Characterisation and prognostic value of tertiary lymphoid structures in oral squamous cell carcinoma

BACKGROUND: Oral squamous cell carcinomas are often heavily infiltrated by immune cells. The organization of B-cells, follicular dendritic cells, T-cells and high-endothelial venules into structures termed tertiary lymphoid structures have been detected in various types of cancer, where their presence is found to predict favourable outcome. The purpose of the present study was to evaluate the incidence of tertiary lymphoid structures in oral squamous cell carcinomas, and if present, analyse whether they were associated with clinical outcome. METHODS: Tumour samples from 80 patients with oral squamous cell carcinoma were immunohistochemically stained for B-cells, follicular dendritic cells, T-cells, germinal centre B-cells and high-endothelial venules. Some samples were sectioned at multiple levels to assess whether the presence of tertiary lymphoid structures varied within the tumour. RESULTS: Tumour-associated tertiary lymphoid structures were detected in 21 % of the tumours and were associated with lower disease-specific death. The presence of tertiary lymphoid structures varied within different levels of a tissue block. CONCLUSIONS: Tertiary lymphoid structure formation was found to be a positive prognostic factor for patients with oral squamous cell carcinoma. Increased knowledge about tertiary lymphoid structure formation in oral squamous cell carcinoma might help to develop and guide immune-modulatory cancer treatments

Presence of tumour high-endothelial venules is an independent positive prognostic factor and stratifies patients with advanced-stage oral squamous cell carcinoma

Accepted manuscript version. The final publication is available at Springer via http://dx.doi.org/10.1007/s13277-015-4036-4Background: Staging of oral squamous cell carcinoma is based on the TNM system, which has been deemed insufficient for prognostic purposes. Hence, better prognostic tools are needed to reflect the biological diversity of these cancers. Previously, high numbers of specialized blood vessels called high-endothelial venules have been reported to be associated with prolonged survival in patients with breast cancer. In this study, we analysed the prognostic value and morphological characteristics of tumour-associated high-endothelial venules in oral cancer. Methods: The presence of tumour-associated high-endothelial venules was evaluated by immunohistochemistry in 75 patients with oral squamous cell carcinoma and analysed with correlation to clinicopathological parameters, patients’ survival, and vessel morphology. Ten of the samples were analysed at multiple levels to evaluate intratumoural heterogeneity. Results: The presence of tumour-associated high-endothelial venules was found to be associated with lower disease-specific death in multivariate regression analyses (P=0.002). High-endothelial venules were present in all (n=53) T1-T2 tumours, but only in two-thirds (n=14) of the T3-T4 tumours. The morphology of high-endothelial venules was heterogeneous and correlated with lymphocyte density. High-endothelial venules were found to be distributed homogeneously within the tumours. Conclusion: We found the presence of tumour-associated high-endothelial venules to be an easy-to-use, robust, and independent positive prognostic factor for patients with oral cancer. Absence of these vessels in advancedstage tumours might identify patients with more aggressive disease. Evaluating the presence of tumour-associated high-endothelial venules might help to tailor the treatment of oral cancer patients to their individual need

Plectin as a prognostic marker in non-metastatic oral squamous cell carcinoma

Background: Oral squamous cell carcinoma (OSCC) is associated with a poor 5-year survival rate. In general, patients diagnosed with small tumors have a fairly good prognosis, but some small tumors have an aggressive behavior leading to early death. There are at present no reliable prognostic biomarkers for oral cancers. Thus, to optimize treatment for the individual patient, there is a need for biomarkers that can predict tumor behavior. Method: In the present study the potential prognostic value of plectin was evaluated by a tissue microarray (TMA) based immunohistochemical analysis of primary tumor tissue obtained from a North Norwegian cohort of 115 patients diagnosed with OSCC. The expression of plectin was compared with clinicopathological variables and 5 year survival. Results: The statistical analysis revealed that low expression of plectin in the tumor cells predicted a favorable outcome for patients with non-metastatic disease (p = 0.008). Furthermore, the expression of plectin was found to correlate (p = 0.01) with the expression of uPAR, which we have previously found to be a potential prognostic marker for T1N0 tumors. Conclusions: Our results indicate that low expression of plectin predicts a favorable outcome for patients with non-metastatic OSCC and the expression level of plectin may therefore be used in the treatment stratification for patients with early stage disease

Prognostic markers in oral squamous cell carcinoma

Avhandlingen er basert på 5 artikler. Vi har retrospektivt innhentet klinisk informasjon om 133 pasienter diagnostisert med cancer i munnhulen ved UNN i perioden 1986-2001, og laget Tissue Micro Arrays (TMA) av tumorvev fra de respektive pasientenes svulster. Den første artikkelen er en epidemiologisk beskrivelse av materialet. Artikkel 2 og 3 omfatter ulike potensielle prognostiske markører for oral cancer, basert på immunhistokjemiske undersøkelser på TMA blokkene. I artikkel 2 er uPAR, PAI-1 de mest interessante, hvor vi finner en statistisk signifikant sammenheng mellom vevsuttrykk og sykdomsspesifikk overlevelse i pasienter med T1-svulster. I artikkel 3 er hovedfokuset på plectin. Uttrykket av plectin i vevet er statistisk signifikant knyttet til overlevelse for alle pasienter uten spredning av sykdommen til regional lymfeknuter(N0)ved diagnose. Vi fant også en sterk korrelasjon mellom uttrykket av uPAR og plectin i tumorvevet. I artikkel 4 har vi gjort undersøkelser på fullsnitt på 80 av svulstene for å kartlegge forekomsten av tertiære lymfoide organer (TLOs) i oral cancer, noe som ikke har vært gjort tidligere. Forekomsten av disse var også signifikant knyttet til prognose. Videre beskriver den siste artikkelen en indirekte, mer praktisk metode for å påvise disse immunologiske strukturene i vevet, ved å identifisere high endothelial venules (HEVs) i omgivelsene rundt TLOs. Pasienter med HEVs hadde signifikant mindre risiko for å dø av sykdommen enn de uten. Vår konklusjon er at vi har gjort flere interessante funn som fortjener å bli validert i en større studie

Clinicopathological characteristics of oral squamous cell carcinoma in Northern Norway: a retrospective study

BACKGROUND: The main aim of the study was to evaluate if patients with oral squamous carcinomas in Northern Norway differ from patients in other countries with regard to clinicopathological characteristics and also study the influence of risk factors. Such a comparison is of demographical interest, and also important for the interpretation of result from studies on prognostic biomarkers. METHODS: We describe clinicopathological characteristics of 133 North Norwegian patients diagnosed with squamous cell carcinoma of the oral cavity in the period 1986–2002, and evaluate the significance of different risk factors. RESULTS: The cohort consisted of 69 men and 64 women, giving male/female ratio of 1.1. Forty-seven of the 133 patients (35%) died of the disease within 5 years from diagnosis. There was no significant difference between the genders concerning time to disease specific death, even though men both smoked and drank more alcohol than women. As expected, the strongest predictors for disease specific death were tumour size and the presence of regional lymph node metastasis. We also found that heavy smokers and drinkers presented with more advanced disease, more often localized to the floor of mouth compared to non-smoking and abstinent patients, who more often presented with tumours of the mobile tongue. CONCLUSIONS: Our results correlate well with previously published clinicopathological data on comparable cohorts, which is important when considering the applicability of results from biomarker studies performed on this material compared to other cohorts, and vice versa

Plectin as a prognostic marker in non-metastatic oral squamous cell carcinoma

Background: Oral squamous cell carcinoma (OSCC) is associated with a poor 5-year survival rate. In general, patients diagnosed with small tumors have a fairly good prognosis, but some small tumors have an aggressive behavior leading to early death. There are at present no reliable prognostic biomarkers for oral cancers. Thus, to optimize treatment for the individual patient, there is a need for biomarkers that can predict tumor behavior. Method: In the present study the potential prognostic value of plectin was evaluated by a tissue microarray (TMA) based immunohistochemical analysis of primary tumor tissue obtained from a North Norwegian cohort of 115 patients diagnosed with OSCC. The expression of plectin was compared with clinicopathological variables and 5 year survival. Results: The statistical analysis revealed that low expression of plectin in the tumor cells predicted a favorable outcome for patients with non-metastatic disease (p = 0.008). Furthermore, the expression of plectin was found to correlate (p = 0.01) with the expression of uPAR, which we have previously found to be a potential prognostic marker for T1N0 tumors. Conclusions: Our results indicate that low expression of plectin predicts a favorable outcome for patients with non-metastatic OSCC and the expression level of plectin may therefore be used in the treatment stratification for patients with early stage disease

Urokinase Plasminogen Activator Receptor (uPAR) and Plasminogen Activator Inhibitor-1 (PAI-1) are potential predictive biomarkers in early stage Oral Squamous Cell Carcinomas (OSCC)

Oral squamous cell carcinoma (OSCC) is often associated with metastatic disease and a poor 5 year survival rate. Patients diagnosed with small tumours generally have a more favourable outcome, but some of these small tumours are aggressive and lead to early death. To avoid harmful overtreatment of patients with favourable prognosis, there is a need for predictive biomarkers that can be used for treatment stratification. In this study we assessed the possibility to use components of the plasminogen activator (PA) system as prognostic markers for OSCC outcome and compared this to the commonly used biomarker Ki-67. A tissue-micro-array (TMA) based immunohistochemical analysis of primary tumour tissue obtained from a North Norwegian cohort of 115 patients diagnosed with OSCC was conducted. The expression of the biomarkers was compared with clinicopathological variables and disease specific death. The statistical analyses revealed that low expression of uPAR (p = 0.031) and PAI-1 (p = 0.021) in the tumour cells was significantly associated with low disease specific death in patients with small tumours and no lymph node metastasis (T1N0). The commonly used biomarker, Ki-67, was not associated with disease specific death in any of the groups of patients analysed. The conclusion is that uPAR and PAI-1 are potential predictive biomarkers in early stage tumours and that this warrants further studies on a larger cohort of patients

Self-reported sleep quality with mandibular advancement device or continuous positive airway pressure: A randomized clinical trial on patients with mild and moderate obstructive sleep apnea

Study - objectives To compare self-reported sleep quality, treatment compliance and respiratory event index (REI) after 4 months of treatment with mandibular advancement device (MAD) or continuous positive airway pressure (CPAP) in mild and moderate obstructive sleep apnea (OSA). Methods - 104 patients with mild or moderate OSA were randomly allocated to MAD or CPAP treatment, and followed for 4 months. Data was collected through type 3 polygraphic sleep recordings, CPAP recordings, medical examination and the Pittsburgh Sleep Quality Index (PSQI). Chi-square test, t-test and Mann-Whitney U test were used to analyze compliance, PSQI global score and REI respectively. Reliable change index (RCI) was used to evaluate change in PSQI global score. Results - 6 patients were lost to follow-up. More patients were compliant to MAD treatment (79.5%) than CPAP treatment (38.9%) at follow-up (p Conclusion - Both MAD and CPAP treatment improve self-reported sleep quality in patients with mild and moderate OSA. More patients comply with MAD treatment which improve sleep quality in more patients than CPAP do, despite REI being lower in the CPAP group. In respect to sleep quality, MAD treatment should be considered a better treatment option than CPAP in mild and moderate OSA

Disease specific survival of patients with T1N0 tumours.

<p>Kaplan-Meier survival plot showing probability for a disease specific survival based on <b>A</b>) uPAR, <b>B</b>) PAI-1, <b>C</b>) uPA and <b>D</b>) Ki-67 expression and related to months after diagnosis. Total number of patients included in the analysis was 27 for uPAR and Ki-67, and 26 for PAI-1 and uPA. *; p<0.05 was regarded as statistically significant.</p