Clinicopathologic correlation case 2: multifocal, symptomatic oral mucosal lesions

Abstract

Clinical Presentation

A 25-year-old otherwise healthy female presented for evaluation of mildly painful, multifocal, episodic oral mucosal lesions. The lesions had been present for several months, and predominantly involved the tongue, buccal mucosa, and soft palatal mucosa. Despite efforts to expedite resolution with topical 0.05% clobetasol gel, a multivalent mouthwash, and 2 regimens of systemic prednisone under the care of her physician, the lesions continued to wax and wane. Upon further inquiry, she noted hair loss around the temples and also endorsed a recent history of an enigmatic, pruritic dermal rash that since resolved. Clinical evaluation revealed superficial white patches of the anterior and posterior dorsolateral and ventral tongue as well as several areas of erythematous mucosa surrounded by yellow-white borders of the bilateral buccal mucosa and soft palate extending to the hard and soft palate junction. (Figures 1, 2a, and 2b). The remainder of the oral mucosa was generally moist, pink, and of uniform contour and consistency.

Differential Diagnosis

The differential diagnosis for white and erythematous lesions affecting multiple sites within the oral cavity is broad and comprises a variety of disorders ranging from immune-mediated conditions to infectious diseases. Considerations in the differential diagnosis include contact hypersensitivity stomatitis, benign migratory stomatitis (geographic stomatitis), lichenoid mucositis, candidiasis, oral hairy leukoplakia, and syphilis.

Contact hypersensitivity stomatitis is a mucosal allergic hypersensitivity reaction to contactants characterized by variably symptomatic white, erythematous, or mixed red and white macular lesions or plaques involving the oral mucosa. This represents a type IV hypersensitivity reaction and is caused by a variety of inciting agents including flavorings found in mouthwashes, dentifrices, and candies/chewing gum, among others.^1,2 Although any mucosal site may be affected, the maxillary labial mucosa is frequently involved. In some instances, a temporal relationship exists between the onset of symptoms and exposition to the inciting agent; however, the underlying cause may not be readily identified. Although the possibility of a contact hypersensitivity reaction could not be entirely excluded in this case, topical corticosteroids are often helpful in expediting resolution, and as the patient endorsed breakthrough symptomatic lesions despite management with topical and systemic corticosteroids, this possibility seems less likely.

Benign migratory stomatitis (geographic stomatitis) is a chronic relapsing/recurring immune-mediated condition of unknown etiology that occurs in roughly 1% to 3% of the population. Although the etiopathogenesis is uncertain, predisposing factors include atopy (patients often endorse a history of environmental allergies, asthma, eczema, and food sensitivities) and concurrent psoriasis.^3,4 Patients with migratory stomatitis have an increased prevalence of HLA-Cw*06 and HLA-B*58.^5,6 Although involvement of the dorsal tongue is most common, any oral mucosal site may be affected. Lesions of migratory stomatitis are characterized by zones of atrophic, erythematous mucosa typically circumscribed by serpiginous, creamy yellow-white borders. This clinical presentation shares some overlap with the patient's presentation. Migratory stomatitis, however, tends to wax and wane, and most patients report no symptoms associated with the condition. Symptomatic disease is rare and can cause a burning sensation and sensitivity to hot or spicy foods, which is, at times, treated with topical corticosteroids. In this case, persistence of the lesions and a lack of symptomatic relief from topical corticosteroid therapy render migratory stomatitis a less likely diagnosis.

Lichenoid mucositis represents a pattern of tissue reaction seen in a group of immune-mediated and autoimmune conditions including contact hypersensitivity reactions, idiopathic lichen planus, medication-associated hypersensitivity reactions, oral lupus erythematosus, chronic ulcerative stomatitis, hepatitis C virus infection, and graft versus host disease.^7,8 Lichenoid mucositis is characterized clinically by the presence of reticular white lesions with variable associated erythema, erosion, ulceration, and discomfort; lesions are typically bilateral, symmetric, and involve classic sites such as the posterior buccal mucosa. Lichenoid mucositis results from T-cell destruction of the basal epithelial cells, and there is significant overlap clinically and histopathologically amongst the various entities that share this presentation. However, lack of systemic medications known to induce lichenoid reactions helps to exclude the possibility of a medication-associated hypersensitivity reaction in this instance. Oral involvement by lupus erythematosus may also present with a lichenoid pattern of tissue reaction. This autoimmune disorder can affect several different organ systems including the kidneys and cardiovascular system. It is thought to arise from a dysfunction of both the innate and adaptive immune systems, resulting in autoantibody and immune-complex production.^9,10 Women are affected more often than men, usually between the third and fourth decades of life. Chronic cutaneous lupus erythematosus represents a mild form of disease and consists of skin and mucosal lesions with little to no systemic involvement. Patients with systemic lupus erythematosus (SLE), however, can develop conditions such as nephritis, thrombocytopenia, and pericarditis as various organs are damaged by the accumulation of immune-complexes.¹¹ Cutaneous lesions are characterized by erythematous macules or plaques, while intraoral lesions appear as erythematous zones of mucosa surrounded by white striae, resembling those of reticular lichen planus.¹² Treatment for lupus erythematosus consists of a varying therapeutic regimen of corticosteroids, nonsteroidal anti-inflammatory drugs, and antimalarials. Therefore, limited oral involvement and no symptomatic relief from corticosteroid therapy aids in ruling out lupus erythematosus as a potential diagnosis. As the patient was otherwise healthy and reported no history of transplant, the other considerations were excluded.

Given the patient's history of multifocal, symptomatic oral mucosal lesions recalcitrant to management with topical corticosteroids, infectious diseases including fungal infections such as candidiasis, viral infection such as oral hairy leukoplakia, and bacterial infections including syphilis were considered.

Candidiasis is the most common oral fungal infection and frequently affects patients with a history of associated risk factors including immunosuppression, recent antibiotic therapy, and xerostomia.¹³ Intraorally, the disease manifests in a variety of clinical presentations with the pseudomembranous type presenting with creamy yellow-white plaques on an erythematous background that can be readily liberated, while patients with the erythematous type present with areas of velvety inflamed mucosa and a painful, burning sensation. Other manifestations include median rhomboid glossitis, which is characterized by central papillary atrophy of the dorsal tongue papillae, sometimes with associated nodularity. Hyperplastic candidiasis is often seen in the context of mucocutaneous disease, immune suppression, and endocrinopathies, and is characterized by white plaques, frequently involving the bilateral commissural mucosa. Mild cases of candidiasis are usually treated with topical antifungals such as clotrimazole or nystatin; immunocompromised individuals or those with extensive involvement by the disease, however, may require treatment with systemic antifungals like fluconazole.¹⁴

Oral hairy leukoplakia is caused by Epstein-Barr virus (EBV) and is most commonly seen in immunosuppressed patients, such as those with HIV/AIDS and in patients postorgan transplant. However, the condition can also arise in otherwise healthy, typically older patients, likely as a result of immunosenescence.¹⁵ Clinically, oral hairy leukoplakia presents as a painless white plaque exhibiting linear vertical fissures, typically involving the bilateral tongue borders. Although this case did present with lateral tongue lesions similar to oral hairy leukoplakia, involvement of other mucosal sites rendered this possibility less likely.

Finally, oral involvement with syphilis was considered. Syphilis has a varied clinical presentation that evolves with the stage of infection, with the secondary form being the most frequent presentation at the time of diagnosis.¹⁶ Secondary syphilis occurs after hematogenous spread within 2-12 weeks of infection, and oral findings include multifocal grayish mucosal plaques (so-called “mucous patches”) and serpiginous, ulcerative “snail-track” lesions. An erythematous dermal rash and condyloma latum may also occur at this stage, and all lesions could resolve spontaneously if left untreated.

Diagnosis and Management

In effort to further characterize the nature of these lesions, a biopsy of representative lesional tissue from the left posterior buccal mucosa was performed and revealed the oral mucosa to be covered by a thin layer of parakeratin. The epithelium exhibited acanthosis, marked neutrophil and lymphocyte transmigration, and many spongiotic pustules (Figures 3, 4, and 5). The epithelial rete ridges were variably tapered and confluent, and there was a moderate lymphoplasmacytic infiltrate present within the lamina propria. Within the deeper lamina propria, a perivascular plasmacytic infiltrate was appreciated (Figure 6). An immunohistochemical study for Treponema pallidum was positive, rendering a diagnosis consistent with secondary syphilis (Figures 7a and 7b). The patient was referred to their physician, and rapid plasma reagin (RPR) nontreponemal test was performed with a titer of 1:256 and subsequent positive treponemal antibody test. Possible anterior uveitis was noted, raising suspicion for neurosyphilis, although no cranial nerve dysfunction or other neurologic abnormalities were identified. Out of an abundance of caution given plausible neurosyphilis, the patient received IV penicillin G for 14 days with follow-up in care of an infectious disease specialist, and her oral mucosal lesions completely resolved (Figures 8, 9a, and 9b).

Discussion

Infection by the spirochete Treponema pallidum results in the development of syphilis. The condition naturally progresses through multiple stages; while neurosyphilis and oral manifestations can arise during any of the stages, oral manifestations most commonly occur throughout the second stage.¹⁶ The oral lesions of secondary syphilis are diverse and include erosions and ulcerations, greyish plaques known as mucous patches, and condyloma lata characterized by sessile, papillary nodules. Patients afflicted by secondary syphilis tend to present with multiple intraoral lesions, as opposed to isolated lesions seen in primary syphilis, as well as with systemic symptoms including malaise and fever.¹⁷ However, because these signs and symptoms are often nonspecific, the differential diagnosis of syphilis is expansive and includes more common pathological entities such as immune-mediated conditions and other infectious diseases. Treatment for syphilis is dependent on the stage at diagnosis but generally consists of antibiotics, namely penicillin G.¹⁸ If untreated, lesions of primary and secondary syphilis often resolve, and the infection can enter a latent period that may last for years prior to the development of tertiary syphilis which may result in multi-organ involvement and death; therefore, early diagnosis and management is prudent in effort to minimize morbidity and mortality.