Markus Stenner

Genetic Signatures of HPV-related and Unrelated Oropharyngeal Carcinoma and Their Prognostic Implications

Purpose: Patients with human papillomavirus (HPV)-containing oropharyngeal squamous cell carcinomas (OSCC) have a better prognosis than patients with HPV-negative OSCC. This may be attributed to different genetic pathways promoting cancer. Experimental Design: We used comparative genomic hybridization to identify critical genetic changes in 60 selected OSCC, 28 of which were associated with HPV-16 as determined by HPV-specific PCR and fluorescence in situ hybridization analysis and positive p16INK4A immunostaining. The results were correlated with HPV status and clinical data from patients. Results: Two thirds of OSCC harbored gain at 3q26.3-qter irrespective of HPV status. In HPV-negative tumors this alteration was associated with advanced tumor stage (P = 0.013). In comparison with HPV-related OSCC, the HPV-negative tumors harbored: (a) a higher number of chromosomal alterations and amplifications (P = 0.03 and 0.039, respectively); (b) significantly more losses at 3p, 5q, 9p, 15q, and 18q, and gains/amplifications at 11q13 (P = 0.002, 0.03; <0.001, 0.02, 0.004, and 0.001, respectively); and (c) less often 16q losses and Xp gains (P = 0.02 and 0.03). Survival analysis revealed a significantly better disease-free survival for HPV-related OSCC (P = 0.02), whereas chromosome amplification was an unfavorable prognostic indicator for disease-free and overall survival (P = 0.01 and 0.05, respectively). Interestingly, 16q loss, predominantly identified in HPV-related OSCC, was a strong indicator of favorable outcome (overall survival, P = 0.008; disease-free survival, P = 0.01) and none of these patients had a tumor recurrence. Conclusions: Genetic signatures of HPV-related and HPV-unrelated OSCC are different and most likely underlie differences in tumor development and progression. In addition, distinct chromosomal alterations have prognostic significance.

Current update on established and novel biomarkers in salivary gland carcinoma pathology and the molecular pathways involved.

This review aims to take stock of the new information that has accumulated over the past decade on the molecular pathology of salivary gland cancer. Emphasis will be placed on established and novel immunohistochemical markers, the pathways involved, and on findings of prognostic importance as well as new therapeutic concepts. Whenever reasonable, analogies to tumors of better explored, histologically related glandular organs such as pancreas and breast are established.

Nuclear translocation of β-catenin and decreased expression of epithelial cadherin in human papillomavirus-positive tonsillar cancer: an early event in human papillomavirus-related tumour progression?

Stenner M, Yosef B, Huebbers C U, Preuss S F, Dienes H‐P, Speel E‐J M, Odenthal M & Klussmann J P

Sialoendoscopy: prognostic factors for endoscopic removal of salivary stones.

OBJECTIVE To detect prognostic factors for successful sialoendoscopic removal of salivary stones. DESIGN Retrospective case series. SETTING Tertiary referral hospital. PATIENTS Forty-nine consecutive patients who underwent sialoendoscopy for sialolithiasis between January 1, 2008, and January 1, 2010, at University Hospital of Cologne, Cologne, Germany. INTERVENTIONS Diagnostic and interventional sialoendoscopy using local anesthesia. MAIN OUTCOME MEASURES Stone removal rate, size, mobility, shape, and location, as well as clinical follow-up data. RESULTS Sixty-one percent (39 of 64) of all salivary stones were removed endoscopically. The cutoff point for endoscopic removal was between 5 and 6 mm in stone diameter. Small size, good mobility, round or oval, and distal location of a salivary stone were positive prognostic factors for sialoendoscopic removal, with sialolith mobility having the greatest effect in multivariate analysis. CONCLUSION Small size, good mobility, round or oval, and distal location of a salivary stone in the main duct predict significantly greater probability of endoscopic removal and consequently are positive prognostic factors.

Integration of HPV6 and downregulation of AKR1C3 expression mark malignant transformation in a patient with juvenile-onset laryngeal papillomatosis.

Juvenile-onset recurrent respiratory papillomatosis (RRP) is associated with low risk human papillomavirus (HPV) types 6 and 11. Malignant transformation has been reported solely for HPV11-associated RRP in 2–4% of all RRP-cases, but not for HPV6. The molecular mechanisms in the carcinogenesis of low risk HPV-associated cancers are to date unknown. We report of a female patient, who presented with a laryngeal carcinoma at the age of 24 years. She had a history of juvenile-onset RRP with an onset at the age of three and subsequently several hundred surgical interventions due to multiple recurrences of RRP. Polymerase chain reaction (PCR) or bead-based hybridization followed by direct sequencing identified HPV6 in tissue sections of previous papilloma and the carcinoma. P16INK4A, p53 and pRb immunostainings were negative in all lesions. HPV6 specific fluorescence in situ hybridization (FISH) revealed nuclear staining suggesting episomal virus in the papilloma and a single integration site in the carcinoma. Integration-specific amplification of papillomavirus oncogene transcripts PCR (APOT-PCR) showed integration in the aldo-keto reductase 1C3 gene (AKR1C3) on chromosome 10p15.1. ArrayCGH detected loss of the other gene copy as part of a deletion at 10p14-p15.2. Western blot analysis and immunohistochemistry of the protein AKR1C3 showed a marked reduction of its expression in the carcinoma. In conclusion, we identified a novel molecular mechanism underlying a first case of HPV6-associated laryngeal carcinoma in juvenile-onset RRP, i.e. that HPV6 integration in the AKR1C3 gene resulted in loss of its expression. Alterations of AKR1C gene expression have previously been implicated in the tumorigenesis of other (HPV-related) malignancies.

Survivin and epidermal growth factor receptor expression in surgically treated oropharyngeal squamous cell carcinoma

The epidermal growth factor receptor (EGFR) and the inhibitor of apoptosis protein survivin play important roles in the regulation of cellular proliferation and survival in squamous cell carcinomas. Their correlation in oropharyngeal squamous cell carcinoma (OSCC) has not been evaluated yet.

Nuclear translocation of ?-catenin and decreased expression of E-cadherin in HPV-positive tonsillar cancer: An early event in HPV-related tumor progression?

Stenner M, Yosef B, Huebbers C U, Preuss S F, Dienes H‐P, Speel E‐J M, Odenthal M & Klussmann J P

Sialendoscopy for sialolithiasis: Early treatment, better outcome

The objective of this study was to investigate whether patients with a short‐term and long‐term disease course of sialolithiasis show differences in the clinical picture and the outcome after sialendoscopy.

Prognostic impact of human papillomavirus status, survivin, and epidermal growth factor receptor expression on survival in patients treated with radiochemotherapy for very advanced nonresectable oropharyngeal cancer†

The influence of human papillomavirus (HPV) status on survival for patients with very advanced inoperable oropharyngeal SCC treated with radiochemotherapy (RCT) was studied.

Topical Therapy in Anosmia: Relevance of Steroid-Responsiveness†

Objectives/Hypothesis: The use of steroids either systemically or topically is known as a common therapy in patients with anosmia. Nevertheless, investigations giving proof for the benefit of a topical therapy are very rare, and no prognostic factors are known. In our study, we for the first time evaluated the additional effect of a topical therapy not only with steroids but also with antibiotics after conventional pretreatment with oral steroids and propose the steroid‐responsiveness of an anosmia as a prognostic factor.