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Tissue Genotyping of 37 In Situ and Invasive Cervical Cancer With a Concomitant Negative HC2 HPV DNA Test

Igidbashian, Sarah MD1; Schettino, Maria Teresa MD2; Boveri, Sara MSc1; Barberis, Massimo MD3; Sandri, Maria Teresa MD4; Carinelli, Silvestro MD3; Cannone, Maria PhD5; Sideri, Mario MD1

Journal of Lower Genital Tract Disease: January 2014 - Volume 18 - Issue 1 - p 87–91
doi: 10.1097/LGT.0b013e3182909f86
Original Articles

Objective The rare occurrence of histology-proven cervical intraepithelial neoplasia grade 3 (CIN 3) or invasive cancer with a negative HC2 result is known. Tissue blocks of 37 cases of histology-diagnosed CIN 3+ with a concomitant negative HC2 test were genotyped to investigate the human papillomavirus (HPV) status within the lesion.

Methods We considered 1,976 cervical excision specimens performed with concomitant HC2 test. Of these, 37 histology-confirmed CIN 3+ resulted HC2 negative. Thirty-three paraffin blocks, derived by the cervical excision, could be genotyped for high- (HR) and low-risk (LR) HPV genotypes.

Results Detailed histology showed 30 CIN 3, 2 squamous cell invasive carcinomas, and 5 invasive adenocarcinomas. One specimen resulted not amplifiable at the genotyping. Twenty-two cases (68.7%) were positive for HR-HPV types, either in single (n = 17) or multiple HR-HPV infection (n = 5). Most of the HR-HPVs found were 16 or 18. Ten cases (31.3%) were negative for HR-HPV types; 5 of these were positive for probable HR-HPV types, not detectable with HC2 HR-probes, 1 was positive to LR-HPV types, while 1 had HPV-69/71. Three cases were negative for HPV DNA, either high or low risk.

Conclusions Of the rare cases of CIN 3+ lesions with concomitant negative HC2 test, 69% are true failures in HR-HPV detection. One third of HC2-negative CIN 3+ is related to the presence of other HPV genotypes not covered by the HC2 panel or to undetectable HPV in the lesion; both these rare occurrences were already described in large cancer series and partially explain the occurrence of HPV-negative CIN 3+.

The investigation confirms that even the best HPV test may result falsely negative and explores possible reasons for a negative HC2 test in CIN 3+ lesions.

1Preventive Gynecology Unit, IEO, Milan; 2Department of Gynecology, Obstetric, and Reproductive Science, Second University of Naples, Naples; 3Histopathologic and Molecular Diagnosis Unit, 4Laboratory Medicine Division, IEO, Milan; and 5Anatomopathology, Gruppo Multimedica, Milan, Italy

Reprint requests to: Sarah Igidbashian, MD, Preventive Gynecology Unit, European Institute of Oncology, via Ripamonti 435, 20141 Milan, Italy. E-mail:

The authors have declared they have no conflicts of interest.

Copyright © 2014 by the American Society for Colposcopy and Cervical Pathology