Metastatic Pleomorphic Lobular Carcinoma of the Breast to the Urinary Bladder: A Report of 10 Cases and Assessment of TRPS1 in the Differential Diagnosis With Plasmacytoid Urothelial Carcinoma.

CONTEXT.­: Metastatic pleomorphic lobular carcinoma (MPLC) to the bladder is rare and has considerable histologic and immunohistochemical overlap with plasmacytoid urothelial carcinoma (PUC). OBJECTIVE.­: To distinguish MPLC from PUC morphologically and immunohistochemically, including a newer marker, TRPS1. DESIGN.­: Ten MPLCs to the bladder were reassessed and stained with estrogen, progesterone, and androgen receptors; GATA3; keratin 5/6; HMWK; GCDFP-15; and TRPS1. Sixteen PUCs constituted controls. RESULTS.­: We studied 4 transurethral resections of bladder tumors and 6 biopsies from 10 women (median age, 69 years) who had breast cancer on average 15 years prior. Microscopic patterns included single cells and cords of cells (n = 4), nests/sheets of dyscohesive cells (n = 2), or both (n = 4). All tumors had cells with voluminous eosinophilic cytoplasm and eccentric nuclei mimicking PUC, and 7 of 10 tumors had signet ring cells. MPLCs were positive for estrogen (8 of 10), progesterone (3 of 7), and androgen receptors (4 of 10); GCDFP-15 (7 of 10); GATA3 (9 of 10); HMWK (7 of 8); and TRPS1 (7 of 10). No MPLCs stained for keratin 5/6 (n = 9). Of 16 PUCs, 2 showed faint and 2 demonstrated strong TRSP1 staining; 7 of 16 were negative for p63. CONCLUSIONS.­: MPLC to bladder often presents in patients with a remote history of breast cancer, exhibiting significant histologic and immunohistochemical overlap with PUC. Based on prior works and the current study, estrogen receptor (particularly SP-1), mammaglobin, and p63 help differentiate MPLC from PUC. Keratin 5/6 may aid in distinguishing a less frequent basal type PUC because it is typically negative in MPLC. Some PUCs express TRPS1. Caution should be exercised because immunophenotypes of these tumors greatly overlap, and ramifications of misclassification are major.

Patterns of Immunoreactivity with TTF-1 Antibodies 8G7G3/1 and SPT24 Suggest Distinct Immunoprofiles Between Most Pulmonary and Nonpulmonary Small Cell Carcinomas.

Introduction. Small cell carcinoma can arise from various sites. Herein, we analyze the ability of 2 thyroid transcription factor-1 (TTF-1) antibodies (SPT24 and 8G7G3/1) to separate pulmonary from nonpulmonary small cell carcinoma. Materials and Methods. We analyzed 26 pulmonary and 83 nonpulmonary small cell carcinomas, and 14 Merkel cell carcinomas. Each tumor was stained with SPT24 and 8G7G3/1. Extent of nuclear staining was scored as diffuse (>50%), focal (11%-50%), rare (1%-10%), or negative (<1%). Results. All pulmonary small cell carcinomas were positive for SPT24 and 8G7G3/1. Four Merkel cell carcinomas (29%) were positive for SPT24 (ranging from rare-to-diffuse), while 2 (14%) showed rare expression with 8G7G3/1. For nonpulmonary small cell carcinomas, 69 (83%) were positive for SPT24 and 40 (48%) were positive for 8G7G3/1. For SPT24 positive tumors, the extent of 8G7G3/1 expression was equal in 17 (25%) and less in 52 tumors (75%), including 29 (42%) that were negative for 8G7G3/1. No nonpulmonary small cell carcinoma had more staining with 8G7G3/1 compared to SPT24. The differences in staining between 8G7G3/1 and SPT24 in the nonpulmonary cohort were statistically significant (P < 0.0001) with no significant difference between primary and metastatic lesions for 8G7G3/1 (P = 0.66) or SPT24 (P = 0.77). Conclusion. Most pulmonary small cell carcinomas are diffusely positive for both SPT24 and 8G7G3/1, whereas most nonpulmonary small cell carcinomas exhibit focal-to-no staining with 8G7G3/1 and significantly less staining with 8G7G3/1 compared to SPT24. However, these trends are not absolute and should be interpreted in conjunction with clinical and radiological findings.

Correction to "New Pathway for Cisplatin Prodrug to Utilize Metabolic Substrate Preference to Overcome Cancer Intrinsic Resistance".

[This corrects the article DOI: 10.1021/acscentsci.3c00286.].

New Pathway for Cisplatin Prodrug to Utilize Metabolic Substrate Preference to Overcome Cancer Intrinsic Resistance.

Tumor cells adapt to diverse survival strategies defying our pursuit of multimodal cancer therapy. Prostate cancer (PCa) is an example that is resistant to one of the most potent chemotherapeutics, cisplatin. PCa cells survive and proliferate using fatty acid oxidation (FAO), and the dependence on fat utilization increases as the disease progresses toward a resistant form. Using a pool of patient biopsies, we validated the expression of a key enzyme carnitine palmitoyltransferase 1 A (CPT1A) needed for fat metabolism. We then discovered that a cisplatin prodrug, Platin-L, can inhibit the FAO of PCa cells by interacting with CPT1A. Synthesizing additional cisplatin-based prodrugs, we documented that the presence of an available carboxylic acid group near the long chain fatty acid linker on the Pt(IV) center is crucial for CPT1A binding. As a result of fat metabolism disruption by Platin-L, PCa cells transition to an adaptive glucose-dependent chemosensitive state. Potential clinical translation of Platin-L will require a delivery vehicle to direct it to the prostate tumor microenvironment. Thus, we incorporated Platin-L in a biodegradable prostate tumor-targeted orally administrable nanoformulation and demonstrated its safety and efficacy. The distinctive FAO inhibitory property of Platin-L can be of potential clinical relevance as it offers the use of cisplatin for otherwise resistant cancer.

Fibromyxoid Nephrogenic Adenoma: A Series of 43 Cases Reassessing Predisposing Conditions, Clinical Presentation, and Morphology.

Nephrogenic adenoma is a benign epithelial lesion of the genitourinary tract that arises from the reimplantation and proliferation of shed renal tubular cells in areas of urothelial injury and denudation. Fibromyxoid nephrogenic adenoma is a rare variant that consists of compressed spindle-shaped renal epithelial cells in a fibromyxoid background. Only 14 observations of this variant are reported in the literature. We performed a retrospective analysis of fibromyxoid nephrogenic adenomas from 3 large reference centers. We identified 43 lesions in 6 women and 36 men (2 in 1 man) with a median age of 72 years (range, 31 to 94 y). Median lesion size was 0.7 cm (range, 0.2 to 5 cm). Nephrogenic adenomas were in the bladder (n=15), prostate/prostatic urethra (n=14), kidney (n=7), ureter (n=3), penile urethra (n=3), and urethral diverticulum (n=1). One of the kidney lesions developed in an end-stage kidney and radiologically mimicked cancer. Of 37 patients with information, 36 had predisposing conditions including prior biopsy, transurethral resection of bladder tumor, resection, Foley catheter, BCG treatment, urinary stones, (chemo)radiation, or diverticulum. Only 4/37 (10.8%) had a history of prior irradiation. Fifteen lesions had pure fibromyxoid morphology and 28 were admixed classic and fibromyxoid patterns. Three nephrogenic adenomas involved prostatic stroma, 3 renal sinus fat, 2 muscularis propria (1 bladder, 1 renal pelvis), 1 perinephric fat, and 1 corpus spongiosum. Ten fibromyxoid nephrogenic adenomas were intermixed with urothelial carcinoma, 1 with prostate adenocarcinoma, and 1 with malignant melanoma. By immunohistochemistry, PAX8 was positive in all the examined lesions (n=31). Napsin A was negative in all examined fibromyxoid nephrogenic adenomas (n=30). Twenty of them had classic nephrogenic adenoma component which was positive for napsin A. Similar to classic nephrogenic adenoma, fibromyxoid nephrogenic adenoma can occur anywhere along the urinary tract and is associated with a prior history that causes urothelial injury. In nearly a quarter of the cases, fibromyxoid nephrogenic adenoma extended beyond the lamina propria. Unlike previously suggested, fibromyxoid nephrogenic adenoma is not specifically related to prior radiation therapy. Awareness of this variant is important to avoid misdiagnosis and overtreatment.

Utility of D2-40, Cytokeratin 5/6, and High-Molecular-weight Cytokeratin (Clone 34ßE12) in Distinguishing Intraductal Spread of Urothelial Carcinoma From Prostatic Stromal Invasion.

Intraductal spread of urothelial carcinoma (UC) is not an uncommon finding in bladder cancer that requires appropriate clinical management. The presence of prostatic stromal invasion in non-muscle-invasive bladder cancer upstages the disease, necessitating cisplatin-based neoadjuvant chemotherapy and subsequent cystroprostatectomy. However, the identification of prostatic stromal invasion can be challenging, especially in biopsy and transurethral resection specimens. We assess the utility of D2-40, CK5/6, and high-molecular-weight cytokeratin (HMWCK) immunohistochemistry as an ancillary tool to differentiate prostatic stromal invasion from intraductal UC spread. We reviewed 13 cystoprostatectomies performed for UC with prostatic involvement. The presence of stromal invasion was histologically determined by the presence of circumferential retraction artifact, paradoxical differentiation, complex architecture, and desmoplastic reaction. The areas of interest were subsequently stained with D2-40, CK5/6, and HMWCK (clone 34ßE12). Four bladder biopsies were used as a control to assess labeling in the benign urothelium. Nine cases had histologic evidence of prostatic stromal invasion (4 transmurally through bladder wall). D2-40 highlighted basal cells in all benign prostatic ducts and was consistently negative in UC, benign urothelium, prostatic adenocarcinoma, and benign luminal prostatic epithelium. D2-40 and CK5/6 performed similarly for intraductal UC, labeling only the basal cell layer with the exception of 1 case with squamous differentiation where CK5/6 exhibited full thickness staining. HMWCK diffusely stained 9 of 10 intraductal UCs without squamous differentiation and 1 intraductal UC with squamous differentiation. All 8 cases of invasive UC without squamous differentiation were negative for D2-40. Seven of these cases had focal CK5/6 and diffuse HMWCK staining. In 1 case of invasive UC with squamous differentiation, all stains were positive. D2-40 is expressed in prostatic basal cells, but it is not expressed in the benign or neoplastic urothelium. D2-40 and CK5/6 effectively highlight the intraductal spread of UC. While invasive UC is negative for D2-40, CK5/6 is usually patchy and localized to the periphery of the tumor nests. HMWCK often demonstrates diffuse staining in both scenarios. However, these stains do not perform well in cases of UC with squamous differentiation. Thus, D2-40 can be used as an ancillary tool to rule out prostatic stromal invasion.

Cathepsin K (Clone EPR19992) Demonstrates Uniformly Positive Immunoreactivity in Renal Oncocytoma, Chromophobe Renal Cell Carcinoma, and Distal Tubules.

Introduction. Cathepsin K is overexpressed in several tumors associated with microphthalmia transcription factor (MiTF) family or mechanistic target of rapamycin (mTOR) upregulation. Among renal neoplasms, MiTF translocation renal cell carcinoma (RCC), perivascular epithelioid cell neoplasms (PEComa), and eosinophilic solid and cystic RCC have demonstrated Cathepsin K immunoreactivity. In this study, we demonstrate a uniform Cathepsin K expression in oncocytoma, chromophobe RCC (CHRCC), and distal tubules. Design. We stained 13 oncocytomas, 13 CHRCC, 14 clear cell RCC (CCRCC), 9 papillary RCC (PRCC), 9 PEComas, and 5 MiTF RCC. Additionally, we assessed immunoreactivity for Cathepsin K in non-neoplastic renal parenchyma. Immunolabeling was performed on regularly charged slides from formalin-fixed paraffin-embedded tissue with monoclonal anti-rabbit antibodies to human Cathepsin K (clone EPR19992, Abcam). Results. All oncocytomas demonstrated diffuse strong cytoplasmic immunolabeling. CHRCC demonstrated uniform less intense immunolabeling in all cases with membranous accentuation. The assessment of the non-neoplastic renal parenchyma in all cases showed strong cytoplasmic immunoreaction in distal tubules and proximal tubules stained faintly. Mesangial cells were not immunoreactive. All MiTF RCC and PEComas were immunoreactive for Cathepsin K, whereas CCRCC and PRCC were negative in all cases. Conclusions. In this study, we expand the spectrum of renal neoplasms reactive with a particular clone of Cathepsin K (EPR19992). Distal tubules are strongly immunoreactive for Cathepsin K. Our conclusions need to be taken into consideration when differential diagnosis includes MiTF RCC or PEComa and this Cathepsin K clone is included in the immunohistochemical panel. This newer antibody clone was not tested in prior publications, potentially explaining the difference in conclusions.

Histopathology and Ultrastructural Findings of Fatal COVID-19 Infections on Testis.

PURPOSE: To evaluate the presence and analyze the pathological changes within the testes of patients who died or recovered from severe acute respiratory syndrome coronavirus 2 (COVID-19) complications. MATERIALS AND METHODS: Testis tissue was collected from autopsies of COVID-19 positive (n=6) and negative men (n=3). Formalin-fixed paraffin-embedded tissues were stained with hematoxylin and eosin (H&E) and subjected to immunofluorescence for angiotensin-converting enzyme 2 (ACE-2) expression. Fluorescent-labeled tissue slides were imaged on a quantitative pathology scope with various zoom levels allowing for qualitative and quantitative interpretation. Tissue from four COVID-19 positive autopsy cases and a live seroconverted patient was imaged with transmission electron microscopy (TEM). RESULTS: H&E histomorphology showed three of the six COVID-19 biopsies had normal spermatogenesis while the remaining three had impaired spermatogenesis. TEM showed the COVID-19 virus in testis tissue of one COVID-19 positive autopsy case and the live biopsy, H&E stain on the same autopsy case demonstrated interstitial macrophage and leukocyte infiltration. Immunofluorescent stained slides from six COVID-19 positive men demonstrated a direct association between increased quantitative ACE-2 levels and impairment of spermatogenesis. CONCLUSIONS: The novel COVID-19 has an affinity for ACE-2 receptors. Since ACE-2 receptor expression is high in the testes, we hypothesized that COVID-19 is prevalent in testes tissue of infected patients. This study suggests the male reproductive tract, specifically the testes, may be targets of COVID-19 infection. We found an inverse association between ACE-2 receptor levels and spermatogenesis, suggesting a possible mechanism of how COVID-19 can cause infertility.