What is the differential diagnosis for unilateral lip swelling?

Differential Diagnosis of Unilateral Lip Swelling

Unilateral lip swelling requires immediate consideration of infection (abscess), angioedema, and granulomatous disease, with the clinical presentation and tempo guiding your diagnostic approach.

Acute Onset (<24-48 hours)

Infectious Causes

• Lip abscess is a rare but critical diagnosis that presents with unilateral swelling, often misdiagnosed as allergic reaction, requiring urgent surgical drainage and IV antibiotics to prevent spread through lymphovascular drainage 1
• Look for localized tenderness, warmth, erythema, and fluctuance on palpation—these distinguish abscess from other causes 1, 2
• Entry points include skin wounds or hematogenous spread in immunocompromised patients 1
• Persistent abscess or necrotic tissue should prompt evaluation for MRSA or underlying immunosuppression 1

Angioedema

• Hereditary angioedema with normal C1 inhibitor (HAE-nC1INH) commonly affects the face and lips, with attacks lasting 2-5 days 3
• HAE-FXII variant shows strong female predominance with estrogen as a major trigger (pregnancy, oral contraceptives), average symptom onset at age 20 years 3
• Tongue swelling is particularly frequent in HAE-PLG variant and can be life-threatening 3
• Key distinguishing feature: angioedema presents without urticaria (hives), unlike allergic reactions 3

Medication-Associated

• ACE inhibitors, dipeptidyl peptidase inhibitors, neprilysin inhibitors, tissue plasminogen activators, and NSAIDs can all cause unilateral or bilateral lip swelling 3
• Requires stopping all potential drug culprits and observing for 1-3 months before considering other diagnoses 3

Chronic/Recurrent Presentation (>weeks to months)

Granulomatous Disease

• Cheilitis granulomatosa presents as persistent, cosmetically disturbing idiopathic lip swelling, part of orofacial granulomatosis (OFG) spectrum 4

• Can occur alone or as part of Melkersson-Rosenthal syndrome (facial palsy + plicated tongue) 4

• Dietary allergens (cinnamon, benzoates) are proposed triggers 4

• Crohn's disease may present with chronic lip swelling as the sole initial manifestation, even before gastrointestinal symptoms develop 5

• Lip biopsy revealing non-caseating granulomas should prompt ileocolonoscopy and video capsule endoscopy to evaluate for intestinal involvement 5

• Children with persistent lip swelling warrant particular vigilance for inflammatory bowel disease 5

• Sarcoidosis must be excluded when evaluating granulomatous lip swelling, as it represents systemic disease requiring different management 4

Neoplastic Causes

• Salivary gland tumors can present as unilateral lip swelling 2, 6
• Dentigerous cysts associated with impacted teeth (mesiodens) can cause slow-growing upper lip swelling 6
• Palpation for hard, non-mobile masses and examination of cervical, submandibular, and submental lymph nodes is essential 2

Critical Diagnostic Approach

Initial Evaluation

• Detailed history must include timing (acute vs chronic), associated symptoms (fever, pain, numbness), medication review, family history, and triggers (trauma, dental procedures, foods, estrogen) 3, 2
• Physical examination requires visual inspection for erythema, ulceration, asymmetry, and palpation for fluctuance, firmness, tenderness, and lymphadenopathy 3, 2
• Examine the oral cavity with dentures removed, inspect all mucosal surfaces, and palpate the floor of mouth 3

Red Flags Requiring Urgent Action

• Rapidly progressive swelling with airway compromise (especially tongue involvement in HAE-PLG) requires immediate intervention 3
• Fever, systemic symptoms, or necrotic tissue suggests severe infection or immunocompromise 1
• Firm, fixed mass with ulceration raises concern for malignancy, particularly in patients >40 years with tobacco/alcohol use 3
• Intraoral ulceration, numbness, or limited tongue mobility may indicate invasive tumor 3

Diagnostic Testing Strategy

• For acute presentations: Consider incision and drainage if abscess suspected, with culture and sensitivity 1
• For angioedema: Check C4, C1-INH antigen and function; if normal, consider targeted gene sequencing for HAE-nC1INH variants 3
• For chronic presentations: Lip biopsy is essential to identify granulomatous inflammation and exclude malignancy 4, 5
• If granulomas found: Perform ileocolonoscopy and video capsule endoscopy to rule out Crohn's disease 5

Common Pitfalls to Avoid

• Do not dismiss unilateral lip swelling as simple allergic reaction without excluding abscess, especially if there is any tenderness or warmth 1
• Do not stop evaluation at "angioedema" without determining the specific subtype, as treatment differs dramatically between histaminergic and bradykinin-mediated forms 3
• Do not delay biopsy in persistent swelling (>2-4 weeks), as this is critical for diagnosing granulomatous disease and excluding malignancy 4, 5
• Do not overlook systemic disease: Chronic lip swelling may be the presenting sign of Crohn's disease or sarcoidosis before other manifestations appear 4, 5