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Mesothelioma is a rare disease with an historically poor prognosis. Over the past decade, a grading system has been developed that is a powerful prognostic tool in epithelioid mesothelioma. Grading of epithelioid mesothelioma is now required or strongly recommended by expert consensus, the College of American Pathologists, the World Health Organization, and the International Mesothelioma Interest Group. The original nuclear grading system for epithelioid mesothelioma, developed in the United States, split epithelioid mesotheliomas into three prognostic groups with marked differences in survival. Now, this three‐tiered nuclear grading system has been combined with the presence or absence of necrosis to form the currently recommended two‐tiered grading system of low‐ and high‐grade epithelioid mesothelioma. This review will focus on the development of this grading system in mesothelioma, the grading system's shortcomings, and the application of the grading system to cytology specimens and other extra‐pleural sites. Lastly, this review will briefly discuss alternative grading systems and future considerations. [ABSTRACT FROM AUTHOR]

Aims: Partial response to neoadjuvant chemoradiotherapy (CRT) presents with one of two main response patterns: shrinkage or fragmentation. This study investigated the relevance of these response patterns in rectal cancer, correlation with other response indicators, and outcome. Methods and results: The study included a test (n = 197) and a validation cohort (n = 218) of post‐CRT patients with rectal adenocarcinoma not otherwise specified and a partial response. Response patterns were scored by two independent observers using a previously developed three‐step flowchart. Tumour regression grading (TRG) was established according to both the College of American Pathologists (CAP) and Dworak classifications. In both cohorts, the predominant response pattern was fragmentation (70% and 74%), and the scoring interobserver agreement was excellent (k = 0.85). Patients with a fragmented pattern presented with significantly higher pathological stage (ypTNM II‐IV, 78% versus 35%; P < 0.001), less tumour regression with Dworak (P = 0.004), and CAP TRG (P = 0.005) compared to patients with a shrinkage pattern. As a predictor of prognosis, the shrinkage pattern outperformed the TRG classification and stratified patients better in overall (fragmented pattern, hazard ratio [HR] 2.04, 95% confidence interval [CI] 1.19–3.50, P = 0.008) and disease‐free survival (DFS; fragmented pattern, HR 2.50, 95% CI 1.23–5.10, P = 0.011) in the combined cohorts. The multivariable regression analyses revealed pathological stage as the only independent predictor of DFS. Conclusions: The heterogeneous nature of tumour response following CRT is reflected in fragmentation and shrinkage. In rectal cancer there is a predominance of the fragmented pattern, which is associated with advanced stage and less tumour regression. While not independently associated with survival, these reproducible patterns give insights into the biology of tumour response. [ABSTRACT FROM AUTHOR]

Aims: The aim of this study was to evaluate human epidermal growth factor receptor 2 (HER2) immunohistochemistry (IHC) in ovarian clear cell carcinoma (OCCC) by using two antibodies and two scoring guidelines in correlation with HER2 amplification and clinicopathological features. Methods and results: A tissue microarray was constructed by use of a total of 71 OCCC cases for IHC (the A0485 antibody and the 4B5 antibody) and dual‐colour silver in‐situ hybridisation (DISH). Two pathologists independently scored the IHC according to the 2018 American Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP) breast cancer guidelines (breast guidelines) and the 2016 ASCO/CAP gastro‐oesophageal adenocarcinoma guidelines (gastric guidelines). IHC concordances between A0485 and 4B5 were 87.3–93.0%. Three to 16 (4.2–22.5%) cases had an IHC score of 2+/3+ with frequent basolateral/lateral membranous staining. The 4B5 antibody yielded fewer IHC 2+ cases than the A0485 antibody (n = 2–6 versus n = 5–12). Five (7.0%) cases had HER2 amplification as determined with DISH. Cases with papillary‐predominant growth patterns were significantly more likely to have HER2 amplification (P = 0.0051). In predicting DISH results, IHC scored according to the gastric guidelines yielded 100%/100% sensitivity and 83.3–95.5%/98.2–100% specificity, and IHC scored according to the breast guidelines yielded 60–80%/33.3–66.7% sensitivity and 95.5–100%/100% specificity (including/excluding IHC 2+ cases). One case had intratumoral heterogeneity, with discordant results between primary and metastatic tumour specimens. Conclusion: We demonstrated HER2 amplification in 7% of OCCC cases, and the molecular change is significantly associated with papillary‐predominant growth patterns. In predicting HER2 amplification, a combination of 4B5 IHC and gastric guidelines provides the best sensitivity and fewer equivocal (IHC 2+) cases. Given the intratumoral heterogeneity, assessment of HER2 status on whole tissue sections and on both primary and metastatic tumour specimens is recommended. [ABSTRACT FROM AUTHOR]

Aims: The American Society of Clinical Oncology/College of American Pathologists (ASCO/CAP) updated the testing guideline in 2018 to address issues arising from uncommon human epidermal growth factor receptor 2 (HER2) fluorescence in‐situ hybridisation (FISH) results according to the 2013 guideline. Next‐generation sequencing (NGS) may be used to better classify patients. The aim of this study was to assess the ERBB2 amplification status of invasive breast carcinoma with equivocal HER2 immunohistochemistry (IHC) results by using NGS, focusing on Group 4 (HER2/CEP17 ratio of <2.0; average HER2 signals/cell of ≥4.0 and <6.0). Methods and results: We retrospectively reviewed HER2 FISH and NGS data of HER2 IHC‐equivocal breast carcinomas at our centre between January 2009 and September 2019, wherein all three assays were performed on the same tissue block, and compared HER2 FISH results, according to the 2018 ASCO/CAP guideline, and the ERBB2 amplification status determined with NGS. A total of 52 HER2 FISH and NGS results from 51 patients with HER2 IHC‐equivocal breast carcinomas were reviewed. The cohort included eight cases classified as 2018 ASCO/CAP in‐situ hybridisation Group 1, three classified as Group 2, three classified as Group 3, 14 classified as Group 4, and 24 classified as Group 5. Thirteen of 14 (92.9%) Group 4 (HER2‐negative) cases were classified as ERBB2‐non‐amplified by the use of NGS; the discordant case was later classified as Group 1 with alternative sample FISH testing. NGS revealed no significant difference in somatic mutations or copy number alterations between Groups 4 and 5. Conclusions: Our NGS findings support the reclassification of HER2 FISH‐equivocal cases as HER2‐negative under the 2018 ASCO/CAP guideline. [ABSTRACT FROM AUTHOR]

The International Collaboration on Cancer Reporting (ICCR) is a not‐for‐profit organisation sponsored by the Royal Colleges of Pathologists of Australasia and the United Kingdom, the College of American Pathologists, the Canadian Association of Pathologists in association with the Canadian Partnership Against Cancer, the European Society of Pathology, the American Society of Clinical Pathology and the Faculty of Pathology, Royal College of Physicians of Ireland. Its goal is to produce standardised, internationally agreed‐upon, evidence‐based datasets for cancer pathology reporting throughout the world. This paper describes the development of a cancer dataset by the multidisciplinary ICCR expert panel for the reporting of carcinoma of the urethra in urethrectomy specimens. The dataset is composed of 'required' (mandatory) and 'recommended' (non‐mandatory) elements, which are based on a review of the most recent evidence and supported by explanatory commentary. Fourteen required elements and eight recommended elements were agreed by the international dataset authoring committee to represent the essential/required (core) and recommended (non‐core) information for the reporting of carcinoma of the urethra in urethrectomy specimens. Use of an internationally agreed, structured pathology dataset for reporting carcinoma of the urethra (in urethrectomy specimens) will provide the necessary information for optimal patient management, will facilitate consistent data collection and will provide valuable data for research and international benchmarking. The dataset will be valuable for those countries and institutions that are not in a position to develop their own datasets. [ABSTRACT FROM AUTHOR]

Aims: The International Collaboration on Cancer Reporting (ICCR) has provided detailed data sets based upon the published reporting protocols of the Royal College of Pathologists, the Royal College of Pathologists of Australasia and the College of American Pathologists. Methods and results: The data set for carcinomas of renal tubular origin treated by nephrectomy was developed to provide a minimum structured reporting template suitable for international use, and incorporated recommendations from the 2012 Vancouver Consensus Conference of the International Society of Urological Pathology (ISUP) and the fourth edition of the World Health Organisation Bluebook on tumours of the urinary and male genital systems published in 2016. Reporting elements were divided into those, which are required and recommended components of the report. Required elements are: specimen laterality, operative procedure, attached structures, tumour focality, tumour dimension, tumour type, WHO/ISUP grade, sarcomatoid/rhabdoid morphology, tumour necrosis, extent of invasion, lymph node status, surgical margin status, AJCC TNM staging and co-existing pathology. Recommended reporting elements are: preoperative treatment, details of tissue removed for experimental purposes prior to submission, site of tumour(s) block identification key, extent of sarcomatoid and/or rhabdoid component, extent of necrosis, presence of tumour in renal vein wall, lymphovascular invasion and lymph node status (size of largest focus and extranodal extension). Conclusions: It is anticipated that the implementation of this data set in routine clinical practice will inform patient treatment as well as provide standardised information relating to outcome prediction. The harmonisation of data reporting should also facilitate international research collaborations. [ABSTRACT FROM AUTHOR]

Aims The 2013 American Society of Clinical Oncology and the College of American Pathologists ( ASCO/ CAP) HER2 guidelines recommend testing all invasive breast cancers for HER2, typically with immunohistochemistry ( IHC) followed by in-situ hybridization ( ISH) when IHC is equivocal. As well-differentiated breast cancers are rarely HER2-positive, we assessed the value of routine reflex HER2 ISH testing for this subset of breast cancers. Methods and results We collected HER2 IHC 2+ cases and fluorescence in-situ hybridization ( FISH) data from primary breast cancers with well-differentiated tumour types (grade 1 ductal carcinomas, classic lobular carcinomas, tubular, cribriform and pure mucinous carcinomas) at our centre from 2010 to 2015. Haematoxylin and eosin (H&E) and IHC slides were reviewed to confirm tumour type, grade and IHC score based on ASCO/ CAP 2013 guidelines and their recent revisions. Of 4633 invasive carcinomas, 1133 had a well-differentiated tumour type; 177 of these were HER2 IHC equivocal, three of which were low-level amplified by FISH (0.3% of all well-differentiated tumours). One amplified case was classic invasive lobular carcinoma and two were invasive ductal carcinomas, grade 1. One amplified case had chromosome 17 monosomy, and one was rescored as HER2 IHC 1+ upon review. 'Basolateral' staining was noted in one amplified case and in 65 of 174 (37.4%) non-amplified cases. This incomplete membranous staining pattern was observed in the majority of invasive ductal carcinomas that were rescored as 1+ according to the revised 2013 guidelines. Conclusions The rate of HER2 amplification among well-differentiated breast cancers is very low. Basolateral staining in well-differentiated tumours may be overinterpreted as HER2 IHC 2+, but is rarely associated with HER2 amplification. [ABSTRACT FROM AUTHOR]

Aims The recent American Society of Clinical Oncology/College of American Pathologists guidelines for human epidermal growth factor receptor 2 ( HER2) testing in breast cancer recommend repeat testing based on tumour grade, tumour type, and hormone receptor status. The aim of this study was to test the value of these criteria. Methods and results HER2 status was concordant in the core biopsies and excision specimens in 392 of 400 invasive carcinomas. The major reasons for discordance were amplification around the cut-off for positivity and tumour heterogeneity. Of 116 grade 3 carcinomas that were HER2-negative in the core biopsy, four were HER2-positive in the excision specimen. Three of these four either showed borderline negative amplification in the core biopsy or were heterogeneous. None of the 55 grade 1 carcinomas were HER2-positive. Review of repeat testing of HER2 in routine practice suggested that it may also be of value for multifocal tumours and if recommended by the person assessing the in-situ hybridization. Conclusions Mandatory repeat HER2 testing of grade 3 HER2-negative carcinomas is not appropriate. This is particularly true if repeat testing is performed after borderline negative amplification in the core biopsy or in HER2-negative heterogeneous carcinomas. [ABSTRACT FROM AUTHOR]

Aims: The updated 2013 American Society of Clinical Oncology/College of American Pathologists (ASCO/ CAP) human epidermal growth factor receptor 2 (HER2) testing guidelines include changes to HER2 in-situ hybridization (ISH) interpretation criteria. We conducted a retrospective review of a consecutive cohort of primary breast carcinomas to assess the impact of updated guidelines on HER2 classification and laboratory resource utilization, and to characterize the pathobiology of HER2 equivocal tumours. Methods and results: A total of 904 dual-probe HER2/ chromosome enumeration probe (CEP17) FISH tests on invasive breast carcinomas were studied. Eighty-five (9.4%) cases had a classification change with the updated guidelines; 66 (7.3%) went from HER2-negative to -equivocal, 15 cases (1.7%) were reclassified as HER2-positive and four cases from HER2-equivocal to - negative. A subset of primary breast cancers, reported initially as HER2-negative but -equivocal by 2013 guidelines, was identified. Traditional pathological factors of this subset were compared to HER2-negative and -positive control cases. The three HER2 groups demonstrated statistically significant differences with respect to prognostic factors, including tumour size, grade and nodal involvement. Conclusions: The updated HER2 testing guidelines will result in the reclassification of approximately 9.4% of primary breast cancers with uncertainty regarding the clinical impact of this reclassification in the majority of cases. Resource utilization will increase as a result of the recommendation for retesting. [ABSTRACT FROM AUTHOR]

The American Society of Clinical Oncology and the College of American Pathologists have issued joint updated comprehensive guideline recommendations for human epidermal growth factor receptor 2 ( HER2) testing in breast cancer. The update not only provides guidelines for the test performance parameters, with the aim of improving test accuracy, reproducibility, and precision, but also provides comprehensive recommendations on the post-analytical interpretation of the results, and requires improved communication among healthcare providers. The updated guidelines are targeted at testing laboratories, pathologists, oncologists, surgeons, and, indirectly, other healthcare providers. Although the guidelines contribute to the improved analytical validity and clinical utility of laboratory assays required for successful molecularly targeted therapy in the era of personalized medicine, the implications of such recommendations have to be acknowledged. Certain recommendations, particularly those related to repeating the test and pathological concordance, have lower levels of supportive evidence than existing key recommendations, and the associated workload implications will be challenging to support in most healthcare systems. In this commentary, we critically address the key updated recommendations and their impact on service provision and patient care. [ABSTRACT FROM AUTHOR]

The article presents a study that aims to validate whole slide imaging (WSI), a technology in which histopathological slides are optically scanned to produce digital images. The guidelines supporting the implementation of WSI for diagnostic purposes has been released by College of American Pathologists. Overall, WSI assessment of laryngeal premalignancies showed interobserver agreement comparable to that obtained with glass slides.