126-132. 10. Burstone CJ. The integumental profile. Am J Orthodont. 1958;44:1-5. REFERENCES 11. Conway H. Macrocheilia due to hyperplasia of the labial salivary glands: operative correction. Surg Gynecol Obstet. 1938;66:1024-1031. 1. Hornstein OP. Melkersson-Rosenthal syndrome: a neuro-muco-cutaneous dis- 12. Mouly R. Correction of hypertrophy of the upper lip. Plast Reconstr Surg. 1970; ease of complex origin. Curr Probl Dermatol. 1973;5:117-156. 46:262-264. 2. Schuermann H, Greither A, Hornstein O, eds. Krankheiten der Mundschleim- 13. Ellitsgaard N, Andersson AP, Worsaae N, Medgyesi S. Long-term results after haut und der Lippen. 3rd ed. Munich, Germany: Urban & Schwarzenberg; 1966: surgical reduction cheiloplasty in patients with Melkersson-Rosenthal syn- 28-32. drome and cheilitis granulomatosa. Ann Plast Surg. 1993;31:413-420. 3. Gottwald W. Melkersson-Rosenthal syndrom: klinik, nosologie, und therapie. Dtsch 14. Medgyesi S. Surgical treatment of the lip in the Melkersson-Rosenthal syndrome. Med Wochenschr. 1976;101:338-344. Ugeskr Laeger. 1972;134:2149-2152. 4. Miescher G. Über essentielle granulomatöse makrocheilie (cheilitis granulomatosa). 15. Glickman LT, Gruss JS, Birt BD, Kohli-Dang N. The surgical management of Melk- Dermatologica. 1945;91:57-85. ersson-Rosenthal syndrome. Plast Reconstr Surg. 1992;89:815-821. 5. Greene RM, Rogers RS III. Melkersson-Rosenthal syndrome: a review of 36 16. Stranc MF, Fogel ML. Lip function: a study of oral continence. Br J Plast Surg. patients. J Am Acad Dermatol. 1989;21:1263-1270. 1984;37:550-557.

Correction

Error in Reference List. In the Study by Kreuter et al titled “Pulsed High-Dose Corticosteroids Combined With Low-Dose Methotrexate in Severe Localized Sclero- derma,” published in the July issue of the ARCHIVES (2005; 141:847-852), the following references were omitted from the reference list. This correction was made previously to online versions of this article.

23. Sato S, Fujimoto M, Kikuchi K, Ihn H, Tamaki K, Takehara K. Soluble CD4 and CD8 in serum from patients with localized scleroderma. Arch Dermatol Res. 1996;288:358-362. 24. Falanga V, Medsger TA Jr, Reichlin M, Rodnan GP. Linear scleroderma: clinical spectrum, prognosis, and laboratory abnormalities. Ann Intern Med. 1986;104:849-857. 25. Heickendorff L, Zachariae H, Bjerring P, Halkier-Sorensen L, Son- dergaard K. The use of serologic markers for collagen synthesis and degradation in systemic sclerosis. J Am Acad Dermatol. 1995; 32:584-588. 26. Hulshof MM, Bouwes Bavinck JN, Bergman W, et al. Double- blind, placebo-controlled study of oral calcitriol for the treatment of localized and systemic scleroderma. J Am Acad Dermatol. 2000;43:1017-1023.

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