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.
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.
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.
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: firstname.lastname@example.org
The authors have declared they have no conflicts of interest.