Human Papillomavirus (HPV) DNA in primary cervical cancer and in cancer free pelvic lymph nodes - correlation with clinico-pathological parameters and prognostic significance

 

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Summary

Objective: To assess whether the presence of human papilloma virus (HPV) DNA and/or several genotypes of HPV DNA in primary cervical cancer and cancer free pelvic lymph nodes are correlated with several clinicopathological parameters of well-defined prognostic significance and whether virological parameters are predictors of long-term survival in cancer patients. Patients and methods: 223 cases of cervical cancer patients included in this retrospective study underwent follow-up evaluation. Survival and cause of death were examined for 204 (91.4 %) patients, with a mean follow-up time of 4.4 years. HPV DNA was detected using the high sensitive polymerase chain reaction (PCR) method followed by HPV DNA sequencing for HPV genotyping. These results were correlated with well-defined clinicopathological parameters and survival data. Results: HPV DNA was detected by PCR in 150 of 203 (73.4 %) tissue specimens of cervical cancer patients. DNA sequence analysis revealed the presence of HPV 16 (n = 68, 45.3 %), HPV 18 (n = 49, 32.6 %) and rare HPV types (n = 33, 22.1 %). HPV genotypes correlated significantly with histological tumor types, node status, blood vessel invasion and lymph space involvment. The presence of HPV DNA in cervical cancer as well as the genotype of HPV 16 could also be confirmed as significant prognostic factors in the univariate Cox Regression Analysis (RR 2.856, p < 0.003 resp. RR 3.444, p < 0.0001). The presence of HPV DNA in cancer free pelvic lymph nodes was significantly correlated to the concomitant manifestation of pelvic lymph node metastases (RR 3.1, p < 0.0001). In the multivariate analysis, however, HPV DNA in primary tumor and in negative pelvic lymph nodes failed to be of prognostic relevance. Exclusively, HPV 16 appears to impact independently on the overall survival in cervical cancer patients (RR 3.653, p < 0.002). Conclusion: The detection of HPV 16 genotype may play an important adjunct role in assessing prognosis of cervical cancer patients. The clinical impact of the presence of HPV DNA in primary tumors and cancer free pelvic lymph nodes remains to be investigated in further studies. The exact mechanisms by which HPV influence the prognosis of cervical cancer patients have to be defined.

Humane Papillomavirus (HPV)-DNA in Zervixkarzinomen und tumorfreien pelvinen Lymphknoten - Assoziation mit klinisch-pathologischen Parametern und prognostische Validität

Zusammenfassung

Fragestellung: Ziel dieser retrospektiven Analyse war es, zu prüfen, ob zwischen dem Nachweis von humaner Papillomavirus (HPV)-DNA/verschiedener HPV-Typen in primären Zervixkarzinomen bzw. in tumorfreien pelvinen Lymphknoten und definierten klinisch-pathologischen Prognosefaktoren ein Zusammenhang besteht und ob der HPV-Status von prognostischer Relevanz für das Gesamtüberleben von Zervixkarzinompatientinnen ist. Patientinnen und Methode: Die vorliegende Studie umfaßte insgesamt 223 Patientinnen mit primärem Zervixkarzinom, wobei der klinische Verlauf von 204 Tumorpatientinnen (91,4 %) mit einer mittleren Nachbeobachtungszeit von 4,4 Jahren dokumentiert wurde. Der Nachweis von HPV-DNA erfolgte mittels der hoch sensitiven Polymerasekettenreaktion (PCR) gefolgt von einer HPV-DNA-Sequenzierung für die HPV-Typisierung. Die Ergebnisse wurden mit definierten klinisch-pathologischen Parametern und Gesamtüberlebensdaten korreliert. Ergebnisse: HPV-DNA konnte mittels PCR in Tumorproben von 150 (73,4 %) Zervixkarzinompatientinnen nachgewiesen werden. Mit Hilfe der DNA-Sequenzierung konnten HPV 16 (n = 68; 45,3 %), HPV 18 (n = 49; 32,6 %) und seltenere HPV-Typen (n = 33; 22,1 %) nachgewiesen werden. Dabei korrelierten HPV 16 und HPV 18 siginifikant mit histologischen Tumortypen, Nodalstatus sowie Hämangio- und Lymphangioinvasion. In der univariaten Regressionsanalyse konnte der Nachweis von HPV-DNA bzw. HPV 16 im Primärtumor als prognostisch relevant objektiviert werden (RR 2.556, p < 0,003 bzw. RR 3.444, p < 0,0001). Der Nachweis von HPV-DNA in tumorfreien pelvinen Lymphknoten zeigte eine statistisch signifikante Assoziation mit der gleichzeitigen Manifestaion von pelvinen Lymphknotenmetastasen und einen signifikanten Einfluß auf das Gesamtüberleben in der univariaten Regressionsanalyse (RR3.1, p < 0,0001). In der multivariaten Regressionsanalyse hingegen konnte ausschließlich HPV 16 mit unabhängigen Einfluß auf das Gesamtüberleben von Zervixkarzinompatientinnen ermittelt werden (RR 3.653, p < 0,002). Schlußfolgerung: Der Nachweis von HPV 16 wird als unabhängiger negativer Prognosefaktor identifiziert. Die klinische Relevanz des Nachweises von HPV-DNA in primären Zervixkarzinomen und tumorfreien pelvinen Lymphknoten bleibt abzuwarten. Die genauen Mechanismen mit denen HPV die Prognose von Zervixkarzinompatientinnen beinflußt, bleibt zu definieren.

MeSH

C4.588.945.418.948.170 cervix neoplasms

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Henryk PilchMD 

Section of Gynecopathology
Department of Obstetrics and Gynecology
Medical Center Mainz
University of Mainz

Langenbeckstr. 1

D-55101 Mainz

Phone: Tel.: 61 31/1 70

Email: E-mail: HPilch3920@aol.com