What is the differential diagnosis for a patient presenting with a rash in the buccal mucosa and tongue?

Differential Diagnosis for Rash in Buccal Mucosa and Tongue

The most critical differential diagnoses to consider are pemphigus vulgaris, oral candidiasis, oral lichen planus, and herpes simplex virus infection, with the specific presentation pattern (erosions vs. white plaques vs. reticular striae) guiding your diagnostic workup.

Primary Diagnostic Categories

Autoimmune Blistering Diseases

Pemphigus vulgaris should be your first consideration if you observe painful erosions or blisters, as the oral mucosa is the initial site of involvement in the majority of cases and may remain confined to mucosal surfaces for months 1. The buccal mucosa, soft palate, lips, and tongue are most frequently affected 1. Key features include:

• Painful erosions that may precede skin involvement by an average of 4 months 1
• Peak frequency in third to sixth decades of life 1
• Historically carried 75% mortality before corticosteroids, though mucosal-only disease has better prognosis (1-17% mortality) 1

Diagnostic confirmation requires perilesional biopsy for histology showing suprabasal acantholysis and direct immunofluorescence (DIF) demonstrating IgG deposition on keratinocyte cell surfaces 1. For isolated oral disease, take the histology specimen from perilesional mucosa and the DIF sample from uninvolved buccal mucosa 1. DIF sensitivity is 71% in oral biopsies versus 61% in normal skin 1.

Infectious Causes

Oral candidiasis presents with three distinct patterns: pseudomembranous (creamy white plaques that scrape off), erythematous (red patches without white plaques), or angular cheilitis 1, 2. The buccal mucosa, oropharynx, and tongue surface are most commonly affected 1, 2.

• Pseudomembranous candidiasis shows white plaques on buccal or oropharyngeal mucosa that can be scraped off 1, 2
• Erythematous candidiasis appears as red patches on the palate or tongue without white plaques 1, 2
• Ulceration is NOT a primary feature of oral candidiasis but indicates progression to esophageal involvement 2

Risk factors include denture use, diabetes mellitus, HIV infection, and immunosuppression 1, 3.

Herpes simplex virus (HSV) and cytomegalovirus (CMV) are common infectious causes in both immunocompromised and immunocompetent patients 4. These require endoscopic evaluation with multiple biopsies if esophageal involvement is suspected 4.

Inflammatory Mucosal Diseases

Oral lichen planus affects the buccal mucosa, tongue, and gingiva most commonly, with palatal lesions being uncommon 5. It presents in multiple forms:

• Reticular pattern (white striae - most common and often asymptomatic) 5, 6
• Erosive pattern (painful erythema and erosions) 6, 7
• Plaque-like, papular, atrophic, or bullous variants 5, 8
• Affects women more than men in a 2:3 ratio 5

The reticular white striae pattern is pathognomonic and helps distinguish lichen planus from other conditions 6, 7.

Diagnostic Algorithm

Step 1: Pattern Recognition

Identify the primary lesion morphology:

• Erosions/blisters with painful presentation → Consider pemphigus vulgaris, bullous pemphigoid, or mucous membrane pemphigoid 1
• White plaques that scrape off → Consider oral candidiasis 1, 2
• White reticular striae → Consider oral lichen planus 5, 6
• White plaques that do NOT scrape off and persist >2 weeks → Consider leukoplakia and obtain biopsy to exclude dysplasia or malignancy 3

Step 2: Obtain Tissue Diagnosis

For suspected autoimmune blistering disease:

• Take perilesional biopsy for routine histology 1
• Take separate biopsy from uninvolved buccal mucosa for DIF (gold standard) 1
• Transport DIF specimen in saline for up to 24 hours (superior to liquid nitrogen) 1
• Obtain 5 mL blood for indirect immunofluorescence and ELISA for desmoglein 1 and 3 antibodies 1

For suspected infectious or inflammatory causes:

• Obtain multiple biopsies from at least 2 levels, as inflammatory conditions can be patchily distributed 1, 4
• Request special stains (PAS for fungal elements, viral culture/PCR for HSV/CMV) 4

Step 3: Risk Factor Assessment

Evaluate for systemic conditions:

• HIV status and CD4 count (if immunocompromised, broader differential including opportunistic infections) 1, 4
• Diabetes mellitus (increases candidiasis risk) 1, 3
• Medication history (lichenoid drug reactions can mimic lichen planus) 6
• Contact allergens including dental materials and flavorings like cinnamates 6

Step 4: If Diagnosis Remains Unclear

When initial workup is non-diagnostic:

• Consult superior pathologists with paraffin-embedded specimens 1
• Perform additional testing: metagenomic sequencing, microorganism culture, immune function measurement 1
• Consider diagnostic treatment with low-dose short-term oral glucocorticoids 1
• Arrange multidisciplinary consultation 1

Critical Pitfalls to Avoid

Do not rely on clinical appearance alone - endoscopic appearance cannot accurately predict etiology; specimen acquisition for laboratory study is mandatory 4. This is especially true for white plaques, which can represent candidiasis, lichen planus, leukoplakia, or even lymphoma 1.

Do not miss pemphigus vulgaris in patients with isolated oral erosions - diagnostic delay is very common when confined to oral mucosa, yet this disease historically carried 75% mortality untreated 1. The oral mucosa is the first site in the majority of cases 1.

Do not assume ulceration equals candidiasis - ulceration is NOT a primary feature of oral candidiasis and should prompt consideration of other diagnoses including pemphigus, HSV, CMV, lymphoma, or tuberculosis 1, 2.

Do not forget malignancy in the differential - persistent white lesions that cannot be scraped off require biopsy to exclude dysplasia or squamous cell carcinoma, particularly with tobacco or alcohol use 3. Nasal-type extranodal NK/T-cell lymphoma can present with oral ulceration 1.

In immunocompromised patients, maintain a lower threshold for extensive biopsy sampling as they have a broader differential including opportunistic infections beyond Candida 4.