Faculty Bibliography

PURPOSE: Problems in management of oral cancers or precancers include identification of patients at risk for metastasis, tumor recurrence, and second primary tumors or risk for progression of precancers (dysplasia) to cancer. Thus, the objective of this study was to clarify the role of genomic aberrations in oral cancer progression and metastasis. EXPERIMENTAL DESIGN: The spectrum of copy number alterations in oral dysplasia and squamous cell carcinomas (SCC) was determined by array comparative genomic hybridization. Associations with clinical characteristics were studied and results confirmed in an independent cohort. RESULTS: The presence of one or more of the chromosomal aberrations +3q24-qter, -8pter-p23.1, +8q12-q24.2, and +20 distinguishes a major subgroup (70%-80% of lesions, termed 3q8pq20 subtype) from the remainder (20%-30% of lesions, non-3q8pq20). The 3q8pq20 subtype is associated with chromosomal instability and differential methylation in the most chromosomally unstable tumors. The two subtypes differ significantly in clinical outcome with risk for cervical (neck) lymph node metastasis almost exclusively associated with the 3q8pq20 subtype in two independent oral SCC cohorts. CONCLUSIONS: Two subtypes of oral lesions indicative of at least two pathways for oral cancer development were distinguished that differ in chromosomal instability and risk for metastasis, suggesting that +3q,-8p, +8q, and +20 constitute a biomarker with clinical utility for identifying patients at risk for metastasis. Moreover, although increased numbers of genomic alterations can be harbingers of progression to cancer, dysplastic lesions lacking copy number changes cannot be considered benign as they are potential precursors to non-3q8pq20 locally invasive, yet not metastatic oral SCC.

BACKGROUND: This multicenter study was undertaken to characterize the metastatic behavior of oral maxillary squamous carcinoma and to determine the role of selective neck dissection. METHODS: A retrospective, multicenter study of patients surgically treated for oral maxillary squamous carcinoma was completed. Data collected included primary tumor location, cervical lymph node status, and neck failure rate. RESULTS: The study included 146 patients. The adjusted regional metastatic rate was 31.4%. Of those N0 (clinically negative) necks treated with or without neck dissection, 14.4% developed cervical metastasis. Within the cohort, 7.5% of patients died with distant disease. The regional salvage rate was 52.9%. None of the patients with locoregional failures were salvaged. CONCLUSIONS: Maxillary palatal, alveolar, and gingival squamous carcinomas exhibit aggressive regional metastatic behavior. Surgical salvage rates for neck failure are low; therefore, selective neck dissection (levels I-III) is recommended at the time of resection of T2, T3, and T4 maxillary squamous carcinomas.

Endothelin-1 is a vasoactive peptide that activates both the endothelin A (ET(A)) and endothelin B (ET(B)) receptors, and is secreted in high concentrations in many different cancer environments. Although ET(A) receptor activation has an established nociceptive effect in cancer models, the role of ET(B) receptors on cancer pain is controversial. EDNRB, the gene encoding the ET(B) receptor, has been shown to be hypermethylated and transcriptionally silenced in many different cancers. In this study we demonstrate that EDNRB is heavily methylated in human oral squamous cell carcinoma lesions, which are painful, but not methylated in human oral dysplasia lesions, which are typically not painful. ET(B) mRNA expression is reduced in the human oral squamous cell carcinoma lesions as a consequence of EDNRB hypermethylation. Using a mouse cancer pain model, we show that ET(B) receptor re-expression attenuates cancer-induced pain. These findings identify EDNRB methylation as a novel regulatory mechanism in cancer-induced pain and suggest that demethylation therapy targeted at the cancer microenvironment has the potential to thwart pain-producing mechanisms at the source, thus freeing patients of systemic analgesic toxicity.

Cancers often cause excruciating pain and rapid weight loss, severely reducing quality of life in cancer patients. Cancer-induced pain and cachexia are often studied and treated independently, although both symptoms are strongly linked with chronic inflammation and sustained production of proinflammatory cytokines. Because nerve growth factor (NGF) plays a cardinal role in inflammation and pain, and because it interacts with multiple proinflammatory cytokines, we hypothesized that NGF acts as a key endogenous molecule involved in the orchestration of cancer-related inflammation. NGF might be a molecule common to the mechanisms responsible for clinically distinctive cancer symptoms such as pain and cachexia as well as cancer progression. Here we reported that NGF was highly elevated in human oral squamous cell carcinoma tumors and cell cultures. Using two validated mouse cancer models, we further showed that NGF blockade decreased tumor proliferation, nociception, and weight loss by orchestrating proinflammatory cytokines and leptin production. NGF blockade also decreased expression levels of nociceptive receptors TRPV1, TRPA1, and PAR-2. Together, these results identified NGF as a common link among proliferation, pain, and cachexia in oral cancer. Anti-NGF could be an important mechanism-based therapy for oral cancer and its related symptoms

Contrary to a clinical aphorism that early head and neck cancer is painless, we show that patients who develop head and neck cancer experience significant pain at the time of initial diagnosis. We compared orofacial pain sensitivity in groups of patients with normal oral mucosa, oral precancer, and newly diagnosed oral cancer. The University of California San Francisco Oral Cancer Pain Questionnaire was administered to these patients at their initial visit, before being prescribed analgesics for pain and before any treatment. In contrast to those with biopsy-proven normal oral mucosa and oral precancer, only oral cancer patients reported significant levels of spontaneous pain and functional restriction from pain. Moreover, oral cancer patients experienced significantly higher function-related, rather than spontaneous, pain qualities. These findings suggest an important predictor for the transition from oral precancer to cancer may be the onset of orofacial pain that is exacerbated during function. Screening patients who have new-onset orofacial pain may lead to a diagnosis of early resectable head and neck cancer and may improve quality of life and survival for head and neck cancer patients. An important predictor for the transition from oral precancer to oral cancer may be the onset of orofacial pain that is exacerbated during function

BACKGROUND AND PURPOSE: Small oral cavity tumors are an imaging challenge. Intimate apposition of vestibular oral mucosa to the alveolar mucosa makes tumor assessment difficult. In CT imaging, the 'puffed cheek' method has been used to separate surfaces, though this is not feasible with long MR imaging sequences. We implemented placement of 2 x 2 inch (6.45 cm) gauze into the oral vestibule before the MR imaging examination, to determine whether this might improve tumor visualization. MATERIALS AND METHODS: MR imaging examinations of all T1 oral malignant tumors treated at University of California, San Francisco, by the Oral and Maxillofacial Department were reviewed by 2 neuroradiologists. Nine patients were included in the final analysis. Six patients were imaged by using a standard protocol. Three patients were imaged with gauze placement. The radiologists evaluated the MR images, assessing whether they could see the tumor and then fully delineate it and its thickness. RESULTS: Fisher exact analysis was performed on questions 1, 2, and 4 with the following results: P value = .048, Can you see the tumor? P value = .012, Can you fully delineate? P value of .012, How confident are you? MR imaging examinations with gauze clearly delineated the tumor with the tumor thickness measurable. MR imaging examinations without gauze did not clearly show the tumor or its thickness. Confidence of interpretation of the findings was also increased when gauze was used. CONCLUSIONS: A 2 x 2 inch (6.45 cm) rolled gauze in the oral vestibule significantly improved tumor localization and delineation at MR imaging. This technique is simple and provides superior preoperative imaging evaluation and treatment planning of small oral cavity tumors

We investigated the effects of cannabinoid receptor agonists on (1) oral cancer cell viability in vitro and (2) oral cancer pain and tumor growth in a mouse cancer model. We utilized immunohistochemistry and Western blot to show that human oral cancer cells express CBr1 and CBr2. When treated with WIN55,212-2 (non-selective), ACEA (CBr1-selective) or AM1241 (CBr2-selective) agonists in vitro, oral cancer cell proliferation was significantly attenuated in a dose-dependent manner. In vivo, systemic administration (0.013M) of WIN55,212-2, ACEA, or AM1241 significantly attenuated cancer-induced mechanical allodynia. Tumor growth was also significantly attenuated with systemic AM1241 administration. Our findings suggest a direct role for cannabinoid mechanisms in oral cancer pain and proliferation. The systemic administration of cannabinoid receptor agonists may have important therapeutic implications wherein cannabinoid receptor agonists may reduce morbidity and mortality of oral cancer

BACKGROUND: Surgical resection of oral cancer can be associated with significant postoperative cardiovascular and respiratory complications that require more sensitive predictors. METHODS: All patients with oral squamous cell carcinoma treated from July 2005 to April 2008 were retrospectively reviewed. The Goldman Revised Cardiac Risk Index (GRCRI) was used to predict cardiovascular complications. Other evidence-based a priori predictors were applied in an h-fold cross-validation model. RESULTS: Operating room (OR) time was an independent predictor of cardiovascular complications (odds ratio = 1.54, p = .002, 95% confidence interval [CI] = 1.18-2.02) and respiratory complications (odds ratio = 1.3, p = .06, 95% CI = 0.99-1.64) after multivariate adjustment. OR time and estimated blood loss predicted cardiovascular complications with 73% sensitivity. The GRCRI achieved 37% sensitivity. OR time and tracheostomy predicted respiratory complications with 75% sensitivity. CONCLUSIONS: The GRCRI was not prognostic for cardiovascular complications in patients with oral cancer. The most sensitive predictors for cardiovascular complications were OR time and estimated blood loss; for respiratory complications they were OR time and tracheostomy