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.

Early life stress exacerbates bone resorption and inhibits anxiety-like behaviour induced by apical periodontitis in rats.

AIM: To evaluate the influence of the early life stress (ELS) on the severity of the apical periodontitis (AP) in Wistar rats. METHODOLOGY: Forty male Wistar rats were divided into four groups (n = 10): Control rats; AP-rats with AP; ELS-rats subject to ELS; AP + ELS-rats exposed to ELS and subject to AP. ELS was induced by maternal separation (MS) for a period of 3 h for 21 consecutive days. AP was induced via pulp exposure of the first and second right maxillary molars to the oral environment for 40 days. Three days before euthanasia, all rats underwent behavioural analysis to measure anxiety levels by elevated zero maze. Then, the rats were euthanized and the maxillas were removed to assess the occurrence and severity of AP. The periapical region was evaluated for the intensity of the inflammatory infiltrate and the extent of bone loss. The Mann-Whitney test was performed for nonparametric data, and the Tukey's or Student's t-test was performed for parametric data (p < .05). RESULTS: The intensity of the inflammatory infiltrate was significantly larger in the AP + ELS group when compared with AP group (p < .05). The AP + ELS group exhibited significantly greater alveolar bone loss, with a periapical lesion size of 103.5 ± 29.88, compared with 72.3 ± 22.28 in the AP group (p < .05). Rats with AP displayed higher anxiety-like behaviour in relation to the control group (p < .05). However, exposure to ELS abolished the AP-induced increased anxiety-like 'behaviour' throughout, since that rats from AP + ELS group attended more the open arms than non-stressed rats with AP (p < .05). CONCLUSION: Early life stress is predictive of the severity of AP exacerbating the inflammatory process and increasing periapical bone resorption.

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.

HIV-related plasmablastic lymphoma causing extensive bone destruction in the mandible.

Plasmablastic lymphoma (PBL) is a rare subtype of large B-cell lymphoma commonly associated with HIV infection. HIV-related PBL has a dismal prognosis. The aggressive clinical course of the disease may lead to the development of rapid-growing swellings, like several benign and malignant conditions. Herein, we reported the case of a 38-year-old woman with a painful swelling in the mandible initially diagnosed as an abscess derived from a tooth extraction. Intraoral examination revealed a painful swelling with reddish, white and purplish areas in the posterior region of the mandible without signs of infection. Imaging exams showed an extensive bone destruction in the left mandibular body. Histopathological examination revealed a high proliferation of plasmacytoid cells with nuclear hyperchromatism. Tumor cells were negative for CD20, and positive for Ki-67, CD138, IgG and lambda chain. The diagnosis of oral PBL was defined and serological test showed positivity for HIV. Eight months after starting treatment, the patient died due to complications of cancer treatment. Lymphoproliferative malignancies related to HIV infection should be included in the differential diagnosis of rapid-growing swellings in the oral cavity.

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.

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.

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.

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.

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.

High p16INK4a immunoexpression is not HPV dependent in oral leukoplakia.

OBJECTIVE: To evaluate the prevalence of HPV DNA detection in fresh tissue from oral leukoplakia by Linear Array assay, and its correlation with p16INK4a immunoexpression in the northwest region of the São Paulo state, Brazil. PATIENTS AND METHODS: Fifty patients diagnosed with oral leukoplakia were included in the study. Sociodemographic, clinicopathologic and lifestyle data, fresh tissue and formalin fixed paraffin embedded (FFPE) tissue samples were collected. The fresh tissue was stored at -80 °C and then submitted to further viral DNA detection by the Linear Array method. Immunohistochemical analysis for the p16INK4a expression was performed. RESULTS: Of the 50 patients included in the study, 62 % were men, and the age ranged from 25 to 82 years. Twenty-three (46 %) were elderly, 46 % were middle-aged adults, and only 12 % were young adults. Most patients were smokers (76 %), 14 % were former smokers, and 10 % were non-smokers. Most patients (56 %) were current drinkers, 22 % were ex-drinkers and 22 % were non-drinkers. Thirty-two percent of the lesions presented some degree of dysplasia. No lesions were positive to HPV by Linear Array detection. Thirty (60 %) OL had p16-low immunoexpression and 20 (40 %) had p16-high immunoexpression. CONCLUSION: HPV was not identified in the population studied. The high p16INK4a immunoexpression is not dependent on HPV in oral leukoplakia. Broader epidemiological studies are required to clarify the geographic variability in the prevalence of HPV in head and neck squamous cell carcinoma and oral potentially malignant lesions.

Head and neck squamous cell carcinoma in young patients: a 26-year clinicopathologic retrospective study in a Brazilian specialized center

BACKGROUND: To describe the clinicopathologic profile of young patients with head and neck squamous cell carcinoma (HNSCC) and compare to middle-aged and elderly adults. MATERIAL AND METHODS: Patients' individual records were reviewed for clinicopathologic data. Eighty-nine patients with age 18-45 years old met the inclusion criteria of the study. Two additional groups of middle-aged (n = 89) and old (n = 89) adults were set to comparative analysis. RESULTS: Young patients represented 11.9% of all patients diagnosed with HNSCC. Women were more affected by HNSCC in the young and elder groups (p= 0.04), and young patients were more prone to be non-smokers (p= 0.01) and have lymph node metastasis at the time of diagnosis (p = 0.04). In the young group, patients diagnosed with the disease in advanced stages were more prone to have a positive familial history of cancer (p= 0.04), a positive status of alcohol consumption (p= 0.03), and to be heavy drinkers (p= 0.01). Survival was not different for the young group in comparison to the other groups. CONCLUSIONS: HNSCC in young patients had a different profile when compared to older patients, especially regarding sex and exposure to the classic risk factors for this disease. The survival of the young group is similar to the older groups and advanced clinical stage is predictor of worse survival

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Diagnosis and Treatment of Oral Venous Malformation in a Child.

Venous malformations (VMs) are congenital disorders that constitute about 40% of all vascular anomalies. These lesions do not regress spontaneously and may increase in size during childhood. The case of a 10-year-old girl with an extensive oral VM is reported. Intraoral examination revealed the presence of purplish nodules in the alveolar mucosa and gingiva from anterior maxilla. Doppler ultrasound showed a well-defined hypoechoic image and increased vascularization with low blood flow for the alveolar mucosa lesion. The patient was submitted to intralesional injections of the ethanolamine oleate/mepivacaine sclerosing solution. After four sessions, there was a significant reduction of the lesions. However, the patient abandoned the treatment and the oral VM grew progressively. After 1 year, sclerotherapy was resumed and performed weekly. After 10 session of sclerotherapy, the oral VM totally regressed. The childhood is a critical period for oral VM growth. Doppler ultrasound and sclerotherapy can be effective for the management of extensive lesions in children.

Benign symmetric lipomatosis in the tongue: an uncommon case.

Symmetric lipomatosis of the tongue (SLT) is rare and characterized by diffuse growth and unencapsulated lipomas. An 87-year-old man was referred for evaluation of tongue lesions. Intraoral findings showed soft yellowish nodules with a smooth shiny surface diffusely on the lateral border of the tongue, bilaterally. Our clinical diagnosis was multiple tongue lipomas and an incisional biopsy was done. Histopathological examination revealed unencapsulated lobules of mature adipocytes with slight variation in the size and shape, confirming the diagnosis of lipoma. The final diagnosis was SLT. On follow-up at 6 months, the tongue findings were unchanged and no new lesions were observed.