Prognostic indicators of survival for patients with oral cavity squamous cell carcinoma in Norway. Outcomes in a retrospective, multicenter cohort, with special focus on oral tongue squamous cell carcinoma, 2005-2009

Oral cavity cancer (OCC) is the most frequent of head and neck cancers, most being squamous cell carcinomas (SCC). Within the oral cavity, the oral tongue is the most common site of cancer. These cancers are very aggressive, with poor survival. The treatment decision is based upon classifications of tumor (T), lymph node (N), and metastasis (M), although tumors with the same classification may act differently in aggressiveness. Treatment of these patients would be primary site surgery, with additional neck-dissection for many. Postsurgical radiotherapy may be added, rarely chemotherapy. The tumor growth pattern may predict the aggressiveness of the tumor, and thereby supplement the TNM classification in treatment decision. There is no established tumor growth pattern in use today that differentiates between those who need an additional neck-dissection and radiotherapy or chemotherapy; this may lead to overtreatment or undertreatment. This study investigated retrospectively a cohort of OCC from 2005-2009, which was called the Norwegian oral cancer (NOROC) study. We used data from the national Cause of Death Registry to calculate survival outcome. Spearman bivariate calculation was used to investigate correlations between the variables. Log-Rank univariate analyses were used to give Kaplan-Meier survival curves. Cox regression was used in multivariate analyses to determine which variables best predicted survival outcome. We found 535 primary treatment-naïve oral cavity SCC. Median age at diagnosis was 67 years; five-year disease-specific survival was 52%. Our data show that high-risk Human Papilloma Virus was not detected in oral tongue (OT) SCC. Growth patterns of tumor depth of invasion (DOI), tumor budding, and WHO differentiation and lympocytic infiltate in a combined histo-score, can predict the aggressiveness. Tumor DOI is already implemented in the new TNM classification. We suggest that other risk-patterns we found can be added to TNM classification for individualized treatment

The Practically Wise Medical Teacher: Medical Education at the University of Tromsø – A Norwegian Case

Source at https://www.hsj.gr/.This article addresses the issue of teaching quality in medical education and investigates what characterizes a professionally competent or practically wise medical teacher through the use of longitudinal data from interviews with 40 medical students. In discussing the findings, Aristotle’s concepts of episteme, techne and phronesis, and theoretical perspectives on professionalism and quality in teaching are applied. The findings highlight that one is either a practically wise medical teacher or a technical medical teacher. The practically wise medical teacher typically focuses on reflection, experience, participation, formative assessment and discussion in an atmosphere of good relations, which stimulate teaching and learning. The technical medical teacher, on the contrary, knows very little about the students and treats them as onlookers in clinical settings. The analysis results indicate that being a practically wise medical teacher requires a perception of what characterizes professionalism in medical education, the ability to use formative assessment and role model consciousness. These findings underline the importance of a good supervisor–learner relationship, which promotes medical teachers’ teaching competence and knowledge of professionalism. The findings also indicate the importance of faculty development in order to improve teaching quality at both the individual and system levels

Tumor budding score predicts lymph node status in oral tongue squamous cell carcinoma and should be included in the pathology report

Background - The majority of oral cavity cancers arise in the oral tongue. The aim of this study was to evaluate the prognostic value of tumor budding in oral tongue squamous cell carcinoma, both as a separate variable and in combination with depth of invasion. We also assessed the prognostic impact of the 8th edition of the American Joint Committee on Cancer’s TNM classification (TNM8), where depth of invasion (DOI) supplements diameter in the tumor size (T) categorization. Methods - Patients diagnosed with primary oral tongue squamous cell carcinoma were evaluated retrospectively. Spearman bivariate correlation analyses with bootstrapping were used to identify correlation between variables. Prognostic value of clinical and histopathological variables was assessed by Log rank and Cox regression analyses with bootstrapping using 5-year disease specific survival as outcome. The significance level for the hypothesis test was 0.05. Results - One-hundred and fifty patients had available material for microscopic evaluation on Hematoxylin and Eosin-stained slides and were included in the analyses. Reclassification of tumors according to TNM8 caused a shift towards a higher T status compared to the previous classification. The tumor budding score was associated with lymph node metastases where 23% of the patients with low-budding tumors had lymph node metastases, compared with 43% of those with high-budding tumors. T-status, lymph node status, tumor budding, depth of invasion, and the combined tumor budding/depth of invasion score were all significantly associated with survival in univariate analyses. In multivariate analyses only N-status was an independent prognosticator of survival. Conclusion - Reclassification according to TNM8 shifted many tumors to a higher T-status, and also increased the prognostic value of the T-status. This supports the implementation of depth of invasion to the T-categorization in TNM8. Tumor budding correlated with lymph node metastases and survival. Therefore, information on tumor budding can aid clinicians in treatment planning and should be included in pathology reports of oral tongue squamous cell carcinomas

Evaluation Challenges in the Validation of B7-H3 as Oral Tongue Cancer Prognosticator

B7-H3 was the only molecule identified with prognostic potential from a recent systematic review of the prognostic value of immune checkpoints in oral cancer. We aimed to validate this finding in a multicenter international cohort. We retrospectively retrieved 323 oral tongue squamous cell carcinoma (OTSCC) samples from three different countries (Brazil, Finland, and Norway) for immunostaining and scoring for B7-H3. We evaluated tumor immunogenicity by analyzing the amount of tumor-infiltrating lymphocytes and divided the tumors into immune hot and cold. To increase the reliability of the results, both digital and manual visual scoring were used. Survival curves were constructed based on the Kaplan-Meier method, and the Cox proportional hazard model was utilized for univariate and multivariate survival analysis. B7-H3 expression was not significantly associated with overall or disease-specific survival in the whole OTSCC cohort. When divided into immune hot and cold tumors, high B7-H3 expression was significantly associated with poor disease-specific and overall survival in the immune hot group, depending on the scoring method and the country of the cohort. This was achieved only in the univariate analysis. In conclusion, B7-H3 was a negative prognosticator for OTSCC patient survival in the subgroup of immune hot tumors, and was not validated as a prognosticator in the full cohort. Our findings suggest that the immune activity of the tumor should be considered when testing immune checkpoints as biomarkers.Peer reviewe

Evaluation Challenges in the validation of B7-H3 as oral tongue cancer prognosticator

B7-H3 was the only molecule identified with prognostic potential from a recent systematic review of the prognostic value of immune checkpoints in oral cancer. We aimed to validate this finding in a multicenter international cohort. We retrospectively retrieved 323 oral tongue squamous cell carcinoma (OTSCC) samples from three different countries (Brazil, Finland, and Norway) for immunostaining and scoring for B7-H3. We evaluated tumor immunogenicity by analyzing the amount of tumor-infiltrating lymphocytes and divided the tumors into immune hot and cold. To increase the reliability of the results, both digital and manual visual scoring were used. Survival curves were constructed based on the Kaplan-Meier method, and the Cox proportional hazard model was utilized for univariate and multivariate survival analysis. B7-H3 expression was not significantly associated with overall or disease-specific survival in the whole OTSCC cohort. When divided into immune hot and cold tumors, high B7-H3 expression was significantly associated with poor disease-specific and overall survival in the immune hot group, depending on the scoring method and the country of the cohort. This was achieved only in the univariate analysis. In conclusion, B7-H3 was a negative prognosticator for OTSCC patient survival in the subgroup of immune hot tumors, and was not validated as a prognosticator in the full cohort. Our findings suggest that the immune activity of the tumor should be considered when testing immune checkpoints as biomarkers

The prognostic role of combining Krüppel-like factor 4 score and grade of inflammation in a Norwegian cohort of oral tongue squamous cell carcinomas

Krüppel-like factor 4 (KLF4) is a zinc-finger transcription factor involved in inflammation, cancer development, and progression. However, the relationship between KLF4, inflammation, and prognosis in oral cancer is not fully understood. KLF4 expression levels were examined in a multicenter cohort of 128 oral squamous cell carcinoma (OSCC) specimens from the tongue (OTSCC) using immunohistochemistry. In two external KLF4 mRNA datasets (The Cancer Genome Atlas/The Genotype-Tissue Expression Portal), lower KLF4 mRNA expression was found in OSCC and head and neck squamous cell carcinomas (HNSCC) than in control oral epithelium. These data indicate that down-regulation of KLF4 mRNA is linked to OSCC/HNSCC progression. Using Cox-multivariate analysis, a significantly favorable 5-year disease-specific survival rate was observed for a subgroup of patients with a combination of high levels of KLF4 expression and inflammation. OSCC cell lines exposed to IFN-γ showed a significant upregulation of nuclear KLF4 expression, indicating a link between inflammation and KLF4 expression in OSCC. Overall, the current data suggest a functional link between KLF4 and inflammation. The combination of high KLF4 nuclear expression and marked/moderate stromal inflammation might be useful as a favorable prognostic marker for a subgroup of OTSCC patients

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

Characterization and prognostic value of lymphatic vessels in an oral tongue squamous cell carcinoma cohort

Tumor lymphangiogenesis increases the area of interaction between lymphatic vessels and tumor cells, and may thereby facilitate metastases. In oral cancer high lymphatic vessel density (LVD) and large lymphatic vessel area (LVA) have been associated with more aggressive tumors, but results from different studies are not conclusive. The aim of this study was to assess the association of tumor-associated LVD and LVA with clinical-pathological data, including patient survival, in a homogenous cohort of oral tongue squamous cell carcinoma (OTSCC) patients. Formalin-fixed, paraffin-embedded tumour samples from 125 OTSCC patients were immunohistochemically stained with the D2-40 antibody to recognize lymphatic vessels. The mean LVD and the mean LVA were analysed in five hotspots per tumour sample and compared to clinical-pathological data as well as 5-year disease-specific survival (DSS). Neither LVD nor LVA were significantly associated with the clinical-pathological variables or 5-year DSS in our patient cohort. In univariate analyses, the N status, tumour stage, tumour differentiation as well as lymphocyte infiltration were the only significant predictors for patient outcome (p<0.001, p<0.001, p<0.001 and p=0.043 respectively). In multivariate analyses, only the N status and tumour differentiation were independent prognostic factors. LVD and LVA are not indicative of 5-year DSS in our OTSCC cohort. More studies on the immunoregulatory, location-dependent role of lymphatic vessels in large, homogeneous OTSCC patient cohorts are needed

High-risk human papilloma virus was not detected in a Norwegian cohort of oral squamous cell carcinoma of the mobile tongue

Objectives - The presence of and the causative role of high‐risk human papilloma virus (HPV) is a subject of controversy in oral squamous cell carcinoma (OSCC). The disagreement can be related to the misclassification of OSCC as oropharyngeal squamous cell carcinoma and/or lack of standard detection methods. This study aimed to examine the presence of transcriptionally active high‐risk HPV in a homogenous Norwegian cohort of primary and second primary OSCC of the mobile tongue (oral tongue squamous cell carcinoma—OTSCC). Methods - Tissue microarrays containing formalin‐fixed and paraffin‐embedded cores of 146 OTSCC from the anterior 2/3 of the tongue (n = 128 primary and n = 18 second primary) from a multicentric Norwegian cohort were examined for the presence of high‐risk HPV by DNA‐ and RNA‐in situ hybridization (ISH) assays and p16 immunohistochemistry. Results -Transcriptionally active HPV (E6/E7 mRNA) was not identified in any of the OTSCC specimens. In parallel, no tumors were positive for HPV by DNA ISH. Although, 61 (42%) OTSCC demonstrated p16 positivity with varying staining intensity and subcellular localization, only two cases demonstrated strong and uniform p16‐staining (both cytoplasmic and nuclear) in >70% of cancer cells. The absence of transcriptionally active high‐risk HPV in this cohort of OTSCC indicates that high‐risk HPV is an unlikely causative factor in the present material

Combined loss of expression of involucrin and cytokeratin13 is associated with poor prognosis in squamous cellcarcinoma of mobile tongue.

Background This study aimed to evaluate the prognostic significance of expression levels of involucrin (IVL), cytokeratin (CK)-10 and -13 at different intratumor sites (tumor center and invading area) of oral tongue squamous cell carcinoma (OTSCC). Methods IVL, CK13 and CK10 expression levels were examined in a multicenter cohort of 146 OTSCCs using immunohistochemistry. External mRNA datasets were used for expression analysis and/or to validate survival associations. Results External transcriptomic datasets showed downregulation of IVL and KRT13 in oral malignancies including OTSCC as compared to normal controls. The combined loss of IVL and CK13 expression at the invading core but not at the center core was significantly associated with poor differentiation and reduced 5-year overall survival. Multivariate Cox analysis confirmed the loss of CK13 and IVL expression to be an independent prognostic factor. Transcriptomic dataset corroborated immunohistochemistry results. Conclusions Combined expression levlels of IVL and CK13 might be useful as prognostic biomarkers in OTSCC