Loss of p16 and high Ki67 labeling index is associated with poor outcome in esophageal carcinoma
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Frank Jacobsen1,*, Jacob Kohsar1,*, Florian Gebauer2, Martina Kluth1, Claudia Hube-Magg1, Ronald Simon1, Maximilian Bockhorn3, Andrea Hinsch1, Eike Burandt1, Andreas M. Lübke1, Stefan Steurer1, Michael Tachezy3, Guido Sauter1, Jacob R. Izbicki3, Wildemar Wilczak1 and Nathaniel Melling3
1 Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
2 Department of Surgery, University Hospital Cologne, Cologne, Germany
3 Department of General, Visceral and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
* These authors contributed equally to this work
Keywords: p16; 9p21; esophageal cancer; TMA; prognosis
Received: March 13, 2019 Accepted: January 13, 2020 Published: March 24, 2020
The p16 tumor suppressor is coded by CDKN2A (9p21) and plays an important role during carcinogenesis and tumor progression in numerous tumor entities. The aim of our study was to evaluate the prognostic role of p16 expression and CDKN2A deletion in esophageal cancer (EC). Therefore, we analyzed p16 and KI67 expression by immunohistochemistry and 9p21 deletion by fluorescence in-situ hybridization on a tissue microarray including 398 adenocarcinomas (AC) and 293 squamous cell carcinomas (SCC) with clinical follow up-data. p16 positivity was found in 30.2% of AC and 13.9% of SCC and CDKN2A deletion in 32.1% of AC and 33.5% of SCC. In SCC p16 immunostaining correlated with low tumor stage (P = 0.014). In AC Ki67 positivity was associated with high tumor stage (P = 0.001), presence of lymph node metastasis (P = 0.009), high UICC stage (P = 0.001) and poor grading (P = 0.005). Overall survival (OS) was shorter for patients with high Ki67 labeling index (Ki67LI; P = 0.009) and negative p16 immunostaining (P = 0.026). In both histological tumor types, CDKN2A deletion showed no association with phenotype or outcome. Proportional cox-regression modeling revealed patients’ age, tumor stage, lymph node metastasis and Ki67 labeling index as independent prognostic markers in AC. In SCC, only patients’ age and tumor stage proved to be independent prognosticators. In summary, our study shows that loss of p16 expression and high Ki67LI is linked to shortened OS in AC. CDKN2A deletion shows no relevant association with tumor phenotype and patient outcome.
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