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Context.--The World Health Organization Classification of Tumours: Female Genital Tract Tumors, 5th edition, published in September 2020, comes 6 years after the 4th edition, and reflects the monumental leaps made in knowledge about the biology of gynecological tumors. Major changes include revised criteria for the assignment of the site of origin of ovarian and fallopian tube tumors, a revision in the classification of squamous and glandular lesions of the lower genital tract based on human papillomavirus association, and an entire chapter devoted to genetic tumor syndromes. This article highlights the changes in the 5th edition relative to the 4th edition, with a focus on areas of value to routine clinical practice. Objective.--To provide a comprehensive update on the World Health Organization classification of gynecological tumors, highlighting in particular updated diagnostic criteria and terminology. Data Sources.--The 4th and 5th editions of the World Health Organization Classification of Tumours. Conclusions.--The World Health Organization has made several changes in the 5th edition of the update on female genital tumors. Awareness of the changes is needed for pathologists' translation into contemporary practice. doi: 10.5858/arpa.2022-0166-RA, This review article summarizes key changes in the 5th edition of the World Health Organization (WHO) 'blue book' on tumors of the female genital tract (FGT) released in 2020. (1) [...]

* Context.--Despite widely prevalent burnout and attendant disengagement in medicine, the specific patterns and drivers within pathology and laboratory medicine are uncommonly studied. Objective.--To assess the prevalence and drivers of burnout among pathology and laboratory medicine professionals, retrospectively, prior to the COVID-19 pandemic. Design.--This was a cross-sectional, mixed-methods study engaging pathology and laboratory medicine professionals as subjects. Results.--Of 2363 respondents, 438 identified as pathologists, 111 as pathology assistants, and 911 as pathology and laboratory professionals. The burnout rate was 58.4% (1380 of 2363) across all respondents in pathology and laboratory medicine. Burnout varied by job role (P < .01) and was highest among pathology and laboratory professionals. Disparities in burnout rate were observed by race. Fifty-six percent (1323 of 2363) of respondents felt that they had at least 1 symptom of burnout and were advancing toward a breaking point. Underlying factors ranked highly among all groups included control over workload and loss of meaning in work. Conclusions.--Data provided from this cohort may help departments create successful strategies to reduce disengagement and burnout in the laboratory, especially during periods of increased stress as experienced during the COVID-19 pandemic. Further, these data may serve as a baseline comparison for future studies. (Arch Pathol Lab Med. 2023;147:808-816; doi: 10.5858/ arpa.2022-0073-OA), Burnout is a disease of civilization. It is a mental health syndrome defined by feelings of exhaustion, cynicism, and inefficacy due to a negative relationship with work and chronic job [...]

Recent insights supporting the fallopian tube epithelium (FTE) and serous tubal intraepithelial carcinomas (STIC) as the tissue of origin and the precursor lesion, respectively, for the majority of high-grade serous ovarian carcinomas (HGSOC) provide the necessary context to study the mechanisms that drive the development and progression of HGSOC. Here, we investigate the role of the E3 ubiquitin ligase RNF20 and histone H2B monoubiquitylation (H2Bub1) in serous tumorigenesis and report that heterozygous loss of RNF20 defines the majority of HGSOC tumors. At the protein level, H2Bub1 was lost or downregulated in a large proportion of STIC and invasive HGSOC tumors, implicating RNF20/H2Bub1 loss as an early event in the development of serous ovarian carcinoma. Knockdown of RNF20, with concomitant loss of H2Bub1, was sufficient to enhance cell migration and clonogenic growth of FTE cells. To investigate the mechanisms underlying these effects, we performed ATAC-seq and RNA-seq in RNF20 knockdown FTE cell lines. Loss of RNF20 and H2Bub1 was associated with a more open chromatin conformation, leading to upregulation of immune signaling pathways, including IL6. IL6 was one of the key cytokines significantly upregulated in RNF20- and H2Bub1-depleted FTE cells and imparted upon these cells an enhanced migratory phenotype. These studies provide mechanistic insight into the observed oncogenic phenotypes triggered by the early loss of H2Bub1. SIGNIFICANCE: Loss of RNF20 and H2Bub1 contributes to transformation of the fallopian tube epithelium and plays a role in the initiation and progression of high-grade serous ovarian cancer.Graphical Abstract: http://cancerres.aacrjournals.org/content/canres/79/4/760/F1.large.jpg.

Context.--: Urinary and Male Genital Tumours is the 8th volume of the World Health Organization Classification of Tumours series, 5th edition. Released in hard copy in September 2022, it presents an update to the classification of male genital and urinary tumors in the molecular age. Building upon previous volumes in this series, significant effort has been made to harmonize terminology across organ systems for biologically similar tumors (eg, neuroendocrine tumors). Genomic terminology has been standardized and genetic syndromes covered more comprehensively. This review presents a concise summary of this volume, highlighting new entities, notable modifications relative to the 4th edition, and elements of relevance to routine clinical practice. Objective.--: To provide a comprehensive update on the World Health Organization classification of urinary and male genital tumors, highlighting updated diagnostic criteria and terminology. Data sources.--: The 4th and 5th editions of the World Health Organization Classification of Tumours: Urinary and Male Genital Tumours. Conclusions.--: The World Health Organization has made several changes in the 5th edition of the update on urinary and male genital tumors that pathologists need to be aware of for up-to-date clinical practice. [ABSTRACT FROM AUTHOR]

To the Editor.--This note is a plea, a call to action to all of us in this specialty, but especially to the leadership. We need to discuss depression and suicide [...]

Context.--The concept of critical diagnoses in anatomic pathology is relatively recent and rigorous study of the issue is quite limited. The College of American Pathologists and Association of Directors of Anatomic and Surgical Pathology issued a consensus statement in 2012. There has been no multi-institutional study of communication policies since then. Objective.--To survey the policies of anatomic pathology laboratories regarding communication of critical values. Design.--A survey of the Association of Directors of Anatomic and Surgical Pathology membership was performed using a 14-question electronic survey tool. Results.--Responses were received from 38 institutions. Thirty-five of 38 (92%) had a policy on anatomic pathology critical values. Twenty-five of 38 (66%) respondents had read the College of American Pathologists/Association of Directors of Anatomic and Surgical Pathology consensus statement. Twelve of 38 (32%) institutions divided critical values into 2 categories, of which 9 used the College of American Pathologists/ Association of Directors of Anatomic and Surgical Pathology terminology; 24 used only a single term, of which 11 used critical value. There was substantial variation in the diagnoses that were considered critical. A direct phone call to the responsible provider was uniformly considered an acceptable means of communication; all other methods had mixed or low support. The most common time frame was same day; many laboratories did not specify a timeframe. Most laboratories document date, time, and person to whom the result was communicated in the final report or an addendum report. Eighteen of 38 (47%) laboratories report an auditing mechanism for communication. Conclusions.--Policies for communication of critical/ urgent/significant, unexpected results in anatomic pathology are the norm. However, there remains significant variation between institutions in the details of these policies. (Arch Pathol Lab Med. 2020;144:1067-1074; doi: 10.5858/arpa.2019-0436-OA), Communication of critical values to providers has long been an established practice in clinical pathology. More than a decade ago, questions began to be raised in the literature about the [...]

ObjectiveTo credential Stathmin 1 (STMN1) and p16(INK4A) (p16) as adjunct markers for the diagnosis of serous tubal intraepithelial carcinoma (STIC), and to compare STMN1 and p16 expression in p53-positive and p53-negative STIC and invasive high-grade serous carcinoma (HGSC).MethodsImmunohistochemistry (IHC) was used to examine STMN1 and p16 expression in fallopian tube specimens (n=31) containing p53-positive and p53-negative STICs, invasive HGSCs, and morphologically normal FTE (fallopian tube epithelium). STMN1 and p16 expression was scored semiquantitatively by four individuals. The semiquantitative scores were dichotomized, and reported as positive or negative. Pooled siRNA was used to knockdown p53 in a panel of cell lines derived from immortalized FTE and HGSC.ResultsSTMN1 and p16 were expressed in the majority of p53-positive and p53-negative STICs and concomitant invasive HGSCs, but only scattered positive cells were present in morphologically normal FTE. Both proteins were expressed consistently across multiple STICs from the same patient and in concomitant invasive HGSC. Knockdown of p53 in immortalized FTE cells and in four HGSC-derived cell lines expressing different missense p53 mutations did not affect STMN1 protein levels.ConclusionsThis study demonstrates that STMN1 and p16 are sensitive and specific adjunct biomarkers that, when used with p53 and Ki-67, improve the diagnostic accuracy of STIC. The addition of STMN1 and p16 helps to compensate for practical limitations of p53 and Ki-67 that complicate the diagnosis in up to one third of STICs.

ObjectiveTo explore the association of a functional germline variant in the 3'-UTR of KRAS with endometrial cancer risk, as well as the association of microRNA (miRNA) signatures and the KRAS-variant with clinical characteristics and survival outcomes in two prospective RTOG endometrial cancer trials.Methods/materialsThe association of the KRAS-variant with endometrial cancer risk was evaluated by case-control analysis of 467 women with type 1 or 2 endometrial cancer and 582 age-matched controls. miRNA and DNA were isolated for expression profiling and genotyping from tumor specimens of 46 women with type 1 endometrial cancer enrolled in RTOG trials 9708 and 9905. miRNA expression levels and KRAS-variant genotype were correlated with patient and tumor characteristics, and survival outcomes were evaluated by variant allele type.ResultsThe KRAS-variant was not significantly associated with overall endometrial cancer risk (14% controls and 17% type 1 cancers), although was enriched in type 2 endometrial cancers (24%, p = 0.2). In the combined analysis of RTOG 9708/9905, miRNA expression differed by age, presence of lymphovascular invasion and KRAS-variant status. Overall survival rates at 3 years for patients with the variant and wild-type alleles were 100% and 77% (HR 0.3, p = 0.24), respectively, favoring the variant.ConclusionsThe KRAS-variant may be a genetic marker of risk for type 2 endometrial cancers. In addition, tumor miRNA expression appears to be associated with patient age, lymphovascular invasion and the KRAS-variant, supporting the hypothesis that altered tumor biology can be measured by miRNA expression, and that the KRAS-variant likely impacts endometrial tumor biology.