Evaluation of MIB-1-Positive Cell Clusters as a Diagnostic Marker for Cervical Intraepithelial Neoplasia

Abstract

The objects of the study were to evaluate MIB-1-positive cell clusters (MIB-C) for distinguishing normal, reactive, and cervical intraepithelial neoplasia (CIN) biopsies and to determine possible pitfalls. Seventy-seven consecutive cervical specimens routinely diagnosed (Dx_orig) as CIN 1 or 2, or no-CIN, were revised independently by two expert gynecopathologists. MIB-1 staining and oncogenic human papillomavirus (HPV) assessment (by polymerase chain reaction) were performed. Independent diagnoses (plus oncogenic HPV status, in case of disagreement between the experts) were used to obtain a final diagnosis (Dx_final) and compared with MIB-C. Four of the 27 (15%) Dx_final = normal were HPV positive. Agreement between the gynecopathologists was 72 of 77 (94%). There were 30 (39%) discrepancies between Dx_orig and Dx_final (23 = 30% downgrades and 7 = 9% upgrades). All 23 downgrades were HPV negative and all seven upgrades were HPV positive. Overall agreement between Dx_orig and MIB-C was 73%, and with Dx_final 99%. Sensitivity, specificity, and positive and negative predictive values of MIB-C were very high without false negatives. Tangential cutting of MIB-1-positive parabasal cells and inflammatory cells can erroneously be overdiagnosed as a MIB-C. One single false positive of the 48 non-CIN cases (an immature squamous metaplasia) showed a special, easily recognizable MIB-1 pattern, different from CIN because the MIB-1 staining in the nuclei is not diffuse (as in CIN) but clumped. Moreover, positive nuclei are somewhat less densely packed than in CIN. When tangentially cut parabasal cells and inflammatory cells are carefully excluded, MIB-C is a strong diagnostic adjunct in distinguishing CIN from normal or benign cervical squamoepithelial lesions.

Histological Features and ki-67 Index in Cervical Atypical Lesions

“…Additionally, cervical reactive/metaplastic conditions and LSIL can also be contemporary present, making the diagnosis also more difficult. Of note, a clear trend to over-diagnose normal, metaplastic or reactive cervical biopsies as HPV associated LSIL has been reported, with therapeutic, reproductive, sexual and social consequences [19,24] . In this study no association was found in AL between HPV status and most of the morphological features investigated, namely, hyperkeratosis, parakeratosis, acanthosis, papillomatosis, mitosis in the lower third of epithelium, hyperplasia of parabasal layers, absence of a distinct basal cell layer.…”

The Indicators of Predicting Disease Outcome in HPV Carcinogenesis

“…MIB-1 expression in the basal and the upper-third layer proved useful in grading SIL with equivocal mitotic index (Popiolek et al, 2004). Immature squamous metaplasia can be MIB-1 cluster positive, but this false-positive case showed a special staining pattern, different from CIN: 1) MIB-1 staining in the nuclei is not diffuse (as in CIN) but clumped; 2) positive nuclei are somewhat less densely packed than in CIN (Kruse et al, 2002). Noteworthy is that the presence of a cluster of at least two MIB-1-positive nuclei (MIB-C) in the upper two thirds of the epithelial thickness is a highly sensitive and specific marker to discriminate between normal epithelium and low-grade squamous intraepithelial lesion (Pirog et al, 2002).…”

“…Expression of Ki-67 (MIB-1) in the upper layers/superficial layers of the epithelium corroborated with more than 15% of basal cells positive for MIB-1 staining can be used to distinguish condyloma from inflammation or squamous metaplasia (Mittal and Palazzo, 1998). Ki-67 evaluation can be also a valuable adjunct in the distinction of CIN from normal or benign cervical squamoepithelial lesions (Kruse et al, 2002;Keating et al, 2001). MIB-1 expression in the basal and the upper-third layer proved useful in grading SIL with equivocal mitotic index (Popiolek et al, 2004).…”

Management of high-risk HPV-positive women for detection of cervical (pre)cancer

“…Simultaneous expression of the antiproliferative p16 protein and the proliferation marker Ki-67 should exclude each other in cells under normal physiological conditions [61][62][63][64]. The simultaneous expression of p16 and Ki-67 in one cell is indicative for cell cycle dysregulation and appears indicative for a transforming hrHPV infection [61][62][63][64].…”

“…Simultaneous expression of the antiproliferative p16 protein and the proliferation marker Ki-67 should exclude each other in cells under normal physiological conditions [61][62][63][64]. The simultaneous expression of p16 and Ki-67 in one cell is indicative for cell cycle dysregulation and appears indicative for a transforming hrHPV infection [61][62][63][64]. Three recent studies have addressed the performance of p16/Ki-67 dualstained cytology for triage of hrHPV-positive women, in population-based screening cohorts (n = 1509 [65] and n = 396 [66]) and a gynecologic outpatient population (n = 446 [67]).…”