Differentials
Behcet syndrome
SIGNS / SYMPTOMS
Patients may present with aphthous-like ulcers occurring on genital or other mucosae; erythema nodosum, acneiform pustular lesions, or other skin lesions; uveitis; joint involvement; or central nervous system manifestations.[1][31]
Seen most commonly in the Middle East, the Far East, and around the Mediterranean.[39]
INVESTIGATIONS
Diagnosis is based on history and clinical features.
Pathergy test is positive in up to 60% of patients, with highest frequency in those of Middle Eastern origin.
May be HLA-B51 genotype, although this association varies with ethnicity.
Malignant ulcer
SIGNS / SYMPTOMS
Persistent, nonhealing ulcers are typical of malignant disease (e.g., oral squamous cell carcinoma); however, red or white lesions or lumps may be present in malignant cases.
Lesion may be indurated and painless; cervical lymphadenopathy may be present.
A solitary ulcer lasting more than 3 weeks may well represent malignancy and would warrant urgent referral to a specialist.[29]
INVESTIGATIONS
Incisional biopsy will show malignant disease (most commonly squamous cell carcinoma).
Folate deficiency
SIGNS / SYMPTOMS
History of a diet poor in sources of folate, or of heavy alcohol use.
Pallor, fatigue, weakness, decreased exercise tolerance, and shortness of breath with exercise may result from the anemia.
INVESTIGATIONS
Anemia is macrocytic (mean corpuscular volume [MCV] >100 femtoliters); serum folate low (<2.5 nanograms/mL); red blood cell folate level <140 nanograms/mL.
Iron deficiency anemia
SIGNS / SYMPTOMS
May present with glossitis, angular stomatitis, and spooning of the nails.
Pallor, fatigue, weakness, decreased exercise tolerance, and shortness of breath with exercise may result.
INVESTIGATIONS
Ferritin is typically low (<50 nanograms/mL) in iron deficiency; a ferritin level of <15 nanograms/mL strongly suggests iron deficiency.
Vitamin B12 deficiency
SIGNS / SYMPTOMS
May present with evidence of peripheral neuropathy or posterior column degeneration (e.g., ataxia).
Pallor, fatigue, weakness, decreased exercise tolerance, and shortness of breath with exercise may result.
INVESTIGATIONS
Anemia is typically macrocytic (mean corpuscular volume [MCV] >100 femtoliters); serum B12 is low (<200 picograms/mL).
HIV/AIDS
SIGNS / SYMPTOMS
HIV-associated infections (candidiasis, hairy leukoplakia) or neoplasms (Kaposi sarcoma, lymphoma); other clinical evidence of, or risk factors for, HIV infection.
In HIV infection, aphthous-like ulceration may be seen independent of the necrotizing ulceration of HIV infection.[40]
INVESTIGATIONS
Diagnosis is based on history and clinical features.
HIV serology will be positive.
Crohn disease
SIGNS / SYMPTOMS
Crohn disease can affect any part of the gastrointestinal tract and symptoms may be extremely variable.
Features may include: bloody diarrhea; weight loss; labial or facial swelling; perioral erythema; cobblestoning of the oral mucosa; and, occasionally, joint manifestations.
INVESTIGATIONS
Colonoscopy will show mucosal inflammation and discrete deep ulcers located transversely and longitudinally, creating a cobblestone appearance.
Full-thickness bowel biopsies demonstrate transmural involvement with noncaseating granulomas present. Oral biopsy may show noncaseating granulomas and lymphangiectasis (dilation of lymph structures reflecting edematous swelling).
Ulcerative colitis
SIGNS / SYMPTOMS
Ulcerative colitis typically presents with features of colitis including left-sided abdominal pain and bloody diarrhea. In addition to oral ulcers, superficial pus-filled blisters (pyostomatitis vegetans) may be present.
INVESTIGATIONS
Colonoscopy will show rectal and continuous uniform involvement, loss of vascular marking, diffuse erythema, mucosal granularity, rare fistulas, and normal terminal ileum (or mild "backwash" ileitis in pancolitis).
Bowel biopsies will show mucin depletion, basal plasmacytosis, and diffuse mucosal atrophy.
Celiac disease
SIGNS / SYMPTOMS
Patients typically present with unexplained gastrointestinal symptoms, chronic diarrhea, unexplained iron deficiency anemia, or a skin rash consistent with dermatitis herpetiformis.
INVESTIGATIONS
Diagnosis is suggested by a positive immunoglobulin A-tissue transglutaminase test.
Duodenal endoscopy will show atrophy and scalloping of mucosal folds, nodularity, and mosaic pattern of mucosa; histology will show presence of intraepithelial lymphocytes, villous atrophy, and crypt hyperplasia.
MAGIC (mouth and genital ulcers with inflamed cartilage) syndrome
SIGNS / SYMPTOMS
Thought to potentially be a variant of Behcet syndrome.
A generalized chondritis may be present.[32]
INVESTIGATIONS
Diagnosis is based on history and clinical features.
Cyclic or other neutropenia
SIGNS / SYMPTOMS
Patients may present with recurrent fevers and recurrent infections.[30]
INVESTIGATIONS
Diagnosis is based on history and clinical features.
CBC may show leukopenia.
PFAPA (periodic fever with aphthae, pharyngitis, and adenitis) syndrome
SIGNS / SYMPTOMS
Comprises periodic fever, aphthae, pharyngitis, and cervical adenitis.
Although rare, it tends to occur in young children.[33]
INVESTIGATIONS
Diagnosis is based on history and clinical features.
CBC may show leukopenia.
TRAPS (tumor necrosis factor receptor-associated periodic syndrome)
SIGNS / SYMPTOMS
Comprises periodic fever and aphthae.[34]
INVESTIGATIONS
Diagnosis is based on history and clinical features.
CBC may show raised erythrocyte sedimentation rate.
Sweet syndrome
SIGNS / SYMPTOMS
Patients have ulceration similar to recurrent aphthous stomatitis but with sudden onset of fever, and well-demarcated plum-colored skin lesions.[41]
There is an associated malignancy (e.g., acute myeloid leukemia) in 50% of patients.
INVESTIGATIONS
Diagnosis is based on history and clinical features.
CBC may show leukocytosis.
Pemphigus
SIGNS / SYMPTOMS
This is a blistering disease. The early phases of oral pemphigus may be characterized by recurring oral ulcers.[1][42]
INVESTIGATIONS
Incisional biopsy and histopathology may show characteristic findings of pemphigus: epithelial acantholysis with suprabasal blistering.
Direct immunofluorescence will show staining for IgG, C3, or both, as a thin linear band on the surface of keratinocytes in the suprabasal epithelium.
Syphilis
SIGNS / SYMPTOMS
Primary syphilis: oral chancre presents as solitary painless indurated ulceration at the site of inoculation, persisting 3-7 weeks and healing without scarring; most likely sites of involvement are lips, tongue, commissures, gingiva, palate, and tonsils; lymphadenopathy is common.
Secondary syphilis: mucous patches presenting as shallow, irregularly shaped plaques or ulcerations with erythematous borders; gray-white necrotic membrane covering may be present; snail track appearance; concurrent cutaneous rash; genital lesions.
Tertiary syphilis: locally destructive granulomas (gummas) or glossitis may be present with mucosal atrophy.
INVESTIGATIONS
Serum treponemal enzyme immunoassay: positive.
Tuberculosis
SIGNS / SYMPTOMS
Painful granulomatous ulceration; lymphadenopathy may be present; lesions may be locally destructive and mimic squamous cell carcinoma; common sites of occurrence are tongue, palate, buccal mucosa, or lips.
INVESTIGATIONS
Sputum smear: positive for acid-fast bacilli.
Mycoses (e.g., histoplasmosis, paracoccidiomycosis)
SIGNS / SYMPTOMS
Granulomatous ulceration may mimic neoplasm.
INVESTIGATIONS
Diagnosis is based on history (e.g., recent foreign travel to endemic areas) and clinical features (e.g., HIV/AIDS).
Positive microbiology or nucleic acid test for fungal infection.
Herpangina
SIGNS / SYMPTOMS
Cervical lymphadenopathy is present, and ulcers are also seen on the soft palate.
INVESTIGATIONS
Diagnosis is clinical.
Hand-foot-and-mouth disease
SIGNS / SYMPTOMS
Most commonly affects children, and causes a low-grade fever and general malaise. Rash is typically present on the palms and/or soles, and may last for up to 10 days.
Oropharynx is inflamed, with scattered papules, macules, vesicles, or superficial ulcers on an erythematous base on the tongue, pharynx, buccal mucosa, gingiva, and occasionally the lips; may be only yellowish ulcerations, as vesicles tend to rupture quickly. Typically heal within 1 week. Occasional serious neurologic complications.
INVESTIGATIONS
Diagnosis is typically clinical.
CBC will show raised WBC count; viral culture will allow isolation of non-polio enterovirus 71 if this is the causative virus.
Epstein-Barr virus (EBV) infection (infectious mononucleosis)
SIGNS / SYMPTOMS
Small superficial ulcers of the oral mucosa may be a feature of EBV infection.
Features of infectious mononucleosis are often present.
INVESTIGATIONS
CBC may show lymphocytosis and atypical lymphocytosis in EBV infection.
Serology will be positive for EBV-specific antibodies: viral capsid antigen (VCA)-IgM, VCA-IgG, early antigen, Epstein-Barr nuclear antigen.
Intra-oral herpes (Herpes simplex)
SIGNS / SYMPTOMS
Herpes simplex virus infection of the oral cavity can usually be differentiated from other causes of recurrent oral ulcerations on the basis of its clinical appearance and distribution.[43]
INVESTIGATIONS
Diagnosis is clinical.
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