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* Context.--To provide high-quality, safe training during the COVID-19 pandemic, our anatomic pathology fellowship program implemented a hybrid virtual/in-person training model with supplemental digital material. Objective.--To evaluate the impact of this model. Design.--We examined Accreditation Council for Graduate Medical Education survey results and board pass rates for fellows before the pandemic (group 1); during the pandemic peak (group 2); and early and late after the pandemic peak (groups 3 and 4). Additionally, we distributed an online survey, including questions related to performance as attending physicians and fellowship experience, to recent graduates. Results.--Information loss during handover, supervision and teaching by faculty, and having at least 4 free days a month exhibited the greatest score declines between group 1 and groups 2, 3, and 4 on the Accreditation Council for Graduate Medical Education surveys. No differences were seen in board passing rates between groups. The groups did not differ in responses regarding preparation for role as attending, confidence in role as attending, or overall impression of the fellowship program. The pandemic-affected groups responded more positively on the perceived utility of supplemental digital material, impact of digital pathology on quality of education, and impact of supplemental digital material on familiarity with digital pathology. The difference was particularly large between group 1 and combined groups 3 and 4. Conclusions.--Despite the limitations noted, the hybrid training model was effective and successfully prepared fellows for their role as attending physicians. Similar studies can be informative for the implementation of similar programs or for the meaningful integration of digital pathology into training curricula., The COVID-19 pandemic continues to have profound impacts on society. As COVID-19 cases rose in the early stage of the pandemic in 2020, residency and fellowship programs that relied on [...]

Objectives We studied the diagnostic accuracy and discordance of upper tract urothelial carcinoma (UTUC) by comparing biopsy and urinary cytology with matched nephroureterectomy specimens. Methods Sixty-nine patients with UTUC without neoadjuvant treatment were retrospectively identified who had matched biopsy and nephroureterectomy specimens. Twenty patients had concurrent upper tract cytology. H&E and cytology slides were re-reviewed. Statistical analysis was performed. Results Patients included 48 men and 21 women with a mean age of 69 years. A concordant grade between biopsy and surgical specimen was present in 49 (71%) patients. The mean size of biopsy specimens in the discordant group was significantly smaller than that in the concordant group. Invasion was evaluated in 48 biopsy cases that had adequate subepithelial tissue, and 33 of them were diagnosed with concordant invasion status. Mean tumor size in both tumor grade and invasion discordant groups was significantly larger than that in the concordant group. High-grade urothelial carcinoma was detected in 84% of cases using urinary cytology. Conclusions Our study demonstrates the diagnostic challenges of UTUC on small biopsy specimens. Biopsy specimen size and tumor size are significantly associated with the diagnostic discordance. Upper tract cytology showed high diagnostic accuracy and should be complementary to the biopsy. [ABSTRACT FROM AUTHOR]

* Context.--Urothelial proliferation of unknown malignant potential (UPUMP) is a 2016 World Health Organization classifier that encompasses prior categories of flat and papillary urothelial hyperplasia. In addition, UPUMP occurs in settings of both de novo and prior bladder neoplasia. Objective.--To identify UPUMP features associated with subsequent neoplastic development. Design.--Sixty-eight patients were identified from the archives, including 26 patients with de novo and 42 patients with prior bladder neoplasia. Patient slides and clinical course were reviewed. Results.--Patients with de novo UPUMP were detected through clinical findings (26/26; 100%), whereas surveillance cystoscopy primarily detected UPUMP in patients with prior neoplasia (29/42; 69%). Histopathologic criteria evaluated included urothelial hyperplasia, urothelial cytology, vascular ingrowth, denudation, inflammation, edema, and fibrosis. Mean clinical follow-up was 68.9 months in patients with de novo neoplasia and 69.5 months in patients with prior neoplasia. Subsequent neoplasia developed in 4 of 26 (15.4%) of patients with de novo UPUMP and was associated with cystoscopic papillary appearance (P = .02) or microscopic thin papillary ingrowths or papillations (P = .02; median time to progression, 4.1 months). Of 42 patients with prior neoplasia, 17 (40.5%) had subsequent neoplasia, significantly associated with an absence of prominent lamina propria edema (P < .001; median time to progression, 11.0 months). A higher rate of progression to high-grade disease was present in patients with a prior neoplasia versus those with de novo disease (58.9% versus 25%). Conclusions.--Urothelial proliferation of unknown malignant potential shows subsequent risk of neoplastic development of 17% in patients with de novo disease and 40% in patients with prior neoplasia. The greatest risk of progression is associated with early papillary formation. (Arch Pathol Lab Med. 2020;144:853-862; doi: 10.5858/arpa.2019-0005-OA), Urothelial proliferation of uncertain malignant potential (UPUMP) is a new term used in the 2016 World Health Organization (WHO) Classification of Tumours of the Urinary System and Male Genital Organs. [...]

* Context.--Serous carcinoma of the gynecologic tract often involves the external bladder wall and can occasionally mimic primary urothelial carcinoma of the bladder.Objective.--To define the spectrum of morphologic and immunohistochemical features that characterize serous carcinoma involving the bladder wall and its distinction from urothelial carcinoma.Design.--We reviewed all cases of serous carcinoma secondarily involving the bladder wall from the University of California San Diego and Polytechnic Institute for histopathologic and immunohistochemical features.Results.--We identified 20 cases of Miillerian high-grade serous carcinoma involving the bladder wall. Five cases were clinical mimics of urothelial carcinoma, including 2 cases that presented as a large, transmural, primary bladder mass without precedent gynecologic history in women younger than 60 years, and 3 cases presumed to be new bladder carcinoma occurring distant to a serous carcinoma diagnosis. A subset of cases were morphologic mimics of urothelial carcinoma, which showed nested growth patterns (2 of 20; 10%), squamouslike foci (2 of 20; 10%), spindled/sarcomatoid growth (2 of 20; 10%), basaloid morphology (3 of 20; 15%), and syncytial growth patterns (1 of 20; 5%). Immunohistochemical stains in 17 cases showed immunoreactivity for CK7 (17 of 17; 100%), WT1 (17 of 17; 100%), uroplakin (UP) II (1 of 17; 6%), p63 (2 of 17; 12%), GATA3 (2 of 17; 12%), and PAX8 (17 of 17; 100%).Conclusions.--A subset of serous carcinomas involving the bladder wall can mimic urothelial carcinoma. Awareness of this mimicker and use of an immunohistochemical panel that includes CK7, WT1, UPII, PAX8, p63, and GATA3 can be helpful in confirming the diagnosis.(Arch Pathol Lab Med. 2018;142:168-177; doi: 10.5858/arpa.2017-0004-OA), Serous carcinoma can arise in the uterus, peritoneum, ovary, or fallopian tube and typically affects postmenopausal women, although younger women can be affected. (1,2) The diagnosis of a gynecologic primary [...]

Cancer-associated genetic alterations induce expression of tumour antigens that can activate [CD8.sup.+] cytotoxic T cells (CTLs), but the microenvironment of established tumours promotes immune tolerance through poorly understood mechanisms (1,2). Recently developed therapeutics that overcome tolerogenic mechanisms activate tumour-directed CTLs and are effective in some human cancers (1). Immune mechanisms also affect treatment outcome, and certain chemotherapeutic drugs stimulate cancer-specific immune responses by inducing immunogenic cell death and other effector mechanisms (3,4). Our previous studies revealed that B cells recruited by the chemokine CXCL13 into prostate cancer tumours promote the progression of castrate-resistant prostate cancer by producing lymphotoxin, which activates an IkB kinase a (IKKα)-BMI1 module in prostate cancer stem cells (5,6). Because castrate-resistant prostate cancer is refractory to most therapies, we examined B cell involvement in the acquisition of chemotherapy resistance. Here we focus on oxaliplatin, an immunogenic chemotherapeutic agent (3,4) that is effective in aggressive prostate cancer (7). We show that mouse B cells modulate the response to low-dose oxaliplatin, which promotes tumour-directed CTL activation by inducing immunogenic cell death. Three different mouse prostate cancer models were refractory to oxaliplatin unless genetically or pharmacologically depleted of B cells. The crucial immunosuppressive B cells are plasmocytes that express IgA, interleukin (IL)-10 and programmed death ligand 1 (PD-L1), the appearance of which depends on TGF0 receptor signalling. Elimination of these cells, which also infiltrate human-therapy-resistant prostate cancer, allows CTL-dependent eradication of oxaliplatin-treated tumours., Using the autochthonous transgenic adenocarcinoma of the mouse prostate (TRAMP) model of metastatic prostate cancer (PC) (8), we examined how lymphocytes affect the response to low-dose oxaliplatin. Although early (≤ [...]

Aim: Optimal management of bladder cancer requires an accurate, standardised and timely pathological diagnosis, and close communication between surgeons and pathologists. Here, we provide an update on pathology reporting standards of transurethral resections of the bladder and cystectomies. Methods: We reviewed recent literature, focusing on developments between 2013 and 2021. Results: Published reporting standards developed by pathology organizations have improved diagnosis and treatment. Tumor sub-staging and subtyping has gained increased attention. Lymph nodes continue to be an area of debate, and their staging has seen minor modifications. Several tasks, particularly regarding specimen preparation ("grossing"), are not yet standardized and offer opportunity for improvement. Molecular classification is rapidly evolving, but currently has only limited impact on management. Conclusion: Pathological reporting of bladder cancer is continuously evolving and remains challenging in some areas. This review provides an overview of recent major developments, with a particular focus on published reporting standards. [ABSTRACT FROM AUTHOR]

Simple Summary: The mammalian target of rapamycin (mTOR) pathway promotes cell growth and metabolism in response to growth factors, nutrients, and cellular energy status. Dysregulation and mutation of the mTOR pathway can contribute to tumor initiation and progression. mTOR pathway abnormalities have been found in approximately 70% of urothelial carcinomas (UCs). This review summarizes recent advances in knowledge of the mTOR pathway, highlights the role of the mTOR pathway in UC, and explores the potential of the mTOR pathway as a therapeutic target in UC. This review also explores current preclinical studies and clinical trials targeting the mTOR pathway, and concludes with future directions of research that could more robustly define and target aberrant mTOR activity in bladder cancer. The mammalian target of rapamycin (mTOR) pathway regulates important cellular functions. Aberrant activation of this pathway, either through upstream activation by growth factors, loss of inhibitory controls, or molecular alterations, can enhance cancer growth and progression. Bladder cancer shows high levels of mTOR activity in approximately 70% of urothelial carcinomas, suggesting a key role for this pathway in this cancer. mTOR signaling initiates through upstream activation of phosphatidylinositol 3 kinase (PI3K) and protein kinase B (AKT) and results in activation of either mTOR complex 1 (mTORC1) or mTOR complex 2 (mTORC2). While these complexes share several key protein components, unique differences in their complex composition dramatically alter the function and downstream cellular targets of mTOR activity. While significant work has gone into analysis of molecular alterations of the mTOR pathway in bladder cancer, this has not yielded significant benefit in mTOR-targeted therapy approaches in urothelial carcinoma to date. New discoveries regarding signaling convergence onto mTOR complexes in bladder cancer could yield unique insights the biology and targeting of this aggressive disease. In this review, we highlight the functional significance of mTOR signaling in urothelial carcinoma and its potential impact on future therapy implications. [ABSTRACT FROM AUTHOR]