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Diagnostic Implications of L1, p16, and Ki-67 Proteins and HPV DNA in Low-grade Cervical Intraepithelial Neoplasia

Gatta, Luisa Benerini Ph.D.; Berenzi, Angiola Ph.D.; Balzarini, Piera Ph.D.; Dessy, Enrico M.D.; Angiero, Francesca Ph.D.; Alessandri, Giulio Ph.D.; Gambino, Angela M.D.; Grigolato, Piergiovanni M.D.; Benetti, Anna M.D.

International Journal of Gynecological Pathology: November 2011 - Volume 30 - Issue 6 - p 597–604
doi: 10.1097/PGP.0b013e31821ac4fd

The expressions of p16, Ki-67, and L1 proteins and human papillomavirus DNA were investigated using polymerase chain reaction (HPV/PCR) and catalyzed signal-amplified colorimetric DNA in situ hybridization (CSAC/ISH) as potential molecular markers for the diagnosis and transforming potential of low cervical intraepithelial neoplasia (CIN1). Ki-67 and p16 protein expression increased linearly from control cases to more dysplastic cases (CIN1, CIN2, and CIN3), peaking in squamous cell carcinoma cases (P<0.05). In contrast, L1 expression was inversely correlated with malignant transformation. Patients with CIN1 were divided into 4 groups: L1p16+, L1+p16, L1p16, and L1+p16+, and the immunohistochemical results were combined with HPV/PCR, L1/PCR, and high-risk E6/E7 genome and CSAC/ISH data. Malignant transformation correlated with L1p16+ patients (100% of CIN2, CIN3, and squamous cell carcinoma cases) and was evident in approximately 23% of CIN1 cases. In addition, the presence of HPV/DNA+ was evident in 52% of CIN1 cases, and within the L1p16+ group. In 4 of 7 cases, the high-risk E6/E7 HPV genome was present and in 1 case it was integrated into the host DNA, as confirmed using CSAC/ISH. In patients with CIN1, investigating the presence of HPV/DNA using PCR and the presence of the high-risk E6/E7 genome is necessary to distinguish high-risk oncogenic patient groups from low-risk groups. This study highlights the importance of combining immunohistochemical analysis with HPV/PCR and CSAC/ISH to identify patients with CIN1 with a risk of neoplastic progression.

Second Department of Pathology (L.B.G., A.B., P.B., E.D., P.G., A.B.), School of Medicine

Department of Gynecology and Obstetrics (A.D.), School of Medicine, University of Brescia, Brescia

Department of Pathology (F.A.), School of Medicine, University of Milan-Bicocca, Monza

Department of Cerebrovascular Diseases (G.A.), Cellular Neurobiology Laboratory, Fondazione Neurological Institute “Carlo Besta,” Milan, Italy

Disclosure: Luisa Benerini Gatta was supported by fellowships from the “Beretta Foundation,” Brescia, and the study was supported by funds from the University of Brescia.

Luisa Benerini Gatta and Angiola Berenzi have equally contributed to this study.

Address correspondence and reprint requests to Luisa Benerini Gatta, PhD, II Anatomia e Istologia Patologica, Spedali Civili, 1, Brescia, 25123. e-mail:

©2011International Society of Gynecological Pathologists