Sandra Ventorin Von Zeidler

PET-CT Surveillance versus Neck Dissection in Advanced Head and Neck Cancer

BACKGROUND The role of image-guided surveillance as compared with planned neck dissection in the treatment of patients with squamous-cell carcinoma of the head and neck who have advanced nodal disease (stage N2 or N3) and who have received chemoradiotherapy for primary treatment is a matter of debate. METHODS In this prospective, randomized, controlled trial, we assessed the noninferiority of positron-emission tomography-computed tomography (PET-CT)-guided surveillance (performed 12 weeks after the end of chemoradiotherapy, with neck dissection performed only if PET-CT showed an incomplete or equivocal response) to planned neck dissection in patients with stage N2 or N3 disease. The primary end point was overall survival. RESULTS From 2007 through 2012, we recruited 564 patients (282 patients in the planned-surgery group and 282 patients in the surveillance group) from 37 centers in the United Kingdom. Among these patients, 17% had nodal stage N2a disease and 61% had stage N2b disease. A total of 84% of the patients had oropharyngeal cancer, and 75% had tumor specimens that stained positive for the p16 protein, an indicator that human papillomavirus had a role in the causation of the cancer. The median follow-up was 36 months. PET-CT-guided surveillance resulted in fewer neck dissections than did planned dissection surgery (54 vs. 221); rates of surgical complications were similar in the two groups (42% and 38%, respectively). The 2-year overall survival rate was 84.9% (95% confidence interval [CI], 80.7 to 89.1) in the surveillance group and 81.5% (95% CI, 76.9 to 86.3) in the planned-surgery group. The hazard ratio for death slightly favored PET-CT-guided surveillance and indicated noninferiority (upper boundary of the 95% CI for the hazard ratio, <1.50; P=0.004). There was no significant difference between the groups with respect to p16 expression. Quality of life was similar in the two groups. PET-CT-guided surveillance, as compared with neck dissection, resulted in savings of £1,492 (approximately

E-cadherin as a potential biomarker of malignant transformation in oral leukoplakia: a retrospective cohort study

2,190 in U.S. dollars) per person over the duration of the trial. CONCLUSIONS Survival was similar among patients who underwent PET-CT-guided surveillance and those who underwent planned neck dissection, but surveillance resulted in considerably fewer operations and it was more cost-effective. (Funded by the National Institute for Health Research Health Technology Assessment Programme and Cancer Research UK; PET-NECK Current Controlled Trials number, ISRCTN13735240.).

Influence of pain severity on the quality of life in patients with head and neck cancer before antineoplastic therapy.

BackgroundNumerous attempts have been made to establish and develop tumor markers that could determine the susceptibility of normal tissues to transform into cancerous ones. To determine whether altered expression patterns of E-cadherin could be an early event in the progression of potentially malignant disorders to oral squamous cell carcinoma, this study aimed to assess the relationship between the immunoexpression of E-cadherin and the different degrees of epithelial dysplasia in oral leukoplakia.MethodsSurgically excised specimens from patients with oral leukoplakia (n = 31), oral cavity squamous cell carcinoma with cervical lymph node metastasis (n = 12) and normal oral mucosa (n = 9) were immunostained for E-cadherin. Oral leukoplakia samples were distributed into low and high risk group according to a binary system for grading oral epithelial dysplasia. Comparative analyses between E-cadherin expression and microscopic features (WHO histological grading and epithelial dysplasia) were performed by Pearson Chi-square test (P < 0.05).ResultsDifferences in E-cadherin expression were observed between normal oral mucosa and low risk oral leukoplakia (P = 0.006), low and high risk oral leukoplakia (P = 0.019), and high risk oral leukoplakia and oral cavity squamous cell carcinoma with cervical lymph node metastasis (P = 0.0001). In addition, as epithelia undergo dysplastic changes, the risk of malignant transformation increases, and there is a reduction or loss of E-cadherin expression by keratinocytes. Reduced E-cadherin expression was an early phenomenon and it was observed in moderate-severe dysplasia, showing that the loss of epithelial cohesion may be an indicator of progression to oral cavity squamous cell carcinoma.ConclusionsE-cadherin could be used as a novel biomarker to identify lesions with potential risk for malignant transformation, which may provide opportunities for prophylactic interventions in high risk patient groups.

PET-NECK: a multicentre randomised Phase III non-inferiority trial comparing a positron emission tomography-computerised tomography-guided watch-and-wait policy with planned neck dissection in the management of locally advanced (N2/N3) nodal metastases in patients with squamous cell head and neck cancer

BackgroundThe aim of this study was to assess the severity of pain and its impact on the quality of life (QoL) in untreated patients with head and neck squamous cell carcinoma (HNSCC).MethodsA study group of 127 patients with HNSCC were interviewed before antineoplastic treatment. The severity of pain was measured using the Brief Pain Inventory (BPI) questionnaire, and the QoL was assessed with the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core-30 (EORTC QLQ-C30) and the head and neck module (QLQ-H&N35).ResultsThe mean age of the patients was 57.9 years, and there was a predominance of men (87.4%). The most frequent site of the primary tumor was the oral cavity (70.6%), and the majority of the patients had advanced cancers (stages III and IV). QoL in early stage of cancer obtained better scores. Conversely, the patients with advanced stage cancer scored significantly higher on the symptom scales regarding fatigue, pain, appetite loss and financial difficulties, indicating greater difficulties. Regard to the severity of pain, patients with moderate-severe pain revealed a significantly worse score than patients without pain.ConclusionsThe severity of pain is statistically related to the advanced stages of cancer and directly affects the QoL. An assessment of the quality of life and symptoms before therapy can direct attention to the most important symptoms, and appropriate interventions can then be directed toward improving QoL outcomes and the response to treatment.

Polymorphisms in methylenetetrahydrofolate reductase and cystathionine beta-synthase in oral cancer - a case-control study in southeastern Brazilians

BACKGROUND Planned neck dissection (ND) after radical chemoradiotherapy (CRT) for locally advanced nodal metastases in patients with head and neck squamous cell carcinoma (HNSCC) remains controversial. Thirty per cent of ND specimens show histological evidence of tumour. Consequently, a significant proportion of clinicians still practise planned ND. Fludeoxyglucose positron emission tomography (PET)-computerised tomography (CT) scanning demonstrated high negative predictive values for persistent nodal disease, providing a possible alternative paradigm to ND. Evidence is sparse and drawn mainly from retrospective single-institution studies, illustrating the need for a prospective randomised controlled trial. OBJECTIVES To determine the efficacy and cost-effectiveness of PET-CT-guided surveillance, compared with planned ND, in a multicentre, prospective, randomised setting. DESIGN A pragmatic randomised non-inferiority trial comparing PET-CT-guided watch-and-wait policy with the current planned ND policy in HNSCC patients with locally advanced nodal metastases and treated with radical CRT. Patients were randomised in a 1 : 1 ratio. Primary outcomes were overall survival (OS) and cost-effectiveness [incremental cost per incremental quality-adjusted life-year (QALY)]. Cost-effectiveness was assessed over the trial period using individual patient data, and over a lifetime horizon using a decision-analytic model. Secondary outcomes were recurrence in the neck, complication rates and quality of life. The recruitment of 560 patients was planned to detect non-inferior OS in the intervention arm with a 90% power and a type I error of 5%, with non-inferiority defined as having a hazard ratio (HR) of no higher than 1.50. An intention-to-treat analysis was performed by Coxs proportional hazards model. SETTINGS Thirty-seven head and neck cancer-treating centres (43 NHS hospitals) throughout the UK. PARTICIPANTS Patients with locally advanced nodal metastases of oropharynx, hypopharynx, larynx, oral or occult HNSCC receiving CRT and fit for ND were recruited. INTERVENTION Patients randomised to planned ND before or after CRT (control), or CRT followed by fludeoxyglucose PET-CT 10-12 weeks post CRT with ND only if PET-CT showed incomplete or equivocal response of nodal disease (intervention). Balanced by centre, planned ND timing, CRT schedule, disease site and the tumour, node, metastasis stage. RESULTS In total, 564 patients were recruited (ND arm, n = 282; and surveillance arm, n = 282; 17% N2a, 61% N2b, 18% N2c and 3% N3). Eighty-four per cent had oropharyngeal cancer. Seventy-five per cent of tested cases were p16 positive. The median time to follow-up was 36 months. The HR for OS was 0.92 [95% confidence interval (CI) 0.65 to 1.32], indicating non-inferiority. The upper limit of the non-inferiority HR margin of 1.50, which was informed by patient advisors to the project, lies at the 99.6 percentile of this estimate (p = 0.004). There were no differences in this result by p16 status. There were 54 NDs performed in the surveillance arm, with 22 surgical complications, and 221 NDs in the ND arm, with 85 complications. Quality-of-life scores were slightly better in the surveillance arm. Compared with planned ND, PET-CT surveillance produced an incremental net health benefit of 0.16 QALYs (95% CI 0.03 to 0.28 QALYs) over the trial period and 0.21 QALYs (95% CI -0.41 to 0.85 QALYs) over the modelled lifetime horizon. LIMITATIONS Pragmatic randomised controlled trial with a 36-month median follow-up. CONCLUSIONS PET-CT-guided active surveillance showed similar survival outcomes to ND but resulted in considerably fewer NDs, fewer complications and lower costs, supporting its use in routine practice. FUTURE WORK PET-CT surveillance is cost-effective in the short term, and long-term cost-effectiveness could be addressed in future work. TRIAL REGISTRATION Current Controlled Trials ISRCTN13735240. FUNDING This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 21, No. 17. See the NIHR Journals Library website for further project information.

Altered β-catenin expression in oral mucosal dysplasia: a comparative study

INTRODUCTION Oral squamous cell carcinoma (OSCC) is a serious public health problem, due to its high mortality rate and worldwide rising incidence. OSCC susceptibility is mediated by interactions between genetic and environmental factors. Studies suggest that genetic variants encoding enzymes involved in folate metabolism may modulate OSCC risk by altering DNA synthesis/repair and methylation process. OBJECTIVE The goals of this study were to evaluate the association of three genotypic polymorphism (MTHFR C677T, MTHFR A1298C and CBS 844ins68) and oral cancer risk in southeastern Brazilians and evaluate the interactions between polymorphisms and clinical histopathological parameters. METHODS This case-control study included 101 cases and 102 controls in the state of Espírito Santo, Brazil. MTHFR genotyping was done by PCR-RFLP (polymerase chain reaction - restriction fragment length polymorphism) and CBS genotyping by PCR (polymerase chain reaction) analysis. RESULTS MTHFR C677T polymorphism was associated with lymph node involvement. Genotype CT+TT acted as a protective factor. MTHFR A1298C AC+CC genotype was associated with tumor differentiation, and possibly with a better prognosis. In risk analysis, no correlation was observed between genotypes and OSCC. CONCLUSION We concluded that MTHFR C677T, MTHFR A1298C and CBS 844ins68 polymorphisms were not associated with OSCC risk in southeastern Brazilians; however, we suggest a prognosis effect associated with MTHFR C677T and A1298C polymorphisms in OSCC.

Atypical esthesioneuroblastoma invading oral cavity: a case report and review of the literature

Objective The current study aimed to investigate the β-catenin expression in oral leukoplakia (OL) with different degrees of epithelial dysplasia and normal oral mucosa. Material and Methods Formalin-fixed, paraffin-embedded tissue samples of 39 OL (mild dysplasia n=19, moderate dysplasia n=13, and severe dysplasia n=7), and 10 normal oral mucosa (control group) were submitted to immunohistochemical reactions to anti-β-catenin primary antibody. A qualitative β-catenin analysis was performed based on the percentage of positive cells. The cellular location and the epithelial layer were also considered. The Chi-square test and the Fisher’s exact test were used to verify possible differences in the β-catenin expression among the OL groups. A p-value of <0.05 was considered statistically significant. Results Membranous expression of β-catenin in parabasal and basal layers was gradually lost in the higher degrees of epithelial dysplasia. In normal oral mucosa, β-catenin was detected only in the cytoplasmic membrane. However, a significant increase in cytoplasmic β-catenin could be observed between mild and moderate dysplasia (Fisher Exact test - p<0.001) and between mild and severe dysplasia (p<0.001). Conclusions The β-catenin cytoplasmic expression observed in this study may represent the initial stage of modifications in the E-cadherin-catenin complex, along with morphological cellular changes.

Clinical features of oral and oropharyngeal squamous cell carcinoma HPV related.

Esthesioneuroblastoma is an uncommon tumour of neuroectodermal origin. The authors describe a rare presentation of an atypical esthesioneuroblastoma invading oral cavity. The clinical presentation, aetiology, diagnosis, and management of this condition are discussed. The patient developed significant swelling in the right anterosuperior alveolar mucosa and had moderate tooth mobility. Conventional x-rays and computed tomography revealed a large osteolytic lesion, with imprecise limits. Histological findings along with immunohistochemical staining results and clinical features led to the diagnosis of high-grade esthesioneuroblastoma. Local recurrences and neck metastasis were detected. The rare oral findings produced delayed in diagnosis which may lead to a compromise in planning and execution of further radical management and thus a poor prognosis.Virtual slidesThe virtual slides for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1168853011139286.

Frequency of Human Papillomavirus infection in squamous cell carcinoma of the oral cavity and oropharynx

Background The oral squamous cell carcinoma (OSCC) is a malignant neoplasm originating from the epithelial lining of the oral cavity, accounting for about 95% of malignant lesions in this region. In Brazil, the oral cavity is the fifth location of the highest incidence of cancer in men and the seventh in women. In 2012, Brazil was estimated at 9,990 new cases of oral cancer in men and 4,180 in women [1]. The oral cavity and oropharynx present in the epithelium coating a wide variety of tissue patterns occupying very close areas. Thus, the study of squamous cell carcinoma of the oral cavity and oropharynx should consider the anatomical site, size and pattern of tumor infiltration as characteristics that may influence the biological behavior of the tumor [2]. This study aimed to evaluate the clinical and pathological aspects related to human papillomavirus (HPV) in squamous cell carcinoma of oral and oropharyngeal.

PERFIL DE METILAÇÃO DO GENE P16 EM MUCOSA ORAL DE INDIVÍDUOS COM CARCINOMA EPIDERMOIDE DA CAVIDADE BUCAL

Background Squamous cell carcinoma of the oral cavity and oropharynx is a public health issue, with over 200,000 new cases worldwide each year [1]. Studies show that the incidence is higher in male individuals, aged between 40 and 55 years. The consumption of tobacco and alcohol are wellestablished risk factors for developing head and neck cancer, and studies have been shown synergism between these substances, which contributes to the increased risk [4]. Recently, persistent infection with high risk Human Papillomavirus (HPV) has been identified as a potential risk factor for the development of these tumors [2]. HPV is a DNA virus that features tropism to epithelial cells. The high risk HPV types, such as types 16 and 18 have the ability to integrate their DNA into the host cell DNA, immortalizing keratinocytes, with great possibilities of causing a cancer by infecting cells [3]. This study aims to evaluate the frequency of HPV infection, smoking and alcohol consumption related to the development of squamous cell carcinomas of the oral cavity and oropharynx.