Shachi Jenny Sharma

Human papillomavirus association is the most important predictor for surgically treated patients with oropharyngeal cancer

Background:Upfront surgery is a valuable treatment option for oropharyngeal squamous cell carcinoma (OPSCC) and risk stratification is emerging for treatment de-escalation in human papillomavirus (HPV)-related OPSCC. Available prognostic models are either based on selected, mainly non-surgically treated cohorts. Therefore, we investigated unselected OPSCC treated with predominantly upfront surgery.Methods:All patients diagnosed with OPSCC and treated with curative intent between 2000 and 2009 (n=359) were included. HPV association was determined by HPV-DNA detection and p16INK4a immunohistochemistry. Predictors with significant impact on overall survival (OS) in univariate analysis were included in recursive partitioning analysis.Results:Risk models generated from non-surgically treated patients showed low discrimination in our cohort. A new model developed for unselected patients predominantly treated with upfront surgery separates low-, intermediate- and high-risk patients with significant differences in 5-year OS (86%, 53% and 19%, P<0.001, respectively). HPV status is the most important parameter followed by T-stage in HPV-related and performance status in HPV-negative OPSCC. HPV status and ECOG remained important parameters in risk models for patients treated with or without surgery.Conclusions:Regardless of treatment strategies, HPV status is the strongest predictor of survival in unselected OPSCC patients. The proposed risk models are suitable to discriminate risk groups in unselected OPSCC patients treated with upfront surgery, which has substantial impact for design and interpretation of de-escalation trials.

Prognostic Impact of AJCC/UICC 8th Edition New Staging Rules in Oropharyngeal Squamous Cell Carcinoma

Introduction The purpose of this study was to test whether the 8th edition of the AJCC/UICC TNM staging system (UICC) precisely differentiates between stages and reflects disease outcome in human papilloma virus (HPV)-associated oropharyngeal squamous cell carcinoma (OPSCC). Patients and methods OPSCC patients that were diagnosed between 2000 and 2016 were included in this analysis and HPV status was determined by combined DNA and p16 testing. Stratification was done according to 7th and 8th UICC staging rules. Incidence trends of HPV-associated tumorigenesis, 5-year overall survival (OS) according to tumor stages as well as the influence of therapy and prognostic factors toward the outcome were calculated using Kaplan–Meier method and Cox proportional-hazards model. Results A significant increase [2000; n = 8/39 (21%)–2015; n = 17/32 (53%); p = 0.002] in HPV-associated OPSCC was seen in the observation period. Together, 150/599 (25.0%) of the patients had HPV-driven OPSCC and 64.7% of curative treatments in all OPSCC patients included upfront surgery of the primary and the neck. 7th edition staging rules led to no discrimination in all respective four UICC stages in HPV OPSCC underlining the need for new staging rules. However, only discrimination between stages I vs. II and III vs. IV was significant in our patients with HPV-OPSCC (94.4 vs. 77.5%; p = 0.031 and 63.9 vs. 25.0%; p = 0.013), and stages II vs. III did not differ in OS rates (p = 0.257), when applying the new staging rules. For HPV-negative OPSCC, significant outcome differences were only seen between UICC stages III vs. IV (57.6 vs. 35.2%; p = 0.012). Discussion While the 7th edition of UICC shows invalid discrimination between stages, the 8th edition is more suitable for HPV-associated carcinoma. Due to lack of differentiation between stages II and III further adaption is essential.

Cone beam computed tomography (CBCT) sialography—an adjunct to salivary gland ultrasonography in the evaluation of recurrent salivary gland swelling

OBJECTIVE Cone beam computed tomography (CBCT) sialography could help improve the visualization of the ductal system of salivary glands. The aim of this retrospective investigation was to monitor the use of CBCT sialography for the diagnosis of pathologies within the intraglandular ductal system when ultrasonography was inconclusive. STUDY DESIGN Fourteen consecutive patients suffering from recurrent swelling of a major salivary gland were evaluated. In 12 patients (8 female; 4 male; average age 46 years), a radiopaque contrast agent could be injected into the ductal system, followed by a routine CBCT. Four blinded examiners evaluated the acquired data sets retrospectively. RESULTS CBCT revealed seven stenosis, two salivary stones, one complete duct atresia, one intraglandular duct ectasia, and one regular duct system. Three of the detected pathologies were strictly intraglandular. CONCLUSIONS CBCT sialography shows promise as a supplementary noninvasive diagnostic tool for the visualization of the intraglandular ductal system of the major human salivary glands. Controlled studies to further validate this method should be undertaken.

Risk Factors for Overall Survival Outcome in Surgically Treated Human Papillomavirus-Negative and Positive Patients with Oropharyngeal Cancer

Analysis of overall survival by number of radium-223 injections received in an international expanded access program (iEAP)Introduction: This study reports the oncological outcome of a non-selected series of patients with human papillomavirus(HPV)-positive and -negative oropharyngeal squamous cell carcinoma (OSCC) preferentially managed with upfront surgery. Methods: Consecutive OSCC cases (n = 378) diagnosed from 2000 to 2010 in our department were evaluated for risk factors, HPV association, therapy and overall survival (OS). HPV status was determined by combined DNA and p16 testing, and treatment was defined as the first course of treatment with any kind of surgery (upfront surgery) or primary chemoradiotherapy. OS of HPV-associated and HPV-negative patients was compared using Kaplan-Meier and multivariable Cox regression analyses. Results: The majority of OSCC patients (215 of 361; 69.5%) received upfront surgery as first-line treatment in curative intent. The 5-year OS rate in patients with HPV-positive and HPV-negative tumors were 81.1 and 39.7%, respectively. Upfront surgery in HPV-negative (p < 0.001) and HPV-positive patients (p = 0.05) resulted in improved OS only in advanced stages. Multivariate analysis for patients revealed age in HPV-associated OSCC as an independent predictor for improved survival, and age, performance, N status and therapy as independent predictors in HPV-negative OSCC. Conclusions: Non-selected OSCC patients amenable to curative therapy show poor 5-year OS. The benefit of upfront surgery remains unclear. A younger patient age was the main factor for a better outcome in patients with HPV-associated OSCC.

Human Papillomavirus-Related Head and Neck Cancer

Human papillomavirus(HPV)-related head and neck cancer is recognized as a distinct tumor entity with rising incidence reported for several countries. These tumors arise from squamous cells, typically in the oropharynx. In contrast to cancer associated with other risk factors, HPV-related cancer is driven by viral oncoprotein activity and has individual profiles regarding protein expression, and genetic and epigenetic alterations. Molecular characteristics are p16IN4A overexpression, absence of p53 inactivating mutations, and PI3K/AKT and Wnt pathway modulation. Patients with HPV-related head and neck cancer have improved survival compared to those with HPV-negative tumors, and p16INK4A staining has been introduced into tumor staging recently. However, no specific or toxicity-reduced treatment modalities have been established for this entity so far. Although the still incomplete and partially inconsistent data in this field needs further study, particular features of HPV-related cancers such as specific microRNA expression, immunology, or gene methylation patterns certainly have the potential to be implemented in future diagnostic and therapeutic concepts.

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.

Intraindividual homogeneity of 18F-FDG PET/CT parameters in HPV-positive OPSCC

OBJECTIVES 18F-FDG PET/CT is widely used in clinical oncology. Human papillomavirus (HPV)-related oropharyngeal squamous cell carcinoma (OPSCC) represents an emerging disease that differs from HPV-negative OPSCC in clinical behavior and tumour biology. In these tumours, HPV-oncogenes might lead to distinct alterations in metabolic pathways. Therefore, we compared metabolic parameters using 18F-FDG PET/CT in HPV-positive and HPV-negative OPSCC in relation to histopathological findings. MATERIALS Eighty-six patients with OPSCC received pre-therapeutic 18F-FDG PET/CT. Standardised uptake volume (SUV), total lesion glycolysis (TLG) and metabolic tumour volume (MTV) were analysed for the primary tumour. SUVmax was determined for neck lymph nodes. HPV-status was determined; overall survival rates (OS) were estimated. RESULTS 32/86 patients (37.2%) had HPV-related OPSCC. Overall, PET-parameters in primary tumours of both groups did not differ significantly. Comparing early with locally advanced primary tumours, there was a significant increase in 18F-FDG uptake in HPV-negative patients (p<0.001). Positive nodes of HPV-related OPSCC showed significantly higher SUVmax values (p=0.039) compared to HPV-negative OPSCC. Strikingly, there was a higher intraindividual homogeneity of 18F-FDG uptake between primary and respective positive nodes in HPV-related primary OPSCC (p=0.001). SUV-max and -mean values did not correlate with OS in HPV-related OPSCC. CONCLUSION The intraindividual homogeneity of 18F-FDG uptake in HPV-related OPSCC could reflect the more homogenously, HPV-triggered carcinogenesis compared to the mutation-driven carcinogenesis in the HPV-negative OPSCC with heterogenic 18F-FDG uptake.

Praxis der Tumorendoskopie an deutschen HNO-Kliniken

BACKGROUND Second primary carcinomas (SPC) essentially influence therapy and the outcome in head and neck cancer. This study presents the current status of tumour endoscopy in German ENT-clinics. MATERIAL AND METHODS A standardised questionnaire regarding indication, time of event, examined anatomical region and technique of tumour endoscopy was compiled, sent to all German ENT-clinics (n=159) and subsequently analysed. RESULTS In 94-100% of the clinics, tumour endoscopy is being conducted when primary carcinoma lies within oral cavity, pharynx, larynx or is a CUP-syndrome. In 80%, 2-stage surgical procedure is preferred. Nasal cavity and tracheobronchial system (47%, 74%) are often not included in the examination. When primary cancer is seen, in 7% of the clinics a standardised biopsy of unsuspicious anatomic areas is conducted. In CUP-syndrome, unsuspicious surfaces within the pharynx do not undergo routine biopsy in 10-20% of the clinics. In tracheobronchoscopy (63.0%) and esophagoscopy (93.3%) rigid scopes are mainly used. 65% of the clinics conduct endoscopy as follow-up care. CONCLUSION Practice of tumour endoscopy in German ENT-clinics is widespread but does not follow standardised mechanisms. Current international literature shows that there is no common consensus on value and techniques of tumour endoscopy, however, due to highly developed radiological diagnostics, risks of rigid endoscopies and unknown incidence of second primary tumours it is discussed more and more negative. To establish future guidelines, controlled studies or analysis of large populations seem to be necessary.

Development and external validation of nomograms in oropharyngeal cancer patients with known HPV-DNA status: a European Multicentre Study (OroGrams)

BackgroundThe proxy marker for human papillomavirus (HPV), p16, is included in the new AJCC 8th/UICC 8th staging system, but due to incongruence between p16 status and HPV infection, single biomarker evaluation could lead to misallocation of patients. We established nomograms for overall survival (OS) and progression-free survival (PFS) in patients with oropharyngeal squamous cell carcinoma (OPSCC) and known HPV-DNA and p16 status, and validated the models in cohorts from high- and low-prevalent HPV countries.MethodsConsecutive OPSCC patients treated in Denmark, 2000–2014 formed the development cohort. The validation cohorts were from Sweden, Germany, and the United Kingdom. We developed nomograms by applying a backward-selection procedure for selection of variables, and assessed model performance.ResultsIn the development cohort, 1313 patients, and in the validation cohorts, 344 German, 503 Swedish and 463 British patients were included. For the OS nomogram, age, gender, combined HPV-DNA and p16 status, smoking, T-, N-, and M-status and UICC-8 staging were selected, and for the PFS nomogram the same variables except UICC-8 staging. The nomograms performed well in discrimination and calibration.ConclusionsOur nomograms are reliable prognostic methods in patients with OPSCC. Combining HPV DNA and p16 is essential for correct prognostication. The nomograms are available at www.orograms.org.

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.