Orofacial Granulomatous Inflammation

Granulomatous inflammation of the oral and oropharyngeal submucosal tissues is not common, but when found it presents a definite diagnostic dilemma because of the wide variety of possible etiologic diseases and the rather generic appearance of the individual lesions. The matter is made more confusing by the common use of the term "granuloma" to describe maxillofacial diseases with little or no resemblance to true granulomas, such as pyogenic granuloma, periapical granuloma, peripheral giant cell granuloma, pulse granuloma, traumatic eosinophilic granuloma, and epulis granulomatosa. The group of true granulomatous diseases is collectively called orofacial granulomatoses.

Until the latter two-thirds of the twentieth century, the most common of the oral granulomatous lesions were those produced by tuberculosis and tertiary syphilis.  Today they are more likely to represent oral manifestations of autoimmune disorders, such as Crohn's disease and sarcoidosis, or localized allergic reactions, or deep fungal infections.  The name of the associated systemic disease is traditionally applied to oral lesions, whenever possible, but a certain number of cases remain idiopathic and are diagnosed simply as granulomatous mucositis or orofacial granulomatosis.  Before such generic terminology can be applied, however, the pathologist must make every effort to rule out histologically distinctive granulomatous diseases and specific granulomatous infectious processes (Table 1). Cases associated with systemic disease may present with or without involvement of extraoral regions at the time of diagnosis.

Granulomatous lesions of the oral and oropharyngeal mucosa usually present as sessile, lobulated, moderately firm and relatively nontender nodules and papules with normal coloration and with little or no surrounding inflammatory mucosal erythema. With time, some of the granulomas may ulcerate centrally and present as a deep, painless ulcer with a nonerythematous rolled border, reminiscent of squamous cell carcinoma. The granulomas of tertiary syphilis, tuberculosis and deep mycotic infections may reach a size of more than 2 cm., but those related to autoimmune phenomenon, especially sarcoidosis, cheilitis granulomatosa and Crohn's disease, typically remain small and often present as multiple nodules and papules, sometimes clustered together to impart a cobblestone appearance to the mucosa.

Several granulomatous diseases have unique clinical features. The granulomas of deep fungal infections, Langerhans cell disease (eosinophilic granuloma), sarcoidosis and Wegener's granulomatosis may destroy underlying bone when located on gingival or alveolar mucosa. This is also true for palatal lesions of tertiary syphilis and tuberculosis, which have a special affinity for perforating the hard palate. Granulomatous gingivitis is the only granulomatous lesion typically associated with pain and, of course, by definition must occur on gingival mucosa.  Extensive involvement of submucosal areas may produce a generalized enlargement of the affected site, especially noticeable on the lips and tongue, as in cheilitis granulomatosa, Melkersson-Rosenthal syndrome and syphilitic glossitis.

Most granulomatous lesions of the oral region present as small, non-caseating granulomas with peripheral lymphocytes, central epithelioid histiocytes and, usually, multinucleated giant cells (Figure 1). Foreign bodies within the giant cells and histiocytes may polarize (Figure 2) and micro-organisms may be identified by appropriate bacterial and fungal stains (Table 1). Wegener's granulomatosis may have no granulomas visible but will show a pattern of mixed inflammatory infiltrates around blood vessels, with focal areas of necrosis and areas with heavy neutrophilic infiltration and nuclear dust. The oral epithelium in this disease may demonstrate severe acanthosis or pseudoepitheliomatous hyperplasia, as may granulomatous infection by blastomycosis, and it is the granulomatous disease most likely to be associated with extravasated erythrocytes.

Many of the granulomatous diseases listed in Table 1 require physical examination and laboratory evaluation for an appropriate diagnosis. These are beyond the scope of the present chapter and will not be further discussed.

The treatment of orofacial granulomatosis and the various forms of granulomatous mucositis will depend on the underlying or systemic cause. Localized lesions without systemic connection can be treated by conservative surgical removal and plastic surgical reconstruction. Prior to surgery, a host of medications may be used with variable results: intralesional and systemic corticosteroids, low-dose radiotherapy, methotrexate, dapsone, salazosulfapyridine (sulfasalazine), hydroxychloroquine sulfate, among others. No therapy has proven to be universally effective in orofacial granulomatosis without systemic involvement.

Many lesions eventually resolve spontaneously with or without therapy, but others continue to progress despite rather aggressive therapy. For those oral lesions which are manifestations of systemic disease, the prognosis of oral lesions will depend on the patient's response to therapies for the systemic disease.

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