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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:
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+.

In Brief

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.

Author Information

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