Introduction: Subgroups with a poorer prognosis exist among patients with human papillomavirus positive oropharyngeal squamous cell carcinoma (HPV-positive OPSCC). This study aims to identify histological and genetic differences within HPV-positive OPSCC and correlate these findings with patient outcomes. Methods: The study included 102 OPSCC patients, all tested positive for high-risk HPV DNA and p16INK4a expression. Based on histomorphological classification (HPV Prediction Classification, HPV PC), all cases were categorized as either classic HPV-positive OPSCC (cHPV) or non-classic HPV-positive OPSCC (non-cHPV). Nextgeneration sequencing (NGS) of selected genes was performed on 55 tumor samples, correlating results with morphological status and survival. Results: Of all cases, 49 % (n = 50/102) were categorized as non-cHPV, histomorphologically resembling HPVnegative OPSCC, and showed significantly poorer overall survival (p = 0.004) and five-year survival rate (5YS: 83.9 % vs. 58.4 %). Multivariate analyses identified HPV PC as an independent prognostic marker (p = 0.027). NGS revealed loss-of-Function (LOF) mutations in TP53 in three non-cHPV samples. Additionally, PIK3CA/PTEN mutations were found in 35.7 % (10/28) of non-cHPV cases. The cumulative burden of gene mutations was higher in the non-cHPV subgroup compared to the cHPV subgroup (n = 53, p = 0.1). Conclusion: HPV PC distinguished two histomorphological subgroups within HPV-positive OPSCCs: cHPV with excellent prognosis and non-cHPV with poorer overall survival. Non-cHPV tumors also exhibited higher overall mutation rates, notably LOF-TP53 and PIK3CA/PTEN mutations. These morphological subtypes, along with their corresponding mutational profiles, warrant further investigation as potential biomarkers for de-escalation intervention trials.

Background Therapeutic options in recurrent/metastatic salivary gland carcinoma (SGC) are scarce. Enfortumab vedotin, a nectin-4-binding antibody-drug conjugate, was recently approved by the FDA and EMA for third-line treatment of urothelial carcinoma.

Therapeutische Optionen in rezidivierten/metastasierten Speicheldrüsenkarzinomen (SGC) sind rar. Enfortumab vedotin, ein Nectin-4 bindendes Antikörper-Wirkstoff-Konjugat, wurde kürzlich durch die FDA und EMA zur Drittlinientherapie des Urothelkarzinoms zugelassen. Eine Immunhistochemie für Nectin-4 wurde für Primärtumoren und korrespondierende Lymphknotenmetastasen von Patienten mit primärem SGC der Glandula parotidea/submandibularis und suffizientem FFPE-Gewebe, die zwischen 1990 und 2019 in kurativer Absicht operiert worden waren, durchgeführt. Klinisch-pathologische Daten wurden aus der kontinuierlich aktualisierten SGC Datenbank extrahiert. Eine Analyse auf statistische Assoziation zwischen der Expression von Nectin-4 und klinisch-pathologischen Daten wurde durchgeführt. Einhundertzweiundzwanzig SGC und 20 Lymphknotenmetastasen (LKM) wurden eingeschlossen. Eine Expression von Nectin-4 wurde in 80,3% aller SGC nachgewiesen. Der mittlere Histo(H)-Score lag bei 61,2. 25,9% der Speichelgangkarzinome (SDC) und 30,7% der adenoidzystischen Karzinome (ACC) zeigten eine moderate oder hohe Expression. 90,0% der LKM waren positiv für Nectin-4. Der mittlere H-Score der LKM lag bei 75,6. SDC mit einem niedrigeren T-Stadium (p=0,04), ohne lokoregionale LKM (p=0,049), ohne Gefäßinvasion (p=0,04) und ohne perineurale Ausbreitung (p=0,03) zeigten einen signifikant höheren mittleren Nectin-4 H-Score. Es zeigte sich eine statistische Tendenz in Richtung eines günstigeren krankheitsfreien Überlebens unter SDC Patienten mit Nectin-4 Expression (p=0,09). Nectin-4 ist in der Mehrzahl der SGC exprimiert und stellt vor allem für Entitäten mit einer hohen Rate an Lokalrezidiven und Fernmetastasen wie das SDC und das ACC ein potenzielles therapeutisches Zielmolekül für Enfortumab vedotin dar.

Intro Die Lymphknoten Ratio (LNR) metastasierter Lymphknoten kann als wichtiger Parameter für das Gesamtüberleben von Patienten mit Kopf-Hals-Karzinomen fungieren. Die logarithmische Odds Ratio positiver Lymphknoten (LODDS) sowie das extrakapsuläre Wachstum (ECS) sind ebenfalls wichtige Prädikatoren. Ziel unserer Arbeit war es mittels einer Datenbank, diese Prädiktoren der Halsmetastasierung im Zusammenhang zum p16 und HPV-Status retrospektiv in einer größeren Kohorte zu untersuchen.

Einführung Oxidativer Stress, ein Ungleichgewicht zwischen reaktiven Sauerstoffspezies (ROS) und Antioxidans-Abwehrmechanismen, beeinflusst die Krebsentstehung. Glutathionperoxidasen (GPX) schützen vor oxidativen Schäden, wobei GPX4 Phospholipidhydroperoxide reduziert. Ergebnisse anderer Arbeitsgruppen zeigen ungünstige Überlebensprognosen bei erhöhter GPX4-Expression im Lungenadenokarzinom.

Introduction Oxidative stress, an imbalance between reactive oxygen species (ROS) and antioxidant defense mechanisms, impacts cancer development. Glutathione peroxidases (GPX) shield against oxidative damage, with GPX4 specifically reducing phospholipid hydroperoxides. Findings from other research groups indicate unfavorable survival prognoses with increased GPX4 expression in lung adenocarcinoma.

Introduction Up to 25% of patients with HPV-positive oropharyngeal carcinoma (HPV+OPSCC) develop recurrence. Biomarkers for the early identification of this subcohort are missing. The aim of this study was to identify a transcriptome (mRNA)-based expression profile associated with the development of recurrence in patients with HPV+OPSCC.

Intro The lymph node ratio (LNR) of metastasized lymph nodes can act as an important parameter for the overall survival of patients with head and neck cancer. The logarithmic odds ratio of positive lymph nodes (LODDS) and extracapsular growth (ECS) are also important predictors. The aim of our work was to use a database to retrospectively investigate these predictors of neck metastasis in relation to p16 and HPV status in a larger cohort.

Background: The incidence of oropharyngeal squamous cell carcinoma (OPSCC) is rapidly increasing in high income countries due to its association with persistent high-risk human papilloma virus (HPV) infection. Recent scientific advances have highlighted the importance of the tumor microenvironment in OPSCC. In this study, including 216 OPSCC patients, we analyze the composition of four established markers of cancer associated fibroblasts (CAFs) in the context of intratumoral CD8 T-cell infiltration.Methods: Immunohistochemical staining for fibroblast activation protein (FAP), platelet-derived growth factor receptor beta (PDGFRb), periostin, alpha smooth muscle actin (α-SMA) and CD8 were analyzed digitally and their association with survival, tumor- and patient characteristics was assessed.Results: Co-expression of CAF markers was frequent but not associated with HPV status. FAPhigh and PDGFRbhigh expression were associated with increased CD8 T-cell infiltration. Low expression of PDGFRb improved patient survival in female patients but not in male patients. We identified PDGFRblow periostinlow α-SMAlow status as an independent predictor of improved survival (hazard ratio 0.377, p = 0.006).Conclusion: These findings elucidate the co-expression of four established CAF markers in OPSCC and underscore their association with T-cell infiltration and patient survival. Future analyses of CAF subgroups in OPSCC may enable the development of individualized therapies.

Einleitung Bis zu 25% der Patienten mit einem HPV-positiven Oropharynxkarzinom (HPV+OPSCC) entwickeln ein Rezidiv. Biomarker zur frühzeitigen Identifikation dieser Subkohorte fehlen. Ziel dieser Studie war es ein Transkriptom (mRNA)-basiertes Expressionsprofil zu identifizieren, welches mit der Entwicklung eines Rezidivs bei Patienten mit einem HPV+OPSCC in Zusammenhang steht.

Many locally advanced and metastatic salivary gland carcinomas (SGC) lack therapeutic targets. Enfortumab vedotin , an antibody–drug conjugate binding to Nectin-4, recently gained FDA approval for third-line urothelial carcinoma. Therefore, the aim of this study was to assess the expression of Nectin-4 in primary SGC and corresponding lymph node metastases and to correlate it with clinicopathological data. Immunohistochemical staining for Nectin-4 was performed for patients who had undergone surgery with curative intent for primary SGC of the parotid or submandibular gland in a tertiary referral center between 1990 and 2019. One hundred twenty-two primary SGC and twenty corresponding lymph node metastases were included. Nectin-4 was expressed in 80.3% of primary SGC with a mean Histo(H-)score of 61.2 and in 90.0% of lymph node metastases with a mean H-score of 75.6. A moderate or high Nectin-4 expression was found in 25.9% of salivary duct carcinomas (SaDu) and in 30.7% of adenoid cystic carcinomas (ACC). SaDu patients with a lower T-stage (p = 0.04), no loco-regional lymph node metastases (p = 0.049), no vascular invasion (p = 0.04), and no perineural spread (p = 0.03) showed a significantly higher mean Nectin-4 H-score. There was a statistical tendency towards a more favorable disease-free survival among SaDu patients with a higher Nectin-4 expression (p = 0.09). Nectin-4 is expressed in SGC and therefore represents a potential therapeutic target, especially in entities with a high rate of local recurrence and metastatic spread such as SaDu and ACC.

Einleitung Bei Patienten mit HPV-positivem Oropharynxkarzinom (HPV+ OPSCC) existieren Subgruppen mit einer ungünstigen Prognose. Ziel dieser Studie ist es morphologische und genetische Unterschiede innerhalb der HPV+ OPSCC zu identifizieren. Diese sollen im Zusammenhang mit der Prognose analysiert werden, um mögliche Korrelation zwischen Morphologie und überleben aufzudecken.

Background Oropharyngeal squamous cell carcinoma (OPSCC) is the only subgroup of head neck cancer that presents with an increased incidence. Gender-specific studies in other cancer entities have revealed differences in treatment response and prognosis. However, only limited data in OPSCC according to gender and human papillomavirus (HPV) status exist. Therefore, we aimed to investigate sex-specific differences in OPSCC and how these may be distributed in relation to HPV and other risk factors. Methods This retrospective, bicentric study included 1629 patients with OPSCC diagnosed between 1992 and 2020. We formed subgroups based on TNM status, American Joint Cancer Committee 8 th edition (AJCC8), HPV status, treatment modality (surgery (± radio(chemo)therapy (RCT) vs. definitive RCT) and patient-related risk factors and investigated gender differences and their impact on patients survival via descriptive-,uni- and multivariate analysis. Results With the exception of alcohol abuse, no significant differences were found in risk factors between men and women. Females presented with better OS than males in the subgroup T1-2, N + , independent of risk factors ( p = 0.008). Males demonstrated significant stratification through all AJCC8 stages (all p < 0.050). In contrast, women were lacking significance between stage II and III ( p = 0.992). With regard to therapy (surgery (± R(C)T) – vs. definitive RCT) women treated with surgery had better OS than men in the whole cohort ( p = 0.008). Similar results were detected in the HPV-negative OPSCC sub-cohort ( p = 0.042) and in high-risk groups (AJCC8 stage III and IV with M0, p = 0.003). Conclusion Sex-specific differences in OPSCC represent a health disparity, particularly according to staging and treatment, which need to be addressed in future studies.

Introduction Subgroups with a reduced prognosis exist patients with HPV-positive oropharyngeal squamous cell carcinoma (HPV+ OPSCC). The aim of this study is to identify morphological and genetic differences within HPV+ OPSCC. These will subsequently be analyzed in relation to prognosis to detect possible correlation between morphology and survival.

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.

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.