Cheilitis Granulomatosa

Etiology

The etiology of CG is still unknown. Several etiologies of different orders have been proposed including genetic, inflammatory, allergic, and microbial. There is not a clear etiological mechanism.[6][7]

The postulated etiological factors include:

• Genetic predisposition: Genetic origin has been suggested considering some cases with involvement of other family members; however, it remains unproven, and no HLA association has been found in patients with CG compared to the general population.
• Immunologic factors: CG is a chronic inflammatory condition characterized by a predominant T helper 1-mediated immune response. The main anomaly is most likely a local alteration of innate immunity of lip mucosa in response to various antigens whose insufficient purification leads to a persistent granulomatous reaction.
• Allergic factors: Allergy to dental materials, foodstuffs, and food additives, has been suspected, but the causal relationship is not well established.
• Microbial factors: Several microbial agents have been incriminated, as eventual factors of deregulation of the immune response. Studies have included especially Mycobacterium tuberculosis and paratuberculosis, Borrelia burgdorferi, Saccharomyces cerevisiae, and Candida albicans. Nevertheless, with conflicting results, the role of these microbes in the pathogenesis of CG remains uncertain.
• Hypersensitivity to ultraviolet (UV)-B radiation.
• As part of the spectrum of Crohn's disease: Although early studies suggested that CG may represent an extra-intestinal variant of Crohn's disease with overt gastrointestinal disease developing much later, the fact that CG is found in less than 1% of patients with Crohn's disease cannot be ignored.

Epidemiology

CG is a rare disease of undefined incidence and prevalence. One study estimated incidence to be 0.08% of the general population. It may have an onset in all age groups but is most commonly seen in adults with peak incidence reported between 20 to 40 years of age. It rarely affects children. However, in two recently published articles, 30 cases in pediatric patients have been described. Most of the literature suggests an equal sex distribution; however, some authors reported that it is more frequently reported in females. Rare familial cases have also been reported.

Histopathology

Histological examination is not necessary for the diagnosis of the complete form of MRS, which can be easily established based on clinical findings. Nevertheless, the histological analysis is necessary for incomplete forms, including CGM, especially to eliminate the differential diagnoses of sarcoidosis, Crohn's disease, and other granulomatous disorders including cutaneous tuberculosis, leishmaniasis, and leprosy, especially in endemic areas. The histological characteristics of CG (including CGM and MRS) are granulomatous infiltrate constituted by epithelioid cells and multinucleate giant cells, without caseous necrosis, associated with some degree of lymphedema and fibrosis. These histopathological features are not constant, and their absence should not formally exclude the diagnosis of CG.

History and Physical

MRS consists of a triad of recurrent or persistent orofacial (lips or face) swelling, peripheral facial nerve paralysis, and fissural or scrotal tongue.[8][9] Labial swelling is initially characterized by recurrent edematous swellings mimicking angioedema. Subsequently, after many episodes, it becomes persistent and indurated. It is a firm non-erythematous non-painful swelling affecting one or both lips. Rarely, the labial swelling can cause difficulties in speech or may result in drooling.

The complete classical triad is uncommon and may be observed in one-fourth to one-third of the patients. In the complete form of MRS, all symptoms rarely appear simultaneously, and long intervals between the occurrence of paralysis and the first swelling have been reported. The disease evolves by flare-ups; nevertheless, permanent edema of the lips, and sometimes on the face, can gradually be observed. The oligosymptomatic and monosymptomatic forms are most frequent at the beginning of the disease, and they represent 40% of the cases. CGM or Miescher syndrome corresponds to an incomplete form of MRS in 28% of the cases. Thus, it represents the most common form of MRS. It generally affects the upper lip and less frequently the lower lip. In addition, changes in the buccal, palatal, sublingual, and gingival mucosa are anecdotally reported.

Oral manifestations of sarcoidosis and Crohn's disease may mimic those of CGM or MRS.[10][11][12]

Evaluation

CG is mainly a clinical diagnosis. Histopathology should be considered and, if positive, may be extremely helpful in diagnostic confirmation. Investigations to rule out sarcoidosis (high-resolution computed tomography scan of chest, serum angiotensin-converting enzyme levels) and purified protein derivative (PPD) testing may be done as per the clinical scenario. Since the period between the onset of lip swelling and the appearance of typical symptoms of Crohn's disease is highly variable and unpredictable, the role of investigations like colonoscopy or gastroduodenoscopy with biopsies in patients without gastrointestinal symptoms remains controversial.

Treatment / Management

The rarity of this disease explains the empiricism of therapeutic proposals and the absence of controlled studies. An effective medical treatment is not available at present. The proposed symptomatic treatments are simply intended to avoid or space recurrences, particularly in the edematous stage. The treatment aims to relieve these patients and to improve their quality of life, often very disturbed by the unsightly and distressing nature of macrocheilitis and oro-facial edema. The spontaneous disappearance of the disease is rare but has been reported.

Corticosteroid therapy is a classic treatment for CG. It may be administered locally, topically, or intralesionally, and at times systemic corticosteroid for short courses (prednisolone: 0.3 to 0.7 mg/kg/day; 25 to 50 mg/day) may be tried. Other treatments have also been tried for their anti-inflammatory or immunomodulatory effects such as topical tacrolimus, or oral clofazimine, thalidomide, dapsone, and doxycycline, with inconsistent results.

Finally, immunosuppressive treatments such as mycophenolate mofetil and azathioprine, as well as inhibitors of tumor necrosis factor-alpha (TNF-alpha), have been tried, alone or in combination, in isolated cases and small series with inconsistently positive results.

Fumaric acid esters have given good results in 50 % of the cases (who were refractory to other modalities).

The cheiloplasty reduction is possible when the lesions are fixed and not evolving.

Differential Diagnosis

The list of differentials of lip swelling are many, including:

• Acquired angioedema due to C1 deficiency
• Hereditary angioedema 
• Glandular cheilitis
• Dental abscess
• Crohn's disease
• Cutaneous manifestation of various granulomatous disorders including sarcoidosis, tuberculosis, leishmaniasis, leprosy, Wegener granulomatosis

The histopathology of angioedema is not granulomatous. Moreover, some conditions often have a family history and episodic bouts of abdominal pain. A dental abscess can be ruled out with a thorough dental examination and swabs. Differentiation from other granulomatous disorders has been discussed above.

Prognosis

Owing to the scarcity of literature, poor understanding of the pathophysiology, and modest response to therapy, the overall prognosis of the CG spectrum or OFG is not encouraging. The monosymptomatic form, i.e., CGM, may resolve with the treatments mentioned above. MRS has the poorest prognosis with no published evidence on the response of neurological complications of MRS to treatment.

Complications

As such, CGM is a benign disorder. But since CG may be a part of MRS, the occurrence of facial palsy later is a distinct possibility. If CG in an individual is representative of evolving Crohn's disease, then complications of inflammatory bowel disease may occur.