Aberrant expression of VEGF-C is related to grade of cervical intraepithelial neoplasia (CIN) and high risk HPV, but does not predict virus clearance after treatment of CIN or prognosis of cervical cancer.
OBJECTIVE
Increased angiogenesis leads to invasion in cervical cancer. Vascular endothelial growth factors (VEGFs) are involved in angiogenesis, but molecular links to the most important aetiological agent, human papillomavirus (HPV), need clarifying.


METHODS
Archival samples-150 squamous cell carcinomas (SCCs) and 152 cervical intraepithelial neoplasia (CIN) lesions-were examined immunohistochemically for anti-VEGF-C antibody and for HPV by polymerase chain reaction (PCR). Follow up data were available for all SCC cases, and 67 CIN lesions were monitored with serial PCR to assess HPV clearance/persistence after treatment.


RESULTS
High risk (HR) HPV types were closely associated with CIN (odds ratio, 19.12; 95% confidence interval, 2.31 to 157.81) and SCC (27.25; 3.28 to 226.09). There was a linear increase of VEGF-C expression-weak in CIN1 and intense in CIN3 and SCC (20.49; 8.69 to 48.26). VEGF-C upregulation was a sensitive (93.5%; 95% CI, 90.1% to 96.9%) marker of HR-HPV type (4.70; 2.17 to 10.21), but lost its significance in multivariate regression-p16(INK4a) and survivin were equally strong independent predictors of HR-HPV. Aberrant expression of VEGF-C did not predict clearance/persistence of HR-HPV after treatment of CIN. In cervical cancer, VEGF-C had no prognostic value in univariate or multivariate survival analysis. After adjustment for HR-HPV, FIGO stage, age, and tumour grade, only FIGO stage and age remained independent prognostic predictors.


CONCLUSIONS
VEGF-C is an early marker of cervical carcinogenesis, with linearly increasing expression starting from low grade CIN. VEGF-C expression is closely related to HR-HPV in cervical lesions, probably because of its p53 independent upregulation by the E6 oncoprotein of HR-HPV.
Branca
M
M
Unità Citoistopatologia, Centro Nazionale di Epidemiologia, Sorveglianza e Promozione della Salute, Istituto Superiore di Sanità (ISS), I-00161 Rome, Italy. mbranca@iss.it
Giorgi
C
C
Santini
D
D
Di Bonito
L
L
Ciotti
M
M
Benedetto
A
A
Paba
P
P
Costa
S
S
Bonifacio
D
D
Di Bonito
P
P
Accardi
L
L
Favalli
C
C
Syrjänen
K
K
D000293:Adolescent; D000328:Adult; D000368:Aged; D014408:Biomarkers, Tumor / Q000378:metabolism*; D018450:Disease Progression; D004812:Epidemiologic Methods; D005260:Female; D006801:Humans; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000378:metabolism; D027383:Papillomaviridae / Q000302:isolation & purification / Q000472:pathogenicity*; D030361:Papillomavirus Infections / Q000150:complications*; D016133:Polymerase Chain Reaction / Q000379:methods; D011379:Prognosis; D016896:Treatment Outcome; D002583:Uterine Cervical Neoplasms / Q000378:metabolism* / Q000473:pathology / Q000821:virology; D042582:Vascular Endothelial Growth Factor C / Q000378:metabolism*; D002578:Uterine Cervical Dysplasia / Q000378:metabolism* / Q000473:pathology / Q000821:virology
D014408:Biomarkers, Tumor; D009363:Neoplasm Proteins; D042582:Vascular Endothelial Growth Factor C