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Electronic-cigarettes (E-cigs) are marketed as a safe alternative to tobacco to deliver the stimulant nicotine, and their use is gaining in popularity, particularly among the younger population. We recently showed that mice exposed to short-term (12 wk) E-cig smoke (ECS) sustained extensive DNA damage in lungs, heart, and bladder mucosa and diminished DNA repair in lungs. Nicotine and its nitrosation product, nicotine-derived nitrosamine ketone, cause the same deleterious effects in human lung epithelial and bladder urothelial cells. These findings raise the possibility that ECS is a lung and bladder carcinogen in addition to nicotine. Given the fact that E-cig use has become popular in the past decade, epidemiological data on the relationship between ECS and human cancer may not be known for a decade to come. In this study, the carcinogenicity of ECS was tested in mice. We found that mice exposed to ECS for 54 wk developed lung adenocarcinomas (9 of 40 mice, 22.5%) and bladder urothelial hyperplasia (23 of 40 mice, 57.5%). These lesions were extremely rare in mice exposed to vehicle control or filtered air. Current observations that ECS induces lung adenocarcinomas and bladder urothelial hyperplasia, combined with our previous findings that ECS induces DNA damage in the lungs and bladder and inhibits DNA repair in lung tissues, implicate ECS as a lung and potential bladder carcinogen in mice. While it is well established that tobacco smoke poses a huge threat to human health, whether ECS poses any threat to humans is not yet known and warrants careful investigation.

The morphologic features of different entities in genitourinary pathology overlap, presenting a diagnostic challenge, especially when diagnostic materials are limited. Immunohistochemical markers are valuable when morphologic features alone are insufficient for definitive diagnosis. The World Health Organization classification of urinary and male genital tumors has been updated for 2022. An updated review of immunohistochemical markers for newly classified genitourinary neoplasms and their differential diagnosis is needed. To review immunohistochemical markers used in the diagnosis of genitourinary lesions in the kidney, bladder, prostate, and testis. We particularly emphasized difficult differential diagnosis and pitfalls in immunohistochemistry application and interpretation. New markers and new entities in the 2022 World Health Organization classifications of genitourinary tumors are reviewed. Recommended staining panels for commonly encountered difficult differential diagnoses and potential pitfalls are discussed. Review of current literature and our own experience. Immunohistochemistry is a valuable tool in the diagnosis of problematic lesions of the genitourinary tract. However, the immunostains must be carefully interpreted in the context of morphologic findings with a thorough knowledge of pitfalls and limitations.

Abstract Objectives To determine the prognostic significance of the maximum allowable percentage of Gleason pattern 4 (GP4) at prostate biopsy compared with adverse pathology observed at radical prostatectomy (RP) to expand active surveillance eligibility among a cohort with intermediate risk of prostate cancer. Methods A retrospective study of patients with grade group (GG) 1 or 2 prostate cancer on prostate biopsy with subsequent RP was performed at our institution. A Fisher exact test was used to understand the relationship among GP4 subgroups (0%, ≤5%, 6%-10%, and 11%-49%) assigned at biopsy and adverse pathologic findings at RP. Additional analyses comparing the GP4 ≤5% cohort’s prebiopsy prostate-specific antigen (PSA) level and GP4 length with adverse pathology at RP were also performed. Results No statistically significant difference in adverse pathology at RP was observed between the active surveillance–eligible control (GP4 0%) and the GP4 ≤5% subgroup. In total, 68.9% of the GP4 ≤5% cohort showed favorable pathologic outcomes. A separate analysis of the GP4 ≤5% subgroup revealed that neither prebiopsy serum PSA levels nor GP4 length showed statistical correlation with adverse pathology at RP. Conclusions Active surveillance may be a reasonable option for management of patients in the GP4 ≤5% group until long-term follow-up data become available.

In prostate cancer, the signals that drive cell proliferation change as tumors progress from castration-sensitive (androgen-dominant) to castration-resistant states. While the mechanisms underlying this change remain uncertain, characterization of common signaling components that regulate both stages of prostate cancer proliferation is important for developing effective treatment strategies. Here, we demonstrate that paxillin, a known cytoplasmic adaptor protein, regulates both androgen- and EGF-induced nuclear signaling. We show that androgen and EGF promoted MAPK-dependent phosphorylation of paxillin, resulting in nuclear translocation of paxillin. We found nuclear paxillin could then associate with androgen-stimulated androgen receptor (AR). This complex bound AR-sensitive promoters, retaining AR within the nucleus and regulating AR-mediated transcription. Nuclear paxillin also complexed with ERK and ELK1, mediating c-FOS and cyclin D1 expression; this was followed by proliferation. Thus, paxillin is a liaison between extranuclear MAPK signaling and nuclear transcription in response to androgens and growth factors, making it a potential regulator of both castration-sensitive and castration-resistant prostate cancer. Accordingly, paxillin was required for normal growth of human prostate cancer cell xenografts, and its expression was elevated in human prostate cancer tissue microarrays. Paxillin is therefore a potential biomarker for prostate cancer proliferation and a possible therapeutic target for prostate cancer treatment.

This morphological and immunohistochemical study demonstrates that tumors currently known as “middle ear adenomas” are truly well-differentiated epithelial neuroendocrine tumors (NETs) composed of cells comparable to normal intestinal L cells, and therefore, these tumors resemble hindgut NETs. These tumors show consistent expression of glucagon, pancreatic polypeptide, PYY, and the transcription factor SATB2, as well as generic neuroendocrine markers and keratins. The same L cell markers are expressed by cells within the normal middle ear epithelium. These markers define a valuable immunohistochemical profile that can be used for differential diagnosis of middle ear neoplasms, particularly in distinguishing epithelial NETs from paragangliomas. The discovery of neuroendocrine cells expressing the same markers in non-neoplastic middle ear mucosa opens new areas of investigation into the physiology of the normal middle ear and the pathophysiology of middle ear disorders.

PurposeTo determine whether multi-parametric magnetic resonance imaging (mpMRI) can reliably predict proximity of prostate cancer to the prostatic urethra in a contemporary series of men undergoing radical prostatectomy (RP) at two academic centers.MethodsClinical characteristics of consecutive men undergoing pre-operative mpMRI prior to RP and whole-mount axial serial step-sectioned pathology examination at two academic centers between Jun 2016 and Oct 2018 were analyzed retrospectively. Every tumor was characterized by its pathologic minimum distance to the prostatic urethral lumen (pMDUL). Only the cancer closest to the urethra represented the prostatic urethral index lesion. The radiologic minimum distance of the index lesion to the prostatic urethral lumen was measured and noted as ≤ 5 mm versus  > 5 mm. The sensitivity, specificity, positive and negative predicting values (PPV and NPV) and area under the receivers operating characteristics curve (AUC) were calculated for performance of mpMRI for predicting pMDUL ≤ 5 mm.ResultsOf the 163 surgical specimens examined, 112 (69%) exhibited a pMDUL ≤ 5 mm. These men had significantly higher grade group (GG) and advanced pathological and clinical stage. The rates of high PI-RADS score and presence of gross extracapsular extension were also significantly greater for the group with pMDUL ≤ 5 mm. The AUC, sensitivity, specificity, PPV, and NPV were 0.641, 51.8, 76.5, 82.9, and 42.4%, respectively, for mpMRI to predict pMDUL < 5 mm.ConclusionsNearly 70% of men undergoing RP present with tumor within 5 mm of the prostatic urethra. These tumors present higher risk characteristics, and mpMRI exhibited moderate performance and high PPV in their pre-operative detection. Physicians performing partial gland ablation should take these results into consideration during treatment selection and planning.

Uroplakins (UP), a group of integral membrane proteins, are major urothelial differentiation products that form 2D crystals of 16-nm particles (urothelial plaques) covering the apical surface of mammalian bladder urothelium. They contribute to the urothelial barrier function and, one of them, UPIa, serves as the receptor for uropathogenic Escherichia coli. It is therefore important to understand the mechanism by which these surface-associated uroplakins are degraded. While it is known that endocytosed uroplakin plaques are targeted to and line the multivesicular bodies (MVBs), it is unclear how these rigid-looking plaques can go to the highly curved membranes of intraluminal vesicles (ILVs). From a cDNA subtraction library, we identified a highly urothelium-specific sorting nexin, SNX31. SNX31 is expressed, like uroplakins, in terminally differentiated urothelial umbrella cells where it is predominantly associated with MVBs. Apical membrane proteins including uroplakins that are surface biotin-tagged are endocytosed and targeted to the SNX31-positive MVBs. EM localization demonstrated that SNX31 and uroplakins are both associated not only with the limiting membranes of MVBs containing uroplakin plaques, but also with ILVs. SNX31 can bind, on one hand, the PtdIns3P-enriched lipids via its N-terminal PX-domain, and, on the other hand, it binds uroplakins as demonstrated by co-immunoprecipitation and proximity ligation assay, and by its reduced membrane association in uroplakin II-deficient urothelium. The fact that in urothelial umbrella cells MVBs are the only major intracellular organelles enriched in both PtdIns3P and uroplakins may explain SNX31's MVB-specificity in these cells. However, in MDCK and other cultured cells transfected SNX31 can bind to early endosomes possibly via lipids. These data support a model in which SNX31 mediates the endocytic degradation of uroplakins by disassembling/collapsing the MVB-associated uroplakin plaques, thus enabling the uroplakin-containing (but 'softened') membranes to bud and form the ILVs for lysosomal degradation and/or exosome formation.

Gender-affirming surgery is part of a multidisciplinary approach in gender transitioning. Deeper histologic examination may strengthen care for transmasculine individuals and increase the understanding of the influence of hormonal therapy in specific organs. To evaluate and catalogue histologic findings of tissue obtained from gender-affirming gynecologic surgery and cervical cytology specimens. This is an institutional review board-approved retrospective study that included transmasculine individuals who underwent gender-affirming gynecologic surgery from January 2015 to June 2020. All surgical gynecologic pathology and cervical cytology slides were reviewed by 2 pathologists. Fifty-five patients were included, which represented 40 uteri, 35 bilateral ovaries, 15 vaginectomy specimens, and 24 cervical cytology results. The median age was 27 years (range, 18-56), and 94% (50 of 53) of patients were receiving testosterone for at least 1 year. Seventy-five percent (30 of 40) of endometria were inactive, while 25% (10 of 40) showed evidence of cycling. Transitional cell metaplasia was the most common finding in the cervix (17 of 40) and vagina (15 of 15), reflecting a high percentage (4 of 24) of unsatisfactory or ASC-US (atypical squamous cells of undetermined significance) cervical cytologies. Prostatic-type glands were identified in 20% (8 of 40) of cervices and 67% (10 of 15) of vaginectomy specimens. Multiple bilateral cystic follicles and evidence of follicular maturation were present in 57% (20 of 35) of cases. Four cases showed paratubal epididymis-like mesonephric remnant hypertrophy. A comprehensive evaluation of tissue from gender-affirming surgery increases knowledge of the changes following androgen therapy in transmasculine individuals and may contribute to optimal patient care by raising awareness of normal histologic variations in this population.

Background Malignant angiomyolipoma is an uncommon tumor of the class of perivasciular epithelioid cell neoplasms (PEComas). These tumors are characteristically driven by deleterious mutations in the tumor suppressors TSC1 and TSC2 , whose gene products typically act to inhibit mTOR. There are several cases of malignant angiomyolipoma which exhibit transient responses to mTOR inhibitors, forming the basis of current practice guidelines in malignant PEComa. However the tumors ultimately acquire resistance, and there is no well-established second-line option. Despite the increasing prevalence of immunotherapy across a wide range of solid tumors, little is known about the immune infiltrate and PD-L1 expression of angiomyolipoma. Furthermore, there is no reported case on the treatment of malignant angiomyolipoma with an immune checkpoint inhibitor. Case presentation A 38 year-old man presented with gross hematuria and was diagnosed with renal epithelioid angiomyolipoma. Despite surgical resection, the tumor recurred and metastasized. Targeted genomic sequencing revealed a deleterious mutation in TSC2 , and the patient was treated with the mTOR inihbitor everolimus. The patient went on to have a partial response but ultimately progressed. He was then treated with the anti-PD-1 immune checkpoint inhibitor nivolumab, and achieved a durable near-complete response which is ongoing after two years of treatment. Immunohistochemical staining of tumor tissue revealed strong PD-L1 expression and a brisk T-cell infiltrate. Conclusions We report on the first durable systemic treatment of malignant epithelioid angiomyolipoima with the use of PD-1 antibody nivolumab. Given the absence of prospective clinical trials in this exceedingly rare disease, particularly in the second-line setting, immune checkpoint inhibitors like nivolumab should be considered.

Autopsies were conducted according to published US Centers for Disease Control and Prevention guidelines.3 Six testes samples were tested by reverse transcription-polymerase chain reaction for 3 regions of the COVID-19 virus gene, ORFlabb, N gene, and E gene. In this analysis, evidence of acute testicular injury is seen and is particularly related to oxidative stress, which has previously been reported in animal models in association with type 2 diabetes mellitus.4 We compared our findings to a control group of 7 testes obtained during autopsy from patients who had similar comorbidities and age distribution but were negative for COVID-19. The observed testicular changes in our control group were mainly related to chronic processes (decreased spermatogenesis, reduced Leydig cells, and hyalinization of seminiferous tubules), whereas the changes in COVID-19-positive patients were acute (sloughing of spermatocytes, elongation of spermatids, and swelling of Sertoli cells).