Latrophilins as Downstream Effectors of Androgen Receptors including a Splice Variant, AR-V7, Induce Prostate Cancer Progression.

Latrophilins (LPHNs), a group of the G-protein-coupled receptor to which a spider venom latrotoxin (LTX) is known to bind, remain largely uncharacterized in neoplastic diseases. In the present study, we aimed to determine the role of LPHNs in the progression of prostate cancer. We assessed the actions of LPHNs, including LPHN1, LPHN2, and LPHN3, in human prostate cancer lines via their ligand (e.g., α-LTX, FLRT3) treatment or shRNA infection, as well as in surgical specimens. In androgen receptor (AR)-positive LNCaP/C4-2/22Rv1 cells, dihydrotestosterone considerably increased the expression levels of LPHNs, while chromatin immunoprecipitation assay revealed the binding of endogenous ARs, including AR-V7, to the promoter region of each LPHN. Treatment with α-LTX or FLRT3 resulted in induction in the cell viability and migration of both AR-positive and AR-negative lines. α-LTX and FLRT3 also enhanced the expression of Bcl-2 and phosphorylated forms of JAK2 and STAT3. Meanwhile, the knockdown of each LPHN showed opposite effects on all of those mediated by ligand treatment. Immunohistochemistry in radical prostatectomy specimens further showed the significantly elevated expression of each LPHN in prostate cancer, compared with adjacent normal-appearing prostate, which was associated with a significantly higher risk of postoperative biochemical recurrence in both univariate and multivariable settings. These findings indicate that LPHNs function as downstream effectors of ARs and promote the growth of androgen-sensitive, castration-resistant, or even AR-negative prostate cancer.

Latrophilin-3 as a downstream effector of the androgen receptor induces urothelial tumorigenesis.

Emerging evidence indicates that androgen receptor (AR) signaling plays a critical role in the pathogenesis of male-dominant urothelial cancer. Meanwhile, latrophilins (LPHNs), a group of the G-protein-coupled receptor to which a spider venom latrotoxin is known to bind, remain largely uncharacterized in neoplastic diseases. The present study aimed to determine the functional role of LPHN3 (encoded by the ADGRL3 gene), in association with AR signaling, in urothelial tumorigenesis. In human normal urothelial SVHUC cells, AR overexpression and androgen treatment considerably increased the expression levels of ADGRL3/LPHN3, while chromatin immunoprecipitation assay revealed the binding of AR to the promoter region of ADGRL3. In SVHUC or SVHUC-AR cells with exposure to a chemical carcinogen 3-methylcholanthrene, LPHN3 activation via ligand (e.g., α-latrotoxin, FLRT3) treatment during the process of the neoplastic/malignant transformation or LPHN3 knockdown via shRNA virus infection induced or reduced, respectively, the oncogenic activity. In N-butyl-N-(4-hydroxybutyl)nitrosamine-treated female mice, α-latrotoxin or FLRT3 injection accelerated the development of bladder tumors. Immunohistochemistry in surgical specimens further showed the significantly elevated expression of LPHN3 in non-muscle-invasive bladder tumors, compared with adjacent normal urothelial tissues, which was associated with a marginally (p = 0.051) higher risk of disease recurrence after transurethral resection. In addition, positivity of LPHN3 and AR in these tumors was strongly correlated. These findings indicate that LPHN3 functions as a downstream effector of AR and promotes urothelial tumorigenesis.

A case of laparoscopic lymphadenectomy for adenocarcinoma of unknown primary incidentally detected as a solitary enlarged lymph node along the common hepatic artery.

BACKGROUND: Even in cancer of unknown primary (CUP), which is rare clinical condition, solitary anterosuperior lymph node (LN) along the common hepatic artery (No.8a LN) enlargement diagnosed as metastatic adenocarcinoma has never been reported. CASE PRESENTATION: A 68-year-old Japanese male, with a history of early gastric cancer that had been completely treated by endoscopic submucosal dissection 26 years ago, was detected a single enlarged nodule along the common hepatic artery, No.8a LN, incidentally by computed tomography performed for monitoring of interstitial pneumonia. Endoscopic ultra-sound-guided fine needle aspiration revealed that this nodule was adenocarcinoma suggestive of metastasis, but other imaging studies, including upper and lower gastrointestinal endoscopy, positron emission tomography, and ultrasonography did not detect any primary cancer. We have finally diagnosed as the LN metastasis of CUP and performed laparoscopic lymphadenectomy for this tumor. The tumor was approximately 5 cm in size, was in close proximity to the pancreas, and involved part of the right gastric artery and vein. LNs in the No.5 and No.8a areas, including this tumor, were dissected laparoscopically, and radical resection was achieved. The patient had no postoperative complication and was discharged on postoperative day 10. Immunohistopathological findings revealed that the tumor was poorly differentiated adenocarcinoma, and different from the histology of gastric cancer resected 26 years ago, although the tumor was suggestive of gastrointestinal origin. Imaging studies performed 2 and 6 months after discharge also did not reveal a primary site. CONCLUSION: We reported a case of solitary No.8a LN adenocarcinoma of CUP. For diagnostic and therapeutic purposes, radical resection is recommended for single enlarged intra-abdominal LN of CUP.

Clinical significance of location of perineural cancer invasion detected on prostate needle core biopsy.

The clinical impact of site-specific perineural invasion (PNI) in prostate cancer remains poorly understood. We compared radical prostatectomy findings and oncologic outcomes in 434 patients with single-site PNI on systematic sextant biopsy. PNI was present in the right apex (n = 62; 14%), right mid (n = 70; 16%), right base (n = 89; 21%), left apex (n = 64; 15%), left mid (n = 58; 13%), and left base (n = 91; 21%). There were no significant differences in biopsy or prostatectomy findings, when comparing apex vs. mid vs. base PNI. Univariate analysis revealed that apex-localized PNI was associated with a significantly higher risk of progression, compared with base (P = 0.037) or mid/base (P = 0.024) PNI. Multivariable analysis showed that apex-localized PNI was an independent risk factor for progression (hazard ratio 2.049, P = 0.002). Among biopsies demonstrating PNI at one sextant site, apex-localized PNI is independently associated with poorer prognosis, though not worse histopathologic features on prostatectomy, compared with mid or base PNI.

Mineralocorticoid receptor signaling inhibits bladder cancer progression.

The biological or clinical significance of mineralocorticoid receptor (MR) in urothelial cancer remains largely unknown. The present study aimed to determine the functional role of MR in bladder cancer progression. In two of the human bladder cancer lines expressing MR, treatment with a natural MR ligand, aldosterone, significantly reduced cell proliferation and migration, which was restored by three MR antagonists clinically used, spironolactone (except colony formation of androgen receptor-positive cells cultured in the presence of androgens), eplerenone, and esaxerenone. Similarly, MR knockdown via shRNA virus infection resulted in significant increases in cell viability/migration, as well as colony formation, compared with control sublines. In addition, MR knockdown augmented the expression of ß-catenin, c-fos, and N-cadherin, and lowered that of E-cadherin and p53, indicating the induction of the cadherin switching. Immunohistochemistry in surgical specimens detected MR signals in 58 (92.1%; 36.5% weakly-positive/1+, 44.4% moderately-positive/2+, and 11.1% strongly-positive/3+) of 63 muscle-invasive bladder cancers, which was significantly lower than in adjacent non-neoplastic urothelial tissues (100%; 15.7% 1+, 37.3% 2+, and 47.1% 3+). Moreover, patients with MR-high (3+) tumor had a significantly lower risk of cancer-specific mortality (P=0.039). Multivariable analysis further showed that strong MR expression was an independent predictor of cancer-specific survival in patients with muscle-invasive bladder cancer (hazard ratio 0.117, P=0.039). These findings suggest that MR signaling functions as a tumor suppressor in urothelial carcinoma and prevents tumor growth. Accordingly, there is a possibility that the concurrent use of anti-mineralocorticoids, particularly eplerenone and esaxerenone, in patients with bladder cancer rather contributes to the promotion of disease progression.

Prostate Cancer Risk Stratification by Simple Scoring of the Current pT3 Lesions: A Proposal for a New Pathologic T-Staging System.

Cancer spread beyond the prostate, including extraprostatic extension (other than seminal vesicle or bladder invasion; EPE)/microscopic bladder neck invasion and seminal vesicle invasion (SVI) currently classified as pT3a and pT3b lesions, respectively, does not uniformly indicate poor oncologic outcomes. Accurate risk stratification of current pT3 disease is therefore required. We herein further determined the prognostic impact of these histopathologic lesions routinely assessed and reported by pathologists, particularly their combinations. We assessed consecutive 2892 patients undergoing radical prostatectomy for current pT2 (n = 1692), pT3a (n = 956), or pT3b (n = 244) disease at our institution between 2009 and 2018. Based on our preliminary findings, point(s) were given (1 point to focal EPE, microscopic bladder neck invasion, or unilateral SVI; 2 points to nonfocal/established EPE or bilateral SVI) and summed up in each case. Our cohort had 0 point (n = 1692, 58.5%; P0), 1 point (n = 243, 8.4%; P1), 2 points (n = 657, 22.7%; P2), 3 points (n = 192, 6.6%; P3), 4 points (n = 76, 2.6%; P4), and 5 points (n = 32, 1.1%; P5). Univariate analysis revealed associations of higher points with significantly worse biochemical progression-free survival, particularly when P4 and P5 were combined. In multivariable analysis (P0 as a reference), P1 (hazard ratio [HR], 1.57; P = .033), P2 (HR, 3.25; P < .001), P3 (HR, 4.01; P < .001), and P4 + P5 (HR, 5.99; P < .001) showed significance for the risk of postoperative progression. Meanwhile, Harrell C-indexes for the current pT staging, newly developed point system, and the Cancer of the Prostate Risk Assessment post-Surgical (CAPRA-S) score were 0.727 (95% CI, 0.706-0.748), 0.751 (95% CI, 0.729-0.773), and 0.774 (95% CI, 0.755-0.794), respectively, for predicting progression. We believe our data provide a logical rationale for a novel pathologic T-staging system based on the summed points, pT1a (0 point), pT1b (1 point), pT2 (2 points), pT3a (3 points), and pT3b (4 or 5 points), which more accurately stratifies the prognosis of prostate cancer.

Clinical impact of perineural invasion encircled completely vs. incompletely by prostate cancer on needle core biopsy.

The clinical significance of the pattern or degree of perineural invasion (PNI) by prostate cancer remains largely unknown. We herein assessed radical prostatectomy findings and postoperative oncologic outcomes in 125 patients who had undergone systematic sextant prostate biopsy exhibiting only a single focus of PNI encircled completely (n = 57; 46 %) vs. incompletely (n = 68; 54 %) by cancer. Between these two cohorts, there were no significant differences in clinicopathological features on biopsy or prostatectomy, including tumor grade, stage, and length or volume, and surgical margin status, as well as the need for adjuvant therapy immediately after prostatectomy. Similarly, survival analysis demonstrated no significant difference in the risk of disease progression following prostatectomy in patients with encircled vs. non-encircled PNI on biopsy (P = 0.679). When the non-encircled cases were further divided into four groups [i.e. 1-25 % enclosed (n = 12; 18 %), 26-50 % enclosed (n = 18; 26 %), 51-75 % enclosed (n = 10; 15 %), 76-99 % enclosed (n = 28; 41 %)], the rates of progression-free survival were comparable among the five groups (P = 0.954). In prostate biopsy specimens exhibiting PNI at only one focus, the degree of nerve involvement thus appears to have little clinical impact. Accordingly, PNI detected on prostate biopsy may need to be similarly taken into consideration irrespective of the degree of nerve involvement.

Circularity of islets is a distinct marker for the pathological diagnosis of adult non-neoplastic hyperinsulinemic hypoglycemia using surgical specimens.

BACKGROUND: Adult non-neoplastic hyperinsulinemic hypoglycemia (ANHH), also known as adult-onset nesidioblastosis, is a rare cause of endogenous hyperinsulinemic hypoglycemia in adults. This disease is characterized by diffuse hyperplasia of pancreatic endocrine cells and is diagnosed by a pathological examination. While diagnostic criteria for this disease have already been proposed, we established more quantitative criteria for evaluating islet morphology. METHODS: We measured the number, maximum diameter, total area, and circularity (representing how closely islets resemble perfect spheres) of islets contained in representative sections of ANHH (n = 4) and control cases (n = 5) using the NIS-Elements software program. We also measured the average cell size, percentage of cells with enlarged nuclei, and percentage of cells with recognizable nucleoli for each of three representative islets. We also assessed the interobserver diagnostic concordance of ANHH between five experienced and seven less-experienced pathologists. RESULTS: There was no significant difference in the number, maximum diameter, or total area of islets between the two groups, even after correcting for these parameters per unit area. However, the number of islets with low circularity (< 0.71) per total area of the pancreatic parenchyma was significantly larger in ANHH specimens than in controls. We also found that the percentage of cells with recognizable nucleoli was significantly higher in the ANHH group than in the controls. There were no significant differences in the average cell size or the number of cells with enlarged nuclei between the groups. The correct diagnosis rate with the blind test was 47.5% ± 6.12% for experienced pathologists and 50.0% ± 8.63% for less-experienced pathologists, with no significant differences noted. CONCLUSIONS: Low circularity, which indicates an irregular islet shape, referred to as "irregular shape and occasional enlargement of islets" and "lobulated islet structure" in a previous report, is a useful marker for diagnosing ANHH. An increased percentage of recognizable nucleoli, corresponding to "macronucleoli in ß-cells," has potential diagnostic value.

GABBR2 as a Downstream Effector of the Androgen Receptor Induces Cisplatin Resistance in Bladder Cancer.

The precise molecular mechanisms responsible for resistance to cisplatin-based chemotherapy in patients with bladder cancer remain elusive, while we have indicated that androgen receptor (AR) activity in urothelial cancer is associated with its sensitivity. Our DNA microarray analysis in control vs. AR-knockdown bladder cancer sublines suggested that the expression of a GABA B receptor GABBR2 and AR was correlated. The present study aimed to determine the functional role of GABBR2 in modulating cisplatin sensitivity in bladder cancer. AR knockdown and dihydrotestosterone treatment considerably reduced and induced, respectively, GABBR2 expression, and the effect of dihydrotestosterone was at least partially restored by an antiandrogen hydroxyflutamide. A chromatin immunoprecipitation assay further revealed the binding of AR to the promoter region of GABBR2 in bladder cancer cells. Meanwhile, GABBR2 expression was significantly elevated in a cisplatin-resistant bladder cancer subline, compared with control cells. In AR-positive bladder cancer cells, knockdown of GABBR2 or treatment with a selective GABA B receptor antagonist, CGP46381, considerably enhanced the cytotoxic activity of cisplatin. However, no additional effect of CGP46381 on cisplatin-induced growth suppression was seen in GABBR2-knockdown cells. Moreover, in the absence of cisplatin, CGP46381 treatment and GABBR2 knockdown showed no significant changes in cell proliferation or migration. These findings suggest that GABBR2 represents a key downstream effector of AR signaling in inducing resistance to cisplatin treatment. Accordingly, inhibition of GABBR2 has the potential of being a means of chemosensitization, especially in patients with AR/GABBR2-positive bladder cancer.

Vitamin D Receptor Antagonist MeTC7 Inhibits PD-L1.

Small-molecule inhibitors of PD-L1 are postulated to control immune evasion in tumors similar to antibodies that target the PD-L1/PD-1 immune checkpoint axis. However, the identity of targetable PD-L1 inducers is required to develop small-molecule PD-L1 inhibitors. In this study, using chromatin immunoprecipitation (ChIP) assay and siRNA, we demonstrate that vitamin D/VDR regulates PD-L1 expression in acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) cells. We have examined whether a VDR antagonist, MeTC7, can inhibit PD-L1. To ensure that MeTC7 inhibits VDR/PD-L1 without off-target effects, we examined competitive inhibition of VDR by MeTC7, utilizing ligand-dependent dimerization of VDR-RXR, RXR-RXR, and VDR-coactivators in a mammalian 2-hybrid (M2H) assay. MeTC7 inhibits VDR selectively, suppresses PD-L1 expression sparing PD-L2, and inhibits the cell viability, clonogenicity, and xenograft growth of AML cells. MeTC7 blocks AML/mesenchymal stem cells (MSCs) adhesion and increases the efferocytotic efficiency of THP-1 AML cells. Additionally, utilizing a syngeneic colorectal cancer model in which VDR/PD-L1 co-upregulation occurs in vivo under radiation therapy (RT), MeTC7 inhibits PD-L1 and enhances intra-tumoral CD8+T cells expressing lymphoid activation antigen-CD69. Taken together, MeTC7 is a promising small-molecule inhibitor of PD-L1 with clinical potential.

Risk Stratification by Quantification of Perineural Cancer Invasion on Prostate Needle Core Biopsy: Should It Be Counted?

PURPOSE: We assessed the prognostic significance of quantification of perineural invasion on prostate biopsy. MATERIALS AND METHODS: We quantified actual perineural invasion foci in the entire prostate biopsy specimens from 724 patients and compared corresponding radical prostatectomy findings and long-term oncologic outcomes. RESULTS: No perineural invasion was detected in 524 (72.4%) prostate biopsies, whereas 1 (n=129; 17.8%), 2 (n=40; 5.5%), 3 (n=18; 2.5%), 4 (n=7; 1.0%), and 5-10 (n=6; 0.8%) perineural invasion foci were present in other cases. We confirmed a higher risk of recurrence after radical prostatectomy in patients with perineural invasion on prostate biopsy than in those with no perineural invasion (P < .001). Remarkably, recurrence-free survival was comparable between those with 0 vs 1 perineural invasion (P = .9) or 2 vs ≥3 perineural invasions (P = .3). Nonetheless, multifocal perineural invasion per prostate biopsy (vs single perineural invasion; P < .001) and >1 perineural invasion per 10-mm tumor (vs ≤1 perineural invasion; P = .008) were associated with worse outcomes. Interestingly, in a subgroup outcome analysis of single vs multifocal perineural invasions per prostate biopsy, there was a significant difference in patients showing perineural invasion involving only 1 of the sextant sites. In multivariable analysis, both multifocal perineural invasion/case (HR=5.48, P < .001) and >1 perineural invasion/10-mm tumor (HR=3.96, P < .001) showed significance for recurrence. Meanwhile, compared with CAPRA (Cancer of the Prostate Risk Assessment) score alone (0.687/0.685), Harrell's C index/AUC for predicting 5-year recurrence-free survival was gradually increased when 1 (0.722/0.740), 2 (0.747/0.773), or 3 (0.760/0.792) point(s) were additionally assigned to multifocal perineural invasion. CONCLUSIONS: Multifocal perineural invasion and >1 perineural invasion per 10-mm tumor on each prostate biopsy were thus found to be associated with poorer prognosis, as independent predictors, in men with prostate cancer undergoing radical prostatectomy.

Comedonecrosis within conventional prostatic adenocarcinoma vs. intraductal carcinoma of the prostate: their clinical significance is not comparable.

It remains controversial if Gleason grade should be assigned to intraductal carcinoma of the prostate (IDC-P) and if the prognostic value of comedonecrosis associated with IDC-P is equivalent to that in conventional/invasive prostatic adenocarcinoma (CPA) as a Gleason grade 5 pattern. We herein assessed radical prostatectomy findings and postoperative outcomes in 287 patients with CPA exhibiting any Gleason pattern 5. Our cases were divided into 4 cohorts according to the absence or presence of necrosis within CPA and/or IDC-P: Cohort-1) no necrosis in CPA/IDC-P (n = 179; 62.4%); Cohort-2) necrosis only in CPA (n = 25; 8.7%); Cohort-3) necrosis only in IDC-P (n = 62; 21.6%); and Cohort-4) necrosis in both CPA and IDC-P (n = 21; 7.3%). Univariate analysis revealed patients with necrosis only in IDC-P (P < .001) or both CPA and IDC-P (P = .001) had a higher risk of progression than those with necrosis only in CPA, while the prognosis was comparable between the no necrosis group vs. the CPA only necrosis group (P = .680) or the IDC-P only necrosis group vs. the CPA/IDC-P necrosis group (P = .715). In a subgroup of patients exhibiting IDC-P (n = 198), the presence of IDC-P necrosis was still associated with a significantly higher progression risk, compared with CPA necrosis only. In multivariable analysis, necrosis only in IDC-P (vs. necrosis only in CPA) showed significantly worse progression-free survival (HR = 3.193, P = .003). IDC-P necrosis, as an independent predictor, was thus found to be associated with significantly worse oncologic outcomes, compared with necrosis only in CPA, and might therefore be better not to be simply considered as a grade 5 pattern.

Protective role of mineralocorticoid receptor signaling in urothelial tumorigenesis.

The expression status of mineralocorticoid receptor (MR) and its biological significance in human urothelial carcinoma remain unknown. The present study aimed to determine the functional role of MR in the development of urothelial cancer. In human normal urothelial SVHUC cells with exposure to a chemical carcinogen 3-methylcholanthrene (MCA), we assessed the effects of a natural MR ligand, aldosterone, and 3 MR antagonists, including spironolactone, eplerenone, and esaxerenone, as well as knockdown of MR via shRNA virus infection, on their neoplastic/malignant transformation. The in vitro system with carcinogen challenge showed that aldosterone and anti-mineralocorticoids significantly prevented and promoted, respectively, the neoplastic transformation of SVHUC cells. Similarly, MR knockdown in SVHUC cells considerably induced MCA-mediated neoplastic transformation, compared with a control subline. In addition, MR knockdown or antagonist treatment resulted in increases in the expression of ß-catenin, c-Fos, and N-cadherin, and a decrease in that of E-cadherin. Meanwhile, spironolactone, which is known to possess anti-androgenic activity, rather suppressed the neoplastic transformation of a SVHUC subline stably expressing wild-type androgen receptor, indicating its dominant effect via the androgen receptor pathway. Immunohistochemistry in surgical specimens detected MR signals in 77 (98.7%; 23.1% weak/1+, 42.3% moderate/2+, and 33.3% strong/3+) of 78 non-invasive bladder tumors, which was significantly (P<0.001) lower than in adjacent non-neoplastic urothelial tissues (100%; 20.5% 2+ and 79.5% 3+). Moreover, the risks for disease recurrence after transurethral surgery were marginally lower in female patients with MR-high (2+/3+) tumor (P=0.068) and significantly lower in all patients with MR-high/glucocorticoid receptor-high tumor (P=0.025), compared with respective controls. These findings suggest that MR signaling functions as a suppressor for urothelial tumorigenesis.

Up-regulation of secretory leukocyte protease inhibitor in human samples might have a potential role of predicting prostate cancer recurrence and progression after surgery and hormonal therapy.

Using new castration-resistant prostate cancer (CRPC) cell lines developed from LNCaP cells as a model for CRPC, we searched for novel biomarkers by analyzing the proteins secreted in culture supernatants. The results showed that the levels of secretory leukocyte protease inhibitor (SLPI) in these cell lines were 4.7-6.7 times higher than those secreted in parental LNCaP. Patients with localized prostate cancer (PC) and who expressed SLPI had a significantly lower prostate-specific antigen (PSA) progression-free survival rate than those who did not. Multivariate analysis revealed that SLPI expression was an independent risk factor for PSA recurrence. By contrast, when immunostaining of SLPI was performed on consecutive prostate tissue samples obtained from 11 patients, both in hormone naive (HN) and castration resistant (CR) conditions, only one patient expressed SLPI in the HNPC state; however, four of the 11 patients expressed SLPI in the CRPC state. In addition, two of these four patients were resistant to enzalutamide, and there was a discrepancy between their serum PSA levels and radiographic progression of the disease. These results suggest that SLPI can be a predictor of prognosis in patients with localized PC and disease progression in CRPC patients.

The Clinical Significance of pT3a Lesions as Well as Unilateral Versus Bilateral Invasion Into the Seminal Vesicle in Men With pT3b Prostate Cancer: A Proposal for a New pT3b Subclassification.

CONTEXT.­: Seminal vesicle invasion (SVI) as pT3b prostate cancer generally, but not uniformly, indicates poor prognosis. OBJECTIVE.­: To determine the clinical impact of pT3a lesions (ie, extraprostatic extension other than seminal vesicle or bladder invasion [EPE], microscopic bladder neck invasion [mBNI]), as well as unilateral (Uni) versus bilateral (Bil) SVI in pT3b disease. DESIGN.­: We assessed radical prostatectomy findings and long-term oncologic outcomes in 248 consecutive patients with pT3b disease. RESULTS.­: Focal EPE, nonfocal EPE, mBNI, Uni-SVI, and Bil-SVI were identified in 13 (5.2%), 206 (83.1%), 48 (19.4%), 109 (44.0%), and 139 (56.0%) cases, respectively. Of possible combinations, we eventually divided our cases into 3 cohorts-Group 1: Uni/Bil-SVI and EPE-/mBNI- (n = 28; 11.3%); Group 2: Uni-SVI and EPE or mBNI (n = 103; 41.5%); and Group 3: Bil-SVI and EPE or mBNI (n = 70; 28.2%) or Uni/Bil-SVI and EPE+/mBNI+ (n = 47; 19.0%). Group 3 patients showed significant adverse histopathologic findings, compared with Group 1 or Group 2 patients. Kaplan-Meier analysis revealed that the prognosis was worse in the following order: Group 1, Group 2, and Group 3; and the differences in progression-free survival between any 2 groups were statistically significant. These significant differences were also seen in subgroups, such as those without or with adjuvant therapy before recurrence and those without lymph node metastasis. Additionally, Group 3 patients had a significantly higher risk of cancer-specific mortality than Group 2 patients. In multivariate analysis (Group 2 as a reference), Group 1 (hazard ratio [HR] = 0.169, P = .01) and Group 3 (HR = 1.620, P = .04) showed significance for progression. CONCLUSIONS.­: From these significant findings, we propose a novel pT3b subclassification, namely pT3b1 (Group 1), pT3b2 (Group 2), and pT3b3 (Group 3), which more accurately stratifies its prognosis.

The Clinical Impact of Comedonecrosis Within Intraductal Carcinoma of the Prostate.

CONTEXT.­: Intraductal carcinoma of the prostate (IDC-P) is considered a distinct form of aggressive prostate cancer where comedonecrosis, a grade 5 pattern, is occasionally present. Meanwhile, assigning a Gleason grade to IDC-P remains controversial. OBJECTIVE.­: To assess the clinical significance of necrosis associated with IDC-P. DESIGN.­: We compared radical prostatectomy (RP) findings and oncologic outcomes in men with prostate cancer exhibiting IDC-P with (IDC-P+/N+) versus without (IDC-P+/N-) comedonecrosis. RESULTS.­: Of the 558 RPs examined, IDC-P was present in 213 cases (38.2%), including 167 (78.4%) with IDC-P+/N- and 46 (21.6%) with IDC-P+/N+. When comparing IDC-P+/N- versus IDC-P+/N+ cases, the presence of necrosis was significantly associated with higher tumor grade, higher incidence of pT3/pT3b or pN1 disease, and larger estimated tumor volume. Outcome analysis revealed a significantly higher risk of disease progression in IDC-P+/N+ patients than in IDC-P+/N- patients (P < .001). Significant differences in progression-free survival between IDC-P+/N- and IDC-P+/N+ patients were also seen in subgroups, such as those without (P = .01) or with (P = .03) adjuvant therapy immediately after RP, those with pN0 disease (P < .001), and, more interestingly, those exhibiting conventional Gleason pattern 5 component (P = .02). Multivariate analysis showed significance for IDC-P+/N+ when IDC-P (grade 4) and IDC-P+/N+ (grade 5) were (hazard ratio, 1.768; P = .049) or were not (hazard ratio, 2.000; P = .008) incorporated into the Gleason score. CONCLUSIONS.­: IDC-P+/N+ was found to be associated with worse histopathologic features on RP and poorer prognosis as an independent predictor. Pathologists may thus need to report the presence or absence of not only IDC-P but also comedonecrosis within IDC-P.

Clinical Significance of Perineural Invasion by Prostate Cancer Detected on Needle Core Biopsy.

OBJECTIVES: The clinical impact of the laterality of perineural invasion (PNI) by prostate cancer remains poorly understood. We herein compared radical prostatectomy (RP) findings and long-term oncologic outcomes in patients with prostate cancer with PNI in two prostate biopsy (PBx) sites. METHODS: We retrospectively assessed 170 consecutive patients undergoing systematic sextant PBx where PNI had been detected in two of six PBx sites, followed by RP. RESULTS: PNI occurred unilaterally in 140 (82.4%) cases and bilaterally in 30 (17.6%) cases. Compared with unilateral PNI, bilateral PNI was significantly associated with a higher number of cancer-positive sites and longer total tumor length on PBx. However, there were no significant differences in RP findings, including tumor grade/stage and tumor volume, between unilateral and bilateral PNI cohorts. Kaplan-Meier analysis revealed that patients with bilateral PNI had a significantly higher risk of disease progression after RP than those with unilateral PNI (P = .038). In multivariate analysis, bilateral PNI (vs unilateral PNI) showed significance for progression (hazard ratio, 2.281; P = .023). CONCLUSIONS: In PBx specimens exhibiting PNI in two sextant sites, bilateral PNI was found to be associated with poorer prognosis as an independent predictor but not worse histopathologic features in RP specimens compared with unilateral PNI.

The Clinical Significance of Either Extraprostatic Extension or Microscopic Bladder Neck Invasion Alone Versus Both in Men With pT3a Prostate Cancer Undergoing Radical Prostatectomy: A Proposal for a New pT3a Subclassification.

The prognosis of prostate cancers exhibiting extraprostatic extension [other than bladder or seminal vesicle invasion (EPE)] and/or microscopic bladder neck invasion (mBNI) is variable, and further risk stratification is required. We herein assessed radical prostatectomy findings and long-term oncologic outcomes in consecutive 957 patients with pT3a disease. The patient cohort was divided into 4 groups, focal EPE (F-EPE) only (n=177; 18.5%), nonfocal/established (E-EPE) only (n=634; 66.2%), mBNI only (n=51; 5.3%). The rate of positive surgical margin and estimated volume of tumor were significantly higher in patients with both EPE and mBNI than in those with either. In addition, compared with F-EPE or mBNI only, E-EPE only was significantly associated with higher Grade Group, lymph node metastasis, and larger tumor volume. Kaplan-Meier analysis revealed a comparable prognosis after prostatectomy between those showing F-EPE only versus mBNI only ( P =0.986), and these 2 cohorts were combined for further analysis. Then, patients showing E-EPE only had a significantly higher or lower risk of progression compared with those showing F-EPE or mBNI only ( P <0.001) or both EPE and mBNI ( P <0.001), respectively. These significant differences in progression-free survival were also seen in subgroups, including those with or without undergoing adjuvant therapy before recurrence and those showing no lymph node metastasis. In multivariate analysis, F-EPE or mBNI only (hazard ratio=0.524, P =0.003) or both EPE and mBNI (hazard ratio=1.465, P =0.039) (vs. E-EPE only) showed significance for progression. Based on these findings, we propose a novel pT3a subclassification, pT3a1 (F-EPE or mBNI alone), pT3a2 (E-EPE alone), and pT3a3 (both EPE and mBNI).