Pathobiology of Mucositis

The Pathobiology of Mucositis

The following article was published by Stephen T Sonis in "Nature Reviews|Cancer", and can be viewed in full at http://www.nature.com/nrc/journal/v4/n4/pdf/nrc1318.pdf, shown below are the edited highlights, provided very kindly by TomF.

Stephen T. Sonis, Division of Oral Medicine, Brigham and Women's Hospital, 75 Francis Street, Boston, MA 02115, USA. From Nature Reviews: Cancer Volume 4, No. 4, pages 277-284, April 2004. 2004 Nature Publishing Group

The oral mucosa is comprised of stratified squamous epithelium that overlies the lamina propria, which consists of fibroblasts and connective tissue, small blood vessels (capillaries), inflammatory cells (macrophages) and extracellular matrix. The epithelium of the movable mucosa (which makes up the cheeks, inner aspects of the lips, ventral surface of the tongue, floor of the mouth and soft palate) is not keratinized, in contrast to the dorsal tongue, hard palate and gingiva. Although all the tissues of the mouth are susceptible to radiation-induced mucositis, only the movable mucosa develops chemotherapy-induced injury. The oral epithelium, like the skin, is a constantly renewing tissue in which proliferating cells in the basal layer produce daughter cells that then migrate to the surface.

Like most diseases, the clinical and symptomatic manifestations of mucositis form a continuum. In its mildest form, mucositis presents an erythematous, atrophic lesion in which the mucosa remains intact. Patients have a sensitivity that is similar to a food burn and can be relatively easily managed. By contrast, patients with more severe mucositis develop ulcerations that penetrate fully into the submucosa and cause severe pain, which routinely necessitates narcotic analgesia.

In addition to the symptoms of mucositis and its impact on quality of life, mucositis adversely affects a variety of other health and economic outcomes. Because the mouth harbours a vast array of microorganisms, loss of epithelial integrity - especially when patients undergo myeloablation - markedly increases the risk of bacteraemia, fungaemia and sepsis.

About 10 days after the administration of stomatotoxic chemotherapy, or at cumulative radiation doses of about 30 Gy, the integrity of the epithelium disintegrates and ulceration occurs. The ulcerative phase is extremely painful, as the protective barrier that overlies the nerve endings in the lamina propria is eliminated. Oral bacteria colonize the ulcer, where they release cell-wall products that penetrate into the connective tissue to stimulate the release of other cytokines. The inflammatory infiltrate is most robust during the ulcerative stage and consists of macrophages, plasma and mast cells. Depending on the bone-marrow status of the patient, neutrophils might also be present. The ulcer can be covered by a fibrinous, bacteria-laden exudate that is referred to as a 'pseudomembrane'. In most cases, spontaneous healing occurs about 2- 3 weeks after the cessation of radiotherapy or by 3 weeks after the administration of chemotherapy. The epithelium migrates from the wound margins as a consequence of signals from mesenchymal cells and extracellular matrix, which determine proliferation, migration and differentiation.

The ulcerative phase of mucositis is the most significant to both the patient and the caregiver. The loss of mucosal integrity results in extremely painful lesions that are prone to superficial bacterial colonization. In the case of neutropenic patients, these breaks in the mucosa serve as portals of entry for the numerous microorganisms that reside in the mouth, and often lead to bacteraemia and sepsis. In addition, cell-wall products from colonizing bacteria are likely to penetrate into the submucosa, where they activate infiltrating mononuclear cells to produce and release additional pro-inflammatory cytokines. This probably promotes the expression of pro-apoptotic genes and potentiates tissue injury. Inflammatory cells then migrate by chemotaxis to the base of the lesion, where they produce damaging enzymes.

The bacterial colonization of ulcerative lesions that occurs in patients with mucositis is thought to prolong and exacerbate the condition. Consequently, various antimicrobial agents have been studied, although the results of this have been inconsistent. Although it is clear that systemic antibiotic therapy is ineffective in treating mucositis, the use of topical therapy has resulted in mixed outcomes. It seems unlikely that primary antimicrobial therapy will be an effective approach, although further studies are required to understand the role of microorganisms in the progression and course of mucositis.

In a study of patients with haematological malignancies, individuals with psoriasis - a papulosquamous dermatological disorder - were 77% less likely to develop mucositis than the non-psoriatic control group. Conversely, patients with either Addison's disease or hypoadrenocorticism developed mucositis 17% more frequently than controls. Of interest is the fact that both of these diseases seem to affect the propensity of cells to undergo apoptosis in opposing ways - levels of apoptosis are reduced in cells from patients with psoriasis and increased in cells from patients with Addison's disease. These results indicate that other factors, such as genetic factors, can determine the risk of developing mucositis. This finding is of particular significance given the variability in the frequency and severity of mucositis among patients of similar demographic backgrounds who were treated with equivalent therapies for the same kinds of tumours.

Although it seems unlikely that there will be a 'magic bullet' that is suitable for treating all patients, targeted, multiagent and sequenced therapy regimens might be a more effective approach. For now, mucositis remains one of the most prominent and important toxicities that are associated with radiation therapy and chemotherapy. With the significant advances that are being made in understanding the mechanisms of mucositis, it seems likely that an intervention will be available in the not-too-distant future.

Many thanks to TomF who found and submitted this article.
One day when I have some time I'll try and contact Steven T. Sonis.