Granulomatous, immune-mediated, and autoimmune conditions

Clinical findings

• A nondescript, painless, or painful papule or nodule occurs at sites of trauma or at sites of iatrogenically introduced substances (such as dermal fillers). The latter are much more common in women and located around the lips, and they are often yellow in color ( Fig. 8.1 ).

  

• Dermal fillers may migrate to a site at some distance from the original injection site and an accurate history helps to confirm the diagnosis.

Etiopathogenesis and histopathologic features

Extrinsic foreign material introduced accidentally (e.g., glass or grit after falls or motor vehicle accidents) or intentionally (e.g., sutures, dermal fillers) excites a foreign body response. Semipermanent or absorbable fillers such as collagen, hyaluronic acid, poly- l -lactic acid, and hydroxyapatite are resorbed by the body, and the last three stimulate collagen production so that effects last 1 to 2 years. Permanent fillers such as silicone (used to treat HIV-associated lipodystrophy), polymethylmethacrylate, and polyalkylimide also stimulate neocollagenesis. Dermal fillers may migrate to sites distant from the original injection, such as to the lips or oral cavity from a nasolabial fold injection. Foreign body granulomas also form as a reaction to endogenous substances, such as cholesterol (from degenerated red blood cells, see Chapter 14 ), keratin (ruptured epidermoid cyst), hair (ruptured hair follicle usually with a fragment of hair that is refractile), and collagen (degenerated collagen in rheumatoid nodules).

• There are clusters of epithelioid histiocytes/macrophages forming granulomas that are usually nonnecrotizing with variable inflammation and variable numbers of multinucleated foreign body giant cells. Refractile or nonrefractile foreign material may be identified, such as fragments of hair ( Fig. 8.2 ), suture material ( Fig. 8.3 A–B), and resorbable gelatin used for hemostasis (see Fig. 8.3 C–D).

  
  

• Poly- l -lactic acid filler (e.g., Sculptra) granulomas form circumscribed nodules containing refractile, fusiform, and geometric structures that often contain asteroid bodies within giant cells. A lymphocytic infiltrate is often present ( Fig. 8.4 ).

  

• Calcium hydroxylapatite (e.g., Radiesse) granulomas are present diffusely in the stroma, often infiltrating between skeletal muscle, and consist of mauve-grey microspheres, 25 to 40 μm in diameter, that are nonrefractile ( Fig. 8.5 ).

  

• Silicone granuloma, a form of lipid granuloma, is present diffusely within the stroma and consists of macrophages with bubbly cytoplasm with variably sized vacuoles ( Fig. 8.6 A–D). Nonsilicone lipid granulomas appear the same and only the history distinguishes between the two ( Fig. 8.6 E–F).

  

• Polymethylmethacrylate (Artecoll) filler consists of microspheres that become surrounded and encapsulated by new collagen that is deposited ( Fig. 8.7 ).

  

• Cholesterol granulomas are common in odontogenic cysts (see Chapter 14 ), granulomas to keratin are often seen in keratinizing squamous cell carcinomas (see Chapter 11 ), and small granulomas may be present around large amalgam particles (see Chapter 9 ).

Differential diagnosis

• Hyaluronic acid fillers (e.g., Juvederm) appear as amorphous, basophilic pools of ground substance that stain for Alcian blue and colloidal iron. They rarely incite a foreign body reaction but may show mild fibrosis, although some cases become inflamed and/or infected ( Fig. 8.8 A-F).

  

• Resorbable collagen membranes appear as thick and thin squiggly collagen bands positive for trichrome stain and tend not to elicit a foreign body reaction (see Fig. 8.8 G–H).

• Palisaded granulomas of granuloma annulare and rheumatoid arthritis are rarely encountered intraorally.

• Atypical lipomatous tumor may resemble a silicone granuloma but will exhibit lipoblasts, nuclear pleomorphism, and positivity for MDM2 and CDK4, while the latter is positive for macrophage markers. A history of use of a filler distinguishes between the two.

Management and prognosis

• Excision is curative.

Clinical features

• Orofacial granulomatosis:

  • This generally affects children and young adults. The lips show diffuse or localized rubbery swelling that unlike angioedema, does not remit and may be so large as to be disfiguring ( Fig. 8.9 A–C). The tissues feel tight and sensitive.

    

  • Less frequently, there is concomitant swelling of the gingiva, and long-standing cases may exhibit cobblestoning and fissuring of the mucosa from edema.

  • Some cases have a staghorn appearance of the distal portion of the submandibular duct ( Fig. 8.9 D).

  • Melkersson-Rosenthal syndrome , in addition to the lip swelling, exhibits fissured tongue and facial palsy from granulomatous involvement of the facial nerve (less than 10% of cases) and it is unclear if this is associated with duration of the condition. The inclusion of a fissured tongue (a fairly common oral condition) in this triad has been questioned.

• Crohn disease: Oral findings precede the diagnosis of intestinal disease in 50% of cases. In addition to the features noted above, there may also be:

  • Papular folds of tissue in the maxillary and mandibular sulci

  • Aphthous-like ulcers (often linear along the maxillary and mandibular vestibule/sulcus)

  • Diffuse erythema

  • Thickened and erythematous appearance of perivermilion skin (see Fig. 8.9 E)

  • Gastrointestinal symptoms

  • uncommonly, pyostomatitis vegetans (see Chapter 7 ).

Patients with Crohn disease often have elevated fecal calprotectin as well as C-reactive protein which can be used to monitor response to treatment.

Etiopathogenesis and histopathologic features

As with other granulomatous disease, orofacial granulomatosis is a hypersensitivity reaction, and most patients are atopic and/or have oral allergy syndrome. Other factors include genetic predisposition or microbial factors. It is often associated with sensitivity to phenolic compounds that are found in flavoring agents such as cinnamaldehyde and in preservatives such as benzoates. Other allergens include chocolate and many fruits as well as silver birch pollen. Crohn disease is thought to be mediated by an abnormal inflammatory response to enteric microflora in genetically susceptible hosts (e.g., polymorphisms in NOD2 / CARD15 and TNFSF and others), mostly related to Th17 cell function. These polymorphisms have not been identified in patients with orofacial granulomatosis.

• Lesions of orofacial granulomatosis and Crohn disease are characterized by nonnecrotizing granulomas that may be subtle in early disease or more florid in later disease ( Fig. 8.10 ). Refractile particulate material is not identified with polarized light.

  

• Granulomas of Crohn disease often contain eosinophils and may occur in salivary glands ( Figs. 8.11 and 8.12 ).

  
  

• Edema and chronic inflammation alone are not sufficient for the diagnosis, and multiple levels should be performed through the block, if necessary, to locate granulomas. A rebiopsy is recommended if there is a strong suspicion for this disorder, but granulomas are not identified in the initial biopsy.

Differential diagnosis

• Infectious granulomatous processes must be ruled out with histochemical or immunohistochemical stains (see Chapter 4 ).

• Granulomas of sarcoidosis are nonnecrotizing, compact, and well-demarcated with little inflammation (“naked”) ( Fig. 8.13 ). Patients are often Black and have hilar lymphadenopathy, pulmonary symptoms, uveitis, and lupus pernio, and genetic susceptibility profiles. Elevated levels of angiotensin-converting enzyme (produced by the granulomas) are not specific for the disease and elevated chitotriosidase (chitinase-1) level is a better option. Oral lesions take the form of gingival hyperplasia, nodules, ulcers, and infrequently gnathic radiolucencies. Labial salivary gland biopsies are positive for disease in up to 48% of cases.

  

• Lesions reported as being orofacial granulomatosis–like after organ (especially liver) transplantation in children may represent a different entity.

Management and prognosis

• Patients with orofacial granulomatosis should be patch tested to determine if hypersensitivity to foods (in particular, phenolic compounds) and other substances exists. Elimination diet is beneficial in 14% to 80% of patients, with 23% exhibiting complete resolution.

• Topical, intralesional, and systemic corticosteroid therapy controls disease in many patients, but relapse is common which is not unexpected if there continues to be systemic antigenic stimulation that is not addressed.

• Minocycline, thalidomide, mycophenolate mofetil, and tumor necrosis factor-α inhibitors show variable success in managing this condition, although the last should be reserved for patients with Crohn disease and orofacial granulomatosis refractory to other treatments.

• Pulse treatment using 500 mg of azithromycin for three consecutive days each week over several months has its advocates and detractors.

• Gastrointestinal evaluation for Crohn disease is indicated if there are intestinal symptoms.

Clinical findings

• This occurs in 1% to 2% of the adult population, usually in the third decade of life, and with a 1.5:1 female predilection. It is a chronic relapsing-recurring condition.

• Well-demarcated, slightly depressed, erythematous depapillation of the tongue dorsum is noted, often surrounded by a raised, linear, arcuate, or circinate white rim, although this rim is absent in resolving lesions. It is associated with a fissured tongue in 15% to 33% of cases ( Fig. 8.14 A–C). Some cases occur on the floor of the mouth, lip mucosa, or other oral sites (see Fig. 8.14 D). This is noted in 6% to 18% of patients with psoriasis.

  

Etiopathogenesis and histopathologic features

There is a strong association with atopy (history of hay fever, eczema, asthma, or food intolerance) and positive reactions to prick and patch tests; some patients have concurrent psoriasis (especially generalized pustular psoriasis). There is increased prevalence of HLA-B*58 and HLA-Cw*06 in patients with this disorder.

• There is loss of filiform and fungiform papillae on the tongue dorsum with psoriasiform epithelial hyperplasia and often keratinocyte edema.

• Spongiosis, neutrophilic transmigration, and spongiotic pustules typically involve one-third to two-thirds of the thickness of the epithelium, which is a hallmark of the condition, although early or late lesions may show only superficial spongiotic pustules. A variable lymphocytic infiltrate is present, and there is vascular ectasia ( Figs. 8.15 and 8.16 ).

  
  

• Stains for candidal hyphae are negative.

Differential diagnosis

• Candidiasis exhibits psoriasiform epithelial hyperplasia and spongiotic pustules that are confined to the superficial two to three layers of keratinocytes. Candidal hyphae are identified with periodic acid–Schiff or methenamine silver stains.

• Spongiotic pustules are present at the edges of ulcers associated with fibrin deposition or in erosions, as well as in traumatized lesions even without ulcers.

• Spongiotic pustules may also be seen in irritant contact lesions (see Chapter 7 ).

• Oral psoriasis shares similar histopathologic features but is an extremely rare condition.

Management and prognosis

• Management of pain and sensitivity is the primary goal because this is a chronic relapsing condition. This is achieved with viscous lidocaine and diphenhydramine used as a swish-and-spit preparation, or either one agent alone. Topical steroids are prescribed for severe cases (see Appendix A ). Although a scoring system for severity has been proposed, most lesions are evanescent and last only a few days.

Clinical findings

• This generally occurs in adult patients and presents as painless or painful, erythematous, white, or red-and-white plaques or macules of the oral mucosa at the site of placement of the offending substance ( Fig. 8.17 ).

  

Etiopathogenesis and histopathologic features

Contact hypersensitivity stomatitis results from a mucosal allergic reaction to the material placed on the mucosa. This is a type IV hypersensitivity reaction similar to contact dermatitis. Some sources of these reactions include flavorings of dentifrices (especially cinnamic aldehyde and mint), dental filling materials (such as amalgams and crowns), and inadequately cured acrylic dentures resulting in exposure to acrylic monomer, a rare phenomenon. The same contactant may cause an irritant stomatitis, contact hypersensitivity reaction, or plasma cell gingivitis.

• Almost all cases exhibit a lichenoid interface process with spongiosis, lymphocyte transmigration, apoptosis, degeneration of the basal cells, and a lymphohistiocytic band at the interface. Beyond that, the following patterns are identified.

  • Primarily spongiotic with spongiosis, acanthosis, variable chronic inflammation, and eosinophils in the lamina propria and epithelium ( Fig. 8.18 ).

    

  • Lymphohistiocytic infiltrate at the interface with well-formed or loosely aggregated nonnecrotizing granulomas ( Fig. 8.19 ); eosinophils may or may not be present.

    

  • Lymphohistiocytic infiltrate at the interface with peri- and paravascular lymphohistiocytic nodules ( Fig. 8.20 ).

    

  • Lymphohistiocytic infiltrate at the interface with peri- and paravascular lymphohistiocytic nodules containing nonnecrotizing granulomas ( Fig. 8.21 ).

    

Differential diagnosis

• Lichen planus often shows a lymphohistiocytic infiltrate at the interface but the histiocytes are diffusely scattered between lymphocytes and not aggregated.

• Lupus erythematosus may be associated with deep lymphoid nodules but direct immunofluorescence studies would exhibit linear IgM (most common), IgG, or IgA at the epithelium–connective tissue interface, or positive lupus band test, and patients would be positive for antinuclear antibodies and anti-Smith antibody.

• Orofacial granulomatosis, unlike lichenoid and granulomatous mucositis, does not exhibit peri- and paravascular nodular lymphocytic infiltrates.