Etiology of OM

Although the pathophysiology of oral mucositis (OM) is not yet fully understood, recent clinical investigations have advanced our understanding of its origin and development. Historically OM was thought to be limited to epithelial events.1 Epithelial cells divide rapidly and were thought to be damaged by the indiscriminant targeting of cancer therapies on rapidly dividing cells.2 Animal studies, however, showed that submucosal tissue damage preceded epithelial lesions by as much as a week.2

Stephen T. Sonis D.M.D., D.M.Sc. (Division of Oral Medicine, Brigham and Women’s Hospital) characterizes the development of OM as comprising five phases:

• Initiation
• Message generation
• Signaling and amplification
• Ulceration
• Healing3

Initiation occurs at the point of administration of antineoplastic chemotherapy or radiation therapy. Cells throughout the oral mucosa and submucosa are damaged by the generation of reactive oxygen species, which in turn causes many other destructive events. Epithelial cells also are killed directly by DNA damage and non-DNA damage. Although all the events that ultimately lead to ulceration have begun at this point, the mucosa still appears normal.3

The damage caused by initiation launches a phase of biochemical message generation and gene upregulation, during which transcription factor NF-kB seems particularly important. Upregulation and transcription generate proteins, including cytokines, which exacerbate damage.3 These mediators not only damage tissue directly, but many also contribute to a feedback cycle that enhances the amplification and signaling cycles and ultimately leads to pro-inflammatory changes that continue after therapy has completed.2

Ulceration occurs when the epithelium is degraded to the point of rupture. Ulceration is not only painful, but it also creates septic risks by allowing microbes to infiltrate. Once microbes begin to colonize, they release cell products that penetrate adjoining tissue, producing further inflammatory response and destructive cytokines.2 Immunosuppressed patients are most susceptible to this outcome, which may lead to infection and potentially fatal sepsis.4

Ultimately, healing begins as cells from the extracellular matrix send messages that cause the epithelial cells to divide and proceed toward renewing the mucosa. Although the mucosa appears normal after healing, OM has had long-lasting effects on cells and tissues throughout the mucosa, making it more likely that OM will develop during future therapy or other similar challenges.1

Both chemotherapy and radiation therapy can cause OM. Because chemotherapy is administered in short intervals, the OM it causes typically is acute and occurs quickly. Oral mucositis resulting from radiation therapy typically is chronic, reflecting the therapy delivery schedule.3

Read about the Consequences of Oral Mucositis in this section.