Linn Woelber1, Katharina Prieske2, Christine Eulenburg3, Leticia Oliveira-Ferrer4, Nikolaus de Gregorio5, Ruediger Klapdor6, Matthias Kalder7, Iona Braicu8, Sophie Fuerst9, Maximilian Klar10, Hans-Georg Strauss11, Matthias Beckmann12, Werner Meier13, Atanas Ignatov14, Alexander Mustea15, Julia Jueckstock9, Georg Schmidt16, Dirk Bauerschlag17, Martin Hellriegel18, Ulrich Canzler19, Karl Ulrich Petry20, Stefan Kommoss21, Peer Hantschmann22, Martin Heubner23, Sven Mahner9, Eike Burandt24. 1. Department of Gynecology and Gynecologic Oncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. Electronic address: lwoelber@uke.de. 2. Department of Gynecology and Gynecologic Oncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; Mildred Scheel Cancer Career Center HaTriCS4, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. 3. Department of Medical Biometry and Epidemiology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; Department for Epidemiology, University Medical Center Groningen, University of Groningen, Groningen, Netherlands. 4. Department of Gynecology and Gynecologic Oncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. 5. Department of Gynecology and Obstetrics, University Hospital of Ulm, Ulm, Germany. 6. Department of Obstetrics and Gynecology, Hannover Medical School, Hannover, Germany. 7. Department of Obstetrics and Gynecology, Philipps-University Marburg, Marburg, Germany. 8. Department of Gynecology and Gynecologic Oncology, Charité Campus Virchow Clinic, Berlin, Germany. 9. Department of Obstetrics and Gynecology, University Hospital, Ludwig Maximilian University of Munich, Munich, Germany. 10. Department of Gynecology and Obstetrics, University Medical Center Freiburg, Freiburg, Germany. 11. Department of Obstetrics and Gynecology, University of Halle, Halle (Saale), Germany. 12. Department of Gynecology and Obstetrics, University Hospital Erlangen, Comprehensive Cancer Center Erlangen-EMN, Friedrich-Alexander University Erlangen-Nuremberg, Erlangen, Germany. 13. Evangelical Hospital Düsseldorf, Düsseldorf, Germany. 14. Department of Gynecology and Gynecologic Oncology, University Hospital Magdeburg, Magdeburg, Germany. 15. Department of Obstetrics and Gynecology, Greifswald University Hospital, Greifswald, Germany; Department of Gynecology and Gynecologic Oncology, University Hospital Bonn, Bonn, Germany. 16. Department of Gynecology, University Hospital of the Technical University Munich, Munich, Germany. 17. Department of Gynecology, University Medical Center Schleswig Holstein, Kiel, Germany. 18. Department of Gynecology and Obstetrics, University of Göttingen, Göttingen, Germany. 19. Department of Gynecology and Obstetrics, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany. 20. Department of Gynecology, Wolfsburg Hospital, Wolfsburg, Germany. 21. Department of Gynecology and Obstetrics, University of Tübingen, Tübingen, Germany. 22. Department of Gynecology, Hospital Altoettingen, Altoettignen, Germany. 23. Department of Gynecology, Essen University Hospital, Essen, Germany; Kantonsspital Baden AG, Baden, Switzerland. 24. Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
Abstract
BACKGROUND: There are 2 known pathways for tumorigenesis of vulvar squamous cell carcinoma-a human papillomavirus-dependent pathway characterized by p16 overexpression and a human papillomavirus-independent pathway linked to lichen sclerosus, characterized by TP53 mutation. A correlation of human papillomavirus dependency with a favorable prognosis has been proposed. OBJECTIVE: The objective of the study was to further understand the role of human papillomavirus and p53 status in vulvar squamous cell carcinoma and characterize its clinical relevance. STUDY DESIGN: The Arbeitsgemeinschaft Gynaecological Oncology Chemo and Radiotherapy in Epithelial Vulvar Cancer-1 study is a retrospective cohort study of 1618 patients with primary vulvar squamous cell carcinoma Fédération Internationale de Gynécologie et d'Obstétrique stage ≥1B treated at 29 gynecologic cancer centers in Germany between 1998 and 2008. For this translational substudy, formalin-fixed paraffin-embedded tissue was collected. A tissue microarray was constructed (n=652 samples); p16 and p53 expression was determined by immunohistochemistry. Human papillomavirus status and subtype were analyzed by polymerase chain reaction. RESULTS: p16 immunohistochemistry was positive in 166 of 550 tumors (30.2%); p53 staining in 187 of 597 tumors (31.3%). Only tumors with available information regarding p16 and p53 immunohistochemistry and without p53 silent expression pattern were further analyzed (n=411); 3 groups were defined: p53+ (n=163), p16+/p53- (n=132), and p16-/p53- (n=116). Human papillomavirus DNA was detected in 85.6% of p16+/p53- tumors; human papillomavirus-16 was the most common subtype (86.3%). Patients with p16+ tumors were younger (64 vs 72 years for p53+, respectively, 69 years for p16-/p53- tumors; P<.0001) and showed lower rates of lymph-node involvement (28.0% vs 42.3% for p53+, respectively, 30.2% for p16-/p53- tumors; P=.050). Notably, 2-year-disease-free and overall survival rates were significantly different among the groups: disease-free survival, 47.1% (p53+), 60.2% (p16-/p53-), and 63.9% (p16+/p53-) (P<.001); overall survival, 70.4% (p53+), 75.4% (p16-/p53-), and 82.5% (p16+/p53-) (P=.002). In multivariate analysis, the p16+/p53- phenotype showed a consistently improved prognosis compared with the other groups (hazard ratio, 0.66; 95% confidence interval, 0.44-0.99; P=.042). CONCLUSION: p16 overexpression is associated with an improved prognosis whereas p53 positivity is linked to an adverse outcome. Our data support the hypothesis of a clinically relevant third subgroup of vulvar squamous cell carcinoma with a p53-/p16- phenotype showing an intermediate prognosis that needs to be further characterized.
BACKGROUND: There are 2 known pathways for tumorigenesis of vulvar squamous cell carcinoma-a human papillomavirus-dependent pathway characterized by p16 overexpression and a human papillomavirus-independent pathway linked to lichen sclerosus, characterized by TP53 mutation. A correlation of human papillomavirus dependency with a favorable prognosis has been proposed. OBJECTIVE: The objective of the study was to further understand the role of human papillomavirus and p53 status in vulvar squamous cell carcinoma and characterize its clinical relevance. STUDY DESIGN: The Arbeitsgemeinschaft Gynaecological Oncology Chemo and Radiotherapy in Epithelial Vulvar Cancer-1 study is a retrospective cohort study of 1618 patients with primary vulvar squamous cell carcinoma Fédération Internationale de Gynécologie et d'Obstétrique stage ≥1B treated at 29 gynecologic cancer centers in Germany between 1998 and 2008. For this translational substudy, formalin-fixed paraffin-embedded tissue was collected. A tissue microarray was constructed (n=652 samples); p16 and p53 expression was determined by immunohistochemistry. Human papillomavirus status and subtype were analyzed by polymerase chain reaction. RESULTS:p16 immunohistochemistry was positive in 166 of 550 tumors (30.2%); p53 staining in 187 of 597 tumors (31.3%). Only tumors with available information regarding p16 and p53 immunohistochemistry and without p53 silent expression pattern were further analyzed (n=411); 3 groups were defined: p53+ (n=163), p16+/p53- (n=132), and p16-/p53- (n=116). Human papillomavirus DNA was detected in 85.6% of p16+/p53- tumors; human papillomavirus-16 was the most common subtype (86.3%). Patients with p16+ tumors were younger (64 vs 72 years for p53+, respectively, 69 years for p16-/p53- tumors; P<.0001) and showed lower rates of lymph-node involvement (28.0% vs 42.3% for p53+, respectively, 30.2% for p16-/p53- tumors; P=.050). Notably, 2-year-disease-free and overall survival rates were significantly different among the groups: disease-free survival, 47.1% (p53+), 60.2% (p16-/p53-), and 63.9% (p16+/p53-) (P<.001); overall survival, 70.4% (p53+), 75.4% (p16-/p53-), and 82.5% (p16+/p53-) (P=.002). In multivariate analysis, the p16+/p53- phenotype showed a consistently improved prognosis compared with the other groups (hazard ratio, 0.66; 95% confidence interval, 0.44-0.99; P=.042). CONCLUSION:p16 overexpression is associated with an improved prognosis whereas p53 positivity is linked to an adverse outcome. Our data support the hypothesis of a clinically relevant third subgroup of vulvar squamous cell carcinoma with a p53-/p16- phenotype showing an intermediate prognosis that needs to be further characterized.
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