Oral cancer patients experience mechanical and chemical sensitivity at the site of the cancer.

INTRODUCTION: Oral cancer patients suffer severe chronic and mechanically-induced pain at the site of the cancer. Our clinical experience is that oral cancer patients report new sensitivity to spicy foods. We hypothesized that in cancer patients, mechanical and chemical sensitivity would be greater when measured at the cancer site compared to a contralateral matched normal site. METHODS: We determined mechanical pain thresholds (MPT) on the right and left sides of the tongue of 11 healthy subjects, and at the cancer and contralateral matched normal site in 11 oral cancer patients in response to von Frey filaments in the range of 0.008 to 300 g (normally not reported as painful). We evaluated chemical sensitivity in 13 healthy subjects and seven cancer patients, who rated spiciness/pain on a visual analog scale in response to exposure to six paper strips impregnated with capsaicin (0-10 mM). RESULTS: Mechanical detection thresholds (MDT) were recorded for healthy subjects, but not MPTs. By contrast, MPTs were measured at the site of the cancer in oral cancer patients (7/11 patients). No MPTs were measured at the cancer patients' contralateral matched normal sites. Measured MPTs were correlated with patients' responses to the University of California Oral Cancer Pain Questionnaire. Capsaicin sensitivity at the site of the cancer was evident in cancer patients by a leftward shift of the cancer site capsaicin dose-response curve compared to that of the patient's contralateral matched normal site. We detected no difference in capsaicin sensitivity on the right and left sides of tongues of healthy subjects. CONCLUSIONS: Mechanical and chemical sensitivity testing was well tolerated by the majority of oral cancer patients. Sensitivity is greater at the site of the cancer than at a contralateral matched normal site.

Measurement of the Association of Pain with Clinical Characteristics in Oral Cancer Patients at Diagnosis and Prior to Cancer Treatment.

Aim: Oral cancer patients suffer pain at the site of the cancer, which degrades quality of life (QoL). The University of California San Francisco Oral Cancer Pain Questionnaire (UCSFOCPQ), the only validated instrument specifically designed for measuring oral cancer pain, measures the intensity and nature of pain and the level of functional restriction due to pain. Purpose: The aim of this study was to compare pain reported by untreated oral cancer patients on the UCSFOCPQ with pain they reported on the Brief Pain Inventory (BPI), an instrument widely used to evaluate cancer and non-cancer pain. Patients and Methods: The correlation between pain measured by the two instruments and clinical characteristics were analyzed. Thirty newly diagnosed oral cancer patients completed the UCSFOCPQ and the BPI. Results: Pain severity measurements made by the UCSFOCPQ and BPI were concordant; however, the widely used BPI average pain over 24 hours score appeared less sensitive to detect association of oral cancer pain with clinical characteristics of patients prior to treatment (nodal status, depth of invasion, DOI). A BPI average score that includes responses to questions that measure both pain severity and interference with function performs similarly to the UCSFOCPQ in detection of associations with nodal status, pathologic T stage (pT stage), stage and depth of invasion (DOI). Conclusion: Pain assessment instruments that measure sensory and interference dimensions of oral cancer pain correlate with biologic features and clinical behavior.

Oncogenes overexpressed in metastatic oral cancers from patients with pain: potential pain mediators released in exosomes.

Oral cancer patients experience pain at the site of the primary cancer. Patients with metastatic oral cancers report greater pain. Lack of pain identifies patients at low risk of metastasis with sensitivity = 0.94 and negative predictive value = 0.89. In the same cohort, sensitivity and negative predictive value of depth of invasion, currently the best predictor, were 0.95 and 0.92, respectively. Cancer pain is attributed to cancer-derived mediators that sensitize neurons and is associated with increased neuronal density. We hypothesized that pain mediators would be overexpressed in metastatic cancers from patients reporting high pain. We identified 40 genes overexpressed in metastatic cancers from patients reporting high pain (n = 5) compared to N0 cancers (n = 10) and normal tissue (n = 5). The genes are enriched for functions in extracellular matrix organization and angiogenesis. They have oncogenic and neuronal functions and are reported in exosomes. Hierarchical clustering according to expression of neurotrophic and axon guidance genes also separated cancers according to pain and nodal status. Depletion of exosomes from cancer cell line supernatant reduced nociceptive behavior in a paw withdrawal assay, supporting a role for exosomes in cancer pain. The identified genes and exosomes are potential therapeutic targets for stopping cancer and attenuating pain.

Peripheral nerve injury and sensitization underlie pain associated with oral cancer perineural invasion.

Cancer invading into nerves, termed perineural invasion (PNI), is associated with pain. Here, we show that oral cancer patients with PNI report greater spontaneous pain and mechanical allodynia compared with patients without PNI, suggesting that unique mechanisms drive PNI-induced pain. We studied the impact of PNI on peripheral nerve physiology and anatomy using a murine sciatic nerve PNI model. Mice with PNI exhibited spontaneous nociception and mechanical allodynia. Perineural invasion induced afterdischarge in A high-threshold mechanoreceptors (HTMRs), mechanical sensitization (ie, decreased mechanical thresholds) in both A and C HTMRs, and mechanical desensitization in low-threshold mechanoreceptors. Perineural invasion resulted in nerve damage, including axon loss, myelin damage, and axon degeneration. Electrophysiological evidence of nerve injury included decreased conduction velocity, and increased percentage of both mechanically insensitive and electrically unexcitable neurons. We conclude that PNI-induced pain is driven by nerve injury and peripheral sensitization in HTMRs.