title: Differentiating high-grade cervical intraepithelial lesion from atrophy in postmenopausal women using Ki-67, cyclin E, and p16 immunohistochemical analysis.
abstract: OBJECTIVE
  In postmenopausal women, differentiating high-grade cervical intraepithelial neoplasia (CIN 2,3) from atrophic uterine cervical squamous epithelium histologically may pose a diagnostic challenge. Recent studies have indicated the value of using a combination of Ki-67, cyclin E, and p16 immunohistochemical analysis in recognizing CIN 2,3. In this study, we compared the staining features of Ki-67, cyclin E, and p16 in cervix specimens from postmenopausal women to distinguish CIN 2,3 from atrophy.
  
  
  METHODS
  Twenty-six formalin-fixed paraffin-embedded archival cervical specimens (4 biopsy, 8 laser cone, and 14 total hysterectomy samples) were selected from 25 women 50 to 80 years of age (mean = 64 years). Cases included CIN 2,3 (n = 10), atrophy (n = 9), and coexistent CIN 2,3 and atrophy (n = 6). Slides were stained with monoclonal antibodies to Ki-67, cyclin E, and p16 using the avidin-biotin-peroxidase method. Strength of staining was graded as 1+ to 3+. Pattern of staining was described as diffuse, patchy, or scattered. Ki-67 staining restricted to the basal/parabasal zone was scored as negative.
  
  
  RESULTS
  All CIN 2,3 cases demonstrated variable positivity for Ki-67, cyclin E, and p16. Most CIN 2,3 cases showed strong p16 (81.3%) and Ki-67 (75.0%) reactivity, while only 31.3% of them showed strong cyclin E activity. Some CIN 2,3 cases demonstrated strong p16 but weak Ki-61 and cyclin E reactivity. All atrophic epithelia were negative for p16, cyclin E, and Ki-67. In coexistent CIN 2,3 and atrophy cases, the three-antibody panel clearly demarcated the transition from benign to neoplastic epithelia.
  
  
  CONCLUSIONS
  P16 is the most valuable marker followed by Ki-67 for differentiating CIN 2,3. While cyclin E appears to add limited value on these two markers. Therefore, although the three-antibody immunohistochemical panel (p16, Ki-67, and cyclin E) can be a valuable adjunct to routine hematoxylin-eosin staining, it is also possible to use the two-antibody panel (p16 and Ki-67) to effectively distinguish CIN 2,3 from atrophy in postmenopausal women.
authors.affiliation: Department of Pathology, Long Island Jewish Medical Center, New Hyde Park, New York, USA. xquiao@lumc.edu
authors.forename: Xiaoying
authors.initials: X
authors.lastname: Qiao
authors.forename: Tawfiqul A
authors.initials: TA
authors.lastname: Bhuiya
authors.forename: Mark
authors.initials: M
authors.lastname: Spitzer
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D001284:Atrophy; D014408:Biomarkers, Tumor / Q000032:analysis*; D019927:Cyclin E / Q000032:analysis; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000032:analysis; D003937:Diagnosis, Differential; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D019394:Ki-67 Antigen / Q000032:analysis; D008875:Middle Aged; D017698:Postmenopause / Q000378:metabolism; D002583:Uterine Cervical Neoplasms / Q000378:metabolism / Q000473:pathology*; D002578:Uterine Cervical Dysplasia / Q000378:metabolism / Q000473:pathology*
chemical_list: D014408:Biomarkers, Tumor; D019927:Cyclin E; D019941:Cyclin-Dependent Kinase Inhibitor p16; D019394:Ki-67 Antigen