J Oral Maxillofac Surg 62:1114-1117, 2004
Orofacial Granulomatosis Presenting as Persistent Lip Swelling: Review of 6 New Cases Michel El-Hakim, DMD, FRCD(c),* and Peter Chauvin, DDS, MSc, FRCD(c)† Purpose:
Orofacial granulomatosis (OFG) is an uncommon disease, which presents usually as a persistent swelling of the soft tissues in the orofacial region and is characterized histologically by a granulomatous inflammation. The term orofacial granulomatosis is used in the literature to describe a nonspecific granulomatous inflammation. A subset, cheilitis granulomatosa (CG), which presents clinically as persistent lip swelling, is a granulomatous inflammation of unknown origin of the lips. CG may also be part of the triad of the Melkersson-Rosenthal syndrome (MRS) and some consider it as an oligosymptomatic form of MRS. Patients and Methods: In a retrospective study, we reviewed the clinical records of all patients between the years 1990 and 2002 with the histologic diagnosis of granulomatous inflammation of the lip from the Department of Pathology at the Montreal General Hospital. The age at biopsy, sex, site of lesion, other signs of MRS, signs and symptoms of systemic granulomatous disease, and the treatment were compiled. Results: Six subjects were included in the study, 5 females and 1 male. Four had swelling of the lower lip and 2 of the upper lip. In one patient a history of facial nerve palsy was reported and in another one a mild fissured tongue was present. No signs or symptoms of systemic granulomatous disease were noted. The treatment consisted of intralesional steroids with good results in 5 out of 6 patients. Conclusion: A thorough work-up to eliminate other etiologies of granulomatous disease is essential when a patient presents with granulomatous inflammation of the lip. CG seems to respond well to steroid treatment and the need for surgery is minimal and should be reserved for recalcitrant cases. © 2004 American Association of Oral and Maxillofacial Surgeons J Oral Maxillofac Surg 62:1114-1117, 2004 Cheilitis granulomatosa (CG) typically presents as a nonspecific granulomatous inflammation of the lip. The more general term, orofacial granulomatosis, introduced in 1985 by Wiesenfeld et al,1 refers to the presence of granulomatous inflammation in the oral and facial regions. It is estimated that the incidence of GC is 0.08% in the population2 The etiology of this lesion is unknown. It was first described
*Formerly, Resident, Division of Oral and Maxillofacial Surgery, McGill University Health Centre, Montreal, Canada. Currently, Private Practice, Montreal, Canada. †Associate Professor, Faculty of Dentistry, McGill University, Montreal, Canada. Address correspondence and reprint requests to Dr Chauvin: Department of Pathology D3-225, Montreal General Hospital, 1650 Cedar Ave, Montreal (Qc), Canada H3G 1A4; e-mail:
[email protected] © 2004 American Association of Oral and Maxillofacial Surgeons
0278-2391/04/6209-0012$30.00/0 doi:10.1016/j.joms.2003.11.013
by Miescher in 1945,3 and may be an oligosymptomatic form of Melkersson-Rosenthal syndrome (MRS), which includes CG, facial palsy, and fissured tongue.4,5 Clinically, CG presents as a persistent, painless, nonpruritic, firm edema of the lips. The first symptoms of CG usually appear in the second decade of life,4 and has a female predilection.5,6 It is often an asymmetrical swelling involving one or both lips. The labial swelling may be associated with orofacial swelling affecting the chin, eyelids, cheeks, gingiva, and oral mucosa. In some instances the mucosa is erythematous. Cheilitis granulomatosa is a recurrent disease, episodic, and intermittent. The probability of complete remission is low. Moreover, CG can be the first presenting symptom of MRS.6 Histologically, it is characterized by noncaseating granulomas consisting of lymphocytes and epithelioid histiocytes. Dilated lymphatics in the superficial lamina propria and perivascular aggregation of histiocytes and plasma cells are present. Stains for acid fast bac-
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Table 1. CHARACTERISTICS OF PATIENTS
Case
Age at Biopsy (yr)
Gender
Clinical Sites
Other Signs
1 2 3 4 5 6
12 39 52 12 20 14
F F F F F M
Bilateral lower lip Right upper lip Lower lip, chin Bilateral upper lip Right lower lip Lower lip R ⬎ L, buccal mucosa
None Mild fissured tongue None History of facial nerve palsy None None
El-Hakim and Chauvin. Orofacial Granulomatosis Presenting as Lip Swelling. J Oral Maxillofac Surg 2004.
teria and fungal organisms are negative and no polarizing foreign materials are present. In this retrospective study of CG, we present the clinical features of 6 cases and evaluate the management of the disease.
Patients and Methods Records of the Department of Pathology, Division of Oral Pathology at the Montreal General Hospital (Montreal, Canada) were retrospectively reviewed from the year 1990 to 2002. All cases with a histologic diagnosis of granulomatous inflammation of the lip and which were treated at the same hospital were considered for this study. The clinical records of the patients were then reviewed to determine age at biopsy, sex, site of the lesion, presence of other signs of MRS, as well as any related systemic granulomatous disease. The results are presented in Table 1. The treatment protocol for steroid injections is presented in Table 2. In evaluating the treatment results, the outcome was recorded as no improvement, moderate, or good results.
side was more affected (Fig 1). The upper lip was involved in 2 cases (Fig 2), with the right side being more affected in 1 case. In 2 cases other orofacial sites were affected (chin and buccal mucosa). Other signs of MRS were noted in 2 patients. A fissured tongue was present in 1 patient, and a history of facial nerve palsy was reported in the other. No signs or symptoms of other granulomatous disease were noted in this group of patients. Five patients had a good result after steroid treatment, with follow-up ranging from 1 to 5 years. One had moderate outcome initially and was lost to followup. In patient l, after initial treatment with intralesional corticosteroids, a recurrence appeared within 6 weeks and additional injections were administered with good outcome at 5 years’ follow-up. Patient 2 responded well to steroid injections but developed secondary candidiasis during treatment; at 5 years’ follow-up she had good results without recurrence. Patient 3 responded moderately to intralesional steroids and further treatment to eliminate dental infections did not show any improvement; the patient was then lost for follow-up. Patient 4 was started on topical steroids with recurrence of swelling at 5 months; intralesional steroids were used with good results
Results Six patients were included in the study, 5 females and 1 male. Mean age at biopsy was 24.8 years, with a range from 12 to 52 years. In 4 patients the swelling involved the lower lip. In 2 cases the lower lip was involved symmetrically and in the other 2 the right Table 2. TREATMENT PROTOCOL
Topical anesthetic of affected sites Each lip was divided into 3 to 4 sites Injection of each site with 0.1 mL of triamcinolone (10 mg/mL) using a tuberculin syringe Application of ice pack for 15 minutes NOTE. The injections were repeated weekly until complete resolution was established. Most patients responded after 3 weekly injections. Recurrence was treated with the same protocol. El-Hakim and Chauvin. Orofacial Granulomatosis Presenting as Lip Swelling. J Oral Maxillofac Surg 2004.
FIGURE 1. Swelling involving the right lower lip (patient no. 5). El-Hakim and Chauvin. Orofacial Granulomatosis Presenting as Lip Swelling. J Oral Maxillofac Surg 2004.
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initially; a recurrence occurred at 1 year postinjections, which was treated with additional injections with good remission at 2 years’ follow-up. Patient 5 had no response to doxycycline treatment after 1 month and was managed with intralesional injections with good results at 1 year. Finally, patient 6 was treated with intralesional injections with mild improvement; further injections 2 months later produced good results that were maintained at the 1-year follow-up.
Discussion Cheilitis granulomatosa is an uncommon disease. The mean age at biopsy in our group was 24.8 years. It has been reported that the first symptoms of CG appear usually during the second decade of life.4,5 Cheilitis granulomatosa has also been reported in childhood.7,8 A female predilection was obvious in our study, with a ratio of 5:1. Although previous articles report various ratios of female predilection, Zimmer et al5 in a literature review of 262 patients with MRS report a female predilection of 56%.5 The relation between CG and MRS is still controversial; some authors support the concept that CG should be considered as a monosymptomatic form of MRS.5,9 This is based on the fact that CG is the presenting symptom in 42% of patients with MRS,6 and the other symptoms will appear at a different time in life. On the other hand, others consider CG and MRS to be different entities because the majority of patients with CG do not develop MRS.10 Our study supports the second concept because no patient presented or developed the MRS triad. Only one patient presented with a history of facial nerve palsy and another presented with fissured tongue. It is impor-
FIGURE 2. Swelling involving the bilateral upper lip (patient no. 4). El-Hakim and Chauvin. Orofacial Granulomatosis Presenting as Lip Swelling. J Oral Maxillofac Surg 2004.
Table 3. DIFFERENTIAL DIAGNOSIS OF GRANULOMATOUS INFLAMMATION OF THE LIP
1. Orofacial granulomatosis (cheilitis granulomatosa, MR syndrome) 2. Crohn’s disease 3. Sarcoidosis 4. Foreign body reaction 5. Mycobacterial infection (tuberculosis, leprosy, atypical mycobacterium) 6. Deep fungal infection 7. Contact allergy 8. Chronic granulomatous disease (of childhood) El-Hakim and Chauvin. Orofacial Granulomatosis Presenting as Lip Swelling. J Oral Maxillofac Surg 2004.
tant to note that a fissured tongue (lingua plicata) is found in 10% of the general population.11 The lower lip was affected in 4 of 6 cases (67%). Kolokotronis et al12 reported a similar predilection for the lower lip, but previous reports suggest that the upper lip is the most commonly affected.5,9,11,13 The etiology of CG is still unknown, but a genetic predisposition may be possible.14 Several entities are known to cause granulomatous inflammation, which could present as a swollen lip. The differential diagnosis of orofacial granulomatosis is presented in Table 3. When the clinician is presented with a history of recurrent swollen lip, a biopsy should be taken. A full-thickness mucosal biopsy should be taken and if possible several lobules of minor salivary tissue should be included. This will increase the likelihood that the pathologist will identify a granuloma. If the pathologic report confirms a granulomatous inflammation, a thorough evaluation should be undertaken to determine the diagnosis. For this evaluation, we recommend a detailed medical and dental history. All possible dental infections should be diagnosed and treated. A consultation with allergy and immunology is indicated when a hypersensitivity reaction is suspected. A negative history of gastrointestinal complaints will obviate the need for further gastrointestinal investigations,10 but in the presence of gastrointestinal complaints a consultation with a gastroenterologist is warranted. Cheilitis granulomatosa may be the first sign of Crohn’s disease, which may only become apparent several years later.15 A normal chest x-ray and normal serum angiotensin-converting enzyme level are needed to rule out sarcoidosis.16,17 Special stains of the specimen will rule out a mycobactrial or deep fungal infection; polarization can help identify a foreign material. If all the investigations’ results are negative, a diagnosis of CG could be given. The diagnosis of CG is therefore a diagnosis of exclusion. The patient should be warned that the
EL-HAKIM AND CHAUVIN
diagnosis may change if the patient develops other signs or symptoms in the future. When the diagnosis of CG is established, treatment is directed toward alleviation of symptoms. Several treatment modalities (medical and surgical) have been proposed to improve function and cosmesis. Medical management includes the administration of nonsteroidal anti-inflammatory drugs, broad-spectrum antibiotics,7 antihistamines, antituberculous drugs,9 antilepromatous agents,18 and steroids9,12 (systemic or intralesional). Surgically, cheiloplasty alone or in combination with steroids has been suggested to be of benefit.19,20 From our experience and according to evidence from the literature, steroids (systemically or intralesionally) should be considered the treatment of choice. Our steroid treatment protocol is presented in Table 2. Systemic steroid therapy was not needed in any of our patients. Intralesional injections showed good results in the majority of patients (5 of 6 [83%]), with a follow-up ranging from 1 to 5 years. Additional intralesional injections were needed in 3 out of 5 patients. We did not need to continue the medication for an indefinite period to control the disease, which was suggested by others.12,20 In cases refractory to steroid treatment, surgical modalities have been suggested in the literature based on case reports.19,20 In our opinion, reduction cheiloplasty should be reserved for recalcitrant cases and the combination of surgery with steroids has shown better results than surgery alone. In this study, we reviewed 6 new cases of orofacial granulomatosis presenting as a swollen lip and its characteristics. No evidence of an association with MRS was obvious. A thorough evaluation should be performed when pathologic diagnosis of granulomatous inflammation is given. The diagnosis of cheilitis granulomatosa is made by exclusion. The treatment of choice is steroids with good results seen in the majority of patients.
References 1. Wiesenfeld D, Ferguson MM, Mitchell DN, et al: Orofacial granulomatosis. A clinical and pathological analysis. Q J Med 54:101, 1985
1117 2. Hornstein OP: Melkersson-Rosenthal syndrome. A neuro-mucocutaneous disease of complex origin. Curr Probl Dermatol 5:117, 1973 3. Miescher G: Uber essentielle granulomatose makrocheilie (cheilitis granulomatosa). Dermatologica 91:57, 1945 4. Worsaae N, Christensen KC, Schiodt M, et al: MelkerssonRosenthal syndrome and cheilitis granulomatosa. A clinicopathological study of thirty-three patients with special reference to their oral lesions. Oral Surg Oral Med Oral Patho l54:404, 1982 5. Zimmer WM, Rogers RS III, Reeve CM, et al: Orofacial manifestations of Melkersson-Rosenthal syndrome. A study of 42 patients and review of 220 cases from the literature. Oral Surg Oral Med Oral Pathol 74:610, 1992 6. Greene RM, Rogers RS III: Melkersson-Rosenthal syndrome: A review of 36 patients. J Am Acad Dermatol 21:1263, 1989 7. Stein SL, Mancini AJ: Melkersson-Rosenthal syndrome in childhood: Successful management with combination steroid and minocycline therapy. J Am Acad Dermatol 41:746, 1999 8. Ziem PE, Pfrommer C, Goerdt S, et al: Melkersson-Rosenthal syndrome in childhood: A challenge in differential diagnosis and treatment. Br J Dermatol 143:860, 2000 9. Allen CM, Camisa C, Hamzeh S, et al: Cheilitis granulomatosa: Report of six cases and review of the literature. J Am Acad Dermatol 23:444, 1990 10. van der Waal RI, Schulten EA, van der Meij EH, et al: Cheilitis granulomatosa: Overview of 13 patients with long-term followup–Results of management. Int J Dermatol 41:225, 2002 11. Gorlin RJ, Pindborg JJ, Cohen C: Syndromes of the Head and Neck. New York, NY, McGraw-Hill, 2001 12. Kolokotronis A, Antoniades D, Trigonidis G, et al: Granulomatous cheilitis: A study of six cases. Oral Dis 3:188, 1997 13. Shaikh AB, Arendorf TM, Darling MR, et al: Granulomatous cheilitis. A review and report of a case. Oral Surg Oral Med Oral Pathol 67:527, 1989 14. Smeets E, Fryns JP, Van den Berghe H: Melkersson-Rosenthal syndrome and de novo autosomal t(9;21)(pl l;pl1) translocation. Clin Genet 45:323, 1994 15. Lloyd DA, Payton KB, Guenther L, et al: Melkersson-Rosenthal syndrome and Crohn’s disease: One disease or two? Report of a case and discussion of the literature. J Clin Gastroenterol 18:213, 1994 16. Neville BW, Damm DD, Allen CM, et al: Allergies and immunologic diseases, in Neville BW, Damm DD, Allen CM (eds): Oral and Maxillofacial Pathology. Philadelphia, PA, Saunders, 2002, pp 294-297 17. Weinberger SE: Sarcoidosis, in Goldman L, Bennett JC (eds): Cecil Textbook of Medicine. Philadelphia, PA, Saunders, 2000, pp 433-436 18. Ridder GJ, Fradis M, Lohle E: Cheilitis granulomatosa Miescher: treatment with clofazimine and review of the literature. Ann Otol Rhinol Laryngol 110:964, 2001 19. Glickman LT, Gruss JS, Birt BD, et al: The surgical management of Melkersson-Rosenthal syndrome. Plast Reconstr Surg 89:815, 1992 20. Krutchfoff D, James R: Cheilitis granulomatosa. Arch Dermatol 114:1203, 1978
