Orofacial granulomatosis – a 20-year review

Orofacial granulomatosis (OFG) is the presence of persistent enlargement of the soft tissues of the oral and maxillofacial region, characterized by non-caseating granulomatous inflammation in the absence of diagnosable systemic Crohn's disease (CD) or sarcoidosis. Over 20 years have passed since OFG was first described and an extensive review of the literature reveals that there is no consensus whether OFG is a distinct clinical disorder or an initial presentation of CD or sarcoidosis. Furthermore, the precise cause of OFG is still unknown although several theories have been suggested including infection, genetic predisposition and allergy. The clinical outcome of OFG patients continues to be unpredictable. Current therapies remain unsatisfactory. Regular clinical review is indicated to identify the development of gastrointestinal or systemic involvement. The aim of this review was to analyse the developments in our understanding of the aetiology, pathogenesis and treatment protocols, with particular emphasis on management and outcomes of OFG since this entity was first described in 1985.     

口腔颌面部肉芽肿性疾病

口腔颌面部肉芽肿性疾病是一组病因不同,但以肉芽肿性炎症和肉芽肿形成为共同病理特征的颌面部疾病的总称,该病发病机制目前仍不清楚,其诊断复杂,在治疗上也存在很大差别.本文将从病因、诊断、治疗等方面,对口腔、颌面部发生的肉芽肿性疾病进行归纳.     

Orofacial granulomatosis: presentation, pathology and management of 13 cases

BACKGROUND: Orofacial granulomatosis (OFG) comprises of a group of conditions, all characterized histologically by the presence of granulomatous inflammation. METHODS: This diagnosis may be determined by exclusion from other conditions that may present with similar clinical and histopathologic features. These include Melkersson-Rosenthal syndrome (MRS), Miescher's cheilitis (an oligosymptomatic form of MRS), Crohn's disease, and sarcoidosis. RESULTS: A great deal of attention has been devoted to the similarity and overlap in clinicopathologic and histomorphologic features of these conditions, suggesting that they may actually represent a spectrum within a single overarching entity. In the review of the 13 cases of OFG retrieved from the files of the Long Island Jewish Medical Center, Department of Dental Medicine, we describe their presentation, clinicopathologic features, and management. These cases comprise examples of MRS (in its oligosymptomatic forms) and Crohn's disease. The similarity, kinship, and overlap between the cases presented are clearly demonstrated. CONCLUSION: In addition, based upon our observations and review, we propose the notion that oral manifestations of Crohn's disease may be classified as an oligosymptomatic form of MRS.     

Antibodies to mycobacterial stress protein in patients with orofacial granulomatosis

Immunoglobulin G antibody liters to the mycobacterial stress protein with molecular weight of 65 kDa (mSP65) were determined by ELISA in sera from 10 patients with orofacial granulomatosis (OFG). Four patients with confirmed Crohn's disease had serum antibodies to mSP65 with liters ranging from 400–950. Of six remaining patients, three patients had serum antibodies to mSP65 with titers ranging from 180–850. whilst no serum antibody to this antigen could be detected in 3 patients. However, other laboratory investigations failed to show any consistent pattern of disturbance in the 10 tested. Thus, the presence of serum antibody to mycobacterial 65 kDa stress protein might prove lo be of a diagnostic value for Crohn's disease.     

The multiform and variable patterns of onset of orofacial granulomatosis

BACKGROUND: The recurrent chronic orofacial swelling caused by orofacial granulomatosis (OFG) can cause significant cosmetic and functional problems but can be prevented if the disease is diagnosed early and promptly treated. Although the enlargement of the lips is described to be the most common presenting complaint, the clinical onset of OFG may be characterized by minor associated mucosal and neurological manifestations, making early diagnosis very difficult or, sometimes, merely presumable. PATIENTS AND METHODS: We retrospectively analyzed the clinical manifestations of 19 patients with OFG, who were examined at our institution between 1998 and 2002, in order to determine their initial manifestations and presenting symptoms. RESULTS: A total of 10 patients showed classical recurrent enlargement of the lips (six lower; four upper) as presenting symptom. In the other nine patients, OFG onset was characterized by transient unilateral facial nerve palsy (two cases), intraoral manifestations (two cases), recurrent swelling of the periorbital area (two cases), of the chin (one case), of the zygomatic area (one case), and of the cheeks (one case). CONCLUSION: Our data underlined that OFG onset could be frequently characterized by widely variable, multiform, and temporary clinical findings. Involvement of atypical sites of the orofacial region and presence of single minor manifestations may occur as presenting symptoms, often preceding the development of traditional clinical findings.     

Onset and progression of clinical manifestations of orofacial granulomatosis

Background:  There remain few studies describing in detail the early occurrence and long-term progression of clinical manifestations of orofacial granulomatosis (OFG) in a substantial number of patients.
Objectives:  The aim of this study was to determine the early and late clinical manifestations of a large case series of patients with OFG.
Patients/methods:  Clinically relevant data of 49 patients with OFG who attended an Oral Medicine unit in the UK were examined retrospectively. The analyzed parameters included occurrence and typology of initial manifestations at onset and with respect to long-term follow-up.
Results:  Five major patterns of disease onset were observed. Recurrent facial swelling with/without intra-oral manifestations was the single most common presentation at onset followed by intra-oral ulcers, and other intra-oral and neurological manifestations. The majority of patients later developed a spectrum of additional features.
Conclusions:  OFG results in multiple manifestations at different time points. The disease onset is characterized by manifestations other than facial swelling in about half of affected individuals. However, patients can develop cosmetically unacceptable lip/facial swelling at a later stage. Nearly all affected individuals ultimately develop lip/facial swelling while about half of all patients develop oral ulceration.     

Orofacial granulomatosis: A diagnostic problem for the unwary and a management dilemma. Case reports

Orofacial granulomatosis is a condition that may be difficult to diagnose for those unfamiliar with the entity. This paper describes two cases and addresses the presentation, pathogenesis and treatment. The clinical recognition of this condition is important as is the subsequent investigation by an appropriate specialist. Management of patients needs to take into account the results of further investigations, the patient's expectations, and the severity of the condition.     

Non-specific influx of T-cell receptor alpha/beta and gamma/delta lymphocytes in mucosal biopsies from a patient with orofacial granulomatosis

Orofacial granulomatosis (OFG) represents an inflammatory disorder of the facial and oral mucosa, histologically characterized by non-caseating epithelioid cell granulomas. Since other granulomatous diseases have been shown to be characterized by a limited heterogeneity of alpha/beta and gamma/delta T cells, we investigated the T-cell diversity of both types of lymphocytes obtained from the same OFG patient. When we compared the T-cell receptor diversity of the lymphocytes accumulating at the site of the lesions with that of the peripheral blood counterpart, we did not find significant differences. Furthermore, no exclusive expansions of different T-cell clones were seen in the patient. From these data we conclude that, in this OFG patient, the majority of T cells have no specificity for a single or for a few antigens and that tissue accumulation of T lymphocytes is the result of a random influx of cells at the site of inflammation.     

Orofacial granulomatosis: 2 case reports and literature review

Orofacial granulomatosis comprises a group of diseases characterized by noncaseating granulomatous inflammation affecting the soft tissues of the oral and maxillofacial region. The most common clinical presentation is persistent swelling of one or both lips. It is important to establish the diagnosis accurately because this condition is sometimes a manifestation of Crohn's disease or sarcoidosis. This article describes 2 cases of orofacial granulomatosis, in one of which the condition was a manifestation of Crohn"s disease. The diagnostic approach to and the treatment of orofacial granulomatosis are reviewed.     

Biologics in oral medicine: oral Crohn's disease and orofacial granulomatosis

Oral Diseases (2012) 18, 633-638 Antitumour necrosis factor (TNF-α) therapy has a potential to benefit patients with oral lesions of Crohn's disease (CD) and patients with orofacial granulomatosis (OFG). The most appropriate use would appear to be in patients with severe or multisystem features, where other available agents have failed or have been associated with adverse effects. TNF-α antagonists (infliximab in particular) have a role in the management of orofacial CD and OFG, but potential adverse effects of TNF-α antagonists include acute infusion reactions, infection and increased risk of malignancy. Thus, a full risk-benefit analysis is indicated, with patient selection, use and subsequent monitoring coordinated with gastroenterologists with appropriate training and experience in biological therapies.     

Lip impressions: a new method for monitoring morphological changes in orofacial granulomatosis

AIM: To develop and evaluate an objective method for assessing lip size and treatment-related morphological changes in orofacial granulomatosis (OFG) patients. MATERIALS AND METHODS: Patients with swollen lips because of OFG (n=21) were enrolled. A light-body polyvinylsiloxane material was used to take lip impressions before and after treatment (n=10), or during treatment (n=11). Plaster models were cast from the impressions and the lips were measured using callipers. The intra-examiner and inter-examiner reproducibility of the technique were assessed. RESULTS: OFG patients had significantly larger lips than controls (P<0.0001). The coefficient of variation on repeated measurements of the same impression was 1.6% and for duplicate impressions was 2.6%. Significant reduction in lip size was shown in all 10 patients after diet restriction (P<0.002). Seven of 11 patients whose impressions were taken at least 3 months after the initiation of cinnamon- and benzoate-free diet also showed reduction in lip size during follow up (P<0.002). CONCLUSIONS: Serial lip impressions appear to be reliable for routine quantification of morphological changes of the lips in OFG patients. We present a new reproducible and sensitive method for assessing changes in lip size in response to treatment in OFG.     

Orofacial sensitivity reactions and the role of dietary components. Case reports

Dietary components have proven to be important aetiological factors in orofacial sensitivity reactions such as plasma cell gingivitis and orofacial granulomatosis. The use of elimination diets to identify these dietary antigens can be instrumental in both diagnosis and effective treatment for these disorders.     

Patch testing for food‐associated allergies in orofacial granulomatosis

J Oral Pathol Med (2011) 40 : 10–13 Background: Food‐associated allergies, especially to benzoates and cinnamon‐related compounds, have been associated with orofacial granulomatosis and both standard and urticarial patch testing have been used to detect such allergies. Elimination diets have also been shown to be effective in some patients. Objectives: To compare the results of standard and urticarial patch testing in a cohort of patients with orofacial granulomatosis. Materials and methods: Records of 120 cases seen in two hospitals were retrieved and examined for patch test details. Results: Standard patch testing was much less likely to detect allergy to benzoates and cinnamon compounds (7%) than urticarial tests (55%). All urticarial tests that were positive had shown a reaction by 60 min. Conclusions: Both standard and urticarial patch tests are required to detect food allergies in orofacial granulomatosis. The difficulties of patient self‐recording of urticarial tests can be eliminated by retaining patients in the testing unit for professional reading of patches at 60 min.     

The epidemiology of lip cancer: a review of global incidence and aetiology

Lip cancer (140 ICD-9) is a form of oral cancer that has a distinctive global epidemiology. This review summarises global incidence rates for male and female lip cancer with the aid of cancer atlases. High male lip cancer rates are reported for regions of North America (12.7 per 100 000 per annum), Europe (12.0 per 100 000 per annum) and Oceania (13.5 per 100 000 per annum), while it is virtually unknown in parts of Asia. Factors commonly cited as important in the aetiology of lip cancer include solar radiation, tobacco smoking and viruses. An attempt is made to summarise the evidence for factors that may be important in lip carcinogenesis. While incidence rates are generally stable or falling among males worldwide, they are rising in many female populations. The aetiology of the disease is far from established and much information regarding its pathogenesis is based on anecdotal rather than case-controlled epidemiological evidence. The epidemiology of lip cancer supports the proposal that the lip should be considered as a distinct cancer site, rather than being included with other forms of intraoral cancer.     

Orofacial trauma and rugby in France: epidemiological survey

Abstract  – A stratified epidemiological survey was carried out among the best French rugby players to assess the prevalence of trauma to the lower or middle part of the face (TLMPF) and the frequency at which the mouthguards (MGs) were worn. The 1140 randomized players (elite 1, elite 2 and national 1 clubs) filled in the same form anonymously. The variables were first subjected to univariate analysis (Chi-square, anova ). Secondly, they were included in a multivariate model (logistic regression). Some 29.57% of players had already been affected by a TLMPF. The risk increased for the oldest forward players. It also increased with the number of yearly competitions and number of hours of weekly training. Some 64.3% of players used a MG. The frequency at which it was worn increased with the number of yearly competitions, for those who had experinced a previous trauma and for the pack players who had been playing for a long time.     

Wegener's granulomatosis: a review of clinical features and an update in diagnosis and treatment

Wegener's granulomatosis (WG) is an idiopathic, systemic inflammatory disease characterized by necrotizing granulomatous inflammation and pauci‐immune small‐vessel vasculitis of upper and lower respiratory tract and kidneys. The condition affects both genders equally, although some inconsistent gender differences have been observed. The aetiology of WG remains unknown although a number of exogenous factors have been suggested to be of aetiological relevance. Most clinical characteristics of this disease are non‐specific, making clinical diagnosis challenging. Histopathological examination of lesional and peritoneal tissue is not pathognomonic, but is an essential investigation to confirm the presence of disease and exclude other disorders. At present, despite the increasingly wide range of potential therapies, cyclophosphamide plus corticosteroids remain the most recognized and effective means of inducing and sustaining remission of WG.     

Characteristics of patients with orofacial granulomatosis

Oral Diseases (2011) 17 , 696–704 Objectives: Orofacial granulomatosis has mostly been described in reports of very small numbers of cases. Few large case groups have been described. The aim of this study was to describe the demographics, symptoms, clinical features and laboratory findings in a large cohort of cases. Subjects and Methods: Clinical and laboratory data for 119 cases of orofacial granulomatosis who attended oral medicine clinics in Dublin, Ireland, were examined for demographic characteristics at the time of first presentation. The male/female ratio was approximately 1:1, with a median age (and range) of 28 (5–84) years. Results: Symptoms had been present for a median duration of 12 weeks. A food association was suspected by 30% of patients. The predominant complaint was lip swelling (77%) with only 15% reporting facial swelling, while 8% complained of both. Almost all patients had clinical evidence of lip or facial swelling (95%). Other common extra‐oral manifestations were lip fissuring (30%), angular cheilitis (28%) and perioral erythema (28%). Common intra‐oral manifestations were cobblestoning of the buccal mucosa (63%), ulcers (36%), granulomatous gingivitis (33%), mucosal tags (29%) and fissured tongue (17%). Over half of the biopsies (56%) performed were reported as typical of orofacial granulomatosis. Conclusion: This is one of the largest cohorts of orofacial granulomatosis patients to have been described in detail.     

Expression of protease-activated receptor-1 and -2 in orofacial granulomatosis

OBJECTIVE: Orofacial granulomatosis (OFG) is a rare condition characterized by non-caseating granulomas in the orofacial region. Protease-Activated Receptors (PARs) play a role in inflammatory diseases in diverse human tissues. The aim of the study was to investigate the expression of PAR-1, PAR-2, MMP-2, MMP-9, COX-1, and COX-2 in tissues taken from OFG patients. METHODS: PAR-1, PAR-2, MMP-2, MMP-9, COX-1, and COX-2 expression was evaluated by immunohistochemistry in biopsies taken from oral Crohn's disease (five cases), Melkersson-Rosenthal syndrome (MRS) (six cases), cheilitis granulomatosa (five cases) and normal oral mucosa (five cases). RESULTS: PAR-1 was observed in mononuclear inflammatory cells in edematous/lichenoid lesions, whereas a strong PAR-2 immunostaining was detected in epithelioid histiocytes and giant cells in granulomatous lesions, irrespective of the clinical features (Crohn vs MRS). MMPs and COX-2 were expressed in the inflammatory component of edematous/lichenoid lesions and markedly overexpressed in granulomatous lesions. COX-1 was weakly and variably expressed in both edematous/lichenoid and granulomatous lesions. CONCLUSION: Thus, PAR-1 and PAR-2 expressions were related to the intensity and type of inflammatory response but not to the type of clinical lesion. Simultaneous overexpression of PARs, MMPs and COXs suggests synergism among these proinflammatory receptors and enzymes.