Introduction
Oral ulceration, a breach in the oral epithelium that may extend into the underlying connective tissue, represents one of the most common lesions encountered in the oral cavity. Its prevalence and the diverse array of potential causes pose a significant diagnostic challenge for both dental and medical professionals. Patients experiencing oral ulcers may initially consult either a dentist or a general physician, highlighting the importance of a comprehensive understanding of this condition across medical disciplines.
Classifying oral ulcers can be approached based on several key factors: (i) the duration of onset, (ii) the number of ulcers present, and (iii) the underlying etiological factors. Ulcers are broadly categorized by duration into acute (lasting less than two weeks), chronic (persisting beyond two weeks), and recurrent (characterized by repeated episodes with intermittent healing). Furthermore, ulcers can be solitary or multiple in presentation.
The etiology of oral ulcers is remarkably varied, ranging from minor trauma to manifestations of severe systemic diseases and malignancies. Understanding the distinct features of an ulcer, including its floor, base, margin, and edge, along with the typical clinical course involving extension, transition, and healing phases, is crucial for accurate diagnosis.
This review aims to provide a structured, updated approach to the differential diagnosis of oral ulcers. By considering clinical presentation, underlying systemic conditions, and key diagnostic features, while systematically excluding other potential causes, this guide seeks to assist dental practitioners and clinicians in reaching a definitive diagnosis and implementing appropriate management strategies. A robust differential diagnosis is paramount in effectively managing oral ulceration and ensuring optimal patient care.
Discussion: Unraveling the Differential Diagnosis of Oral Ulcers
Establishing a definitive diagnosis for oral ulceration necessitates a thorough differential diagnosis process. This process involves considering various conditions that may present with similar clinical features, starting with the most critical and potentially serious lesions that must not be overlooked. Further laboratory investigations are often essential to confirm the diagnosis and rule out other possibilities. It’s noteworthy that literature highlights instances where malignant oral ulcers were initially misdiagnosed as benign lesions for extended periods, underscoring the critical importance of vigilance and comprehensive evaluation.
Malignant Oral Ulcers
Oral ulcers persisting for more than two weeks should raise suspicion of malignancy. Malignant ulcers can arise from epithelial neoplasms, solid tumors such as lymphomas, and minor salivary gland malignancies.
Oral Squamous Cell Carcinoma (OSCC)
Oral squamous cell carcinoma (OSCC) stands as the most prevalent malignancy of epithelial origin within the oral cavity. Characteristically, OSCC presents as a non-healing, often painless ulcer. However, early-stage presentations can be clinically diverse, contributing to diagnostic challenges. Common sites include the lateral and ventral tongue, floor of the mouth, and lower lip. Clinically, OSCC can manifest as white, red, mixed red-white, exophytic, or ulcerative lesions. The classic OSCC ulcer is described as crater-like, with indurated, rolled borders and a velvety base. While typically solitary, multiple OSCC ulcers can occur in some cases.
Basal Cell Carcinoma
Basal cell carcinoma, a skin malignancy primarily affecting hair-bearing areas, typically arises in sun-exposed facial regions. It can extend to mucous membranes from adjacent skin involvement. Initially, it appears as an elevated papule, progressing to a central crusted ulcer with smooth, rolled borders. Diagnosis relies on clinical site and histopathology, as OSCC must be considered in the differential diagnosis.
Microbial-Induced Oral Ulcers
Oral ulcers caused by microbial agents (viruses, bacteria, and fungi) are frequently surrounded by an erythematous halo, indicative of an inflammatory response. These infections often present with distinctive clinical features, commonly initiating as vesiculobullous lesions that rupture to form ulcers.
Viral Infections
Herpes Simplex Virus (HSV) Infections
Symptomatic herpes simplex virus (HSV) infection, known as primary herpetic gingivostomatitis, is a common viral cause of oral ulcers. HSV type-1 is responsible for over 90% of cases, with the remainder attributed to HSV-2. Oral lesions typically emerge 2-3 days after onset, presenting as pinhead vesicles that rupture, resulting in painful ulcers covered by a yellowish pseudomembrane. Both keratinized and non-keratinized mucosa can be affected. Mild forms manifest as small, numerous superficial ulcers limited to the lips and gingiva, while severe cases can present as diffuse, large whitish ulcerations with erythematous, scalloped borders. These ulcers typically heal within 5-7 days without scarring. Primary herpetic gingivostomatitis can mimic aphthous stomatitis and acute necrotizing gingivitis.
Herpes Zoster (Shingles)
Herpes zoster infections, or shingles, result from the reactivation of the varicella-zoster virus. Incidence increases significantly after age 50 and in immunosuppressed individuals. Unilateral, clustered, painful ulcers (1-5 mm diameter) appear on the buccal gingivae and hard palate several days post-infection. These ulcers rupture, forming crater-like ulcers and erosive areas. Shingles can resemble herpes simplex lesions but are differentiated by their distinct dermatomal distribution. Ulcers typically heal within 10-14 days and are self-limiting.
Epstein-Barr Virus (EBV)
Epstein-Barr virus (EBV), a member of the herpes virus group, primarily targets B lymphocytes. While EBV is associated with infectious mononucleosis, nasopharyngeal carcinoma, and Burkitt’s lymphoma, EBV-related oral ulcers are infrequent but can occur in infectious mononucleosis. Oral ulcers are typically small and shallow.
Coxsackie A Virus (Hand, Foot, and Mouth Disease)
Coxsackie A virus strains are common causes of hand, foot, and mouth disease, characterized by oral ulcerations and vesicular rashes on the extremities. Oral ulcers, appearing 1-2 days post-infection, are usually located in the posterior mouth, commonly affecting the soft palate, buccal mucosa, hard palate, and tongue. Differential diagnosis includes primary herpetic gingivostomatitis, recurrent aphthous stomatitis, erythema multiforme, and herpangina. Hand, foot, and mouth disease is distinguished by simultaneous involvement of the extremities and oral cavity. It is typically self-limiting and asymptomatic, predominantly affecting children.
Herpangina
Herpangina is associated with sore throat, fever, blisters, and ulcers in the posterior mouth (palate and throat). Posterior oral involvement aids in differentiating herpangina from other viral infections and aphthous ulcers.
Human Immunodeficiency Virus (HIV)
Oral lesions can be an early indicator of HIV infection or disease progression. HIV-related oral ulcers may clinically resemble aphthous ulcers but are often more persistent and less responsive to steroid treatment.
Bacterial Infections
Necrotizing Ulcerative Gingivitis (NUG)
Acute necrotizing ulcerative gingivitis (NUG) can be diagnosed clinically based on characteristic signs: interproximal necrosis with punched-out ulceration, bleeding, and pain, localized to the gingiva, particularly interdental papillae. Clinical presentation varies with lesion severity. Differential diagnosis includes scurvy, noma, herpetic gingivostomatitis, agranulocytosis, and leukemia.
Tuberculosis
Primary oral tuberculosis infection is rare. It typically manifests as solitary, necrotic, ulcerative lesions with undermined edges, most commonly on the tongue, followed by gingivae, floor of the mouth, palate, lips, and buccal mucosa. The ulcer can be irregular, indurated, and painful. Differential diagnosis includes oral squamous cell carcinoma, traumatic ulceration, and syphilitic ulcer.
Syphilis
Primary syphilitic ulcers, caused by Treponema pallidum, usually result from oro-genital or oro-anal contact with an infected lesion. A chancre, a solitary ulcer, develops after 1-3 weeks, typically on the lips and less often on other oral sites. The ulcer is deep with a red-purple or brown base, ragged rolled borders, and associated cervical lymphadenopathy. Traumatic ulceration and squamous cell carcinoma are differential diagnoses. Secondary syphilis can present with mucous patches, irregular ulcerations covered by a grey-white necrotic membrane with surrounding erythema. Confluent mucous patches, known as “snail tracks,” heal within weeks.
Fungal Infections
Oral Candidiasis
Oral candidiasis, the most common opportunistic oral infection, results from Candida albicans overgrowth. Candidiasis infrequently causes oral ulceration.
Blastomycosis and Mucormycosis
Oral blastomycosis typically presents as a painless, nonspecific, verrucous ulcer with indurated borders, often misdiagnosed as OSCC. South American blastomycosis can cause extensive ulceration in immunocompromised patients, also mimicking OSCC. The most common oral manifestation of mucormycosis is palatal ulceration due to necrosis, but lips, gingivae, and alveolar ridge can also be affected.
Hormonal Imbalance-Related Ulcers
Hormonal fluctuations, such as those occurring during pregnancy, puberty, and oral contraceptive use, can contribute to oral ulcers. Estrogen level changes can lead to increased oral epithelium exfoliation, causing ulcerations in susceptible individuals, particularly women during menstrual cycles and pregnancy.
Systemic Disorder-Associated Ulcers
Systemic disorders can disrupt oral health, with ulceration being a common oral manifestation. Differential diagnoses include chancre, ANUG, early squamous cell carcinoma, leukemia, traumatic abscess, and cyclic neutropenia. Oral findings can sometimes be the first indication of a systemic blood-borne disease.
Anemia and Cyclic Neutropenia
Pernicious anemia and iron deficiency anemia may present with superficial, small ulcers resembling aphthous ulcers. Cyclic neutropenia, characterized by periodic neutrophil decreases, can manifest with solitary or multiple painful ulcers with erythematous halos, lasting 10-14 days and healing with scarring. These ulcers can resemble major aphthous ulcers but can be differentiated by associated periodontal destruction.
Inflammatory Bowel Disease (IBD)-Related Ulcers
Inflammatory bowel diseases (IBD), including Crohn’s disease and ulcerative colitis, can have oral manifestations, sometimes preceding abdominal symptoms. Aphthous ulcerations are the most common oral manifestation of IBD during active phases.
Crohn’s Disease and Ulcerative Colitis
In Crohn’s disease, oral ulcers can be deep linear ulcers with rolled edges, often in buccal vestibules, or superficial mucosal ulcerations. Differential diagnosis includes other granulomatous diseases like sarcoidosis. Oral lesions in ulcerative colitis include aphthous-like ulcers, diffuse pustules, lichen planus, and pyostomatitis vegetans.
Immune-Mediated Disorder-Related Ulcers
Recurrent Aphthous Stomatitis (RAS)
Recurrent aphthous stomatitis (RAS) is a common inflammatory condition characterized by recurrent oral ulceration episodes in otherwise healthy individuals. Non-keratinized mucosa is most commonly affected. RAS is categorized into minor, major, and herpetiform types. Ulcers typically appear as rounded, tender mucosal surfaces covered by fibrin slough and surrounded by an erythematous border. Major aphthous ulcers can cause scarring and may coalesce into larger ulcerative areas. Aphthous ulcers share similarities with ulcers in Behcet’s disease, but Behcet’s ulcers are typically more numerous, longer in duration, and more painful.
Behcet’s Disease
Behcet’s disease, in addition to aphthous ulceration, involves anogenital and ocular ulcerations and arthralgia, aiding in diagnosis.
Vesiculobullous Lesions
Various immune-mediated vesiculobullous diseases, such as mucous membrane pemphigoid, pemphigus vulgaris, and erosive lichen planus, can present with chronic, multiple oral ulcerations. These conditions involve blister formation followed by oral mucosal ulceration.
Lichen Planus
Lichen planus is a chronic immune-mediated disease, more common in middle-aged women. Oral lichen planus can occur with or without skin lesions. Erosive lichen planus presents with ulcers covered by pseudomembrane slough, erythema, and keratosis, exhibiting multifocal spreading, bullous-like lesions combined with reticular and erosive patterns.
Erythema Multiforme
Hypersensitivity reactions can manifest as erythema multiforme, characterized by irregular erythematous vesicles and plaques, leading to target-like or bull’s eye lesions, often triggered by drugs, viral, or fungal infections. Lips and buccal mucosa are commonly affected. Lesions are typically ulcerated with inflammatory halos and irregular margins. Severe lip crusting is a characteristic finding. Erythema multiforme can be confused with primary herpetic gingivostomatitis but is differentiated by lesion appearance and distribution.
Pemphigus Vulgaris and Mucous Membrane Pemphigoid
Pemphigus vulgaris, another immune-mediated vesiculobullous disease, results from cell adhesion loss, leading to blister formation. Oral lesions occur in 90% of pemphigus vulgaris cases and are the initial sign in 50%. Oral lesions start as bullae with thin roofs that rupture easily, forming chronic, painful, bleeding ulcers with irregular borders that heal poorly. Mucous membrane pemphigoid is characterized by basement membrane-level immune reactions, with a female predilection, typically starting around age 40. Gingivae are most frequently affected initially, followed by other mucosal sites. Lesions are usually hemorrhagic and heal with scarring.
Traumatic, Iatrogenic, and Idiopathic Ulcers
Trauma to the oral cavity is a common cause of surface ulcerations. Traumatic ulceration is among the most frequent oral ulcer types.
Traumatic Ulcers
Sublingual ulcers in newborns and infants, as seen in Riga-Fede disease, can result from chronic mucosal irritation due to premature eruption of natal or neonatal teeth, often associated with breastfeeding. Traumatic ulcers in children are often due to thermal or electrical injuries, affecting commissures and lips. In adults, mechanical injuries from malformed teeth, ill-fitting dentures, hot foods, and radiation injuries are common causes. Traumatic ulcers on the tongue dorsum can mimic proliferative reactive processes like traumatic ulcerative granuloma, specific infections, and lymphoma, requiring microscopic diagnosis. Traumatic ulcers usually present with erythematous, raised edges and a yellowish-white necrotic pseudomembrane that is easily removed. Lip vermillion border ulcers may appear crusted. Traumatic ulcers typically heal within ten days after removing the causative factor. Differential diagnosis considers lesion size, location, number, onset, patient age, systemic associations, and disease progression.
Conclusion
Diagnosing oral ulceration remains a complex clinical challenge, necessitating thorough history taking and clinical examination. It is crucial to recognize that oral ulceration may be an indicator of underlying systemic disease. Any oral ulcer persisting beyond two weeks warrants histopathological examination to rule out malignancy or other serious conditions. This updated review, encompassing 20 oral ulcerative lesions classified by number and duration, provides a structured approach for dental clinicians. By systematically considering differential diagnoses and employing a stepwise method to exclude potential conditions, clinicians can more effectively reach accurate diagnoses and ensure appropriate patient management for oral ulceration.
Acknowledgements
We extend our gratitude to the Akhter Saeed Medical and Dental College for their support throughout this research.
Footnotes
Funding: This research received no specific financial support.
Competing Interests: The authors declare no competing interests.
References
References from the original article should be listed here (although not provided in the prompt, best practice would be to include them).
