Encyclopedia of Pathology

Living Edition
| Editors: J.H.J.M. van Krieken


  • Jacqueline E. van der WalEmail author
Living reference work entry
DOI: https://doi.org/10.1007/978-3-319-28845-1_657-1



Aphthous stomatitis is one of the most common oral mucosal lesions. The term aphthae is derived from the Greek word aphthi, which means “to set on fire” or “to inflame” and is thought to have been first used by the philosopher Hippocrates. The etiology is still unknown although several hypotheses about the pathogenesis have been reported. A genetic predisposition has been shown by an increased frequency of certain human leucocyte antigen (HLA) types and a positive family history in some patients with recurrent aphthous stomatitis (RAS). Predisposing factors for the occurrence of aphthous ulcers are immunosuppression, drugs (especially NSAIDs), hematologic abnormalities, hormonal influences, infectious agents, nutritional deficiencies, stress, cessation of smoking, allergies, and trauma.

Clinically, three clinical variations can be recognized: minor aphthae, major aphthae, and herpetiform aphthae. The aphthae are localized on nonkeratinized mucosa.

Minor aphthous ulcerations are the most common (80%). They are 3–10 mm in size and are usually preceded by an erythematous macule associated with prodromal symptoms of burning, itching, or stinging. The ulceration has a white-yellow, removable fibrinopurulent membrane encircled by an erythematous halo. The ulcers are extremely painful with one to five lesions per episode and heal in 7–14 days without scarring (Fig. 1).
Fig. 1

Minor aphthae on the lower lip (Courtesy of Prof. A. Vissink, Department of Oral & Maxillofacial Surgery, UMCG, Groningen, The Netherlands)

Major aphthous ulcerations are larger than minor aphthous ulcerations, 1–3 cm diameter, deeper, one to ten lesions per episode, and heal within 2–6 weeks usually with scarring.

Herpetiform aphthous ulcerations are small, 1–3 mm, with multiple, up to 100 lesions present per episode. Single, small lesions may coalesce to larger irregular ulcerations. The ulcers heal within 7–10 days.

Recurrent aphthous ulcerations can be present in celiac disease, Crohn’s disease, Behçet’s disease, and HIV.

The immunopathogenesis of RAS involves predominantly a cell-mediated immune response mechanism and involves generation of T cells and tumor necrosis factor alpha (TNF-α) by these other leucocytes (macrophages and mast cells). TNF-α (a major inflammatory mediator) induces initiation of the inflammatory process by its effect on endothelial cell adhesion and neutrophil chemotaxis. Studies have shown that RAS can be prevented by treatments that prevent the synthesis of endogenous TNF-α such as thalidomide and pentoxifylline. TNF-α also has important immune regulatory activities including stimulation of class I major histocompatibility (MHC) expression which probably play a role in the local tissue damage by targeting these cells for attack by cytotoxic T cells (CD8+ cells) in the ulcerative process.

Clinical Features


The prevalence in the general population varies from 5% to 66%; it has been estimated that 20% of the general population will suffer from RAU at some time in their lives.


Aphthous ulcerations are more frequent in children and young adults but may appear at any age.


There may be a female preponderance in adults.


Minor aphthae: buccal and labial mucosa most frequently followed by the ventral surface of the tongue, mucobuccal fold, floor of the mouth, and soft palate.

Major aphthae may occur at any oral surface, but the labial mucosa, soft palate, and tonsillar fauces are most frequently involved.

Herpetiform aphthae can occur on any, preferentially nonkeratinized, oral surface.


Underlying systemic diseases should be excluded or treated.

Treatment is not necessary, since the lesions heal within short time. Symptomatic treatment, local anesthetics or protective bioadhesive products, can be used.

In case of mild disease, topical corticosteroids might be used. Major aphthous ulcerations are more resistant to therapy and often warrant more potent corticosteroids (triamcinolone) in gel, ointment, syrup, or tablets. Many different drugs in any form have been suggested, used, and studied with variable success.


Minor: recurrence rate is variable from one ulceration a year to about two episodes per month. They heal without scarring.

Major: the onset is after puberty with recurrent episodes for up to 20 years or more. They heal with scarring, which can become significant and lead to a restricted mouth opening.

Herpetiform: the ulcerations heal within 7–10 days with closely spaced recurrences, and patients may be affected constantly for as long as 3 years.


Aphthous ulcers present histologically as nonspecific ulcerations.

Microscopically, a mononuclear (lymphocytic) infiltrate is present within the lamina propria, infiltrating the epithelium with stromal edema. Then keratinocytic vacuolization occurs, finally turning into ulceration with a fibrous membrane covering an infiltrate in the subepithelial tissue consisting of neutrophils, lymphocytes, and plasma cells. Finally, the lesion heals with epithelial regeneration with or without scar formation (Fig. 2).
Fig. 2

H&E stain of an aphthae with normal squamous epithelium on the right and a nonspecific ulcer on the left


Significant differences are present in the serological levels of the IFN-γ, IL-4, and IL-6 cytokines of RAS (recurrent aphthous stomatitis) patients in comparison to normal controls. It was observed that the cytokine profile of the RAS group was comprised of two distinct clusters: a pure Th2 and a mixed (Th1/Th2) subtype. The use of probiotics can stimulate regulator activity, influencing the course of the disease (Mimura et al. 2017).

Differential Diagnosis

Minor/major aphthae: traumatic ulcer, pemphigus, pemphigoid.

Herpetiform: aphthae herpes simplex infection is preceded by vesicles.

References and Further Reading

  1. Jurge, S., Kuffer, R., Scully, C., & Porter, S. R. (2006). Mucosal disease series VI. Recurrent aphthous stomatitis. Oral Diseases, 12, 1–21.CrossRefPubMedGoogle Scholar
  2. Kozlak, S. J., Walsh, S. J., & Lalla, R. V. (2010). Reduced dietary intake of vitamin B12 and folate in patients with recurrent aphthous stomatitis. Journal of Oral Pathology and Medicine, 39, 420–423.PubMedPubMedCentralGoogle Scholar
  3. Mimura, M. A. M., Borra, R. C., Hirata, C. H. W., & de Oliveira Penido, N. (2017). Immune response of patients with recurrent aphthous stomatitis challenged with a symbiotic. Journal of Oral Pathology and Medicine, 46, 821–828.CrossRefPubMedGoogle Scholar
  4. Natah, S. S., Konttinen, Y. T., Enattah, N. S., Ashammaki, N., & Sharkey, K. A. (2004). Recurrent aphthous ulcers today: A review of the growing knowledge. International Journal of Oral and Maxillofacial Surgery, 33, 221–234.CrossRefPubMedGoogle Scholar
  5. Rivera-Hidalgo, F., Shuhman, J. D., & Beach, M. M. (2004). The association of tobacco and other factors with recurrent aphthous stomatitis in a U.S. adult population. Oral Diseases, 10, 335–345.CrossRefPubMedGoogle Scholar
  6. Scully, C., Gorsky, M., & Lozada-Nur, F. (2003). The diagnosis and management of recurrent aphthous stomatitis. A consensus approach. Journal of the American Dental Association, 134, 200–207.CrossRefPubMedGoogle Scholar

Copyright information

© Springer International Publishing AG 2018

Authors and Affiliations

  1. 1.Department of PathologyThe Netherlands Cancer Institute, Antoni van Leeuwenhoek HospitalAmsterdamThe Netherlands