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While women pathologists have made up over one-third of pathologists in the Australian workforce for over 15 years and at least 50% since 2019, they are under-represented in senior leadership roles, scientific publications, grant recipients, editorial boards, key presentations, and professional awards. This is not unique to pathology and is seen in the broader medical and academic community. Barriers to gender equity and equality in pathology, medicine and academia include gender stereotypes, gender-based discrimination, structural and organisational barriers as well as broader social and cultural barriers. A diverse leadership reflective of the whole professional body and the broader community is important for optimal health outcomes. It is the responsibility and moral duty of individuals and organisations to address any gender disparities, inequities, and inequalities by monitoring, identifying, and acting on gender biases and systemic barriers that hinder appropriate levels of representation by women., (Crown Copyright © 2023. Published by Elsevier B.V. All rights reserved.)

Diagnosis and assessment of patients with prostate cancer is dependent on accurate interpretation and grading of histopathology. However, morphology does not necessarily reflect the complex biological changes occurring in prostate cancer disease progression, and current biomarkers have demonstrated limited clinical utility in patient assessment. This study aimed to develop biomarkers that accurately define prostate cancer biology by distinguishing specific pathological features that enable reliable interpretation of pathology for accurate Gleason grading of patients. Online gene expression databases were interrogated and a pathogenic pathway for prostate cancer was identified. The protein expression of key genes in the pathway, including adaptor protein containing a pleckstrin homology (PH) domain, phosphotyrosine-binding (PTB) domain, and leucine zipper motif 1 (Appl1), Sortilin and Syndecan-1, was examined by immunohistochemistry (IHC) in a pilot study of 29 patients with prostate cancer, using monoclonal antibodies designed against unique epitopes. Appl1, Sortilin, and Syndecan-1 expression was first assessed in a tissue microarray cohort of 112 patient samples, demonstrating that the monoclonal antibodies clearly illustrate gland morphologies. To determine the impact of a novel IHC-assisted interpretation (the utility of Appl1, Sortilin, and Syndecan-1 labelling as a panel) of Gleason grading, versus standard haematoxylin and eosin (H&E) Gleason grade assignment, a radical prostatectomy sample cohort comprising 114 patients was assessed. In comparison to H&E, the utility of the biomarker panel reduced subjectivity in interpretation of prostate cancer tissue morphology and improved the reliability of pathology assessment, resulting in Gleason grade redistribution for 41% of patient samples. Importantly, for equivocal IHC-assisted labelling and H&E staining results, the cancer morphology interpretation could be more accurately applied upon re-review of the H&E tissue sections. This study addresses a key issue in the field of prostate cancer pathology by presenting a novel combination of three biomarkers and has the potential to transform clinical pathology practice by standardising the interpretation of the tissue morphology., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Testing for BRAF mutations in metastatic melanoma is pivotal to identifying patients suitable for targeted therapy and influences treatment decisions regarding single agent versus combination immunotherapy. Knowledge of BRAF V600E immunohistochemistry (IHC) results can streamline decisions during initial oncology consultations, prior to DNA-based test results. In the absence of formal guidelines that require pathologist initiated ('reflex') BRAF mutation testing, our institution developed a local protocol to perform BRAF V600E IHC on specimens from all stage III/IV melanoma patients when the status is otherwise unknown. This study was designed to evaluate the application of this protocol in a tertiary referral pathology department. A total of 408 stage III/IV melanoma patients had tissue specimens accessioned between 1 January and 31 March in three consecutive years (from 2019 to 2021), reported by 32 individual pathologists. The BRAF mutation status was established by pathologists in 87% (352/408) of cases. When a prior BRAF mutation status was previously known, as confirmed in linked electronic records (202/408), this status had been communicated by the clinician on the pathology request form in 1% of cases (3/202). Pathologists performed BRAF V600E IHC in 153 cases (74% of cases where the status was unknown, 153/206) and testing was duplicated in 5% of cases (20/408). Reflex BRAF IHC testing was omitted in 26% of cases (53/206), often on specimens with small volume disease (cytology specimens or sentinel node biopsies) despite adequate tissue for testing. Incorporating BRAF IHC testing within routine diagnostic protocols of stage III/IV melanoma was both feasible and successful in most cases. Communication of a patient's BRAF mutation status via the pathology request form will likely improve implementation of pathologist initiated BRAF mutation testing and may result in a reduction of duplicate tests. To improve pathologist reflex testing rates, we advocate for the use of an algorithmic approach to pathologist initiated BRAF mutation testing utilising both IHC and DNA-based methodologies for stage III/IV melanoma patients., (Copyright © 2022 Royal College of Pathologists of Australasia. Published by Elsevier B.V. All rights reserved.)

A small subset of lung adenocarcinomas harbour ROS1 gene arrangements and are amenable to tyrosine kinase inhibitor therapy. Current practice in Australia involves screening for ROS1 rearrangements in adenocarcinomas using ROS1 immunohistochemistry (IHC) followed by confirmatory molecular testing such as fluorescence in situ hybridisation (FISH), if other known genetic driver alterations are absent. The best threshold to determine ROS1 IHC positivity is not well defined, however, and this study aims to determine the optimal threshold for ROS1 IHC screening to identify ROS1-rearranged lung adenocarcinomas. A total of 177 lung adenocarcinomas tested for a ROS1 rearrangement by FISH at our institution between 2017 and 2020 due to presence of ROS1 IHC staining were included in the study. ROS1 IHC staining was assessed by scoring the staining intensity (0, 1, 2, or 3+) and multiplying by the percentage of positive cells to generate an H-score. IHC H-scores were compared with FISH. Of 177 cases, 32 (18%) were ROS1 FISH-positive and 145 (82%) were negative. FISH-positive cases had a median H-score of 300 (range 200-300; mean 290.3) and negative cases had a median H-score of 40 (range 0-300; mean 63). All FISH-positive cases showed strong and diffuse IHC positivity. Using a threshold H-score of 200, the sensitivity of identifying ROS1 rearrangements was 100% and the specificity was 95% amongst cases referred with ROS1 IHC positivity. Adenocarcinomas with a FISH-confirmed ROS1 rearrangement demonstrate diffuse, strong (2-3+) IHC staining. Cases with weak, patchy ROS1 IHC staining are not associated with ROS1 rearrangements and in these cases FISH testing is of little to no utility., (Copyright © 2021 Royal College of Pathologists of Australasia. All rights reserved.)

Targeted therapy (BRAF inhibitor plus MEK inhibitor) is now among the possible treatment options for patients with BRAF mutation-positive stage III or stage IV melanoma. This makes prompt BRAF mutation testing an important step in the management of patients diagnosed with stage III or IV melanoma; one that can help better ensure that the optimal choice of systemic treatment is initiated with minimal delay. This article offers guidance about when and how BRAF mutation testing should be conducted when patients are diagnosed with melanoma in Australia. Notably, it recommends that pathologists reflexively order BRAF mutation testing whenever a patient is found to have American Joint Committee on Cancer (AJCC)/Union for International Cancer Control (UICC) stage III or IV melanoma (i.e., any metastatic spread beyond the primary tumour) and that patient's BRAF mutation status is hitherto unknown, even if BRAF mutation testing has not been specifically requested by the treating clinician (in Australia, Medicare-subsidised BRAF V600 mutation testing does not need to be requested by the treating clinician). When performed in centres with appropriate expertise and experience, immunohistochemistry (IHC) using the anti-BRAF V600E monoclonal antibody (VE1) can be a highly sensitive and specific means of detecting BRAF V600E mutations, and may be used as a rapid and relatively inexpensive initial screening test. However, VE1 immunostaining can be technically challenging and difficult to interpret, particularly in heavily pigmented tumours; melanomas with weak, moderate or focal BRAF V600E immunostaining should be regarded as equivocal. It must also be remembered that other activating BRAF V600 mutations (including BRAF V600K ), which account for ∼10-20% of BRAF V600 mutations, are not detected with currently available IHC antibodies. For these reasons, if available and practicable, we recommend that DNA-based BRAF mutation testing always be performed, regardless of whether IHC-based testing is also conducted. Advice about tissue/specimen selection for BRAF mutation testing of patients diagnosed with stage III or IV melanoma is also offered in this article; and potential pitfalls when interpreting BRAF mutation tests are highlighted., (Copyright © 2021 Royal College of Pathologists of Australasia. Published by Elsevier B.V. All rights reserved.)

Immunotherapy with checkpoint inhibitors is well established as an effective treatment for non-small cell lung cancer and melanoma. The list of approved indications for treatment with PD-1/PD-L1 checkpoint inhibitors is growing rapidly as clinical trials continue to show their efficacy in patients with a wide range of solid tumours. Clinical trials have used a variety of PD-L1 immunohistochemical assays to evaluate PD-L1 expression on tumour cells, immune cells or both as a potential biomarker to predict response to immunotherapy. Requests to pathologists for PD-L1 testing to guide choice of therapy are rapidly becoming commonplace. Thus, pathologists need to be aware of the different PD-L1 assays, methods of evaluation in different tumour types and the impact of the results on therapeutic decisions. This review discusses the key practical issues relating to the implementation of PD-L1 testing for solid tumours in a pathology laboratory, including evidence for PD-L1 testing, different assay types, the potential interchangeability of PD-L1 antibody clones and staining platforms, scoring criteria for PD-L1, validation, quality assurance, and pitfalls in PD-L1 assessment. This review also explores PD-L1 IHC in solid tumours including non-small cell lung carcinoma, head and neck carcinoma, triple negative breast carcinoma, melanoma, renal cell carcinoma, urothelial carcinoma, gastric and gastroesophageal carcinoma, colorectal carcinoma, hepatocellular carcinoma, and endometrial carcinoma. The review aims to provide pathologists with a practical guide to the implementation and interpretation of PD-L1 testing by immunohistochemistry., (Copyright © 2020 Royal College of Pathologists of Australasia. Published by Elsevier B.V. All rights reserved.)

In the past, the only critical point of distinction in the pathological diagnosis of lung cancer was between small cell and non-small cell lung cancer (NSCLC). The emergence of new targeted therapies and clinical trials demonstrating differing efficacy and toxicity of treatments according to specific histological subtypes of NSCLC, has resulted in an increasing need for improvements in pathological diagnosis. Accurate distinction between adenocarcinoma and squamous cell carcinoma is now critical as histological subtyping has the potential to influence clinical decision making and impact on patient outcome. While morphological criteria remain the most important feature to distinguish NSCLC subtypes, use of mucin and immunohistochemical stains (TTF-1, p63 and CK5/6) can be of assistance in difficult small biopsy cases. With the emergence of selective kinase inhibitors targeting epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK), there is a corresponding need to identify the subset of NSCLCs harbouring specific genetic mutations associated with sensitivity to these agents, almost all of which are found in adenocarcinomas. In this review, the importance of accurately subtyping NSCLC is discussed, along with a suggested approach for distinguishing histological subtypes in small biopsy specimens. The significance of EGFR and ALK mutations in NSCLC and the impact of these genotypes on pathology and clinical practice are also reviewed.