Upfront Surgery vs. Primary Chemoradiation in an Unselected, Bicentric Patient Cohort with Oropharyngeal Squamous Cell Carcinoma-A Matched-Pair Analysis.

The two pillars of therapy for oropharyngeal squamous cell carcinoma (OPSCC) are upfront surgery and primary chemoradiotherapy. Substantial regional preferences exist with regard to the selection of treatment. Despite new therapeutic approaches, patient survival remains poor, with an approximate overall survival (OS) rate of 50% at five years. This study was conducted to investigate a potential survival benefit depending on the treatment modality in OPSCC patients. We retrospectively collected data of 853 patients with histologically confirmed OPSCC from the Giessen and Maastricht cancer databases. To identify risk factors affecting survival, a Cox-proportional hazard model was applied to 442 patients with complete data sets. Based on this cohort a matched-pair analysis with 158 patients was performed to compare OS rates of patients treated either with upfront surgery or primary chemoradiation. For the collective cohort, patients treated with upfront surgery had significantly improved OS rates compared to patients treated with primary chemoradiation. In the matched-pair analysis adjusted for patients' T-, N- and HPV-status as well as risk profile, we observed that both treatment approaches offered equivalent OS rates. Our study emphasizes that treatment recommendations should be made whenever possible on the basis of side-effect profiles caused by the therapeutic approach used. To draw further conclusions, results of the ongoing "best of" (NCT2984410) study are eagerly awaited, investigating the functional outcome after treatment of OPSCC patients.

PD-L1 Expression and a High Tumor Infiltrate of CD8+ Lymphocytes Predict Outcome in Patients with Oropharyngeal Squamous Cells Carcinoma.

Carcinogenesis of human papillomavirus (HPV)-related (+) oropharyngeal squamous cell carcinoma (OPSCC) differs from HPV-negative (-) OPSCC. HPV-related immune-escape-mechanism could be responsible for the development and progression of HPV+ tumors and an immunophenotype different from HPV- OPSCC is expected. The purpose of this study was to analyze the expression of programmed cell death protein 1 ligand 1 (PD-L1) and its prognostic relevance in relation to CD8+ tumor infiltrating lymphocytes (TILs) and the major histocompatibility complex (MHC) I expression in OPSCC. We quantified PD-L1 expression on tumor cells (TC) and macrophages and MHC I expression in association to CD8+ TILs by immunohistochemistry on tissue microarray derived from 171 HPV+/-OPSCC. HPV-status was determined by p16INK4a immunohistochemistry/HPV-DNA detection. Presence of CD8+ TILs, PD-L1 expression on TC, and a more frequent loss of MHC I in HPV+ compared to HPV- OPSCC was detected. A high amount of CD8+ TILs in the whole cohort and in HPV+ OPSCC and PD-L1 expression on TC in HPV- OPSCC was associated with favorable overall survival. There was a trend for an improved outcome according to PD-L1 expression (macrophages) in HPV+ OPSCC without reaching statistical significance. CD8+ TILs and PD-L1-expression have prognostic impact in OPSCC and might present useful biomarkers for predicting clinical outcome and personalized therapy concepts.

LAG-3, TIM-3 and VISTA Expression on Tumor-Infiltrating Lymphocytes in Oropharyngeal Squamous Cell Carcinoma-Potential Biomarkers for Targeted Therapy Concepts.

Tumor growth and survival requires a particularly effective immunosuppressant tumor microenvironment (TME) to escape destruction by the immune system. While immunosuppressive checkpoint markers like programmed cell death 1 ligand (PD-L1) are already being targeted in clinical practice, lymphocyte-activation-protein 3 (LAG-3), T-cell immunoglobulin and mucin-domain containing-3 (TIM-3) and V-domain Ig suppressor of T cell activation (VISTA) inhibitors are currently under investigation in clinical trials. Reliable findings on the expression status of those immune checkpoint inhibitors on tumor-infiltrating lymphocytes (TILs) in the TME of oropharyngeal squamous cell carcinoma (OPSCC) are lacking. This work aims to describe the expression of LAG-3, TIM-3, and VISTA expression in the TME of OPSCC. We created a tissue microarray of paraffin-embedded tumor tissue of 241 OPSCC. Expression of the immune checkpoint protein LAG-3, TIM-3, and VISTA in OPSCC was evaluated using immunohistochemistry and results were correlated with CD8+ T-cell inflammation and human papillomavirus (HPV)-status. 73 OPSCC stained positive for LAG-3 (31%; HPV+:44%; HPV-:26%, p = 0.006), 122 OPSCC stained positive for TIM-3 (51%; HPV+:70%; HPV-:44%, p < 0.001) and 168 OPSCC (70%; HPV+:75%; HPV-:68%, p = 0.313) for VISTA. CD8+ T-cells were significantly associated with LAG-3, TIM-3 and VISTA expression (p < 0.001, p < 0.001, p = 0.007). Immune checkpoint therapy targeting LAG-3, TIM-3, and/or VISTA could be a promising treatment strategy especially in HPV-related OPSCC. Future clinical trials investigating the efficacy of a checkpoint blockade in consideration of LAG-3, TIM-3, and VISTA expression are required.

Rigid Triple Endoscopy Improves Clinical Staging of Primary Head and Neck Cancer.

BACKGROUND: Correct pre-therapeutic staging of the first primary carcinoma (FPC) and detection of simultaneous second primary carcinomas (SSPCs) decisively influence therapy and prognosis of head and neck squamous cell carcinomas (HNSCC). The aim of this study was to determine the benefit of pre-therapeutic triple endoscopy for detection of SSPC and pre-therapeutic T category. METHODS: A cohort of 234 HNSCC patients with completed triple endoscopy was reviewed, focusing on pre-therapeutic T category and SSPC. Risk stratification for different subsites was evaluated. RESULTS: The risk for SSPC was 5.56%. FPC of the oral cavity and oropharynx had the highest prevalence of SSPC (46.15%, 38.46%); most SSPCs were found in the hypopharynx. No SSPCs were found in the oral cavity, nasopharynx and oesophagus. Significant results in correct pre-therapeutic T staging have been achieved for the larynx (p = 0.021) and the oropharynx (p = 0.001). CONCLUSIONS: Triple endoscopies seem to be inadequate for SSPC detection in HNSCC patients. Endoscopies of the trachea and oesophagus should be reconsidered. Alternatively, risk-directed endoscopies of the hypopharynx might be performed in patients with oral cancer. For evaluation of resectability, conducting triple endoscopy could be reduced to a single endoscopy because the complication rate is low and pre-therapeutic T staging can be improved.

Hypoxia-inducible factor-1α activation in HPV-positive head and neck squamous cell carcinoma cell lines.

PURPOSE: Human papillomavirus (HPV) is a causative agent for a rising number of head and neck squamous cell carcinomas (HNSCC), which are characterized by distinct tumor biology. Hypoxia inducible-factor (HIF) signaling influences initiation and progression of carcinogenesis and HPV oncoproteins have evolved to highjack cellular pathways for viral reproduction. Therefore, we investigated whether HPV activates HIF-1α expression in HNSCC. EXPERIMENTAL TECHNIQUE: HPV-positive and -negative HNSCC cells were examined for adaptive responses to hypoxia. Expression of HIF-1α, prolyl hydroxylase-domain protein 2 (PHD2) and E-cadherin was analyzed by Western blotting, immunofluorescence (IF) microscopy and migration/wound healing assays. RESULTS: HPV-positive HNSCC cells showed higher HIF-1α and PHD2 protein levels under normoxia and hypoxia. HIF-1α hydroxylation was reduced in HPV-positive HNSCC cell lines under PHD and proteasomal inhibition. In vitro wound healing assays showed impairment of migration and proliferation by HIF-1α pathway activation in HPV-negative cell lines only. In contrast, migration and proliferation in HPV-positive cell lines was impaired by HIF-1α specific siRNA. CONCLUSIONS: HPV-positive HNSCC cells show activation of the HIF pathway and adaptation to HIF-1α upregulation, representing potential therapeutic targets in this emerging tumor entity.

Extracardiac juvenile rhabdomyoma of the larynx: a rare pathological finding.

The extracardiac juvenile rhabdomyoma is extremely rare in the field of Otorhinolaryngology. The tumour usually arises from the soft tissue of the face or from mucosal sites, especially the oropharynx and the oral cavity but only sporadic endolaryngeal cases have been described in literature so far with predominance of young males. Here, we describe the very rare case of endolaryngeal extracardiac juvenile rhabdomyoma in a 42-year-old male. Clinical examination showed a mass of the right vocal cord, resembling a cystic lesion. Microlaryngoscopy revealed a non-encapsulated lesion and histopathology including immunohistochemistry which consecutively led to the correct diagnosis. This case suggests that the endolaryngeal extracardiac juvenile rhabdomyoma can be easily confused with a vocal cord cyst. Malignant transformations have not been reported but recurrences have been described. When total excision cannot be accomplished, reoperation or narrow follow-up is indicated to prevent advanced revision surgeries.