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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
  1. M Branca1,
  2. C Giorgi2,
  3. D Santini3,
  4. L Di Bonito4,
  5. M Ciotti5,
  6. A Benedetto5,
  7. P Paba5,
  8. S Costa3,
  9. D Bonifacio4,
  10. P Di Bonito2,
  11. L Accardi2,
  12. C Favalli5,
  13. K Syrjänen6,
  14. on behalf of the HPV-Pathogen ISS Study Group
  1. 1Unità Citoistopatologia, Centro Nazionale di Epidemiologia, Sorveglianza e Promozione della Salute, Istituto Superiore di Sanità (ISS), I-00161 Rome, Italy
  2. 2Department of Infectious, Parasitic and Immunomediated Diseases, ISS
  3. 3Dipertimento di Ginecologia e Ostetrica, Azienda Ospedaliera, S. Orsola Malpighi, I-40138 Bologna, Italy
  4. 4U.C.O. Anatomia Patologica, Istopatologia e Citodiagnostica, Ospedale Maggiore, I-34127 Trieste, Italy
  5. 5Laboratory of Clinical Microbiology and Virology, University Hospital “Policlinico Tor Vergata”, Rome, ItalyGinecologia e Ostetrica, IFO, Istituto Regina Elena, I-00133 Rome, Italy
  6. 6Department of Oncology and Radiotherapy, Turku University Hospital, FIN-20521 Turku, Finland
  1. Correspondence to:
 Dr M Branca
 Unità di Citoistopatologia, Centro Nazionale di Epidemiologia, Sorveglianza e Promozione della Salute, Istituto Superiore di Sanità, Viale Regina Elena, 299, I-00161 Roma, Italy; mbranca{at}


Aims: 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.

Material/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—p16INK4a 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.

  • CI, confidence interval
  • CIN, cervical intraepithelial neoplasia
  • COX, cyclooxygenase
  • ERK, extracellular signal regulated kinase
  • HPV, human papillomavirus
  • HR, high risk
  • IHC, immunohistochemistry
  • LR, low risk
  • MVD, microvascular density
  • NPV, negative predictive value
  • OR, odds ratio
  • PCR, polymerase chain reaction
  • PPV, positive predictive value
  • pRB, retinoblastoma protein
  • SCC, squamous cell carcinoma
  • VEGF, vascular endothelial growth factor
  • VEGFR, vascular endothelial growth factor receptor
  • vascular endothelial growth factor C
  • angiogenesis
  • human papillomavirus
  • cervical intraepithelial neoplasia
  • cervical cancer
  • prognosis
  • virus clearance
  • high risk human papillomavirus
  • conisation

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