Orofacial granulomatosis (OFG) is an uncommon disease characterized by persistent or recurrent soft tissue enlargement, oral ulceration and a variety of other orofacial features. It could be an oral manifestation of a systemic disease. For a correct differential diagnosis, local and systemic conditions characterized by granulomatous inflammation should be excluded using appropriate clinical and laboratory investigations. In fact, the diagnosis of OFG may be confirmed only by histopathological identification of noncaseating granulomas. The literature from 1943 to 2014 was reviewed with emphasis on the etiology of OFG and on clinical manifestations of systemic pathologies associated with OFG. The precise cause of OFG is still unknown, although several theories have been suggested, such as infection, hereditary factors and allergy. OFG is a disease that has a wide spectrum of presentation, which may include the oral manifestation of a systemic condition such as Crohn's disease, sarcoidosis, granulomatosis with polyangiitis and Melkersson-Rosenthal syndrome.

Orofacial granulomatosis (OFG) includes a group of diseases characterized by the presence of noncaseating granulomatous inflammation affecting the soft tissues of the oral and maxillofacial region [1]. OFG may be the oral manifestation of a systemic condition such as inflammatory bowel disease (IBD), sarcoidosis, granulomatosis with polyangiitis (GPA) and Melkersson-Rosenthal syndrome (MRS) [2,3,4]. These pathologies are part of a differential diagnosis of other granulomatous diseases, such as tuberculosis, leprosy, systemic fungal infections and foreign body reactions [5]. The diagnosis of OFG is made by histopathological identification of noncaseating granulomas. Local and systemic conditions characterized by granulomatous inflammation should be excluded by appropriate clinical and laboratory investigations [6]. This review focuses on the oral clinical aspects and the etiology of OFG.

A review of the literature was carried out using the computerized database ‘PubMed Medline' without specifying the year of publication. Inclusion criteria were papers searched by key word or titles using the following combinations: orofacial granulomatosis, oral manifestations of inflammatory bowel disease, oral sarcoidosis, oral manifestations of granulomatosis with polyangiitis and Melkersson-Rosenthal syndrome. The abstracts of the articles were reviewed in order to exclude irrelevant studies, and clinical opinion papers were excluded. Attention was paid to other articles that did not appear in the main search, by the reference lists of key articles in the field. Only English abstracts were included in the study. Following the preliminary identification of 123 articles, only 24 were identified as meeting the inclusion criteria. The following oral manifestations were observed: IBD, sarcoidosis, GPA and MRS.

IBD comprises two chronic clinical entities: Crohn's disease (CD) and ulcerative colitis (UC), both immunologically based [7]. CD can cause transmural inflammation and affect any part of the gastrointestinal tract (most commonly, the terminal ileum or the perianal region) in a discontinuous type. CD is commonly associated with complications such as abscesses, fistulas and strictures, but UC is characterized by mucosal inflammation and limited to the colon [8,9,10]. The key factors responsible for IBD include genetic components, environmental factors, microbial flora and immune responses. IBD arises from an extremely complex interaction among genetic and environmental factors, dysregulated immune responses and alterations in the microbiota, but none of these factors alone is likely to cause the disease [11]. Bowel symptoms are predominant, but extraintestinal complications may occur in these pathologies, including the involvement of the oral cavity. CD and UC are commonly associated with abdominal pain, diarrhea, rectal bleeding, weight loss and signs of malnutrition [12]. Approximately one third of IBD patients develop extraintestinal manifestations in the course of their disease [13]. The most common extraintestinal manifestations involve the joints, skin, eyes and biliary tract [14].

The association between OFG and IBD was especially noted in CD rather than in other IBD events. Oral manifestations have a prevalence ranging from 20 to 50%, and initial presenting signs occur in 5-10% of affected patients (fig. 1a). Lesions are usually more severe during active disease, but up to 30% of patients may continue to manifest oral lesions despite disease control [15]. The most common intraoral site seems to be the lips. The oral manifestations of CD can be divided into specific and nonspecific lesions, based on the presence/absence of granuloma during the histopathological examination (table 1). Specific lesions are less common than nonspecific ones and, at histopathological examination, present typical granuloma characteristics [16].

Table 1

Specific and nonspecific oral lesions of CD

Specific and nonspecific oral lesions of CD
Specific and nonspecific oral lesions of CD
Fig. 1

a Intraoral manifestation of CD. b Oral sarcoidosis: intraoral granulomatosis. c Histological sample of oral tissues in a patient with sarcoidosis. d Radiological aspect of the lung in a patient with sarcoidosis. e Strawberry-like gingivitis in a patient with GPA. f MC in a patient with MRS.

Fig. 1

a Intraoral manifestation of CD. b Oral sarcoidosis: intraoral granulomatosis. c Histological sample of oral tissues in a patient with sarcoidosis. d Radiological aspect of the lung in a patient with sarcoidosis. e Strawberry-like gingivitis in a patient with GPA. f MC in a patient with MRS.

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Indurated tag-like lesions are white reticular tags referred to as mucosal tags, epithelial tags or folds. Another kind of presentation is called ‘cobblestoning', which means fissured swollen buccal mucosa with corrugation and hyperplastic behavior of the mucosa. The lesions often appear as mucosal-colored papules that produce firm plaques on the buccal mucosa and palate. These lesions are pathognomonic for CD but are not associated with intestinal CD activity [17,18]. Another oral involvement common to CD is a particular form of mucogingivits. The whole gingiva, up to the mucogingival line, might be involved. The gingiva may become edematous, granular and hyperplastic with or without ulceration [19,20]. Other specific lesions are deep swelling with vertical fissures and deep linear ulceration. These lesions could cause pain and are a discomfort to the patients; they are not associated with intestinal activity. Nonspecific lesions are not pathognomonic of CD (table 1).

Sarcoidosis is a systemic granulomatous disease of unknown cause affecting mostly young and middle-aged adults. The highest annual incidence of sarcoidosis has been observed in northern European countries (5-40 cases per 100,000 people) [21]. This pathology affects multiple organs, especially the lungs, lymph nodes, skin and eyes. Some studies confirm a genetic predisposition to sarcoidosis and present evidence for the allelic variation at the HLA-DRB1 locus as a major cause [22]. In the maxillofacial region, the salivary glands are often involved, and this may cause xerostomia or bilateral parotid swelling [23,24,25]. The involvement of the oral cavity seems to be rare with an unknown prevalence. Oral sarcoidosis usually appears in patients with chronic multisystemic sarcoidosis and presents as first manifestation of the disease in one third to almost two thirds of patients [26]. In 1943, Poe [27] reported the first documented case of oral sarcoidosis; since then, there have been only 68 well-documented cases of isolated oral sarcoidosis reported in the English literature. These lesions were localized swellings or nodules (n = 34; fig. 1b), ulcers (n = 4), swelling with multiple ulcers (n = 2), gingivitis (n = 3), gingival hyperplasia (n = 3) and gingival recession (n = 1). In 24 cases, these oral lesions were the first manifestation of systemic sarcoidosis [28,29].

Only some cases of oral sarcoidosis require treatment, because in nearly 60% of patients, the symptoms resolve spontaneously within 2 years. When lesions are localized, surgical excision is commonly employed, allowing both histopathological confirmation of sarcoidosis and treatment with systemic corticosteroids (fig. 1c, d) [30].

GPA is a systemic inflammatory disease characterized by necrotizing granulomatous inflammation and small-vessel vasculitis of the upper and lower respiratory tract and kidneys; however, other organs or tissues may be affected [31]. The world prevalence of GPA seems to be 23.7-156.5 cases per million [32], with an estimated annual incidence of 3.0-14.4 cases per million [33]. Oral manifestations of GPA range from 6 to 13% of patients, and the mouth may be the initial site of clinical presentation in 5-6% of cases [34,35]. The most common oral manifestations of GPA are strawberry-like gingivitis, erythema, osteonecrosis of the palate, desquamation and nodular masses of the lips, petechiae and ulceration. Particularly strawberry-like gingivitis or hyperplastic gingival lesions are suggested to be a characteristic sign of GPA (fig. 1e) [36,37,38]. This sign consists of reddish-purple exophytic gingival swellings with petechial hemorrhages, thus similar to strawberries. This lesion can remain localized in the oral cavity for unusually long periods of time before multiorgan involvement occurs [39].

MRS is a rare, noncaseating granulomatous disease consisting of persistent or recurrent orofacial edema, relapsing peripheral facial paralysis and a fissured tongue [40]. Similar oral granulomatous reactions that are not associated with other detectable systemic diseases or foreign bodies may be present in Miescher's cheilitis (MC). MC is a term used when lip swelling is the unique clinical sign (fig. 1f) [41]. MRS is also associated with some other syndromes, including trigeminal neuralgia, paresthesias, ocular palsies, blepharospasm, epiphora, keratitis, psychotic episodes, uveitis and migraine [42,43]. MC may occur without other signs of the disease but may also be part of MRS; it could be a manifestation of CD and, rarely, of sarcoidosis. It is still debated whether MC should be considered as one of the extraintestinal manifestations of CD which can optionally be preceded by a few years of digestive problems or as a different disease entity. Van der Waal et al. [44], in a study of 13 MC cases, reported the appearance of gastrointestinal lesions of CD in 2 cases after a follow-up period of 2 years. This association has been supported by the results of another study [45]. Because of this association, in patients with MC, Pittock [46] recommended a screening for gastrointestinal lesions especially in children and young patients. The value of a systematic research of gastrointestinal lesions of MC has been reinforced by the fact that about one third of patients with OFG manifestations may have asymptomatic intestinal inflammatory lesions [44]. The treatment of MRS is controversial. Various modes of treatment have been proposed, including nonsteroidal antiinflammatory drugs, antibiotics, antihistamines, lymecycline, systemic and intralesional corticosteroids and methotrexate [47,48,49]. The fissured tongue is congenital and is usually asymptomatic and benign and does not require any treatment [45].

Introduced by Wiesenfeld et al. [2] in 1985, the term ‘etiology of orofacial granulomatosis' is used to describe diseases which have a variety of clinical presentations but also a similar histopathological picture to nonspecific, noncaseating granulomatous inflammation. OFG is either considered a different pathology or a manifestation of systemic disease [2,50]. The precise cause of OFG is still unknown, although several theories have been suggested including infection, hereditary factors and allergy. A genetic predisposition has been evaluated in different studies; some of these suggested the occurrence of the disease in families and a frequent expression of some HLA antigens among the patients compared with the normal population, possibly of autosomal dominant transmission with incomplete penetration and translocation at chromosome 9p11 [51,52]. It seems that consistent HLA genotypes are evident in patients with OFG, in particular A2/3, B7 and DR 2/3/4. These genotypes are known to occur in haplotype association. More studies are needed to validate these claims [53]. The possible role of infection in the pathogenesis of OFG has been suggested because of its involvement in CD and sarcoidosis [54]. Most studies have focused on Mycobacterium tuberculosis, M. paratuberculosis, Staphylococcus aureus and Borrelia burgdorferi [50,51,52,53]. Apaydin et al. [55] had used a ribosomal RNA amplification-based Gen-Probe amplified M. tuberculosis direct test to determine the presence of the M. tuberculosis complex in skin biopsy specimens from 5 patients with MRS and 1 patient with OFG. Three (all belonging to the MRS samples) of the 6 patients were positive; 1 of the positive specimens also showed positive Ziehl-Neelsen staining. M. paratuberculosis was investigated by Riggio et al. [56] in 1997 using polymerase chain reaction on 37 samples (30 OFG and 7 CD). The results of this study suggested that in this patient group, M. paratuberculosis did not appear to be associated with OFG or the oral lesions of CD [56]. S. aureus had been detected in mouths of 4 patients cultured using the oral rinse technique. It could represent a potential cause of panstomatitis in patients with OFG [57]. Some Chinese studies that evaluated the role of spirochetes in the etiology of OFG using Warthin-Starry special stain detected antibodies against B. burgdorferi in up to 82% of patients with cheilitis granulomatosa and MRS [58,59]. However, Muellegger et al. [60] who examined a retrospective study of 12 patients with OFG using polymerase chain reaction, ELISA and immunoblot test suggested that B. burgdorferi was not involved in the pathogenesis of OFG [60]. Hence, more studies are needed to clarify the role of this spirochete as an etiological factor of OFG.

Allergy in the form of hay fever, atopic eczema or asthma has been reported as being more prevalent, affecting 12-60% of OFG patients compared to 15% in the general population [61,62]. Many diseases affecting the orofacial region have an allergic basis, and the role of dietary antigens, in particular in the etiopathogenesis of OFG, seems to be compelling [63]. Examples include cinnamon and benzoates which were positive on patch tests in patients with a variety of oral mucosal diseases including OFG [64]. A study of 48 patients with OFG who were patch tested for their reaction to common food additives showed that 10 had a positive skin reaction and 7 showed improvement in their OFG with an elimination diet [62,65]. Occasionally, even delayed hypersensitivity to dental materials had been implicated in the etiology of OFG. Granulomatous reactions have been found in amalgam tattoos and in subcutaneous deposits of inorganic mercury [66,67]. One study assessing the utility of the cutaneous patch test showed that patients with OFG had more reactions to food additives, especially benzoic acid and chocolate, than other disease cohorts or controls [64]. However, there is no conclusive evidence to support a role for allergy as the cause of OFG.

OFG is a disease with a wide spectrum of presentations. OFG may be the oral manifestation of a systemic condition, such as IBD, sarcoidosis, GPA and MRS. The precise cause of OFG is still unknown. However, several theories have suggested an important role for infection, hereditary factors and allergy.

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