Expression of ß1- and ß2-adrenergic receptors in oral squamous cell carcinoma and their association with psychological and clinical factors.

BACKGROUND: Psychological stressors have been related to tumor progression through the activation of beta-adrenergic receptors (ß-AR) in several types of cancer. PURPOSE: This study aimed to investigate the expressions of ß1- and ß2-AR and their association with psychological and clinicopathological variables in patients with oral squamous cell carcinoma. METHODS: Tumor samples from 99 patients diagnosed with OSCC were subjected to immunohistochemical reaction to detect the expression of ß1-AR and ß2-AR. Anxiety and depression symptoms were assessed using the Beck Anxiety Inventory and Beck Depression Inventory (BDI), respectively. The Brunel Mood Scale was used for measuring affective mood states. RESULTS: Univariate analyzes revealed that higher expression of ß1-AR was associated with increased alcohol consumption (p = 0.032), higher education (p = 0.042), worse sleep quality (p = 0.044) and increased levels of pain related to the primary tumor (p < 0.001). Higher expression of ß2-AR was related with regional metastasis (p = 0.014), increased levels of pain related to the primary tumor (p = 0.044), anxiety (p < 0.001) and depressive (p = 0.010) symptoms and higher mood scores of angry (p = 0.010) and fatigue (p = 0.010). Multivariate analysis identified that patients with advanced clinical stage had lower ß1-AR expression (OR=0.145, 95% CI=0.025-0.828, p = 0.003). Higher anxiety symptoms and higher mood fatigue are independent factors for increased ß2-AR expression (OR=4256, 95% CI=1439-12606, p = 0.009; OR=3816, 95% CI=1258-11,573, p = 0.018, respectively). CONCLUSION: This study reveal that anxiety, fatigue symptoms, and clinical staging are associated with tumor expression of beta-adrenergic receptors in patients with oral cancer.

Influence of different methods for classification of lymph node metastases on the survival of patients with oral squamous cell carcinoma.

BACKGROUND: Despite the advances in the classification of oral squamous cell carcinoma (OSCC) based on its extension by the TNM system, there is still a need for methods to better classify the patients to predict prognosis and indicate adjuvant therapy. OBJECTIVES: To analyze the influence of the number of positive lymph nodes (PN), lymph node ratio (LNR), and log odds of positive lymph nodes (LODDS) in survival of patients with OSCC. METHODS: Clinicopathologic data from patients with OSCC who were treated with curative purposes by surgery and neck dissection (ND) with or without subsequent adjuvant therapies from 1991 to 2015 was retrospectively assessed. The impact of the PN, LNR, LODDS, and other variables on overall survival (OS) and disease-free survival (DFS) was analyzed in univariate and multivariate analyses. RESULTS: One hundred nineteen patients were included in this study. In the univariate analysis the PN had a significant impact on OS (p = 0.001) and DFS (p = 0.020), and the LNR had a significant impact on the OS (p = 0.042). In the multivariate analysis with other relevant clinicopathologic variables, the PN was the only significantly independent factor influencing in the OS (p = 0.017) but not in DFS (p = 0.096). CONCLUSIONS: The PN is an independent prognostic indicator for OS and DFS in patients with OSCC and has the potential to aggregate the current AJCC classification. The LNR has potential to be an important prognostic indicator, but the methods for this classification require lapidation. The LODDS did not demonstrate prognostic potential.

Potential of lymph-node ratio as a prognostic factor for patients with oral squamous cell carcinoma.

BACKGROUND: To analyze the influence of the lymph node ratio (LNR) in survival of patients with OSCC METHODS: Clinicopathologic data from patients with OSCC who were treated with curative surgery and neck dissection (ND) with or without adjuvant therapies from 1991 to 2015 was retrospectively assessed. The impact of LNR and other variables on overall survival (OS) and disease-free survival (DFS) was analyzed in univariate and multivariate analyses. RESULTS: One hundred nineteen patients were included. In the univariate analysis the LNR had a significant impact on OS (p = 0.01) and DFS (p = 0.01). In the multivariate analysis, the LNR was the only significantly independent factor influencing in the OS (p = 0.03). The adjuvant therapies did not influence on the OS (p = 0.42) and DFS (p = 0.10). CONCLUSIONS: The LNR is an independent prognostic factor in patients with OSCC. The LNR alone is not recommended to indicate the performance of adjuvant therapies.

Predisposing factors for increased cortisol levels in oral cancer patients.

Cancer patients may have a dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis and abnormal secretion of cortisol. Increased cortisol levels have been associated with worse prognosis in patients with different types of tumors. Although anxiety and depression can trigger an abnormal cortisol secretion, little is known regarding the influence of these emotional disorders on HPA axis dysregulation in cancer patients when evaluating together with demographic, clinicopathological and biobehavioral variables. This cross-sectional study analyzed the pre-treatment plasma cortisol levels of 133 patients with oral squamous cell carcinoma (OSCC) and its association with demographic, clinicopathological, biobehavioral and psychological variables. Plasma cortisol levels were measured by electrochemiluminescence, and anxiety and depression symptoms were assessed using Beck Anxiety Inventory (BAI) and Depression (BDI), respectively. Demographic, clinicopathological and biobehavioral data were collected from patients' medical records. Results from multivariate analysis showed that the occurrence of cancer-induced pain was predictive for higher cortisol levels (OR = 5.388, p = 0.003). Men with OSCC were 4.5 times more likely to have higher plasma cortisol levels than women (OR = 4.472, p = 0.018). The effect of sex on cortisol concentrations was lost in the adjusted model for clinical staging (OR = 2.945, p = 0.116). The absence of chronic alcohol consumption history was a protective factor for highest hormone concentrations in oral cancer patients (OR = 0.104, p = 0.004). Anxiety symptoms measured by BAI as "hands trembling" (OR = 0.192, p = 0.016) and being "nervous" (OR = 0.207, p = 0.0004) were associated with lower cortisol levels. In contrast, the feeling of "fear of losing control" was a risk factor for highest hormone concentrations (OR = 6.508, p = 0.0004). The global score and specific symptoms of depression measured by the BDI were not predictive for plasma hormone levels (p > 0.05). Together, our results show that pain, alcohol consumption and feeling fear are independent factors for increased systemic cortisol levels in patients with oral cancer. Therefore, psychological intervention, as well as control of pain and alcohol consumption, should be considered to prevent the negative effects of cortisol secretion dysregulation in cancer patients.

Garlic burn trauma of the oral mucosa in a patient with trigeminal neuralgia: A case report.

Garlic is one of the most common medicinal plants used since ancient times to treat diverse diseases within several cultures worldwide. Nevertheless, this plant has the potential to cause chemical burns of the skin and mucosa. This report presents a case of a garlic burn in the palate of a 57-year-old woman who applied garlic to the palate to relieve the pain of trigeminal neuralgia. This case demonstrates the potential of garlic to cause chemical burns to the oral mucosa and raises an alert to oral health professionals regarding inappropriate self-treatment methods.

Assessment of the knowledge of canalis sinuosus amongst dentists and dental students: An online-based cross-sectional study.

INTRODUCTION: Canalis sinuosus (CS) is a neurovascular canal that corresponds to a small branch of the infraorbital canal. This study aimed at assessing the knowledge and detection performance of CS amongst dentists and dental students. MATERIALS AND METHODS: Four-hundred and five dentists and dental students answered a questionnaire with three parts: 1. Socio-demographical; 2. Clinical cases with cone- beam computed tomography (CBCT) sections showing CS and 3. Previous knowledge about CS. The chi-squared test and Spearman's correlation test were used to compare results as appropriate. p-values below .05 were considered statistically significant. RESULTS: Most participants did not identify CS in any CBCT. There was an association between the number of correct answers and dental specialties. Most individuals had not learned about CS previously. There was an association between past knowledge of CS and gender, highest academic degree, working environment, dental specialty and number of correct answers but not with age or experience in Dentistry. CONCLUSION: This study suggests that most dentists are not aware about CS and do not know how to diagnose it. Previous knowledge about CS positively influenced its identification in CBCT.

Pleomorphic sarcoma of maxillary sinus: Clinical report of a patient initially diagnosed with denture-induced fibrous hyperplasia.

Undifferentiated pleomorphic sarcoma is a high-grade soft-tissue malignant tumor that is rare in the head and neck region. A 74-year-old woman displayed a large nodular lesion in the maxillary alveolar mucosa, which was initially identified as denture-related fibrous hyperplasia. Although her prosthodontist has adjusted the maxillary complete denture to relieve pressure on the lesion, it increased in size over time. Computed tomography images of the maxillary sinus showed an extensive destructive lesion. A biopsy was performed, and microscopic examination revealed a poorly differentiated malignancy with numerous spindle cells. Immunohistochemistry reactions were negative for CD45, CD30, CD68, CD34, cytokeratin, S100, desmin, and smooth muscle actin. These findings led to the diagnosis of an undifferentiated pleomorphic sarcoma of the maxillary sinus.

Blastoid variant of mantle cell lymphoma in palatine tonsil.

Blastoid variant of mantle cell lymphoma (MCL) is an aggressive and extremely rare malignancy. MCL may be diagnosed in lymph nodes and/or extranodal sites exhibiting a poor prognosis. MCL with primary presentation in palatine tonsils has been rarely reported. Herein, we report the case of a 73-year-old man with a painless nodular mass on the right palatine tonsil. A biopsy was performed, and microscopic analysis revealed a neoplasm composed of small to medium sized lymphocytes with finely dispersed chromatin, roundish nucleus and many mitoses. The tumor cells were positive for CD20 (L26), CD5 (4C7), Cyclin D1 (EP12), Bcl2 (124) and Ki-67 (MIB-1; 90%), and negative for Bcl6 (PG-B6p), MUM1 (MUM1p) and CD3 (Polyclonal). These findings led to the diagnosis of blastoid variant of MCL. Diagnostic workup with computed tomography scan excluded other sites of disease. The patient was treated successfully with cyclophosphamide, doxorubicin, vincristine and prednisolone (mini-CHOP regimen). Although the blastoid variant of MCL is rare, it should be included in the differential diagnosis of rapid-growing masses in the palatine tonsil.

Stress hormones promote DNA damage in human oral keratinocytes.

Chronic stress increases the systemic levels of stress hormones norepinephrine and cortisol. As well as tobacco-specific carcinogen NNK (4-(methylnitrosamine)-1-(3-pyridyl)-1-butanone), they can induce expressive DNA damage contributing to the cancer development. However, it is unknown whether stress hormones have genotoxic effects in oral keratinocytes. This study investigated the effects of stress hormones on DNA damage in a human oral keratinocyte cell line (NOK-SI). NOK-SI cells stimulated with norepinephrine or cortisol showed higher DNA damage compared to untreated cells. Norepinephrine-induced DNA damage was reversed by pre-treatment with beta-adrenergic blocker propranolol. Cells treated with NNK combined to norepinephrine displayed reduced levels of caspases 3 and 7. Cortisol also reduced the activity of pro-apoptotic enzymes. NNK or norepinephrine promoted single-strand breaks and alkali-label side breaks in the DNA of NOK-SI cells. Pre-treatment of cells with propranolol abolished these effects. Carcinogen NNK in the presence or absence of cortisol also induced DNA damage of these cells. The genotoxic effects of cortisol alone and hormone combined with NNK were blocked partially and totally, respectively, by the glucocorticoid receptor antagonist RU486. DNA damage promoted by NNK or cortisol and carcinogen combined to the hormone led to intracellular γH2AX accumulation. The effects caused by NNK and cortisol were reversed by propranolol and glucocorticoid receptor antagonist RU486, respectively. Propranolol inhibited the oxidation of basis induced by NNK in the presence of DNA-formamidopyrimidine glycosylase. DNA breaks induced by norepinephrine in the presence or absence of NNK resulted in higher 8OHdG cellular levels. This effect was also induced through beta-adrenergic receptors. Together, these findings indicate that stress hormones induce DNA damage of oral keratinocytes and could contribute to oral carcinogenesis.

Social isolation stress facilitates chemically induced oral carcinogenesis.

Social isolation has affected a large number of people and may lead to impairment of physical and mental health. Although stress resulting from social isolation may increase cancer progression, its interference on tumorigenesis is poorly known. In this study, we used a preclinical model to evaluate the effects of social isolation stress on chemically induced oral carcinogenesis. Sixty-two 21-day-old male Wistar rats were divided into isolated and grouped groups. After 90 days of age, the rats from both groups underwent oral carcinogenesis with 4-nitroquinoline 1-oxide (4NQO) for 20 weeks. All rats were assessed for depressive-like behavior and euthanized for oral squamous cell carcinoma (OSCC) diagnosis and measurement of inflammatory mediators in the tumor microenvironment. Social isolation stress increased the OSCC occurrence by 20.4% when compared to control. Isolated rats also showed higher tumor volume and cachexia than the grouped rats. Social isolation did not induce changes in the depressive-like behavior after carcinogenic induction. Tumors from stressed rats had increased levels of the inflammatory mediators, TNF-alpha, IL1-beta and MCP-1. The concentrations of TNF-alpha and MCP-1 were significantly increased in the large tumors from isolated animals. Higher tumor levels of TNF-alpha, IL-6, IL1-beta and MCP-1 were positively correlated with OSCC growth. This study provides the first evidence that social isolation stress may facilitate OSCC occurrence and tumor progression, an event accompanied by increased local levels of inflammatory mediators.

Tongue Nodule as Primary Manifestation of American Cutaneous Leishmaniasis in an Immunocompetent Patient.

Leishmaniasis is a parasitic disease considered an endemic public health problem in developing countries, where it is a reportable disease. Isolated oral manifestation is rare, and its clinical manifestations are variable. In this paper we describe an unusual case of an immunocompetent patient, 57-year-old man with a painless reddish submucosal nodule located on the tongue dorsum. Microscopical analysis showed chronic inflammatory infiltrate with macrophages containing leishmania in cytoplasmic vacuoles. PCR assays confirmed the diagnosis and patient was treated with meglumine antimoniate for 30 days. Absence of the parasite was confirmed by PCR. Thirteen years after treatment, a scar fibrosis persisted on the tongue dorsum. The case reported reveals that leishmaniasis should be considered in the diagnosis of tongue nodules in immunocompetent patients.

In situ melanoma of oral cavity: Diagnosis and treatment of a rare entity.

Oral melanoma is an extremely aggressive and rare tumor. Commonly, oral melanomas are diagnosed as invasive tumors, which considerably reduces the chances of cure. In situ oral melanomas being exceedingly rare, which makes its clinicopathological and prognostic characteristics poorly known. Herein, we report a case of 67-year-old non-white woman with a large black patch on the maxillary alveolar mucosa. A biopsy was made and microscopical analysis revealed moderate atypical junctional melanocytic. Tumor cells were positive for S100 (Polyclonal), Melan-A (Clone A103) and Melanosome (HMB-45). The diagnosis of in situ oral melanoma was made and the patient was treated surgically with partial maxillectomy and rehabilitated with obturator prosthesis. Although extremely rare in situ melanomas should be considered in the differential diagnosis of non-invasive pigmented lesions of the oral mucosa.

Beta-adrenergic blocker inhibits oral carcinogenesis and reduces tumor invasion.

PURPOSE: Beta-adrenergic signaling can influence cancer progression and the use of beta blockers as adjuvant drugs in oncologic patients has been suggested. However, the involvement of beta-adrenergic blockers in tumorigenesis is poorly understood. This study investigated the action of beta-adrenergic blocker propranolol on tumor onset using a preclinical model of chemically induced oral cancer. METHODS: Thirty-two male Wistar rats were subjected to daily subcutaneous injection of beta-blocker propranolol (10 mg/kg; SubQ), while another 32 rats received only a PBS injection (sham group). One week after starting propranolol treatment, all rats were submitted to chemical induction of oral carcinogenesis with 4-nitroquinoline-1-oxide (4NQO). After 16 weeks, they were assessed for occurrence of oral squamous cell carcinoma (OSCC), in addition to measurement of tumor volume and thickness, and tissue levels of cytokines IL-6, TNF-alpha and IL-10 in the tumor microenvironment. RESULTS: Propranolol treatment reduced the occurrence of OSCC by 31%, 95% CI ( - 127, 216). Beta-adrenergic blocker significantly decreased thickness of OSCC when compared with PBS. Rats treated with propranolol exhibited a lower tumor volume when compared with control rats, but this result did not reach statistical significance. Tumors from propranolol-treated rats exhibited reduced concentrations of pro-inflammatory cytokines IL-6 and TNF-α. There was no difference in the IL-10 levels between tumors from propranolol- and sham-treated rats. CONCLUSION: Beta-adrenergic signaling may be one of the mechanisms associated with chemically induced oral carcinogenesis.

Canalis sinuosus: An Anatomic Repair that May Prevent Success of Dental Implants in Anterior Maxilla.

Canalis sinuosus (CS) is a neurovascular canal that corresponds to a small branch of the infraorbital canal. It contains the anterior superior alveolar nerve and vessels, supplying the anterior maxilla. Despite having been described 81 years ago, CS is not recognized by many dental practitioners and may be the cause of unintended injuries during dental procedures. The aims of this study are to report a case of a patient who suffered pain due to exposure of the CS, to provide a comprehensive review of other CS cases that were challenging to diagnose, and to propose guidelines for preoperative examination of patients undergoing surgical procedures in the anterior maxilla. The review of the literature revealed six cases, in addition to the one presented here, of unintended or potential damage to CS. Five out of seven cases were related to dental implant placement and resulted in postoperative pain and/or paresthesia. The dental implant was removed in 4 out of the 5 cases. This study reinforces the importance of awareness of CS by dental practitioners and provides a protocol for the preoperative examination of the patient to prevent avoidable injuries to CS.

Pineal gland protects against chemically induced oral carcinogenesis and inhibits tumor progression in rats.

Clinical investigations suggest that melatonin suppression and circadian dysfunction may be related to cancer development in shift workers. Studies also show that melatonin suppression after pinealectomy increases cancer incidence in preclinical models. However, no study evaluated the influence of pinealectomy on oral cancer development. In the current study, we investigated the effects of pinealectomy on oral squamous cell carcinoma (OSCC) occurrence and progression in rats. Rats submitted to sham surgery were used as control. Pinealectomy promoted an increase of 140% in OSCC occurrence when compared to sham animals. Tumors from pinealectomized rats displayed a higher volume and thickness than the tumors from sham-operated animals. Pinealectomy induced atrophy of the epithelium adjacent to the oral lesions. Pinealectomized rats showed higher mean number of tumor-associated macrophages and eosinophils in the invasive front of OSCC. In addition, nuclear overexpression of ERK1/2 and p53 was also observed in the front of carcinomas from pinealectomized rats. These results reveal that pineal gland plays a protective role against oral carcinogenesis. The melatonin suppression caused by the pinealectomy might contribute to oral cancer development by acting on ERK1/2 and p53 pathways and regulating tumor inflammation.