Orofacial granulomatosis: A case report with review of literature.

Orofacial granulomatosis (OFG) encompasses conditions characterized by non-necrotizing granulomatous inflammation of the oral and maxillofacial region that present clinically as labial enlargement, perioral and/or mucosal swelling, oral ulcerations, and gingivitis. The unifying term "OFG" has been introduced to integrate the spectrum of various disorders, including Melkersson-Rosenthal syndrome and granulomatous cheilitis (which is sometimes considered to be a monosymptomatic form of Melkersson-Rosenthal syndrome), and has been shown to be associated with Crohn's disease, sarcoidosis, and infectious diseases such as tuberculosis. Although various etiological agents such as food substances, food additives, dental materials, and various microbiological agents have been implicated in the disease process, its precise pathogenesis is yet to be elucidated. Delayed type of hypersensitivity reaction appears to play a significant role, although the exact antigen inducing the immunological reaction varies in individual patients. However, evidence for the role of genetic predisposition to the disease is sparse. The underlying immunological mechanism appears to show some similarities between OFG and Crohn's disease, emphasizing the need for more comparative studies of the two entities. The aim of this article is to report a case of OFG, along with a detailed literature review of the facts and variations associated with its nomenclature, clinical presentation, and etiology. It also projects the challenges that a professional has to face in the diagnosis and treatment planning of such cases.

INTRODUCTION

Orofacial granulomatosis (OFG) is an uncommon clinical entity presented by swelling of the soft tissues of the oral and maxillofacial region, with the histological evidence of non-caseating granulomatous inflammation, in the absence of diagnosable systemic Crohn's disease or sarcoidosis.

The precise cause of OFG is unknown.[1] Several theories have been suggested, including infection, genetic predisposition, and allergy.[2-6] The classic presentation of OFG is a nontender, recurrent labial swelling that eventually becomes persistent.[7] This swelling may affect one or both lips, causing lip hypertrophy.[8] The swelling is initially soft, but becomes firmer with time as fibrosis ensues. However, the clinical presentation can be highly variable, making the diagnosis difficult to establish.

Intraoral involvement may take the form of hypertrophy, erythema, or nonspecific erosions involving the gingiva, oral mucosa, or tongue.[89] The diagnostic dilemma may be further complicated by the fact that OFG may be the oral manifestation of a systemic condition such as Crohn's disease, sarcoidosis or, more rarely, Wegener's granulomatosis.[10] In addition, several conditions, including tuberculosis (TB), leprosy, systemic fungal infections, and foreign body reactions, may show granulomatous inflammation on histologic examination.[1]

The diagnosis of OFG is made by histopathologic identification of noncaseating granulomas. Local and systemic conditions characterized by granulomatous inflammation must be excluded by appropriate clinical and laboratory investigations.

This article, apart from reporting a case, is a succinct review of OFG, which highlights the challenges in determining the precise cause, in diagnosis and developing effective therapy.

CASE REPORT

A male patient aged 11 years reported with the complaint of swelling of the gums since 6 months. A detailed history was taken and revealed no positive features.

On clinical examination, the patient had gingival enlargement in the upper arch. This enlargement involved attached gingiva and covered almost one-third to one-half of the crown length. Periodontal probing showed presence of false pocket with no signs of clinical attachment loss. As the patient was in mixed dentition stage, few primary teeth were mobile. There was presence of grade II local factors.

Provisional diagnosis

Looking at the history and clinical picture, the enlargement was considered to be due to the local factors and the mixed dentition stage that made the maintenance difficult by the patient.

Treatment

He was treated with scaling followed by gingivectomy operation. The patient was perfectly fine. Regular follow-ups could not be carried out due to patient's poor compliance.

After 4 years of treatment, the patient came with milder form of gingival enlargement. This time, the enlargement was accompanied by swelling of upper lip.

On elaborating the history, the swelling of gingiva began before 2 months with no change in the oral hygiene or food habits. His medical history was unremarkable and he had no history of any intestinal disease, TB, or any signs of chronic fatigue.

The gingival examination revealed rubbery consistency involving the attached gingiva, with the presence of false pockets, slight bleeding on probing, and very less local deposits [Figure 1]. This enlargement was resembling the previous enlargement in all aspects except the severity which was less this time. On palpation, the upper lip felt nontender and soft in consistency. There were no appreciable changes on the dorsal surface of the tongue. The rest of the intraoral examination was unremarkable.

Figure 1

(a) Preoperative; (b) Postoperative – after 3 months; (c) Postoperative – 2 years

Upper lip enlargement with the given background and good oral hygiene led us to think about the granulomatous disease. The clinical differential diagnosis included OFG, angioedema (idiopathic or hereditary), sarcoidosis, Crohn's disease, and an allergic reaction.

Melkersson-Rosenthal syndrome (MRS) was ruled out because of the absence of facial paralysis and clinically normal tongue.

To rule out Crohn's disease, chest radiography and a series of blood tests were requested. They turned out to be normal. An in-depth gastrointestinal investigation did not appear justified in this case, since there were no signs of anemia or symptoms suggestive of Crohn's disease.

A biopsy sample of the upper lip was obtained for histopathologic evaluation. The histopathologic analysis showed nodular tuberculoid granulomatous inflammation in patchy pattern throughout the submucosa. The granuloma consisted of lymphocytes, histiocytes, epitheloid cells, and occasional plasma cells with scattering of neutrophils. Overlying epidermis showed mild spongiosis and slight hyperplasia, giving the histological impression of granulomatous cheilitis [Figure 2]. The results of the other investigations were negative. Therefore, a final diagnosis of idiopathic OFG was made.

Figure 2

(a) Histopathologic picture showing granulomatous lesion in connective tissue; (b) Histopathologic slide showing granulomatous infiltrates

Once the diagnosis was made, we started with the local treatment. To our surprise, as it occurs in very rare cases, the lip swelling reduced in size without any intervention during this investigation period. So, we decided to wait for further reduction and treat the gingival enlargement by gingivectomy meanwhile. The patient was explained regarding the recurrence and was kept on regular follow-up regimen. After 2 months of treatment, the lip swelling subsided completely. He is responding well with the recent recall showing no signs of recurrence even after 2 years.

DISCUSSION

OFG is an increasingly recognized entity. The exact etiology of OFG is not clear, and therefore the precise treatment and long-term prognosis remain uncertain. The differential diagnosis of OFG includes many granulomatous diseases and requires skilled clinical judgment with the assistance of laboratory and histopathologic investigations. In this respect, a clinician should know about the history, variable clinical features, and proposed etiopathogenesis of the disease, so as to provide various means of treatment alternatives to the patients.

The term and its history

The nomenclature of OFG has been a matter of debate since long.[11] Available literature shows that the term OFG lacks specificity and whether to consider it as a separate disease entity or not.

In 1928, Merkelsson described a case of orofacial edema with facial palsy.

In 1932, Rosenthal subsequently proposed the term Melkersson-Rosenthal syndrome to describe a triad of persistent lip or facial swelling, recurrent facial paralysis, and fissured tongue.

In 1945, Meischer described a variant of MRS - presence of granulomas of lip with marked lip swelling as cheilitis granulomatosa.

In 1951, Sheingold and Shengold noted the presence of similar granulomas in TB.

In 1985, Weisenfeld found this condition to be associated with sarcoidosis.

In 2000, Crohn et al. linked similar oral and perioral features with Crohn's disease.

Finally, Wiesenfeld introduced the term OFG to describe granulomas in orofacial region in the absence of any recognizable systemic conditions.

In 2002, Neivelle et al. suggested that MRS and Crohn's Granulomatosis should not be considered as a distinct entity, but should be included in the spectrum of OFG.[12]

Clinical features

Labial swelling: A nontender, recurrent labial swelling that may eventually become persistent.[912] When severe, may lead to median cheilitis and/or angular cheilitis. The swelling is non-pitting and varies in consistency from soft to rubbery. This swelling is usually due to lymphatic blockage caused by granulomas, leading to diffuse swelling from lymphedema.

Oral ulcers: Oral ulcers associated with OFG are of three types.[13] The most common types are Chronic, deep with wide erythmatous margins and slightly raised surroundings occurring usually in vestibules.[14] Less common type of ulcers is superficial aphthous like ulcer on any mucosal surface. The least common type of these ulcers is multiple small superficial erosions on gingival, vestibule, or soft palate.

Mucosal swelling: Mucosal swelling gives rise to "cobblestone" appearance.

Mucosal tags: Painless mucosal tags arising from vestibules or in the retromolar region are also seen.

Gingival enlargement: Painless enlargement of free and/or attached gingiva arises in the localized or generalized pattern. It varies in color from normal to salmon pink to red.[15]

Tongue: Lateral aspects of the dorsum of the tongue are usually fissured.

Facial palsy: A lower motor neuron palsy of facial nerve may rarely arise in OFG.[16]

Cervical lymphadenopathy: Cervical lymphadenopathy of variable size is found with rubbery consistency.[17]

Epidemiology

Nowadays, OFG is seen increasingly more frequently in children and young adults.[918]

Etiopathogenesis

Etiology of OFG has been a matter of discussion since the term was first coined. The following five causes have been proposed:[11]

Genetics

The literature does not provide adequate data to support the contention that OFG has a genetic background. In a study of 42 patients with OFG and their 171 relatives, lingua plicata was seen in 10 (23%) families, and other features, such as recurrent mild unilateral peripheral palsy and facial swelling, were seen in 6 of the 42 families.[5] An association between OFG and human leukocyte antigen (HLA) has been investigated and the two studies available do not show a strong link between HLA and pathogenesis of OFG.[19] More recently, in a study of HLA typing of 16 patients with biopsy-proven OFG, Gibson and Wray[20] found a significant increase in certain HLA alleles in the OFG patients compared to a group of 516 patients from the same region.

Food allergy

Various food substances and food additives have been purported to be either the cause or the precipitant event in OFG. Such antigenic irritants are thought to evoke a delayed type hypersensitivity and this general concept is supported by research showing that up to 60% of a group of 75 patients with OFG are atopic.[17] A study of 48 patients with OFG who were patch tested for reaction to common food additives showed that 10 had a positive skin reaction and 7 of these patients had improvement in their OFG with an elimination diet. Thus, at least in some patients, there appears a role for allergy to food substances; however, the question remains whether these substances are the prime causative agents or just exacerbate the existing disease process.

Allergy to dental materials

Literature on the role of dental materials in OFG consists of three separate studies attempting to make this link. The first reported a patient with OFG purportedly associated with intra-oral cobalt,[20] the second described a 61-year-old female with intra-oral unilateral soft tissue swelling adjacent to an amalgam filling, who also had a positive patch test for mercury.[19] Following total amalgam replacement, the soft tissue swelling completely resolved.[19] The final study outlines a patient with biopsy-proven OFG and positive patch testing for mercury, who refused total amalgam replacement and the symptoms were exacerbated.[19] These latter authors attempt to link the continuation of the symptoms of OFG to the presence of amalgam dental material. All these three patients showed non-caseating granulomas on biopsy of the soft tissue swelling as well as a positive cutaneous patch test to dental filling material. However, cutaneous patch test reactions to mercury and other metallic salts, indicating reactions to amalgam, were not observed in patients with OFG. Thus, there appears to be no conclusive evidence to support a role for dental materials as the cause of OFG.

Infections

The implication of microbiological agents in the causation of OFG follows documentation of infective agents associated with chronic granulomatous conditions such as CD, sarcoidosis, and TB. These studies have focused on Mycobacterium tuberculosis, Mycobacterium paratuberculosis, Saccharomyces cerevisiae, and Borrelia burgdorferi. Analyzing all these studies, it appears that there is insufficient evidence to support a definitive role for infections in the causation of OFG.

Immunology

Various studies support the hypothesis that OFG is a disease not driven by a single antigen, but rather by a random influx of inflammatory cells. An assessment of the beta region of the variable portion of lesional TCR (TCR-VB) in a single patient with OFG showed that this variability was restricted suggesting a delayed hypersensitivity reaction rather than a super antigen. More recently, an immunohistochemical study of 10 patients with OFG assessed the inflammatory cell infiltrate for the expression of cytokines, chemokines, and chemokine receptors.[19] These investigators provide evidence that the immune response in OFG patients is excessive cell-mediated immune response [Table 2].

Table 2

Possible results of various investigations of OFG and similar diseases

Diagnosis

The diagnosis of OFG is made by the clinical presentation of recurring orofacial swellings that histologically consist of non-caseating granulomas [Table 3]. Other conditions that are also characterized by granulomatous formation are summarized in Table 1. CD, sarcoidosis, and TB must be excluded by appropriate clinical and laboratory investigations.

Table 3

Management possibilities of orofacial granulomatosis

Table 1

Differential diagnosis of OFG

Management

Spontaneous remission of OFG is rare,[26] and the treatment of symptomatic patients continues to be unrewarding, especially if there is a delay in diagnosis. After recurrent attacks at regular intervals, the swelling becomes indurated[20] and permanent resulting in significant cosmetic concern, and can interfere with speaking and eating.[27] For reasons of the uncertainty of the etiology of the disease, rational therapy is as yet not available.[20]

Elimination diets to identify and exclude dietary allergens have been advocated in a number of case studies.[22021] The data supporting the efficacy of these extensive, time-consuming diets are limited and often very unrewarding for individual patients.

Corticosteroids have been shown to be effective in reducing facial swelling and preventing recurrences and are considered the mainstay of therapy. The criteria for choice of treatment would seem to be subjective with little scientific basis for selecting one treatment protocol over another. However, the escalation of treatment depending upon the clinical findings appears clinically rational.

Clofazimine has been reported to be effective in the management of OFG.[24] Ofazimine is a lipophilic dye that is thought to be a scavenger of hypochloric acid, reducing the chlorination of proteins by neutrophils; however, the exact mechanism in OFG remains unknown.

Low-dose thalidomide has been shown to be successful in treating five patients with clinical features of OFG recalcitrant to previous topical and systemic immunosuppressant therapy.[25]

Tumor necrosis factor alpha (TNF-α) has been postulated as having a central cytokine in the pathogenesis of CD, and recently, inflixamab, a chimeric monoclonal antibody directed against TNF-α, has been shown to be highly efficacious in patients with colitis associated with CD.[26] Adalimumab, a recombinant monoclonal antibody that also binds to TNF-a receptors, has been shown with preliminary data to have similar efficacy to inflixamab in CD patients.

Following table gives a systematic review of the treatment modalities and their expected outcome.

CONCLUSION

OFG, being increasingly recognized nowadays, has become a topic of interest to all professionals and poses a great challenge to us at all levels starting from its diagnosis to the prognosis and treatment.

The advantages of an early diagnosis, regular clinical review to determine if there is any development of gastrointestinal involvement, and limited use of systemic steroids on long-term patient outcome are highlighted in the literature. Although there are several treatment options emerging, such as anti-TNF-a antibodies, the mainstay of treatment for patients with OFG appears to be individually tailored depending on a changing clinical presentation. Both clinician and patient need to be aware of the extremely frustrating nature of OFG and the common need to change treatment depending upon the changing severity of the disease process. An escalation through a number of topical medications with variable strength and efficacy, the occasional need for a course of intralesional injections, and ultimately, the possibility of requiring long-term systemic medication must be contemplated and openly discussed.