Granulomatous cheilitis


Evidence Levels: A Double-blind study B Clinical trial ≥ 20 subjects C Clinical trial < 20 subjects D Series ≥ 5 subjects E Anecdotal case reports

Granulomatous cheilitis is characterized by chronic, painless swelling of one or both lips, with histologic evidence of non-caseating granulomatous inflammation. Granulomatous cheilitis exists along the spectrum of orofacial granulomatosis, which encompasses localized disease (cheilitis granulomatous, Miescher cheilitis) to multisystem disease (Melkersson–Rosenthal syndrome). Melkersson–Rosenthal syndrome describes the triad of recurrent orofacial edema, recurrent facial nerve palsy, and lingua plicata (fissured tongue). Many investigators consider isolated granulomatous cheilitis to be a monosymptomatic form of Melkersson–Rosenthal syndrome.

Management Strategy

The treatment of granulomatous cheilitis is very challenging. Because the etiology is unknown, a variety of therapeutic strategies with varying degrees of success have been attempted. No randomized clinical trials or comparative studies have been performed. Given the evanescent nature of the condition, treatment outcomes are difficult to assess. Spontaneous remission of granulomatous cheilitis rarely occurs, further confounding assessment of therapies. Furthermore, a recent retrospective study demonstrated long-term treatment with topical medications and/or combination therapy may be required.

The aim of treatment is to prevent permanent labial deformity. Conservative measures for acute granulomatous cheilitis involve symptomatic relief, including cold compresses and oral antihistamine s to reduce erythema and ointments to protect against fissuring of the lips. Initial therapy frequently includes corticosteroids, either topical, intralesional, or systemic. Initial topical therapy may include either triamcinolone or clobetasol (compounded into Orabase). Intralesional steroids may be used in doses ranging from 10 to 40 mg/kg. Nerve blocks may reduce patient discomfort in cases where large volumes at low concentrations are needed. Although short courses of prednisone (25–50 mg/day) will frequently improve tissue swelling, flares are often noted on cessation.

Clofazimine has been reported to treat granulomatous cheilitis successfully. Response to therapy has been variable. Possible side effects include transient orange-pink discoloration of the skin, nausea, and vomiting. Fatal enteropathy may occur but only at higher doses than those recommended for granulomatous cheilitis treatment . Thalidomide can also be considered, especially in refractory cases. Patients must be monitored for the development of peripheral neuropathy and warned of its teratogenicity. Monotherapy with metronidazole , tetracyclines , azithromycin , hydroxychloroquine , or sulfasalazine , although less well substantiated, may be attempted. These medications may be used with corticosteroids. The addition of minocycline 100 mg twice daily or tetracycline 500 mg daily may prevent rebound after prednisone discontinuation. The value of dapsone and topical tacrolimus in the treatment of granulomatous cheilitis is unclear. Biologics, including infliximab and adalimumab, have also been successful treatments.

Granulomatous cheilitis may become persistent. Patients who suffer from permanent esthetic deformity or functional impairment may benefit from cheiloplasty. Surgical intervention should be performed only when more conservative approaches have failed and when inflammation is quiescent. An important consideration for Melkersson–Rosenthal syndrome patients undergoing anesthesia for surgical intervention or any surgical procedures is the risk of urticarial reaction due to anesthetic triggers during the procedure. In the past, remission was maintained with the use of postoperative corticosteroid injections. More recent reports, however, have described long remissions after surgery, with no additional treatment needed.

Granulomatous cheilitis has characteristics that are associated with several conditions that may require evaluation, including Crohn disease, sarcoidosis, infections (tuberculosis, leprosy, deep fungal, human immunodeficiency virus (HIV), and syphilis), acquired or hereditary angioedema, cheilitis glandularis, and leukemic infiltrates. It is also important to rule out any provocative cause such as odontogenic infections or allergenic sensitizers. Orofacial granulomatosis is associated with Crohn disease, especially in children, and may precede even minimal gastrointestinal symptoms.

Initial biopsies of granulomatous cheilitis may reveal dilated lymphatic channels, non-specific inflammatory infiltrates, and edema. In the later stages, the classic non-caseating granulomas are found. Absence of granulomata on biopsy does not exclude the diagnosis of granulomatous cheilitis. Granulomatous cheilitis is primarily a clinical diagnosis.

Specific Investigations

  • Biopsy for histopathologic examination: polarization and stains/cultures for fungi and acid-fast bacilli

  • Complete blood count and chemistry profile, including serum calcium

  • Angiotensin-converting enzyme level

  • Chest radiograph

  • C1-esterase inhibitor; C1-esterase inhibitor functional assays; C1, C2, and C4 levels

  • Consultation with dental professional if odontogenic infection suspected

  • Consultation with gastroenterologist if there are any gastrointestinal complaints

  • Standard patch testing (metal, bakery, dental, and other specialized patch series may be required) and food allergy testing to determine whether an allergen is causative

Cheilitis granulomatosa (Miescher Melkersson Rosenthal Syndrome)

Gossman W, Agrawal M, Jamil RT, et al. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2020 Jan. Available from: https://www.ncbi.nlm.nih.gov/books/NBK470396/ .

Orofacial granulomatosis

Miest R, Bruce A, Rogers RS. Clin Dermatol 2016; 34: 505–13.

This article reviews orofacial granulomatosis and provocative factors and discusses possible etiologies and differential diagnoses.

Characteristics of patients with orofacial granulomatosis

McCartan BE, Healy CM, McCreary CE, et al. Oral Dis 2011; 17: 696–704.

The largest review of clinical and laboratory findings in 119 patients with orofacial granulomatosis. Mean age of 28, with an equal male-to-female ratio. Almost all patients had clinical evidence of lip and/or facial swelling. Over 50% of biopsies showed granulomatous inflammation.

Melkersson–Rosenthal syndrome: a review of 36 patients

Greene RM, Rogers RS 3rd. J Am Acad Dermatol 1989; 21: 1263–70.

Cheilitis granulomatosa: overview of 13 patients with long-term follow-up: results of management

Int J Dermatol 2002; 41: 225–9.

Orofacial granulomatosis: clinical features and long-term outcome of therapy

Al Johani KA, Moles DR, Hodgson TA, et al. J Am Acad Dermatol 2010; 62: 611–20.

Anesthetic management of patients with Melkersson–Rosenthal syndrome

Tekin M, Kati I. J Anesth 2008; 22: 294–6.

Is orofacial granulomatosis in children a feature of Crohn’s disease?

Khouri JM, Bohane TD, Say AS. Acta Paediatr 2005; 94: 501–4.

Orofacial granulomatosis as the initial presentation of Crohn’s disease in an adolescent

Bogenrieder T, Lehn N, Landthaler M, et al. Dermatology 2003; 206: 273–8.

Cutaneous Crohn’s disease mimicking Melkersson–Rosenthal syndrome: treatment with methotrexate

Tonkovic-Capin V, Galbraith SS, Rogers RS III, et al. J Eur Acad Dermatol Venereol 2006; 20: 449–52.

Asymptomatic granulomatous vulvitis and granulomatous cheilitis in childhood: the need for Crohn disease workup

Nabatian AS, Shah KN, Iofel E, et al. J Pediatr Gastroenterol Nutr 2011; 53: 100–1.

Orofacial granulomatosis: three case reports illustrating the spectrum of disease and overlap with Crohn’s disease

Smith VM, Murphy R. Clin Exp Dermatol 2013; 38: 33–5.

These articles highlight the possibility of Crohn disease presenting with, or subsequent to, the diagnosis of granulomatous cheilitis. Narbutt et al. note that although the treatment of granulomatous cheilitis can be mostly cosmetic, Crohn disease is a systemic illness with multiple potential complications.

Although there are many similar clinical and histologic features between oral Crohn disease and orofacial granulomatosis, its relationship is controversial. Some contend that adolescent granulomatous cheilitis is a predictor of future Crohn disease. It is unknown what percentage of patients with granulomatous cheilitis will develop Crohn disease, but it may be prudent to discuss this issue with granulomatous cheilitis patients.

Melkersson–Rosenthal syndrome and cheilitis granulomatosa. A clinicopathologic study of thirty-three patients with special reference to their oral lesions

Worsaae N, Christensen KC, Schiødt M, et al. Oral Surg Oral Med Oral Pathol 1982; 54: 404–13.

The elimination of odontogenic infections led to inactivity of orofacial edema in 11 of 18 patients.

Contact hypersensitivity in patients with orofacial granulomatosis

Armstrong DKB, Biagonia P, Lamey PJ, et al. Am J Contact Dermatol 1997; 1: 35–8.

Ten of 48 patients showed positive reactions to an oral battery on standard patch testing. Of these 10, seven showed an improvement on an elimination diet. In most cases this was not a complete result.

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