| Abstract|| |
Granulomatosis is any condition characterized by the formation of multiple nodules or granulomas in the soft tissues. Differential diagnosis for orofacial region includes a wide spectrum of diseases, but most of these lesions present histopathologically as noncaseating granulomas, giving a nonspecific depiction and leading to a diagnostic impasse. In the absence of any diagnosable entity, the disease is labelled as “orofacial granulomatosis”. A nine-year-old girl child reported with recurrent gingival enlargement and persistent macrochelia which histopathologically presented as noncaseating granulomas. The disease was progressive raising the suspicion of being oral manifestation of a systemic disorder such as Sarcoidosis or Crohn's disease. This paper throws some light on this rare entity and reports rarer features of this disease, like eye involvement and staphylococcal mucositis in the case report.
Keywords: Crohn's disease, orofacial granulomatosis, sarcoidosis
|How to cite this article:|
Bhagde PA, Bhavthankar JD, Mandale M. Orofacial granulomatosis: A disease or a concealed warning.??. Indian J Pathol Microbiol 2017;60:556-9
| Introduction|| |
Orofacial granulomatosis is a relatively new entity presenting as swelling of the soft tissues of the oral and maxillofacial region, with the histological evidence of noncaseating granulomatous inflammation, in the absence of diagnosable systemic Crohn's disease or sarcoidosis. It also encompasses Melkersson Rosenthal syndrome and cheilitis granulomatosa. The true prevalence of this disease is unknown but is suggested to be 0.8% (Mahler and Kiesewetter, 1996). It is principally a condition of children and young adults, common in both genders  with slight female predilection. Diagnosis of the disease is based on exclusion.
| Case History|| |
A 9-year-old girl child reported with the chief complaint of diffuse swelling on the face, marked labial swelling, and recurrent gingival enlargement since three years. Patient had history of being treated for the same with various topical and systemic medications which she had stopped since past six months. The disease started with appearance of vesicles on the lips mucosae followed by swelling of lips, gingival enlargement, and mild diffuse swelling of the cheeks. She underwent gingival enlargement excision and lip biopsy, which were reported as noncaseating granulomatous lesion.” Meanwhile, she was treated by various general physicians with Deflazacort, Cefadroxil, Colchicine, Hydroxyzine hydrochloride, cephalosporin, Prednisolone, fusidic acid, antifungals, and Sodium fusidate with disease not succumbing.
Extraoral examination revealed mild diffuse facial swelling, pronounced swelling of the lips causing eversion and watering of the eyes and slight periorbital edema [Figure 1]. Intraorally, there was generalized gingival enlargement of grade III with slight pus discharge from gingival pockets [Figure 2]. Submental and submandibular lymph nodes were enlarged.
|Figure 2: Generalized gingival enlargement involving both the jaws and normal tongue|
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Gingival biopsy showed severe submucosal chronic inflammatory cell infiltrate and in deeper tissues isolated, loosely arranged noncaseating granulomas were seen. The granulomas were composed of epitheloid cells and occasional giant cells with peripheral inflammatory cells and slight fibrosis [Figure 3]. This was in accordance with the patient's previous gingival and lip biopsy exhibiting chronic noncaseating granulomatous inflammation. Staining for acid fast bacillus and periodic acid-Schiff yielded negative results ruling out tuberculosis (TB) and fungal infections respectively. Pus culture from oral cavity showed methicillin resistant Staphylococcus aureus (MRSA). Radiographic examination (X ray chest, pelvis, Orthopantomogram), Liver and kidney function tests and urine analysis were within normal limits. Red cell indices showed mild microcytic hypochromic anemia. The diagnosis of chronic noncaseating granulomatous inflammation consistent with OFG was made.
|Figure 3: Severe submucosal chronic inflammatory cell infiltrate. Deeper tissue showing noncaseating granulomas with epithelioid cells, giant cells, and lymphocytes|
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Systemic corticosteroids (prednisolone 5 mg OD) were continued with remission in few months. After one and half year the patient reported with progression of the disease with severely increased manifestations, diffuse facial swelling, severe periorbital edema leading to left eye closure [Figure 4] and [Figure 5]. Serum angiotensin-converting enzyme and C-reactive protein were done to check for development of systemic Sarcoidosis or CD; both were within normal limits. Patient was advised to follow strict treatment regimen and follow-up to check for progression into any systemic disease. Currently, the patient is on intermittent dosages of steroids with decreased symptoms.
|Figure 4: Marked facial swelling. Periorbital edema leading to secondary ptosis more pronounced with the left eye|
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|Figure 5: Severe macrochelia with eversion of the lips, marked angular, and median chelitis with bleeding on slight provocation. Gingival enlargement could also be seen|
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| Discussion|| |
OFG was first introduced by Wiesenfeld et al. and included the previously recognized clinical entities of Melkersson–Rosenthal syndrome and cheilitis granulomatosa. Melkersson–Rosenthal syndrome is a triad of recurrent orofacial swelling, relapsing facial paralysis, and fissured tongue. However, in current practice, the term OFG is causing bewilderment among the clinicians and is often used to encompass other granulomatous conditions when restricted to oral tissues. Earlier reports that all OFG cases progress to CD are not now accepted. Both OFG and Oral Crohn's Disease (OCD) appear to be distinct clinical disorders. It may be logical to use the term idiopathic OFG when all the other possibilities are excluded. In the present case, no other systemic disease could be sought out as of now. In the light of clinical features (more labial presentation, less ulcerations, absence of mucosal tags and cobblestone appearance) and serology, we consider it to be Idiopathic OFG.”
The clinical features of this disease extraorally in the frequency of occurrence are swelling of lips and face which become persistent as the disease progresses, fissuring of lips, angular cheilitis, and perioral erythema. Intraoral manifestations include cobblestone appearance of buccal mucosa, ulcers, granulomatous gingivitis, mucosal tags, and fissured tongue rarely. Gingival enlargement reported by few authors was not a feature in a study of 119 OFG patients. In the reported instance, generalized gingival enlargement was present which recurred after excising once. A new type of stomatitis has been described relatively recently in oral manifestations of OFG and CD that represents an oral mucosal infection with Staphylococcus aureus. It has not previously been reported in patients with inflammatory bowel disease. However, in the present case, MRSA was obtained on pus culture emphasizing the need for meticulous antibiotic therapy to any OFG patient. The involvement of eyes in the present case to such a severe extent is very rare. The eyelid swelling is reported to be typically painless, nonpruritic with nonpitting edema, and may fluctuate over time and involve other parts of the face.
Many theories have been postulated about the etiopathogenesis of OFG; however, no consensus is yet achieved. Role of genetics, environmental, dietary, and infective factors is suspected. It is generally accepted that orofacial CD and OFG without proven CD share a similar etiopathogenesis. In OFG, a delayed type of hypersensitivity reaction appears to be involved, although the exact antigen appears to vary in individual patients. Evidence for a simultaneous overexpression of Protease-Activated Receptors, MMPs and COXs were obtained in a study, suggesting that these receptors and enzymes could synergistically contribute to the proinflammatory mechanisms of OFG.
The initial description of the disease was presence of multiple noncaseating giant cell granulomata, considered to be histologically indistinguishable from those found in systemic CD and Sarcoidosis. However, later, it was seen that the histology in this condition is fairly specific with the differential lymphocyte count showing overstimulation of the Th2 CD4+ leucocyte pathway. This T cell clonality is absent in OCD, and Th1 CD4+ lymphocytes are a hallmark in OCD. Higher number of CD3+ T cells and dendritic cells were observed in OFG compared to OCD suggesting different composition of the inflammatory infiltrate. Moreover, loose macrophage clusters, granulomatous lymphangitis, fibrosis which are present in OCD are unlikely in OFG.
The differential diagnosis of the disease includes lesions presenting as noncaseating granulomatous inflammation. Histopathologically, TB sometimes presents with nonnecrotizing granulomas (24% in a study), hence should be considered in the differential diagnosis. Lesions may be primary or secondary to systemic infection with an incidence of 0.05–1.5%. Although most common sign is chronic nonhealing ulcer with slightly undermined edge, oral TB is also reported to manifest in the form of generalized gingival enlargement. Diagnosis of oral TB is confirmed by demonstration of acid fast bacilli in the lesional tissue or by culture. Chest radiographic examination and Mantoux test should be sought to rule out systemic TB. In the present case the lesional tissue was negative for AFB and normal chest radiograph was present.
Sarcoidosis, a chronic systemic disorder of unknown etiology affecting multiple organs is characterized by formation of noncaseating granulomas in the affected organs without staining for any organism or tissue architecture derangement. It has rare occurrence in pediatric population. Pulmonary infiltration and hilar lymphadenopathy are the common presentations. Oral involvement though less common may sometimes be the first manifestation presenting in the form of nodules, ulcers, or papules of the mucosa or reddish gingival enlargement. Diagnosis of Sarcoidosis is confirmed by chest radiography for hilar lymphadenopathy, elevated serum ACE and calcium levels and biochemical markers for liver and kidney function tests. However, in the reported case all the parameters were within normal range with normal chest radiography.
CD is inflammatory disease of the bowel with the terminal ileum being most commonly affected. The disease is common in the western countries affecting higher socioeconomic group and adults. Most common symptoms include long-standing diarrhea, weight loss, and abdominal pain. Traditional teaching states that CD is a disorder affecting “the mouth to the anus; however, isolated CD of the upper gastrointestinal tract and especially OCD is a relatively uncommon finding where understanding of its pathogenesis is evolving. Currently, OCD and OFG are separated on clinical grounds, where OFG tends to present with more labial pathology and less oral ulceration. Laboratory abnormalities include elevated Erythrocyte sedimentation rate and CRP. In more severe disease, findings include hypoalbuminemia, anemia, and leucocytosis. Current patient presented with no GI symptoms and the clinical features of more labial pathology helped to rule out CD along with normal albumin, leucocyte, CRP, and ESR.
Spontaneous remission of OFG is rare. For reasons of the uncertainty of the etiology of the disease, rational therapy is, as yet, not available. Both the patient and the clinician should be well aware of the frustrating nature of OFG, and the treatment modality should be changed depending on the changing severity. Corticosteroids act as mainstay of therapy and other immunomodulatory agents have been used. It includes number of topical, intralesional and systemic medications. Intralesional triamcinolone can be used with pimecrolimus 1%, though role of pimecrolimus is unclear. Systemic corticosteroids like prednisolone may give remission in up to 50% of cases. Clofazimine 100 mg 4 times weekly for 3–11 months is tried with complete remission in 5 out of 11 patients. Recently, antitumor necrosis factor-α drugs have been studied with some success and are used in severe cases where other available agents have failed. Thalidomide is tried in recalcitrant cases. However, many times the treatment is unrewarding when the diagnosis is delayed. Hence, early diagnosis and prompt treatment are must.
| Conclusion|| |
Recently, the cases of OFG are on an upsurge the reason could be wide recognition of the disease; however, every patient should be meticulously tested for other granulomatous diseases. Further emphasis should be given on long-term follow-up of the patients. Clinicians should be aware of the unpredictable nature of the disease, should always motivate both patients and their guardians as this disease frequently affects children, is recalcitrant and requires long-term follow-up.
Declaration of patient consent
The authors certify that they have obtained all appropriate patient consent forms. In the form, the patient has given his consent for his images and other clinical information to be reported in the journal. The patient understand that name and initials will not be published and due efforts will be made to conceal identity, but anonymity cannot be guaranteed.
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Conflicts of interest
There are no conflicts of interest.
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Dr. Priya Anil Bhagde
Government Dental College and Hospital, Aurangabad, Maharashtra
Source of Support: None, Conflict of Interest: None
[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5]