Clonality analysis and human papillomavirus infection in squamous metaplasia and atypical immature metaplasia of uterine cervix: is atypical immature metaplasia a precursor to cervical intraepithelial neoplasia 3?

Atypical immature squamous metaplasia (ISM) of the uterine cervix often has histological features that overlap with the histological characteristics of high-grade cervical intraepithelial neoplasia. To identify the cellular basis and clinical significance of atypical immature metaplasia (AIM), 10 cases of AIM were analyzed for the clonal status, and the presence of human papillomavirus (HPV) infection. The physical status of HPV was also evaluated in HPV type 16 (HPV-16)-positive cases. Squamous metaplasias with no nuclear atypia (29 mature squamous metaplasias [SMs]) and a single case of ISM were analyzed as a control. Nine AIMs, 20 SMs, and a single case of ISM were informative for clonal analysis. Monoclonal composition of the lesion was demonstrated in 8 (89%) of 9 AIMs, but only in 2 (10%) of 21 cases of SM without atypia (AIM vs SM + ISM, 8/9 vs 2/21; P < 0.0001). High-risk HPV was detected in 6 (60%) of 10 AIMs, all were HPV-16, but only in 3 (13%) of 24 SMs with no atypia (2/23 SM and 1/1 ISM). The frequency of high-risk HPV infection was also significant between AIMs and SM with no atypia (6/10 vs 3/24; P < 0.001). Among the cases, which were informative for clonal analysis, all 5 AIMs positive for high-risk HPV were monoclonal in composition. Physical status of HPV was examined in HPV-16-positive cases. Human papillomavirus type 16 was present as a mixture of episomal form and integrated form in 4 of 6 AIMs. These observations imply that unlike SMs with no atypia, which arises as a result of reactive or inflammatory process, lesions with the histological characteristics of AIM may be indeed true precursors of cervical carcinoma.