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Aim: To compare HER-2 scoring reproducibility by subjective and digital image analysis (DIA) scores with each other and with fluorescence in situ hybridization (FISH) assessed HER-2 amplification., Methods: Herceptest-stained Tissue Micro Arrays of 219 breast carcinomas were scored (DAKO protocol) by 3 observers (both independent and as consensus), scored by DIA and both scores were compared with FISH amplification results., Results: Interobserver subjective scores reproducibility was good (kappa 0.82 to 0.86) but therapeutically important 3+/2+discrepancies occurred in 11% to 16% of all 3+ cases. Subjective scores and FISH results differed considerably. Consensus scores by 3 pathologists correlated better with FISH, reducing the number of both Immunohistochemical (IHC) negative/FISH positives and IHC 3+/FISH negatives. DIA scores were well reproducible and correlated better with FISH amplification than did subjective scores., Conclusions: DIA scores were comparable with consensus scores between 3 expert pathologists, were very well reproducible and performed better in classifying IHC 3+/FISH+ cases than did subjective scores.

Objective: To prospectively validate, in early cervical intraepithelial neoplasia (CIN), routine assessment of a previously developed prognostic Ki-67 immunoquantitative progression-risk model., Study Design: Two hundred sixty-six consecutive cervical biopsies taken for an abnormal cytologic smear were routinely diagnosed by experienced pathologists as CIN. Ki-67 immunoquantitation was performed routinely by 3 technicians blinded to clinical and pathologic information. Progression of CIN 1-2 to CIN 3 in histologic follow-up biopsies was used as the intermediate end point., Results: In 58 (22%) biopsies, technical shortcomings prevented Ki-67 immunoquantitation, and in 22 biopsies no follow-up was available. The routine diagnosis in the 186 remaining biopsies was CIN 1 = 24, CIN 2 = 56 and CIN 3 = 106. In 52 marker biopsies with expert review diagnosis of CIN 1-2 and adequate follow-up, histologic biopsies revealed CIN 3 in 9 (17%) cases: 9 of 34 (26%) of Ki-67 high-risk and 0 of 18 (0%) of Ki-67 low-risk lesions (log rank = 5.0, P = .03). Routine CIN grade (1 or 2) was not prognostic (P = .65). Eleven (55%) of 20 CIN 1 and 7 of 32 (22%) CIN 2 cases were Ki-67 low risk and none progressed, contrasting with 4 of 9 (44%) progressions of Ki-67 high risk CIN 1s and 5 of 25 (20%) high risk CIN 2s. Expert CIN grades were stronger prognostically than routine CIN grade, but Ki-67 was still stronger., Conclusion: Routine Ki-67 immunoquantitative progression prediction in CIN 1-2 is more predictive of CIN 3 in follow-up than are routine and review CIN grades.

The purpose of this study was to evaluate the influence of koilocytosis on the progression of cervical intraepithelial neoplasia (CIN) to a higher grade during follow-up in cervical biopsy specimens with CIN 1 and 2. In adequate, consecutive, biopsy specimens of 103 CIN 1 and 2 patients, CIN grade and presence or absence of koilocytosis were assessed. Patients were followed by colposcopy and cytology according to protocol. When recurrent CIN was suspected with either of the techniques, a re-biopsy was taken. Progression of the CIN was defined as an increase of grade by at least 1. Univariate analysis was applied to all patients and in the CIN 1 and 2 subgroups separately. An experienced gynecological pathologist using strict criteria reviewed koilocytosis. The Kappa test was used to assess interobserver reproducibility of koilocytosis. Koilocytosis was found in 70 (68%) of the specimens (18 of 29=62% of the CIN 1 and 52 of 74=70% of the CIN 2 cases). Twenty-one of 103 (20%) dysplasias progressed and 10 of these (48%) showed koilocytosis. Koilocytosis was found more frequently (73%, 60 of 82) in the cases that showed no progression. Follow-up showed that patients with koilocytosis had a significantly lower likelihood of progression (log-rank=5.5, p=0.02). In CIN 1, progression without and with koilocytosis was 27% and 0%, respectively, log-rank=4.9, p=0.03. In CIN 2, a similar trend was found: only 10 of 52 (19%) CIN 2 cases with koilocytosis progressed, whereas 8 of 22 (36%) lesions lacking koilocytosis progressed, a difference just below significance (p=0.06). In agreement with other studies, interobserver diagnosis of koilocytosis was poorly reproducible. In conclusion, the presence of koilocytosis is associated with a lack of progression in CIN 1 lesions, but reproducibility of koilocytosis assessment is not optimal. Therefore, other more objective and better reproducible criteria are required to extract the potentially important prognostic information contained in the microscopic image of CIN 1 and 2 lesions.

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.