Pseudo-class part prototype networks for interpretable breast cancer classification.

Interpretability in machine learning has become increasingly important as machine learning is being used in more and more applications, including those with high-stakes consequences such as healthcare where Interpretability has been regarded as a key to the successful adoption of machine learning models. However, using confounding/irrelevant information in making predictions by deep learning models, even the interpretable ones, poses critical challenges to their clinical acceptance. That has recently drawn researchers' attention to issues beyond the mere interpretation of deep learning models. In this paper, we first investigate application of an inherently interpretable prototype-based architecture, known as ProtoPNet, for breast cancer classification in digital pathology and highlight its shortcomings in this application. Then, we propose a new method that uses more medically relevant information and makes more accurate and interpretable predictions. Our method leverages the clustering concept and implicitly increases the number of classes in the training dataset. The proposed method learns more relevant prototypes without any pixel-level annotated data. To have a more holistic assessment, in addition to classification accuracy, we define a new metric for assessing the degree of interpretability based on the comments of a group of skilled pathologists. Experimental results on the BreakHis dataset show that the proposed method effectively improves the classification accuracy and interpretability by respectively 8 % and 18 % . Therefore, the proposed method can be seen as a step toward implementing interpretable deep learning models for the detection of breast cancer using histopathology images.

Dataset for reporting of the invasive carcinoma of the breast: recommendations from the International Collaboration on Cancer Reporting (ICCR).

BACKGROUND AND OBJECTIVES: Current national or regional guidelines for the pathology reporting on invasive breast cancer differ in certain aspects, resulting in divergent reporting practice and a lack of comparability of data. Here we report on a new international dataset for the pathology reporting of resection specimens with invasive cancer of the breast. The dataset was produced under the auspices of the International Collaboration on Cancer Reporting (ICCR), a global alliance of major (inter-)national pathology and cancer organizations. METHODS AND RESULTS: The established ICCR process for dataset development was followed. An international expert panel consisting of breast pathologists, a surgeon, and an oncologist prepared a draft set of core and noncore data items based on a critical review and discussion of current evidence. Commentary was provided for each data item to explain the rationale for selecting it as a core or noncore element, its clinical relevance, and to highlight potential areas of disagreement or lack of evidence, in which case a consensus position was formulated. Following international public consultation, the document was finalized and ratified, and the dataset, which includes a synoptic reporting guide, was published on the ICCR website. CONCLUSIONS: This first international dataset for invasive cancer of the breast is intended to promote high-quality, standardized pathology reporting. Its widespread adoption will improve consistency of reporting, facilitate multidisciplinary communication, and enhance comparability of data, all of which will help to improve the management of invasive breast cancer patients.

The role of multidisciplinary team meeting histopathology review and its impact on revised reports: Analysis of a national quality improvement program.

OBJECTIVES: We conducted the first Irish national study assessing the value of multidisciplinary team meeting review in pathology practice and its impact on error detection before treatment. METHODS: Public and private pathology laboratories across Ireland capture their quality activities using standardized codes and submit their data to a centralized database (National Quality Assurance Intelligence System) overseen by the National Histopathology Quality Improvement (NHQI) program. A total of 1,437,746 histopathology and cytopathology cases submitted to the NHQI program over a 60-month period (January 2017 to December 2021) were included in this study. Cases were analyzed with respect to multidisciplinary team meeting peer review and the presence of a revised report (amended or corrected report), a surrogate marker for error detection before treatment. RESULTS: Across all cases assessed, 13.74% (197,587) underwent multidisciplinary team meeting discussion. Cases discussed at review had a statistically significantly higher rate of revised reports (1.25% [2470]) than cases not discussed at review (0.16% [1959]) (Pearson χ2, 6619.26; P < .0001; odds ratio, 8.00 [95% CI, 7.54-8.49]). Overall, multidisciplinary team meeting review made it 8 times more likely to detect an error before treatment. Cancer resections had the highest rate of review at 55.29% (46,806), reflecting the prioritization of oncology case discussion at review meetings. CONCLUSIONS: The multidisciplinary team meeting review process plays a valuable role in pathology error detection. A pathologist's participation in the review process comes with a clinically significant workload that needs to be recognized for future workforce planning. This study highlighted the positive role pathologists play in enhancing patient safety.

Principles of Analytic Validation of Immunohistochemical Assays: Guideline Update.

CONTEXT.­: In 2014, the College of American Pathologists developed an evidence-based guideline to address analytic validation of immunohistochemical assays. Fourteen recommendations were offered. Per the National Academy of Medicine standards for developing trustworthy guidelines, guidelines should be updated when new evidence suggests modifications. OBJECTIVE.­: To assess evidence published since the release of the original guideline and develop updated evidence-based recommendations. DESIGN.­: The College of American Pathologists convened an expert panel to perform a systematic review of the literature and update the original guideline recommendations using the Grading of Recommendations Assessment, Development and Evaluation approach. RESULTS.­: Two strong recommendations, 1 conditional recommendation, and 12 good practice statements are offered in this updated guideline. They address analytic validation or verification of predictive and nonpredictive assays, and recommended revalidation procedures following changes in assay conditions. CONCLUSIONS.­: While many of the original guideline statements remain similar, new recommendations address analytic validation of assays with distinct scoring systems, such as programmed death receptor-1 and analytic verification of US Food and Drug Administration approved/cleared assays; more specific guidance is offered for validating immunohistochemistry performed on cytology specimens.

Remote support of an external quality assessment program in 10 laboratories in Bhutan, Uganda, and Malawi: Pathologists Overseas experience between 2009 and 2017.

OBJECTIVES: This article describes Pathologists Overseas (PO) experience supporting external quality assessment (EQA) programs in 10 clinical laboratories across 3 countries between 2009 and 2017. METHODS: Laboratories were enrolled in the condensed chemical pathology EQA program provided by the Royal College of Pathologists of Australasia Quality Assurance Program. Participants were given an initial 2- to 4-day in-person training, followed by 1 year of active feedback on performance via emails or phone calls by a PO volunteer. RESULTS: There were 2 performance metrics: percentage of reported results as a measure of compliance and percentage of acceptable reported results as a measure of accuracy. Laboratories demonstrated high compliance with result reporting, with medians of 69.9%, 71.7%, and 81.3% before, during, and after feedback, respectively. Concomitant medians for the percentage of acceptable reported results were 41.2%, 57.3%, and 53.5%, respectively. Six laboratories had low performance in terms of accuracy at baseline (<60%). Active feedback improved the percentage of acceptable reported results for these lower-performing laboratories. CONCLUSIONS: External quality assessment programs can be successfully adopted long term by laboratories in low-resource settings. Active feedback requires significant time and effort but could be especially beneficial for laboratories with poor baseline performance.

Impact of COVID-19 pandemic on accredited programs and graduates who sat for the American Society for Clinical Pathology Board of Certification examination: graduates' perspective.

OBJECTIVE: Students in health profession education programs were severely affected by the COVID-19 pandemic at both didactic and clinical training levels. The purpose for this American Society for Clinical Pathology Board of Certification (ASCP BOC) study was to determine the impact of the COVID-19 pandemic on graduates. This study represents the perspectives of laboratory professional graduates who sat for the BOC certification in their respective professional disciplines. METHODS: A survey was sent to all graduates from the National Accrediting Agency for Clinical Laboratory Science (NAACLS), Accrediting Bureau of Health Education Schools (ABHES), and Commission on Accreditation of Allied Health Education Programs (CAAHEP) accredited programs who sat for the ASCP BOC examination in 2020 and 2021 to determine the impact of COVID-19 on laboratory professional graduates during the pandemic. RESULTS: A total of 180 graduates responded to the survey. The majority of graduates indicated that at least 1 didactic program component was shifted to an online system during the pandemic and that both clinical and nonclinical student laboratories were affected. Although program completion for most graduates was not delayed, one-third of graduates delayed taking their respective BOC exam. Due to the lack of knowledge application through practical hands-on laboratory experience in their educational programs, graduates reported feeling a lack of readiness with regards to preparing for the national certification examination as well as for employment. CONCLUSION: The study results showed the pandemic greatly impacted the education experience and readiness for the ASCP BOC examinations for graduates. Factors such as the absence of in-person learning and hands-on experience-both crucial aspects in laboratory training-and the ripple effects as a result of the pandemic, such as job loss, financial constraints, and health concerns, contributed to the decreased quality of education for graduates.

Swiss digital pathology recommendations: results from a Delphi process conducted by the Swiss Digital Pathology Consortium of the Swiss Society of Pathology.

Integration of digital pathology (DP) into clinical diagnostic workflows is increasingly receiving attention as new hardware and software become available. To facilitate the adoption of DP, the Swiss Digital Pathology Consortium (SDiPath) organized a Delphi process to produce a series of recommendations for DP integration within Swiss clinical environments. This process saw the creation of 4 working groups, focusing on the various components of a DP system (1) scanners, quality assurance and validation of scans, (2) integration of Whole Slide Image (WSI)-scanners and DP systems into the Pathology Laboratory Information System, (3) digital workflow-compliance with general quality guidelines, and (4) image analysis (IA)/artificial intelligence (AI), with topic experts for each recruited for discussion and statement generation. The work product of the Delphi process is 83 consensus statements presented here, forming the basis for "SDiPath Recommendations for Digital Pathology". They represent an up-to-date resource for national and international hospitals, researchers, device manufacturers, algorithm developers, and all supporting fields, with the intent of providing expectations and best practices to help ensure safe and efficient DP usage.

Accuracy of Pathology Reports on Neck Dissection Specimens: A Retrospective Case Series Study.

BACKGROUND: Accuracy of the number and location of pathological lymph nodes (LNs) in the pathology report of a neck dissection (ND) is of vital importance. OBJECTIVES: To quantify the error rate in reporting the location and number of pathologic LNs in ND specimens. METHODS: All patients who had undergone a formal ND that included at least neck level 1 for a clinical N1 disease between January 2010 and December 2017 were included in the study. The error rate of the pathology reports was determined by various means: comparing preoperative imaging and pathological report, reporting a disproportionate LN distribution between the different neck levels, and determining an erroneous location of the submandibular gland (SMG) in the pathology report. Since the SMG must be anatomically located in neck level 1, any mistake in reporting it was considered a categorical error. RESULTS: A total of 227 NDs met the inclusion criteria and were included in the study. The study included 128 patients who had undergone a dissection at levels 1-3, 68 at levels 1-4, and 31 at levels 1-5. The best Kappa score for correlation between preoperative imaging and final pathology was 0.50. There were nine cases (3.9%) of a disproportionate LN distribution in the various levels. The SMG was inaccurately reported outside neck level 1 in 17 cases (7.5%). CONCLUSIONS: At least 7.5% of ND reports were inaccurate in this investigation. The treating physician should be alert to red flags in the pathological report.

Appropriate use criteria for ancillary diagnostic testing in dermatopathology: New recommendations for 11 tests and 220 clinical scenarios from the American Society of Dermatopathology Appropriate Use Criteria Committee.

BACKGROUND: Appropriate use criteria (AUC) provide patient-centered physician guidance in test selection. An initial set of AUC was reported by the American Society of Dermatopathology (ASDP) in 2018. AUC reflect evidence collected at single timepoints and may be affected by evolving evidence and experience. The objective of this study was to update and expand AUC for selected tests. METHODS: RAND/UCLA (RAND Corporation [Santa Monica, CA]/University of California Los Angeles) methodology used includes the following: (a) literature review; (b) review of previously rated tests and previously employed clinical scenarios; (c) selection of previously rated tests for new ratings; (d) development of new clinical scenarios; (e) selection of additional tests; (f) three rating rounds with feedback and group discussion after rounds 1 and 2. RESULTS: For 220 clinical scenarios comprising lymphoproliferative (light chain clonality), melanocytic (comparative genomic hybridization, fluorescence in situ hybridization, reverse transcription polymerase chain reaction, telomerase reverse transcriptase promoter), vascular disorders (MYC), and inflammatory dermatoses (periodic acid-Schiff, Gömöri methenamine silver), consensus by panel raters was reached in 172 of 220 (78%) scenarios, with 103 of 148 (70%) rated "usually appropriate" or "rarely appropriate" and 45 of 148 (30%), "appropriateness uncertain." LIMITATIONS: The study design only measures appropriateness. Cost, availability, test comparison, and additional clinical considerations are not measured. The possibility that the findings of this study may be influenced by the inherent biases of the dermatopathologists involved in the study cannot be excluded. CONCLUSIONS: AUC are reported for selected diagnostic tests in clinical scenarios that occur in dermatopathology practice. Adhering to AUC may reduce inappropriate test utilization and improve healthcare delivery.

Deep learning-based transformation of H&E stained tissues into special stains.

Pathology is practiced by visual inspection of histochemically stained tissue slides. While the hematoxylin and eosin (H&E) stain is most commonly used, special stains can provide additional contrast to different tissue components. Here, we demonstrate the utility of supervised learning-based computational stain transformation from H&E to special stains (Masson's Trichrome, periodic acid-Schiff and Jones silver stain) using kidney needle core biopsy tissue sections. Based on the evaluation by three renal pathologists, followed by adjudication by a fourth pathologist, we show that the generation of virtual special stains from existing H&E images improves the diagnosis of several non-neoplastic kidney diseases, sampled from 58 unique subjects (P = 0.0095). A second study found that the quality of the computationally generated special stains was statistically equivalent to those which were histochemically stained. This stain-to-stain transformation framework can improve preliminary diagnoses when additional special stains are needed, also providing significant savings in time and cost.

Dataset for the reporting of carcinoma of the exocrine pancreas: recommendations from the International Collaboration on Cancer Reporting (ICCR).

AIMS: Current guidelines for pathology reporting on pancreatic cancer differ in certain aspects, resulting in divergent reporting practices and a lack of comparability of data. Here, we report on a new international dataset for pathology reporting on resection specimens with cancer of the exocrine pancreas (ductal adenocarcinoma and acinar cell carcinoma). The dataset was produced under the auspices of the International Collaboration on Cancer Reporting (ICCR), which is a global alliance of major (inter)national pathology and cancer organisations. METHODS AND RESULTS: According to the ICCR's rigorous process for dataset development, an international expert panel consisting of pancreatic pathologists, a pancreatic surgeon and an oncologist produced a set of core and non-core data items based on a critical review and discussion of current evidence. Commentary was provided for each data item to explain the rationale for selecting it as a core or non-core element and its clinical relevance, and to highlight potential areas of disagreement or lack of evidence, in which case a consensus position was formulated. Following international public consultation, the document was finalised and ratified, and the dataset, which includes a synoptic reporting guide, was published on the ICCR website. CONCLUSIONS: This first international dataset for cancer of the exocrine pancreas is intended to promote high-quality, standardised pathology reporting. Its widespread adoption will improve the consistency of reporting, facilitate multidisciplinary communication, and enhance the comparability of data, all of which will help to improve the management of pancreatic cancer patients.

Pathology Residency Curriculum: Time for a Change?

The current Anatomical and Clinical Pathology residency curriculum, as outlined by the American Board of Pathology (ABP), emphasizes resident exposure to a wide variety of subjects without in-depth training. This has led to a large number of residents pursuing fellowship training. With the demand for further sub-specialization, there is a necessity for the establishment of an updated curriculum that not only encompasses the basic knowledge of pathology but is also focused on training residents in their desired subspecialty.We herein propose a new comprehensive AP/CP residency syllabus. The new curriculum will be divided into two major categories: preliminary and subspecialty training. The curriculum will require residents to undergo basic pathology training within the first two preliminary years, followed by two subspecialty years. In their subspecialty years, each resident will be required to either pick two subjects as majors, each having a duration of one year, or one subject as a major and two subjects as minors, in which case the major will have a one-year duration and the minors will each be six months in length. The proposed curriculum meets the current guidelines of the ABP, reduces the burden of residents to complete multiple fellowships, and allows residents earlier entrance into the workforce.

Evolution of anatomic pathology workload from 2011 to 2019 assessed in a regional hospital laboratory via 574,093 pathology reports.

OBJECTIVE: Quantify changes in workload in relation to the anatomic pathologist workforce. METHODS: In house pathology reports for cytology and surgical specimens from a regional hospital laboratory over a nine- year period (2011-2019) were analyzed, using custom computer code. Report length for the diagnosis+microscopic+synoptic report, number of blocks, billing classification (L86x codes), billings, national workload model (L4E 2018), regional workload model (W2Q), case count, and pathologist workforce in full-time equivalents (FTEs) were quantified. Randomly selected cases (n = 1,100) were audited to assess accuracy. RESULTS: The study period had 574,093 pathology reports that could be analyzed. The coding accuracy was estimated at 95%. From 2011 to 2019: cases/year decreased 6% (66,056 to 61,962), blocks/year increased 20% (236,197 to 283,751), L4E workload units increased 23% (165,276 to 203,894), W2Q workload units increased 21% (149,841 to 181,321), report lines increased 19% (606,862 to 723,175), workforce increased 1% (30.42 to 30.77 FTEs), billings increased 13% ($6,766,927 to $7,677,109). W2Q in relation to L4E underweights work in practices with large specimens by up to a factor of 2x. CONCLUSIONS: Work by L4E for large specimens is underrated by W2Q. Reporting requirements and pathology work-up have increased workload per pathology case. Work overall has increased significantly without a commensurate workforce increase. The significant practice changes in the pathology work environment should prompt local investment in the anatomic pathology workforce.

Addressing the Diagnostic Miscommunication in Pathology.

OBJECTIVES: The pathology report serves as a crucial communication tool among a number of stakeholders. It can sometimes be challenging to understand. A communication barrier exists among pathologists, other clinicians, and patients when interpreting the pathology report, leaving both clinicians and patients less empowered when making treatment decisions. Miscommunication can lead to delays in treatment or other costly medical interventions. METHODS: In this review, we highlight miscommunication in pathology reporting and provide potential solutions to improve communication. RESULTS: Up to one-third of clinicians do not always understand pathology reports. Several causes of report misinterpretation include the use of pathology-specific jargon, different versions of staging or grading systems, and expressions indicative of uncertainty in the pathologist's report. Active communication has proven to be crucial between the clinician and the pathologist to clarify different aspects of the pathology report. Direct communication between pathologists and patients is evolving, with promising success in proof-of-principle studies. Special attention needs to be paid to avoiding inaccuracy while trying to simplify the pathology report. CONCLUSIONS: There is a need for active and adequate communication among pathologists, other clinicians, and patients. Clarity and consistency in reporting, quantifying the level of confidence in diagnosis, and avoiding misnomers are key steps toward improving communications.

Improving tumor budding reporting in colorectal cancer: a Delphi consensus study.

Tumor budding is a long-established independent adverse prognostic marker in colorectal cancer, yet methods for its assessment have varied widely. In an effort to standardize its reporting, a group of experts met in Bern, Switzerland, in 2016 to reach consensus on a single, international, evidence-based method for tumor budding assessment and reporting (International Tumor Budding Consensus Conference [ITBCC]). Tumor budding assessment using the ITBCC criteria has been validated in large cohorts of cancer patients and incorporated into several international colorectal cancer pathology and clinical guidelines. With the wider reporting of tumor budding, new issues have emerged that require further clarification. To better inform researchers and health-care professionals on these issues, an international group of experts in gastrointestinal pathology participated in a modified Delphi process to generate consensus and highlight areas requiring further research. This effort serves to re-affirm the importance of tumor budding in colorectal cancer and support its continued use in routine clinical practice.

[Histopathologic grading of breast cancer; large variation with major consequences?] / Histopathologische gradering van het mammacarcinoom.

The pathologist's assessment of tumor tissue plays a critical role in therapeutic decision-making in early-stage invasive breast cancer. In daily practice, however, there appears to be considerable variation in grading between the different Dutch pathology laboratories and between individual pathologists within the same laboratory. This underlines the need to standardize grading by pathologists as much as possible in order to minimize the risk of a worse outcome for patients due to under-treatment and of unnecessary toxicity from over-treatment. Therefore, two initiatives were launched, i.e. laboratory-specific feedback reports and an e-learning module in which pathologists were trained in grading of invasive breast cancer. While these initiatives have yielded encouraging results, the overall variation in grading remains significant. Awareness of this variation, and of the inherent difficulties of subjective grading, among the various clinicians involved in breast cancer management, is therefore of utmost importance to improve clinical decision-making for patients.

Actualización de la recomendación para la determinación de biomarcadores en el carcinoma colorrectal. Consenso Nacional de la Sociedad Española de Oncología Médica y de la Sociedad Española de Anatomía Patológica / Update of the recommendations for the determination of biomarkers in colorectal carcinoma. National Consensus of the Spanish Society of Medical Oncology and the Spanish Society of Pathology

En esta actualización del consenso de la Sociedad Española de Oncología Médica (SEOM) y la Sociedad Española de Anatomía Patológica (SEAP) se revisan los avances producidos en el análisis de biomarcadores en cáncer colorrectal (CCR) avanzado, así como en los marcadores de susceptibilidad del CCR hereditario y los biomarcadores moleculares del CCR localizado. También se evalúan la información publicada recientemente sobre la determinación imprescindible de las mutaciones de KRAS, NRAS y BRAF y la conveniencia de determinar la amplificación del receptor del factor de crecimiento epidérmico 2 (HER2), la expresión de las proteínas de la vía reparadora de ADN y el estudio de las fusiones de NTRK. Desde el punto de vista anatomopatológico, se revisa la importancia de analizar la presencia de células tumorales aisladas o en pequeños grupos de menos de 5 en el frente invasivo tumoral del CCR y su valor pronóstico en el CCR. También se revisa la incorporación de tecnologías pangenómicas, como la secuenciación de nueva generación (next-generation sequencing [NGS]) y la biopsia líquida, en el manejo clínico del paciente con CCR. Todos estos aspectos se desarrollan en la presente guía que, como la anterior, permanecerá abierta a cualquier revisión necesaria en el futuro

This update of the consensus of the Spanish Society of Medical Oncology (Sociedad Española de Oncología Médica - SEOM) and the Spanish Society of Pathology (Sociedad Española de Anatomía Patológica - SEAP), reviews the advances in the analysis of biomarkers in advanced colorectal cancer (CRC) as well as susceptibility markers of hereditary CRC and molecular biomarkers of localized CRC. Recently published information on the essential determination of KRAS, NRAS and BRAF mutations and the possible benefits of determining the amplification of human epidermal growth factor receptor 2 (HER2), the expression of proteins in the DNA repair pathway and the study of NTRK fusions are also evaluated. From a pathological point of view, the importance of analysing the tumour budding and poorly differentiated clusters and its prognostic value in CRC is reviewed, as well as the impact of molecular lymph node analysis on lymph node staging in CRC. The incorporation of pan-genomic technologies, such as next-generation sequencing (NGS) and liquid biopsy in the clinical management of patients with CRC is also outlined. All these aspects are developed in this guide which, like the previous one, will be revised when necessary in the future

An International Consensus to Standardize Integration of Histopathology in Ulcerative Colitis Clinical Trials.

BACKGROUND & AIMS: Histopathology is an emerging treatment target in ulcerative colitis (UC) clinical trials. Our aim was to provide guidance on standardizing biopsy collection protocols, identifying optimal evaluative indices, and defining thresholds for histologic response and remission after treatment. METHODS: An international, interdisciplinary expert panel of 19 gastroenterologists and gastrointestinal pathologists was assembled. A modified RAND/University of California, Los Angeles appropriateness methodology was used to address relevant issues. A total of 138 statements were derived from a systematic review of the literature and expert opinion. Each statement was anonymously rated as appropriate, uncertain, or inappropriate using a 9-point scale. Survey results were reviewed and discussed before a second round of voting. RESULTS: Histologic measurements collected using a uniform biopsy strategy are important for assessing disease activity and determining therapeutic efficacy in UC clinical trials. Multiple biopsy strategies were deemed acceptable, including segmental biopsies collected according to the endoscopic appearance. Biopsies should be scored for architectural change, lamina propria chronic inflammation, basal plasmacytosis, lamina propria and epithelial neutrophils, epithelial damage, and erosions/ulcerations. The Geboes score, Robarts Histopathology Index, and Nancy Index were considered appropriate for assessing histologic activity; use of the modified Riley score and Harpaz Index were uncertain. Histologic activity at baseline should be required for enrollment, recognizing this carries operational implications. Achievement of histologic improvement or remission was considered an appropriate and realistic therapeutic target. Current histologic indices require validation for pediatric populations. CONCLUSIONS: These recommendations provide a framework for standardized implementation of histopathology in UC trials. Additional work is required to address operational considerations and areas of uncertainty.

Recommendations for cellular and molecular pathology input into clinical trials: a systematic review and meta-aggregation.

The SPIRIT (Standard Protocol Items: Recommendations for Interventional Trials) 2013 Statement was developed to provide guidance for inclusion of key methodological components in clinical trial protocols. However, these standards do not include guidance specific to pathology input in clinical trials. This systematic review aims to synthesise existing recommendations specific to pathology practice in clinical trials for implementation in trial protocol design. Articles were identified from database searches and deemed eligible for inclusion if they contained: (1) guidance and/or a checklist, which was (2) pathology-related, with (3) content relevant to clinical trial protocols or could influence a clinical trial protocol design from a pathology perspective and (4) were published in 1996 or later. The quality of individual papers was assessed using the AGREE-GRS (Appraisal of Guidelines for REsearch & Evaluation - Global Rating Scale) tool, and the confidence in cumulative evidence was evaluated using the GRADE-CERQual (Grading of Recommendations Assessment, Development and Evaluation-Confidence in Evidence from Reviews of Qualitative research) approach. Extracted recommendations were synthesised using the best fit framework method, which includes thematic analysis followed by a meta-aggregative approach to synthesis within the framework. Of the 10 184 records screened and 199 full-text articles reviewed, only 40 guidance resources met the eligibility criteria for inclusion. Recommendations extracted from 22 guidance documents were generalisable enough for data synthesis. Seven recommendation statements were synthesised as follows: (1) multidisciplinary collaboration in trial design with early involvement of pathologists, particularly with respect to the use of biospecimens and associated biomarker/analytical assays and in the evaluation of pathology-related parameters; (2) funding and training for personnel undertaking trial work; (3) selection of an accredited laboratory with suitable facilities to undertake scheduled work; (4) quality assurance of pathology-related parameters; (5) transparent reporting of pathology-related parameters; (6) policies regarding informatics and tracking biospecimens across trial sites; and (7) informed consent for specimen collection and retention for future research.