Oral mucosal diseases in dogs: How helpful are the fundamentals of dermatopathology? Cynthia M. Bell, MS, DVM, Diplomate ACVP Associate Professor, Kansas State University Manhattan, KS, USA [email protected] The objective of this presentation is to provide a broad overview of stomatitis in dogs, including immune-mediated mucosal and mucocutaneous diseases. There is little emphasis on gingivitis since this condition is so often related to primary dental and periodontal disease. Particular attention is given to regionally extensive or generalized oral mucosal inflammation, with emphasis on distinguishing features that will help the pathologist formulate and rank a differential diagnosis. Oral mucosal diseases in dogs • Plaque-associated stomatitis/CUPS • Immune-mediated/autoimmune diseases o Skin diseases with oral involvement § Pemphigus vulgaris § Mucous membrane pemphigoid § Paraneoplastic pemphigoid § Erythema multiforme § Lupus erythematosus, mostly DLE o Chronic stomatitis • Mucosal drug eruption • Other infectious (Candidiasis, acute viral infection) • Other non-infectious causes (thermal or chemical burn, uremia) • Neoplasia (e.g. epitheliotropic T cell lymphoma) Plaque-associated stomatitis (aka. contact stomatitis, CUPS) The most singular form of stomatitis in dogs has, for the past ~20 years, been referred to as CUPS (canine ulcerative paradental stomatitis). As a disease entity, CUPS was conceived within the clinical setting; therefore, many pathologists may not be aware of or have only a casual familiarity with the syndrome. It is common for dogs to develop oral mucosal ulcerations (“kissing lesions”) at sites of contact—usually where the buccal mucosa and lateral lingual mucosa contacts the larger tooth surfaces (i.e. canine teeth and carnassial teeth). 1 This condition is thought to be an exaggerated immune-mediated inflammatory response to plaque on the tooth surface (“plaque intolerance”), therefore, “plaque associated stomatitis” is a term that is favored by many veterinarians, myself included. The occurrence and severity of plaque-associated stomatitis generally correlates with the amount of plaque and dental calculus, but it is not as simple as that. Some dogs are clearly more sensitive than others, some cases have no obvious contact with plaque, and some cases progress from localized to generalized throughout the oral mucosae. Chronic stomatitis would be a more appropriate term for these cases—more on this below. Common histological findings for plaque-associated stomatitis include lichenoid and perivascular infiltrates in which plasma cells predominate. The epithelium is not consistently ulcerated, despite the implication of name CUPS, where “U” is for ulcerative. There is usually considerable spongiosis of the epithelium, exocytosis of neutrophils and individual lymphocytes, vacuolar change of the basal cells, and individual necrotic/apoptotic epithelial cells. When ulcerated, the vascular proliferation and neutrophils are abundant. The histological presentation of plaque-associated stomatitis/CUPS is strikingly similar to mucocutaneous pyoderma (Gross), although the distribution is strictly oral and not mucocutaneous. The histological pattern of plaque- associated stomatitis in dogs also resembles allergic contact stomatitis, but secondary bacterial involvement helps to explain the density of plasma cells and the fact that many dogs respond to treatment while on antibiotics. Based on the assumption that plaque is a key factor, the usual first line of treatment is strict plaque control through professional dental prophylaxis and home-based care (i.e. brushing +/- antimicrobial rinse). If plaque control is insufficient, dogs are often treated with antibiotics and/or anti-inflammatory doses of glucocorticoids. Still, response may be only partial and relapse is common. At this point, veterinary dentists may recommend selective extractions of teeth associated with ulcerations or, in refractory cases, full mouth extractions. Oral Lesions Associated with Immune-mediated/Autoimmune Skin Disease The autoimmune/immune-mediated skin diseases that are expected to affect the oral cavity of dogs are mucous membrane pemphigoid (MMP), pemphigus vulgaris (PV), erythema multiforme (EM), and the various forms of lupus erythematosus. [Note: Oral involvement is uncommon for bullous pemphigoid. Only low levels of desmoglein-1 are expressed in the oral mucosal epithelium, therefore pemphigus foliaceus rarely involves the oral cavity.2] Discoid lupus erythematosus (DLE) is the most common of these in dogs.3 Although rare, MMP is most likely to affect the oral cavity.3,4 In general, these diseases present with the same histological changes in the oral cavity as in the skin, therefore I refer the reader to an excellent dermatopathology text.3 It is fairly straightforward to distinguish between plaque-associated stomatitis and the bullous or acantholytic diseases (e.g. MMP and PV). However, the interface or lichenoid diseases (e.g. DLE and EM) can have histological features very much like plaque-associated stomatitis and chronic stomatitis. The pattern of involvement, if giving in the history or demonstrated by a photograph, can be very helpful for formulating a logical, ranked differential diagnosis even before seeing the histopathology. In the oral cavity, discoid and mucocutaneous variants of lupus erythematosus (DLE and MCLE) are likely to affect keratinized oral epithelium, as are pemphigus vulgaris and mucous membrane pemphigoid.2-4 This is a very handy fact to keep in mind; the keratinized oral mucosa—hard palate, gingiva, and dorsal surface of the tongue—are the oral sites most likely affected by DLE, MCLE, PV or MMP. Regarding diagnostic methods that are designed to differentiate between the various dermatopathies (e.g. direct and indirect immunofluorescence), my opinion is that these are unlikely to clarify cases of canine stomatitis in the diagnostic setting. However, they may be useful as a research tool as we characterize the pathogenesis of chronic canine stomatitis. Chronic Stomatitis Generalized or non-specific, chronic stomatitis in dogs presents a significant challenge for both pathologists and clinicians. As stated, one pathway to generalized stomatitis is through progression of localized plaque-associated stomatitis. These dogs should respond well to aggressive plaque control, but some do not. A recent article described Canine Chronic Ulcerative Stomatitis (CCUS) as a T cell mediated reaction in dogs that is usually bilaterally symmetrical and most consistently affects the buccal mucosa.5 Whereas plaque-associated stomatitis tends to be plasmacytic, CCUS is more lymphocytic. Epithelial changes include rete ridge hyperplasia, erosion and ulceration, spongiosis, and basal cell vacuolization and/or apoptosis. CCUS is also more likely to be refractory to treatment and does not consistently occur at contact sites. Mucosal Drug Reactions Oral mucosal reactions to systemic drug administration may include erythema multiforme, but that is just the beginning of the complexity. In the field of human oral pathology, there are many patterns of drug-related oral mucosa disease, including but not limited to anaphylactic stomatitis, lichenoid drug reactions, lupus erythematosus-like eruptions, pemphigus-like drug reactions, and nonspecific vesiculoerosive lesions.2 Essentially, a drug reaction could look like nearly ANY type of allergic or autoimmune oral mucosal disease. Fortunately, if this process is suspected, then discontinuation of the drug (assuming that the therapy is not essential) is the next step regardless of the histological pattern. Oral Lesions due to Systemic Disease I will say very little about oral manifestations of other systemic diseases. Some dogs with hypothyroidism and diabetes mellitus are more prone to stomatitis, gingivitis and/or periodontal disease.6 I have personally seen cases of necroulcerative glossitis as a result of soft tissue mineralization in dogs with hyperadrenocorticism. Uremia is a well-known cause of oral mucosal ulceration, particularly along the ventrolateral margin of the tongue. Summary Fortunately, the fundamentals of dermatopathology ARE helpful both in terms of identifying defined conditions (i.e. autoimmune dermatopathies with oral involvement) and concise communication with descriptive terms (e.g. interface and lichenoid are as appropriate for oral mucosa as skin). However, this presentation is a caution against over extrapolation of histological changes, particularly when evaluating inflamed oral mucosa or gingiva. Diagnostic pathologists are encouraged to provide a rational and ranked differential diagnosis and we have an obligation to stand up for what we need in terms of clinical history. Improving our understanding of chronic stomatitis in dogs will require 1. careful attention to the distribution of the lesions, 2. careful attention to the nature of the lesions (vesicular, ulcerative, proliferative or hyperkeratinized), 3. complete history with respect to drug administration or contact exposure (e.g. oral rinses, chew toys, etc.), and 4. careful and specific description of histological changes. Above all else is excellent and open communication—between clinician and pathologist and among pathologists. Key Points - Oral mucosal diseases in dogs • Plaque-associated stomatitis (a.k.a. CUPS) is common, plasmacytic, and has features intermediate between a lichenoid contact allergy and mucocutaneous pyoderma. • It is necessary to separate plaque-associated stomatitis (a.k.a.