Pathology and Classification
Stage 1 – soreness and erythema
The initiation phase is characterized by direct DNA injury caused by radiation or chemotherapy and subsequent strand breaks that result in clonogenic death of basal epithelial cells. Even more significant from the standpoint of ultimate tissue damage is the generation of reactive oxygen species (ROS). It has been recently suggested that cells damaged by chemotherapy and radiation may release endogenous damage associatedpattern molecules (CRAMPs), which then bind to specific receptors and contribute to the initiation of stage 2.
Stage 2 – erythema, ulcers, patients can swallow solid diet
Chemotherapy, radiation, ROS, and CRAMPs initiate a series of cascading and interacting biological events, including the activation of a number of transcription factors, such as nuclear factor Kappa-B (NF-κB), Wnt, p53, and their associated canonical pathways. Of the many canonical pathways that contribute to the development of mucositis, the NF-κB pathway is one of the best studied and provides an excellent example of the complexity of the process leading to ulceration. Chemotherapy and radiation can directly activate NF-κB. Indirectly, it can be activated by ROS or by receptor-bound CRAMPs.
As a result, up to 200 genes may be expressed. Among these are genes associated with the production of molecules, which have demonstrated activity in the pathogenesis of mucositis including proinflammatory cytokines and cytokine modulators, stress responders (eg, COX-2, inducible NO-synthase, superoxide dismutase), and cell adhesion molecules. Furthermore, cell death (via apoptosis) may occur following NF-κB activation. Other pathways have also been identified as playing significant roles in regimen-related mucosal injuries. Among the most significant are those associated with nitrogen metabolism, Toll-like receptor signaling, B-cell-receptor signaling, P13K/AKT signaling and mitogen-activated protein kinase (MAPK) signaling, to name a few. In addition, other radiation- and chemotherapy-induced mucosal damage is associated with the ceramide pathway and fibrinolysis and the stimulation of matrix metalloproteinases (MMPs).
The first two phases of mucositis development begin almost immediately after patients receive treatment. The majority of these changes are seen within the cells and tissues of the submucosa and both direct and indirect destruction of epithelial stem cells starts soon thereafter. However, from a clinical standpoint, the impact of all of these destructive activities is not realized for about 4 to 5 days following chemotherapy/radiation therapy challenge. And in the case of fractionated radiation, the precipitating events that lead to extensive mucositis occur in daily increments.
Stage 3 – ulcers, extensive erythema, patients cannot swallow solid diet
Many of the molecules induced by the primary response have the ability to positively or negatively feedback and alter the local tissue response. For example, tumor necrosis factor (TNF) may positively feedback on NF-κB to amplify its response, and initiate MAPK signaling, leading to activation of Jun N-terminal kinase (JNK) signaling.
Stage 4 – mucositis to the extent that alimentation is not possible
For the patient and the clinician, the most significant stage of mucositis is the development of mucosal ulceration. This is the stage that is most symptomatic, prone to infection, and requisite for increased resource use. Because regimen-related ulceration is the consequence of damage at the basal layers of the epithelium, ulcers transect the full epithelial thickness. Once formed, ulcers are colonized by both gram positive and gram negative oral bacteria, which spew out cell wall products. These molecules are capable of extending mucosal damage as they stimulate infiltrating macrophages to release additional levels of pro-inflammatory cytokines.