Comprehensive analysis of 130 multicentric intraepithelial female lower genital tract lesions by HPV typing and p16 expression profile.
OBJECTIVE
HPV associated cervical transformation is characterized by well-defined steps, including persistent HPV infection and deregulated oncogene expression. Recent studies have suggested that a number of lower genital tract lesions are clonally related to cervical lesions. In the current study, HPV infections and oncogene expression were assessed in a large series of patients with multicentric lower genital tract disease to analyze the transformation steps in extracervical disease.


METHODS
One hundred and thirty biopsies of 52 women treated for multicentric synchronous or metachronous lower genital tract intraepithelial neoplasias were collected. Up to seven multicentric specimens taken from one patient were studied with a maximum follow up of 20 years. HPV typing and p16(ink4a) immunostaining was performed.


RESULTS
HPV DNA was present in 121 of 130 specimens (93%). HPV16 was frequently found in VIN, VaIN and AIN (73, 60 and 77%, respectively), whereas only 37% of CIN were HPV16 positive. Infections with identical HPV types in multicentric lesions were diagnosed in 46% of the HPV positive patients. p16INK4a expression was negative in the nine HPV negative lesions whereas about 90% of the high grade lesions showed diffuse p16 staining.


CONCLUSIONS
Our findings indicate that multicentric lower genital tract disease evolves through different pathways. Some cases were related to a high susceptibility towards HPV infections, while others exhibited features of clonal propagation of transformed cervical cell clones. The clinical management of the latter group is particularly challenging, because malignant cell clones can persist over a long time course.
Hampl
Monika
M
Department of Gynecology and Obstetrics, University Hospital of Duesseldorf, Moorenstr. 5, 40 225 Duesseldorf, Germany. hampl@med.uni-duesseldorf.de
Wentzensen
Nicolas
N
Vinokurova
Svetlana
S
von Knebel-Doeberitz
Magnus
M
Poremba
Cristopher
C
Bender
Hans G
HG
Kueppers
Volkmar
V
D000328:Adult; D001005:Anus Neoplasms / Q000175:diagnosis / Q000235:genetics / Q000473:pathology / Q000821:virology; D014408:Biomarkers, Tumor; D003127:Colposcopy; D017931:DNA Primers; D004279:DNA, Viral / Q000145:classification / Q000235:genetics / Q000302:isolation & purification; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D015967:Gene Expression Regulation, Viral; D019942:Genes, p16; D005833:Genital Neoplasms, Female / Q000175:diagnosis / Q000473:pathology / Q000821:virology*; D052162:Human papillomavirus 16 / Q000235:genetics / Q000302:isolation & purification; D006801:Humans; D008875:Middle Aged; D027383:Papillomaviridae / Q000145:classification* / Q000235:genetics / Q000302:isolation & purification; D030361:Papillomavirus Infections / Q000175:diagnosis / Q000235:genetics / Q000473:pathology / Q000821:virology*; D016133:Polymerase Chain Reaction / Q000379:methods*; D011230:Precancerous Conditions / Q000175:diagnosis / Q000235:genetics / Q000473:pathology / Q000821:virology; D002583:Uterine Cervical Neoplasms / Q000175:diagnosis / Q000235:genetics / Q000473:pathology / Q000821:virology; D014625:Vaginal Neoplasms / Q000175:diagnosis / Q000235:genetics / Q000473:pathology / Q000821:virology; D014846:Vulvar Neoplasms / Q000175:diagnosis / Q000235:genetics / Q000473:pathology / Q000821:virology; D002578:Uterine Cervical Dysplasia / Q000175:diagnosis / Q000473:pathology / Q000821:virology*
D014408:Biomarkers, Tumor; D017931:DNA Primers; D004279:DNA, Viral