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Aims: The diagnosis of focal nodular hyperplasia (FNH) and the interpretation of glutamine synthetase (GS) staining can be challenging on biopsies. We aimed to evaluate the reproducibility of needle biopsy diagnosis of FNH, the effect of GS immunohistochemistry on FNH diagnosis, and which histological features are most useful for the diagnosis of FNH. Methods and results: The study included virtual needle biopsies generated from 75 resection specimens (30 FNHs, 15 hepatocellular adenomas, 15 hepatocellular carcinomas, and 15 non‐lesional liver specimens). Pathologists were reasonably accurate (83.1%) in the diagnosis of FNH with haematoxylin and eosin alone. Ductular reaction and nodularity had the highest sensitivity for a diagnosis of FNH (88.1% and 82.2%, respectively), whereas central scar was the most specific feature (90.6%). The presence of two or more of the classic histological features had 89.6% sensitivity and 86.2% specificity for a diagnosis of FNH. Diagnostic accuracy was significantly higher with the addition of a GS stain. A map‐like GS staining pattern was highly specific (99.3%) for FNH. However, GS staining was interpreted as non‐map‐like in 14.4% of reviews of true FNH cases, and overall interobserver agreement for interpretation of the GS staining pattern was only moderate (kappa = 0.42). Conclusions: Pathologists are reasonably accurate in the diagnosis of FNH on virtual biopsies, and GS staining improves accuracy. However, a subset of FNH cases remain challenging. Steatosis and a pseudo‐map‐like GS staining pattern were associated with increased difficulty. Therefore, although a map‐like GS staining pattern is useful for confirmation of a diagnosis, the lack of a map‐like GS staining pattern on needle biopsy does not necessarily exclude a diagnosis of FNH. [ABSTRACT FROM AUTHOR]

Aims: Human epidermal growth factor receptor 2 (HER2) amplification in endometrial cancer (EC) is almost completely confined to the p53‐abnormal (p53abn) molecular subtype and independent of histological subtype. HER2 testing should therefore be molecular subtype‐directed. However, the most optimal approach for HER2 testing in EC has not been fully established. Therefore, we developed an EC‐specific HER2 immunohistochemistry (IHC) scoring method and evaluated its reproducibility and performance to establish an optimal diagnostic HER2 testing algorithm for p53abn EC. Methods and results: HER2 IHC slides of 78 p53abn EC were scored by six gynaecopathologists according to predefined EC‐specific IHC scoring criteria. Interobserver agreement was calculated using Fleiss' kappa and the first‐order agreement coefficient (AC1). The consensus IHC score was compared with HER2 dual in‐situ hybridisation (DISH) results. Sensitivity and specificity were calculated. A substantial interobserver agreement was found using three‐ or two‐tiered scoring [κ = 0.675, 95% confidence interval (CI) = 0.633–0.717; AC1 = 0.723, 95% CI = 0.643–0.804 and κ = 0.771, 95% CI = 0.714–0.828; AC1 = 0.774, 95% CI = 0.684–0.865, respectively]. Sensitivity and specificity for the identification of HER2‐positive EC was 100 and 97%, respectively, using a HER2 testing algorithm that recommends DISH in all cases with moderate membranous staining in >10% of the tumour (IHC+). Performing DISH on all IHC‐2+ and ‐3+ cases yields a sensitivity and specificity of 100%. Conclusions: Our EC‐specific HER2 IHC scoring method is reproducible. A screening strategy based on IHC scoring on all cases with subsequent DISH testing on IHC‐2+/‐3+ cases has perfect test accuracy for identifying HER2‐positive EC. [ABSTRACT FROM AUTHOR]

Aims: The nuclear proliferation marker Ki67 assayed by immunohistochemistry has multiple potential uses in breast cancer, but an unacceptable level of interlaboratory variability has hampered its clinical utility. The International Ki67 in Breast Cancer Working Group has undertaken a systematic programme to determine whether Ki67 measurement can be analytically validated and standardised among laboratories. This study addresses whether acceptable scoring reproducibility can be achieved on excision whole sections. Methods and results: Adjacent sections from 30 primary ER+ breast cancers were centrally stained for Ki67 and sections were circulated among 23 pathologists in 12 countries. All pathologists scored Ki67 by two methods: (i) global: four fields of 100 tumour cells each were selected to reflect observed heterogeneity in nuclear staining; (ii) hot‐spot: the field with highest apparent Ki67 index was selected and up to 500 cells scored. The intraclass correlation coefficient (ICC) for the global method [confidence interval (CI) = 0.87; 95% CI = 0.799–0.93] marginally met the prespecified success criterion (lower 95% CI ≥ 0.8), while the ICC for the hot‐spot method (0.83; 95% CI = 0.74–0.90) did not. Visually, interobserver concordance in location of selected hot‐spots varies between cases. The median times for scoring were 9 and 6 min for global and hot‐spot methods, respectively. Conclusions: The global scoring method demonstrates adequate reproducibility to warrant next steps towards evaluation for technical and clinical validity in appropriate cohorts of cases. The time taken for scoring by either method is practical using counting software we are making publicly available. Establishment of external quality assessment schemes is likely to improve the reproducibility between laboratories further. [ABSTRACT FROM AUTHOR]

Aims: The four‐tiered peritoneal regression grading score (PRGS) assesses the response to chemotherapy in peritoneal metastasis (PM). The PRGS is used, for example, to assess the response to pressurised intraperitoneal aerosol chemotherapy (PIPAC). However, the reproducibility of the PRGS is currently unknown. We aimed to evaluate the inter‐ and intraobserver variability of the PRGS. Methods and results: Thirty‐three patients who underwent at least three PIPAC treatments as part of the PIPAC‐OPC1 or PIPAC‐OPC2 clinical trials at Odense University Hospital, Denmark, were included. Prior to each therapy cycle, peritoneal quadrant biopsies were obtained and three haematoxylin and eosin (H&E)‐stained step sections were scanned and uploaded to a pseudonymised web library. For determining interobserver variability, eight pathologists assessed the PRGS for each quadrant biopsy, and Krippendorff's alpha and intraclass correlation coefficients (ICCs) were calculated. For determining intraobserver variability, three pathologists repeated their own assessments and Cohen's kappa and ICCs were calculated. A total of 331 peritoneal biopsies were analysed. Interobserver variability for PRGS of each biopsy and for the mean and maximum PRGS per biopsy set was moderate to good/substantial. The intraobserver variability for PRGS of each biopsy and for the mean and maximum PRGS per biopsy set was good to excellent/almost perfect. Conclusions: Our data support the PRGS as a reproducible and useful tool to assess response to intraperitoneal chemotherapy in PM. Future studies should evaluate the prognostic and predictive role of the PRGS. [ABSTRACT FROM AUTHOR]

Aims: Robust prognostic markers for ductal carcinoma in situ (DCIS) of the breast require high reproducibility and thus low interobserver variability. The aim of this study was to compare interobserver variability among 13 pathologists, in order to enable the identification of robust histopathological characteristics. Methods and results: One representative haematoxylin and eosin‐stained slide was selected for 153 DCIS cases. All pathologists independently assessed nuclear grade, intraductal calcifications, necrosis, solid growth, stromal changes, stromal inflammation, and apocrine differentiation. All characteristics were assessed categorically. Krippendorff's alpha was calculated to assess overall interobserver concordance. Cohen's kappa was calculated for every observer duo to further explore interobserver variability. The highest concordance was observed for necrosis, calcifications, and stromal inflammation. Assessment of solid growth, nuclear grade and stromal changes resulted in lower concordance. Poor concordance was observed for apocrine differentiation. Kappa values for each observer duo identified the 'ideal' cut‐off for dichotomisation of multicategory variables. For instance, concordance was higher for 'non‐high versus high' nuclear grade than for 'low versus non‐low' nuclear grade. 'Absent/mild' versus 'moderate/extensive' stromal inflammation resulted in substantially higher concordance than other dichotomous cut‐offs. Conclusions: Dichotomous assessment of the histopathological features of DCIS resulted in moderate to substantial agreement among pathologists. Future studies on prognostic markers in DCIS should take into account this degree of interobserver variability to define cut‐offs for categorically assessed histopathological features, as reproducibility is paramount for robust prognostic markers in daily clinical practice. A new prognostic index for DCIS might be considered, based on two‐tier grading of histopathological features. Future research should explore the prognostic potential of such two‐tier assessment. [ABSTRACT FROM AUTHOR]

Aims: Tumour budding is considered to be a good marker for progression and prognosis in colorectal carcinomas. A uniform classification system has been established recently. The natural element of uncertainty in the practice of human medicine is also exhibited in the assessment of tumour budding. We tested the hypothesis that interobserver variability can be estimated during the assessment process and investigated its potential clinical implication. Methods and results: Six investigators with different levels of experience could perceive different levels of difficulty (LOD) and estimated different levels of interobserver variability (LOIV) (Li1, lower than average; Li2, average; Li3, higher than average) during the assessment of tumour budding in 244 cases of colon cancer (pT3/4). In total, the LOIV showed following distribution: Li1: 36.1%, Li2: 43.9% and Li3: 20.0%. The LOIV was correlated significantly with the LOD given by the investigator. In total, the agreement rates with the final consensus classification were: Li1: 93.4%, Li2: 78.5% and Li3: 58.4%. The relative risk of disagreement with the final consensus classification was more than six times higher when a case was estimated to have a high rather than a low interobserver variability. Conclusion: Our data show that the investigator can estimate the interobserver variability during the ongoing rating process in pT3/4 colon cancer. The LOIV/LOD seems to be a valuable parameter of the assessment quality. For Li3 cases further measures seem mandatory. [ABSTRACT FROM AUTHOR]

Aims Lymphovascular invasion ( LVI) and the histological pattern of invasion ( POI) at the invasive tumour front have been reported as adverse prognosticators in oral squamous cell carcinoma ( SCC). However, assessment of these parameters is hampered by variation in the criteria used for their evaluation. Our objective was to evaluate interobserver variability in the assessment of the POI and LVI in SCC of the floor of the mouth ( FOM), and to study the impact of the POI on clinical outcomes by using varying quantitative cut-offs. Methods and results Fifty-eight cases of FOM SCC were independently evaluated for the POI and LVI by three pathologists. Interobserver variability was analysed by the use of Fleiss kappa statistics. Interobserver agreement was substantial for the assessment of LVI [κ = 0.64, 95% confidence interval ( CI) 0.60-0.68]. Interobserver agreement was moderate for evaluation of the POI with a 50% cut-off (κ = 0.58, 95% CI 0.54-0.62), a 20% cut-off (κ = 0.58, 95% CI 0.54-0.62) cut-off, and worst POI (κ =0 .43, 95% CI 0.39-0.46). A consensus diagnosis of the POI was a significant predictor of locoregional recurrence ( LRR), disease-specific survival ( DSS) and overall survival ( OS) on univariate analysis when a 50% cut-off was used ( LRR, P = 0.01; DSS, P = 0.01; OS, P = 0.01) and when a 20% cut-off was used ( LRR, P = 0.02; DSS, P = 0.02; OS, P = 0.03), but was not significant when worst POI was used ( LRR, P = 0.18; DSS, P = 0.16; OS, P = 0.17). Conclusions Interobserver agreement in the diagnosis of LVI was substantial. The POI at the 50% and 20% cut-offs is moderately reproducible, and has prognostic value in FOM SCC. Further studies are necessary to establish the optimum quantitative cut-off for the POI. [ABSTRACT FROM AUTHOR]

Aims To assess the interobserver reproducibility of individual Gleason grade 4 growth patterns. Methods and results Twenty-three genitourinary pathologists participated in the evaluation of 60 selected high-magnification photographs. The selection included 10 cases of Gleason grade 3, 40 of Gleason grade 4 (10 per growth pattern), and 10 of Gleason grade 5. Participants were asked to select a single predominant Gleason grade per case (3, 4, or 5), and to indicate the predominant Gleason grade 4 growth pattern, if present. 'Consensus' was defined as at least 80% agreement, and 'favoured' as 60-80% agreement. Consensus on Gleason grading was reached in 47 of 60 (78%) cases, 35 of which were assigned to grade 4. In the 13 non-consensus cases, ill-formed (6/13, 46%) and fused (7/13, 54%) patterns were involved in the disagreement. Among the 20 cases where at least one pathologist assigned the ill-formed growth pattern, none (0%, 0/20) reached consensus. Consensus for fused, cribriform and glomeruloid glands was reached in 2%, 23% and 38% of cases, respectively. In nine of 35 (26%) consensus Gleason grade 4 cases, participants disagreed on the growth pattern. Six of these were characterized by large epithelial proliferations with delicate intervening fibrovascular cores, which were alternatively given the designation fused or cribriform growth pattern ('complex fused'). Conclusions Consensus on Gleason grade 4 growth pattern was predominantly reached on cribriform and glomeruloid patterns, but rarely on ill-formed and fused glands. The complex fused glands seem to constitute a borderline pattern of unknown prognostic significance on which a consensus could not be reached. [ABSTRACT FROM AUTHOR]

Aims To compare the reproducibility of the current (2003) World Health Organization ( WHO), endometrial intraepithelial neoplasia ( EIN) and European Working Group ( EWG) classifications of endometrial endometrioid proliferations. Methods and results Nine expert gynaecological pathologists from Europe and North America reviewed 198 endometrial biopsy/curettage specimens originally diagnosed as low-grade lesions. All observers were asked to classify the cases by using the categories described in each scheme: six for WHO, four for EIN, and three for EWG. The results were evaluated by kappa statistics for more than two observations. The analysis was repeated using only two major categories (benign versus atypical/carcinoma). Both the WHO and EIN classifications showed poor interobserver agreement ( κ = 0.337 and κ = 0.419, respectively), whereas the EWG classification showed moderate agreement ( κ = 0.530). Full agreement between pathologists occurred in only 28% for the WHO classification, 39% for the EIN classification, and 59% for the EWG classification. With only two diagnostic categories, kappa values increased in all classifications, but only the EWG classification reached a substantial level of agreement ( κ = 0.621); similarly, full agreement among all pathologists increased to 70% for the WHO classification, 69% for the EIN classification, and 72% for the EWG classification. Conclusions A two-tier classification of endometrial endometrioid proliferative lesions improves reproducibility, and should be considered for the diagnosis of endometrial biopsy/curettage specimens. [ABSTRACT FROM AUTHOR]

AimsAssessment of lesser or doubtful degrees of gastric atrophy can be difficult, especially in the antrum, since well established criteria are lacking. At the Houston Working Party on Gastritis in 1994 a visual analogue scale was designed for the grading of histopathological parameters. This was done to promote uniformity in grading by acting as a reference. The purpose of the present study was to measure interobserver variation between pathologists familiar with the Houston visual analogue scale in a specifically selected set of biopsies from patients with lesser or doubtful degrees of atrophy. Methods and results Thirty cases with biopsies of the antrum and corpus from a long-term follow-up study on Helicobacter pylori gastritis comprised the current study material. The cases were selected from that study because there had been uncertainty or disagreement on the presence of gastric atrophy. The study set of haematoxylin and eosin (H & E) slides was circulated amongst gastrointestinal pathologists familiar with the visual analogue scale who were unaware of the source of the study set nor had any other clinical information. Interobserver variability was analysed using kappa statistics. The overall agreement for the grade of atrophy in antral biopsies was 0.461; the kappa value was 0.18 (95% confidence limits 0.12–0.24), which is considered poor agreement. The kappa value was nevertheless statistically significant (P < 0.01). The overall agreement on the grade of atrophy in the corpus biopsies was apparently good (0.833), but the kappa which adjusts for chance agreement was only moderate (0.48; 95% confidence limits 0.42–0.55; P < 0.001). ConclusionThe studied series comprised a self-selected sample in which there was doubt about the grade of atrophy and such a sample will produce lower kappa values than a random sample of gastric biopsies. The results nevertheless confirm that better guidelines and firm criteria are needed to properly diagnose and grade gastric atrophy. It is suggested that the use of two grades, low- and high-grade atrophy, akin to that in use for grading inflammatory bowel disorder (IBD)- associated dysplasia, could improve agreement. Furthermore optimal biopsy quality with full thickness mucosa and proper orientation appears important for grading gastric atrophy. [ABSTRACT FROM AUTHOR]