Radical prostatectomy cancer grade and percentage of Gleason pattern 4 estimated by global vs individual tumor grading correlate differently with the risk of biochemical recurrence in Grade Group 2 and 3 cancers.

OBJECTIVES: There are 2 grading approaches to radical prostatectomy (RP) in multifocal cancer: Grade Group (GG) and percentage of Gleason pattern 4 (GP4%). We investigated whether RP GG and GP4% generated by global vs individual tumor grading correlate differently with biochemical recurrence. METHODS: We reviewed 531 RP specimens with GG2 or GG3 cancer. Each tumor was scored separately with assessment of tumor volume and GP4%. Global grade and GP4% were assigned by combining Gleason pattern 3 and 4 volumes for all tumors. Correlation of GG and GP4% generated by 2 methods with biochemical recurrence was assessed by Cox proportional hazard regression and receiver operating characteristic curves, with optimism adjustment using a bootstrap analysis. RESULTS: Median age was 63 (range, 42-79) years. Median prostate-specific antigen was 6.3 (range, 0.3-62.9) ng/mL. In total, the highest-grade tumor in 371 (36.9%) men was GG2 and in 160 (30.1%) men was GG3. Global grading was downgraded from GG3 to GG2 in 37 of 121 (30.6%) specimens with multifocal disease, and 145 of 404 (35.9%) specimens had GP4% decreased by at least 10%. Ninety-eight men experienced biochemical recurrence within a median of 13 (range, 3-119) months. Men without biochemical recurrence were followed up for a median of 47 (range, 12-205) months. Grade Group, GP4%, and margin status correlated with the risk of biochemical recurrence using highest-grade tumor and global grading, but the degrees of these correlations varied and were statistically significantly different between the 2 grading approaches. CONCLUSIONS: Grade Group, GP4%, and margin status derived by global vs individual tumor grading predict postoperative biochemical recurrence statistically significantly differently. This difference has important implications if results derived from cohorts graded using different methods are compared.

Histopathological assessment of depth of coagulation necrosis with Holmium, Moses, and Thulium fiber lasers in human prostate tissue.

PURPOSE: To evaluate coagulation necrosis depth (CND) of Holmium (HL), Moses (ML), and Thulium fiber laser (TFL) in ex vivo human prostate tissue at various energy settings. METHODS: After endoscopic HL enucleation, small prostate tissue fragments were removed from the bladder with graspers and used for study. Immediately after surgery, a single incision was made on the surface of the tissue kept under normal saline at room temperature using a hand-held 550-µm laser fiber. Variable energy settings were tested for all three lasers. Two pathologists measured the CND with light microscopy using ocular micrometer. Impact of various laser settings on CND was analyzed. The differences in CND of all three lasers at similar laser power were compared. RESULTS: Mean CND was 0.56 ± 0.53 mm for long-pulse HL, 0.54 ± 0.53 mm for ML, 0.67 ± 0.67 mm for low-pulse TFL, and 0.81 ± 0.78 mm for high-pulse TFL. There was no significant difference between mean CND of HL and ML at various laser settings ranging from 10 to 120 W and CND with long- and short-pulse settings of TFL at settings from 10 to 60 W. There was a trend of increasing CND in HL and ML with increasing laser power; however, it was not statistically significant. TFL had similar tissue effects as HL and ML. CONCLUSION: There is no significant difference in CND of HL, ML, and TFL in ex vivo human prostate tissue. Other factors besides laser type and settings need to be studied to explain clinical differences among various lasers used for prostate enucleation.

Prostate cancer upgrading and adverse pathology in Hispanic men undergoing radical prostatectomy.

PURPOSE: Radical prostatectomy (RP) outcomes in Hispanic men with prostate cancer are not well-described. Prior studies showed varying results regarding the rate of upgrading and upstaging, and these studies included limited pathologic data and lack of central pathology review. We characterized the rate of upgrading, adverse pathology, and oncologic outcomes in Hispanics after prostatectomy using a large institutional database. METHODS: We included Hispanic white (HW), non-Hispanic white (NHW), and black men who underwent (RP) between 2010 and 2021 at a single institution. We recorded differences in grade group between biopsy and prostatectomy and performed multivariable analyses for odds of upgrading and adverse pathologic findings. The primary outcome was rate of upgrading in HWs. Using a sub-cohort with follow-up data, we assessed race/ethnicity and upgrading as a predictor of biochemical recurrence (BCR)-free survival. RESULTS: Our cohort included 1877 men: 36.7% were NHW, 40.6% were HW, and 22.7% were black. Rates of upgrading were not different between NHW, NHW, and black men at 34.0, 33.8, and 37.3%, respectively (p = 0.4). In the multivariable analysis for upgrading, significant predictors for upgrading were older age (p = 0.002), higher PSA (p < 0.001), and lower prostate weight (p = 0.02), but race/ethnicity did not predict upgrading. In patients with available follow-up (1083, 58%), upgrading predicted worse BCR-free survival (HR 2.17, CI 1.46-3.22, p < 0.0001) but race/ethnicity did not. CONCLUSIONS: HW men undergoing RP had similar rates of upgrading and adverse pathologic outcomes as NHW men. Race/ethnicity does not independently predict upgrading or worse oncologic outcomes after RP.

Localized Amyloidosis of the Seminal Tract is not Associated With Subsequent Development of Systemic Amyloidosis.

OBJECTIVE: To investigate if localized amyloidosis of the seminal tract (LAST) is associated with subsequent development of systemic amyloidosis. Prior reports recorded no systemic amyloidosis at the time of LAST diagnosis. However, no follow-up studies exist to confirm that LAST is not a risk factor for subsequent development of systemic amyloidosis. METHODS: Our study cohort included patients whose prostate biopsy (PB) or radical prostatectomy (RP) specimen demonstrated LAST between 2014-2021. Clinical variables including age, race/ethnicity, prostate specific antigen (PSA), and prostate weight were analyzed. Patients were assessed for clinical and laboratory evidence of systemic amyloidosis and lymphoproliferative conditions during the follow-up period. RESULTS: Thirty-six men (26 RPs, 9 PBs, and 1 cystoprostatectomy) had LAST. Our study cohort included 18 white Hispanic, 9 white non-Hispanic, 7 black, and 1 Asian men. Median age was 67 years, mean PSA was 9.8 ng/mL. Over a median follow-up period of 20 months (mean, 30) in 27 men, none developed systemic amyloidosis. Frequency of LAST in RP specimens was 1.2% (26/2,135) and corelated with age (67 vs 63 years, P-value = .004). Race/ethnicity, PSA, and prostate weight were not associated with the incidence of LAST. CONCLUSIONS: LAST is not a harbinger of systemic disease. The incidence of LAST in a contemporary RP cohort is significantly lower than in previously published studies. While patient age positively corelates with LAST, PSA and prostate weight are not associated with the condition. There is no difference in the frequency of LAST between white Hispanic, white non-Hispanic, and black men.

Variance of Tumor Grade at Radical Prostatectomy With Assessment of Each Tumor Nodule Versus Global Grading.

CONTEXT.­: Multifocal prostate cancer at radical prostatectomy (RP) may be graded with assessment of each individual tumor nodule (TN) or global grading of all TNs in aggregate. OBJECTIVE.­: To assess case-level grade variability between these 2 grading approaches. DESIGN.­: We reviewed 776 RPs with multifocal prostate cancer with 2 or more separate TNs of different Grade Groups (GGs). Two separate grades were assigned to each RP: one based on the TN with the highest grade and a global grade based on the Gleason pattern volumes for all TNs. We then compared the results of these 2 methods. RESULTS.­: The case-level grade changed by 1 or more GGs between the 2 grading methods in 35% (132 of 374) of GG3 through GG5 cases. Twelve percent (37 of 309) of GG2 cases with Gleason pattern 4 of more than 5% based on individual TN grading decreased their Gleason pattern 4 to less than 5% based on the global approach. Minor tertiary pattern 5 (Gleason pattern 5 <5%) was observed in 6.8% (11 of 161) of GG4 (Gleason score 3 + 5 = 8 and 5 + 3 = 8) and GG5 cases with global grading. The risk of grade discrepancy between the 2 methods was associated with the highest-grade TN volume (inverse relationship), patient age, and number of TNs (P < .001, P = .003, and P < .001, respectively). CONCLUSIONS.­: The global grading approach resulted in a lower grade in 35% of GG3 through GG5 cases compared with grading based on the highest-grade TN. Two significant risk factors for this discrepancy with a global grading approach occur when the highest-grade TN has a relatively small tumor volume and with a higher number of TNs per RP. The observed grade variability between the 2 grading schemes most likely limits the interchangeability of post-RP multi-institutional databases if those institutions use different grading approaches.

Anterior or Posterior Prostate Cancer Tumor Nodule Location Predicts Likelihood of Certain Adverse Outcomes at Radical Prostatectomy.

CONTEXT.­: Effect of tumor nodule (TN) location in the prostate on adverse radical prostatectomy (RP) outcomes is not well studied in contemporary cohorts. OBJECTIVE.­: To investigate the significance of TN location with respect to extraprostatic extension (EPE), seminal vesicle invasion (SVI), and positive surgical margin (SM+) in 1388 RPs. DESIGN.­: Each TN at RP was independently graded, staged, and volumetrically assessed. TNs with at least 80% of their volume occupying either the anterior or posterior part of the prostate were categorized accordingly and included in our study, while all other TNs were excluded. RESULTS.­: A total of 3570 separate TNs (median = 3 per RP; range = 1-7 per RP) were scored. There were 1320 of 3570 (37%) anterior TNs and 2250 of 3570 (63%) posterior TNs. Posterior TNs were more likely to be higher grade, and exhibit EPE (18% versus 9.4%) and SVI (4% versus 0.15%), all P < .001. Anterior TNs with EPE were more likely to exhibit SM+ than posterior TNs with EPE (62% versus 30.8%, P < .001). TN location, grade, and volume were significant factors associated with adverse RP outcomes in our univariable analysis. When we controlled for grade and tumor volume in a multivariable analysis using anterior TN location as a reference, posterior TN location was an independent predictor of EPE and SVI and was less likely to be associated with SM+ (odds ratio = 3.1, 81.5, and 0.7, respectively). CONCLUSIONS.­: These associations may be useful in preoperative surgical planning, particularly with respect to improving radiographic analysis of prostate cancer.

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.

Prostatic Ductal Adenocarcinoma Controlled for Tumor Grade, Stage, and Margin Status Does Not Independently Influence the Likelihood of Biochemical Recurrence in Localized Prostate Cancer After Radical Prostatectomy.

CONTEXT.­: Prostatic ductal adenocarcinoma (PDA) has historically been considered to be an aggressive subtype of prostate cancer. OBJECTIVE.­: To investigate if PDA is independently associated with worse biochemical recurrence (BCR)-free survival after radical prostatectomy. DESIGN.­: A review of 1584 radical prostatectomies was performed to grade, stage, and assess margin status in each tumor nodule. Radical prostatectomies with localized PDA (ie, those lacking metastasis) in the tumor nodule with the highest grade and stage and worst margin status were matched with prostatic acinar adenocarcinoma according to grade, stage, and margin status. The effect of PDA on BCR was assessed by multivariable Cox regression and Kaplan-Meier analyses. RESULTS.­: Prostatic ductal adenocarcinoma was present in 171 cases. We excluded 24 cases because of lymph node metastasis (n = 13), PDA not in the highest-grade tumor nodule (n = 9), and positive surgical margin in a lower-grade tumor nodule (n = 2). The remaining 147 cases included 26 Grade Group (GG) 2, 44 GG3, 6 GG4, and 71 GG5 cancers. Seventy-six cases had extraprostatic extension, 33 had seminal vesicle invasion, and 65 had positive margins. Follow-up was available for 113 PDA and 109 prostatic acinar adenocarcinoma cases. Prostate-specific antigen density (odds ratio, 3.7; P = .001), cancer grade (odds ratio, 3.3-4.3; P = .02), positive surgical margin (odds ratio, 1.7; P = .02), and tumor volume (odds ratio, 1.3; P = .02) were associated with BCR in multivariable analysis. Prostatic ductal adenocarcinoma, its percentage, intraductal carcinoma, and cribriform Gleason pattern 4 were not significant independent predictors of BCR. CONCLUSIONS.­: Advanced locoregional stage, higher tumor grade, and positive surgical margin status rather than the mere presence of PDA are more predictive of worse BCR-free survival outcomes following radical prostatectomy in men with a component of PDA.

Percentage of Gleason pattern 4 and tumor volume predict adverse pathological stage and margin status at radical prostatectomy in grade Group 2 and grade Group 3 prostate cancers.

BACKGROUND: Increasing percentages of Gleason pattern 4 (GP4%) in radical prostatectomy (RP) correlate with an increased likelihood of nonorgan-confined disease and earlier biochemical recurrence (BCR). However, there are no detailed RP studies assessing the impact of GP4% and corresponding tumor volume (TV) on extraprostatic extension (EPE), seminal vesicle (SV) invasion (SV+), and positive surgical margin (SM) status (SM+). METHODS: In 1301 consecutive RPs, we analyzed each tumor nodule (TN) for TV, Grade Group (GG), presence of focal versus nonfocal EPE, SV+ , and SM+. Using GG1 (GP4% = 0) TNs as a reference, we recorded GP4% for all GG2 or GG3 TNs. We performed a multivariable analysis (MVA) using a mixed effects logistic regression that tested significant variables for risk of EPE, SV+, and SM+, as well as a multinomial logistic regression model that tested significant variables for risks of nonorgan-confined disease (pT2+, pT3a, and pT3b) versus organ-confined disease (pT2). RESULTS: We identified 3231 discrete TNs ranging from 1 to 7 (median: 2.5) per RP. These included GG1 (n = 2115), GG2 (n = 818), GG3 (n = 274), and GG4 (n = 24) TNs. Increasing GP4% weakly paralleled increasing TV (tau = 0.07, p < .001). In MVA, increasing GP4% and TV predicted a greater likelihood of EPE (odds ratio [OR]: 1.03 and 4.41), SV+ (OR: 1.03 and 3.83), and SM+ (1.01, p = .01 and 2.83), all p < .001. Our multinomial logistic regression model demonstrated an association between GP4% and the risk of EPE (i.e., pT3a and pT3b disease), as well as an association between TV and risk of upstaging (all p < .001). CONCLUSIONS: Both GP4% and TV are independent predictors of adverse pathological stage and margin status at RP. However, the risks for adverse outcomes associated with GP4% are marginal, while those for TV are strong. The prognostic significance of GP4% on BCR-free survival has not been studied controlling for TV and other adverse RP findings. Whether adverse pathological stage and margin status associated with larger TV could decrease BCR-free survival to a greater extent than increasing RP GP4% remains to be studied.

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.

Prostatic Ductal Adenocarcinoma Controlled for Cancer Grade and Tumor Volume Does Not Have an Independent Effect on Adverse Radical Prostatectomy Outcomes Compared to Usual Acinar Prostatic Adenocarcinoma.

OBJECTIVE: To study if prostatic ductal adenocarcinoma (PDA) controlled by Grade Group (GG), PSA, and tumor volume (TV) is an independent predictor of adverse radical prostatectomy (RP) outcomes. MATERIALS: One-hundred and twenty-eight PDA and 1141 acinar continuous RPs were studied. Each tumor nodule (TN) was individually graded, staged, and its TV measured. Univariate analysis (UVA) identified features associated with lymph node metastasis (LN+), extraprostatic extension (EPE), positive surgical margins (SM+), and seminal vesicle invasion (SV+). We then assessed PDA effect on RP outcomes in a multivariate analysis (MVA). RESULTS: In 127 cases PDA was present in 1 TN and no TN was pure PDA. One-hundred and twenty-three cases had PDA in TNs with highest grade, stage, and TV. Patients with PDA were older (65 vs 63 years, P < 0.001), had higher GG (P < 0.001), and LN+ (6.3% vs 2.7%, P = 0.049). Controlling these variables by GG eliminated statistical significance. Overall, there were 3249 separate TNs (129 PDA and 3120 acinar). In UVA, PDA predicted EPE (92/124 vs 517/3045), SV+ (28/1129 vs 116/3,120), and SM+ (51/129 vs 296/3120), all P < 0.001. In MVA, PDA lost its effect on EPE (OR = 0.88, P = 0.64), SM+ (OR = 0.86, P = 0.5), and SV+ (OR = 0.99, P = 0.98). CONCLUSION: Controlled for grade and TV, PDA was not an independent predictor of adverse RP outcomes, but former 2 were. Hence, higher GG and TV associated with PDA TNs may be predictive of adverse RP outcomes rather than PDA by itself. These conclusions may be used in preoperative risk stratification and definitive therapy planning when PDA is identified on needle biopsy.