A nomogram to predict the absence of clinically significant prostate cancer in males with negative MRI

PURPOSE: To create a nomogram to predict the absence of clinically significant prostate cancer (CSPCa) in males with non-suspicion multiparametric magnetic resonance imaging (mpMRI) undergoing prostate biopsy (PBx). MATERIALS AND METHODS: We identified consecutive patients who underwent 3T mpMRI followed by PBx for suspicion of PCa or surveillance follow-up. All patients had Prostate Imaging Reporting and Data System score 1-2 (negative mpMRI). CSPCa was defined as Grade Group ≥2. Multivariate logistic regression analysis was performed via backward elimination. Discrimination was evaluated with area under the receiver operating characteristic (AUROC). Internal validation with 1,000x bootstrapping for estimating the optimism corrected AUROC. RESULTS: Total 327 patients met inclusion criteria. The median (IQR) age and PSA density (PSAD) were 64 years (58-70) and 0.10 ng/mL2 (0.07-0.15), respectively. Biopsy history was as follows: 117 (36%) males were PBx-naive, 130 (40%) had previous negative PBx and 80 (24%) had previous positive PBx. The majority were White (65%); 6% of males self-reported Black. Overall, 44 (13%) patients were diagnosed with CSPCa on PBx. Black race, history of previous negative PBx and PSAD ≥0.15ng/mL2 were independent predictors for CSPCa on PBx and were included in the nomogram. The AUROC of the nomogram was 0.78 and the optimism corrected AUROC was 0.75. CONCLUSIONS: Our nomogram facilitates evaluating individual probability of CSPCa on PBx in males with PIRADS 1-2 mpMRI and may be used to identify those in whom PBx may be safely avoided. Black males have increased risk of CSPCa on PBx, even in the setting of PIRADS 1-2 mpMRI.

Clinical, pathological, and therapeutic features of newly diagnosed prostate cancer predominantly detected by opportunistic PSA screening: A survey of Shiga Prefecture, Japan.

BACKGROUND: In all the prefectures of Japan, with the exception of Shiga Prefecture, more than half of local governments have an organized prostate-specific antigen (PSA) screening system in place. However, in the Shiga Prefecture, only a single city performed PSA screening over the time period of this survey. The purpose of the present study was to determine the clinical, pathological, and therapeutic features of newly diagnosed prostate cancer in localities where a formally organized screening system was almost entirely absent. METHODS: A multicenter observational study was conducted in the Shiga Prefecture, which has the lowest rate of population-based PSA-screening in Japan. Patients' age, initial PSA, reasons for PSA testing, Gleason score, clinical stage, and primary treatments were surveyed. We stratified patients according to the reasons for PSA measurement, and compared the differences between groups subject to organized versus opportunistic screening. RESULTS: In the 2 years 2012 and 2017, 984 newly diagnosed prostate cancer patients were analyzed. Of these, 954 (97%) were opportunistically tested (i.e., not as part of an organized screening system), with the remaining 29 (3%) measured as part of an organized screening program. Patients in the former group exhibited a higher initial PSA value than in the organized screening group (median: 11.49 vs. 5.67 ng/ml). They also had worse clinical features, including higher Gleason score and TNM stage. More patients in the organized screening group were treated curatively than in the nonorganized screening group in terms of the primary treatment. The results were similar in a subanalysis of the patients of age 50-69 years. CONCLUSIONS: Organized PSA screening contributes to increasing the number of patients diagnosed with early-stage cancer who can be treated curatively.

Systematic Biopsy of the Prostate can Be Omitted in Men with PI-RADS™ 5 and Prostate Specific Antigen Density Greater than 15.

PURPOSE: We evaluated the prostate cancer and clinically significant prostate cancer detection on systematic biopsy (SB), target biopsy (TB) alone and combined SB and TB in men with Prostate Imaging Reporting and Data System™ (PI-RADS™) 5 lesion. MATERIALS AND METHODS: From a prospectively maintained prostate biopsy database, we identified consecutive patients with PI-RADS 5 lesion on multiparametric magnetic resonance imaging. The patients underwent multiparametric magnetic resonance imaging followed by transrectal TB of PI-RADS 5 lesion and 12-core SB. The prostate cancer and clinically significant prostate cancer (Grade Group, GG ≥2) detection on SB, TB and SB+TB were determined for all men and accordingly to prostate specific antigen density. Statistic significant was set a p <0.05. RESULTS: Overall, 112 patients met inclusion criteria. The detection rate of prostate cancer for SB, TB and SB+TB was 89%, 93% and 95%, respectively, and for clinically significant prostate cancer it was 72%, 81% and 85%, respectively. SB added 2% prostate cancer and 4% clinically significant prostate cancer detection to TB. A total of 78 patients had prostate specific antigen density >0.15 ng/ml2, and the detection rate of PCa for SB, TB and SB+TB was 92%, 97% and 97%, respectively, and for clinically significant prostate cancer it was 79%, 91% and 95%, respectively. In this population, if SB was omitted, 0 prostate cancer and only 4% (3) of clinically significant prostate cancer would be missed. The clinically significant prostate cancer detection rate improved with increased prostate specific antigen density for SB (p=0.01), TB (p <0.0001) and combined SB+TB (p=0.002). CONCLUSIONS: In patients with PI-RADS 5 on multiparametric magnetic resonance imaging and prostate specific antigen density >0.15 ng/ml2, SB marginally increases clinically significant prostate cancer detection, but not overall prostate cancer detection in comparison to TB alone. Systematic biopsy did not affect patients' management and can be omitted on this population.

Multiparametric magnetic resonance imaging facilitates reclassification during active surveillance for prostate cancer.

OBJECTIVE: To investigate the utility of multiparametric magnetic resonance imaging (mpMRI) in the reassessment and monitoring of patients on active surveillance (AS) for Grade Group (GG) 1 prostate cancer (PCa). PATIENTS AND METHODS: We identified, from our prospectively maintained institutional review board-approved database, 181 consecutive men enrolled on AS for GG 1 PCa who underwent at least one surveillance mpMRI followed by MRI/prostate biopsy (PBx). A subset analysis was performed among 68 patients who underwent serial (at least two) mpMRI/PBx during AS. Pathological progression (PP) was defined as upgrade to GG ≥2 on follow up biopsy. RESULTS: Baseline MRI was performed in 34 patients (19%). At a median follow-up of 2.2 years for the overall cohort, the PP was 12% (6/49) for Prostate Imaging Reporting and Data System (PI-RADS) 1-2 lesions and 37% (48/129) for the PI-RADS ≥3 lesions. The 2-year PP-free survival rate was 84%. Surveillance prostate-specific antigen density (P < 0.001) and surveillance PI-RADS ≥3 (P = 0.002) were independent predictors of PP on reassessment MRI/PBx. In the serial MRI cohort, the 2-year PP-free survival was 95% for the No-MRI-progression group vs 85% for the MRI-progression group (P = 0.02). MRI progression was significantly higher in the PP (62%) than in the No-PP (31%) group (P = 0.04). If serial MRI were used for PCa surveillance and biopsy were triggered based only on MRI progression, 63% of PBx might be postponed at the cost of missing 12% of GG ≥2 PCa in those with stable MRI. Conversely, this strategy would miss 38% of those with upgrading to GG ≥2 PCa on biopsy. Stable serial mpMRI correlates with no reclassification to GG ≥3 PCa during AS. CONCLUSION: On surveillance mpMRI, PI-RADS ≥3 was associated with increased risk of PCa reclassification. Surveillance biopsy based only on MRI progression may avoid a large number of biopsies at the cost of missing many PCa reclassifications.

MRI predicts prostatic urethral involvement in men undergoing radical prostatectomy: implications for cryo-ablation of localized prostate cancer.

PURPOSE: To 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. METHODS: Clinical 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. RESULTS: Of 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. CONCLUSIONS: Nearly 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.

Five-alpha reductase inhibitors in men undergoing active surveillance for prostate cancer: impact on treatment and reclassification after 6 years follow-up.

OBJECTIVES: To evaluate the impact of 5-alpha reductase inhibitors (5-ARIs) on definitive treatment (DT) and pathological progression (PP) in patients on active surveillance (AS) for prostate cancer. METHODS: We identified 361 consecutive patients, from an IRB-approved database, on AS for prostate cancer with minimum 2 years follow-up. Patients were grouped into two cohorts, those using 5-ARIs (5-ARI; n = 119) or not using 5-ARIs (no 5-ARI; n = 242). Primary and secondary endpoints were treatment-free survival (TFS) and PP-free survival (PPFS), which were evaluated by Kaplan-Meier analysis. Univariate and multivariable cox regression analysis were used to identify predictors for PP and DT. A p value < 0.05 was considered statistically significant. RESULTS: Baseline characteristics and the prostate biopsy rate were similar between the two groups. Median (range) follow-up was 5.7 (2.0-17.2) years. Five-year and 10-year TFS was 92% and 59% for the 5-ARI group versus 80% and 51% for the no 5-ARI group (p = 0.005), respectively. Five-year and 10-year PPFS was 77% and 41% for the 5-ARI group versus 70% and 32% for the no 5-ARI group (p = 0.04), respectively. Independent predictors for treatment and PP were not taking 5-ARIs (p = 0.005; p = 0.02), entry PSA > 2.5 ng/mL (p = 0.03; p = 0.01) and Gleason pattern 4 on initial biopsy (p < 0.001; p < 0.001), respectively. The main limitation is the retrospective study design. CONCLUSIONS: 5-ARIs reduces reclassification and cross-over to treatment in men on active surveillance for prostate cancer. Further, taking 5-ARIs was an independent predictor for prostate cancer progression and definitive treatment.

High Intensity Focused Ultrasound Hemigland Ablation for Prostate Cancer: Initial Outcomes of a United States Series.

PURPOSE: We report outcomes of hemigland high intensity focused ultrasound ablation as primary treatment for localized prostate cancer in the United States. MATERIALS AND METHODS: A total of 100 consecutive men underwent hemigland high intensity focused ultrasound (December 2015 to December 2019). Primary end point was treatment failure, defined as Grade Group 2 or greater on followup prostate biopsy, radical treatment, systemic therapy, metastases or prostate cancer specific mortality. IIEF (International Index of Erectile Function), I-PSS (International Prostate Symptom Score) and 90-day complications were reported. RESULTS: At study entry patients had very low (8%), low (20%), intermediate favorable (50%), intermediate unfavorable (17%) and high (5%) risk prostate cancer. Median followup was 20 months. The 2-year survival free from treatment failure, Grade Group 2 or greater recurrence, repeat focal high intensity focused ultrasound and radical treatment was 73%, 76%, 90% and 91%, respectively. Bilateral prostate cancer at diagnosis was the sole predictor for Grade Group 2 or greater recurrence (p=0.03). Of men who underwent posttreatment biopsy (58), 10 had in-field and 8 out-of-field Grade Group 2 or greater positive biopsy. Continence (zero pad) was maintained in 100% of patients. Median IIEF-5 and I-PSS scores before vs after hemigland high intensity focused ultrasound were 22 vs 21 (p=0.99) and 9 vs 6 (p=0.005), respectively. Minor and major complications occurred in 13% and 0% of patients. No patient had rectal fistula or died. CONCLUSIONS: Short-term results of focal high intensity focused ultrasound indicate safety, excellent potency and continence preservation, and adequate short-term prostate cancer control. Radical treatment was avoided in 91% of men at 2 years. Men with bilateral prostate cancer at diagnosis have increased risk for Grade Group 2 or greater recurrence. To our knowledge, this is the initial and largest United States series of focal high intensity focused ultrasound as primary treatment for prostate cancer.

Higher expression of phosphodiesterase type 5 in the anterior fibromuscular stroma of the human prostate.

PURPOSE: To examine phosphodiesterase type 5 (PDE5) expression in the anterior fibromuscular stroma (AFMS) of the prostate. Although PDE5 expression was identified in the human prostate, differences in PDE5 expression in intra-prostatic regions are unknown. The AFMS in the prostate has peculiar innervations that could contribute to voiding function. Here, we examined regional differences in PDE5 expression in the prostate with special reference to the AFMS. METHODS: A total 18 human prostate and bladder specimens were obtained. Tissue specimens were processed by hematoxylin-eosin (H&E) staining and immunohistochemistry for PDE5. Immunoreactivity with PDE5 was evaluated using computer-assisted image analysis in the following regions: the AFMS, bladder neck, stromal hyperplasia in the transition zone, glandular hyperplasia in the transition zone (TZ gland), and the peripheral zone (PZ). The correlation between PDE5 expression in the AFMS and clinical data was analysed. RESULTS: Image analysis revealed that the median ratio of the PDE5-immunoreactive area to smooth muscle area by H&E staining was 74.7% in the AFMS. There was significantly higher PDE5 expression in the AFMS than in the TZ gland (p = 0.034) and PZ (p = 0.002). PDE5 expression in the AFMS was not significantly correlated with age, prostate volume, transition zone volume, or transition zone index. However, older men had a tendency to have higher PDE5 expression in the AFMS. CONCLUSIONS: We found higher PDE5 expression in the AFMS compared with other prostatic regions, which suggested that the AFMS is a target region of PDE5 inhibitors in the prostate.

One-Stop MRI and MRI/transrectal ultrasound fusion-guided biopsy: an expedited pathway for prostate cancer diagnosis.

PURPOSE: To assess the feasibility, safety, and outcomes of an expedited One-Stop prostate cancer (PCa) diagnostic pathway. PATIENTS AND METHODS: We identified 370 consecutive patients who underwent multiparametric magnetic resonance imaging (mpMRI) and transrectal ultrasound fusion prostate biopsy (MRI/TRUS-PBx) from our institutional review board-approved database. Patients were divided according to diagnostic pathway: One-Stop (n = 74), with mpMRI and same-day PBx, or Standard (n = 296), with mpMRI followed by a second visit for PBx. mpMRIs were performed and interpreted according to Prostate Imaging-Reporting and Data System (PI-RADS v2). Grade group ≥ 2 PCa defined clinically significant PCa (csPCa). Statistical significance was considered when p < 0.05. RESULTS: Age (66 vs 66 years, p = 0.59) and PSA density (0.1 vs 0.1 ng/mL2, p = 0.26) were not different between One-Stop vs Standard pathway, respectively. One-Stop patients lived further away from the hospital than Standard patients (163 vs 31 km; p < 0.01), and experienced shorter time from mpMRI to PBx (0 vs 7 days; p < 0.01). The number (p = 0.56) and distribution of PI-RADS lesions (p = 0.67) were not different between the groups. All procedures were completed successfully with similar perioperative complications rate (p = 0.24). For patients with PI-RADS 3-5 lesions, the csPCa detection rate (49% vs 41%, p = 0.55) was similar for One-Stop vs Standard, respectively. The negative predictive value of mpMRI (PI-RADS 1-2) for csPCa was 78% for One-Stop vs 83% for Standard (p = 0.99). On multivariate analysis, age, prostate volume and PI-RADS score (p < 0.01), but not diagnostic pathway, predicted csPCa detection. CONCLUSION: A One-Stop PCa diagnostic pathway is feasible, safe, and provides similar outcomes in a shorter time compared to the Standard two-visit diagnostic pathway.

Hemigland Cryoablation of Localized Low, Intermediate and High Risk Prostate Cancer: Oncologic and Functional Outcomes at 5 Years.

PURPOSE: We evaluated 5-year oncologic and functional outcomes of hemigland cryoablation of localized prostate cancer. MATERIALS AND METHODS: We reviewed the records of 160 consecutive men who underwent hemigland cryoablation of localized prostate cancer. Recurrent and/or residual clinically significant prostate cancer was defined as Grade Group 2 or greater on followup biopsy. A prostate specific antigen nadir plus 2 ng/ml according to the Phoenix criteria was used to define biochemical failure. Radical treatment was defined as any whole gland therapy. Treatment failure was defined as any radical and/or whole gland treatment, systemic therapy initiation, metastasis or prostate cancer specific mortality. The study primary end point was treatment failure-free survival. The secondary end points were survival free of biochemical failure, clinically significant prostate cancer and radical treatment. Followup biopsy and functional outcomes were also evaluated. Statistical analysis included the Kaplan-Meier method, and univariate and multivariable Cox and logistic regression with significance considered at p <0.05. RESULTS: Median patient age was 67 years, baseline prostate specific antigen was 6.3 ng/ml and followup was 40 months. A total of 131 patients (82%) had D'Amico intermediate (66%) or high risk (16%) prostate cancer. At 5 years the treatment failure-free survival rate was 85%, the biochemical failure-free survival rate was 62% and the survival rate free of clinically significant prostate cancer was 89%. Higher baseline prostate specific antigen independently predicted treatment failure (p <0.001), biochemical failure (p=0.048), recurrence and radical treatment (p <0.01). Grade Group 3 or greater independently predicted treatment failure (p=0.04). The metastasis-free survival rate was 100% at 5 years. Pad-free continence and potency (erections sufficient for intercourse) were retained in 97% and 73% of patients, respectively. There was no rectal fistula or mortality. CONCLUSIONS: Hemigland cryoablation of localized prostate cancer provides effective midterm oncologic outcomes with good continence and potency. Patients with higher baseline prostate specific antigen are at increased risk for biochemical failure, recurrent cancer and treatment failure.

[A Case of Primary Testicular Mucinous Carcinoma].

A 68-year-old man presented withleft testicular painless swelling. His carbohydrate antigen 19-9 and carcinoembryonic antigen levels were elevated but his germ cell tumor markers were not high. Magnetic resonance imaging showed multiloculated cystic lesions with solid components in his left testis. Abdominal and chest computed tomography revealed multiple lung metastases, peritoneal dissemination and multiple lymph node metastases. Left high orchiectomy was performed. Histopathological examination demonstrated testicular mucinous carcinoma withsimilarity to gastric cancer. Since no tumor was found by the endoscopy of the upper gastrointestinal and the lower digestive tract, we diagnosed the patient with primary testicular mucinous carcinoma. Standard chemotherapy for gastric cancer, which consisted of tegafur, gimeracil and oteracil (TS-1) and cisplatin was administered for 16 months, and there was no progression of the disease. He died from testicular mucinous cancer 30 months after the diagnosis. In the literature, only 4 cases of testicular mucinous carcinoma have been reported. TS-1 and cisplatin are useful chemotherapeutic options for testicular mucinous carcinoma withmetastasis.

[Spontaneous Subcapsular Renal Hemorrhage of Papillary Renal Cell Carcinoma].

A 75-year-old man with a history of chronic kidney disease (CKD) visited our emergency room after the sudden onset of severe right lower abdominal pain and nausea. Computed tomography (CT) showed right perirenal hematoma and renal tumor, which was diagnosed as a spontaneous rupture of the right renal tumor. It was difficult to correctly diagnose the tumor as benign or malignant with magnetic resonance imaging (MRI). Because of CKD, a shunt was implanted, and dynamic enhanced CT was performed. Dynamic enhanced CT showed a slightly enhanced area of the tumor, and it was diagnosed as renal cell carcinoma (RCC). Radical nephrectomy was performed, and he has not experienced recurrence within 7 months after the surgery. Pathological diagnosis was papillary renal carcinoma. Spontaneous renal hemorrhage is relatively uncommon, but the most common cause of spontaneous renal hemorrhage is renal cell carcinoma (26.1%). CT is useful for diagnosis, but it is not highly accurate. Therefore, it is necessary to discuss surgical indication carefully.

Assessment of permanent brachytherapy combined with androgen deprivation therapy in an intermediate-risk prostate cancer group without a Gleason score of 4 + 3: a single Japanese institutional experience.

OBJECTIVES: To evaluate the outcome of low-dose-rate permanent brachytherapy combined with anti-androgen deprivation therapy for intermediate-risk prostate cancer excluding biopsy Gleason score 4 + 3. METHODS: Patients included in the intermediate-risk group were those presenting clinical stage T1c to T2c (by magnetic resonance imaging staging), Gleason score 3 + 4 or lower and/or prostate-specific antigen less than 20 ng/mL, whereas those with clinical stage T1c to T2a, Gleason score 3 + 3 and prostate-specific antigen less than 10 ng/mL represented the low-risk group, and were used as controls. In the intermediate-risk group, therapy with a luteinizing hormone-releasing hormone analog was continued for at least 6 months before and after permanent brachytherapy. RESULTS: A total of 147 low-risk group patients and 139 intermediate-risk group patients were included in the study. The median follow up was 51 and 52 months for the intermediate-risk group and low-risk group, respectively. The 5-year overall, cause-specific and distant-metastasis-free survival rates in the low-risk group and intermediate-risk group were 97.6/99.2, 100/100 and 100/100%, respectively. The 5-year biochemical disease-free survival in these groups were 95.9 and 92.5%, respectively (P = 0.18). There was no sexual activity and desire for erection before treatment in 50%, and in 46% of the patients in the low-risk group and intermediate-risk group, respectively. Overall satisfaction score at 2 years after permanent brachytherapy significantly improved, compared with pretreatment (P = 0.0399). CONCLUSIONS: In intermediate-risk prostate cancer, excluding biopsy Gleason score 4 + 3, permanent brachytherapy combined with androgen deprivation therapy for 6 months or more represents an effective treatment option in Japanese patients, based on a favorable prognosis, adverse event profile and quality of life analysis.

Low muscle mass in patients with stroke on admission reduces walking ability at discharge.

BACKGROUND & AIMS: Reduced skeletal muscle mass may negatively influence postural retention and walking function. This study aimed to examine the influence of the skeletal muscle mass index on walking function in patients with stroke. METHODS: This study included patients with cerebral infarction aged ≥65 years. The Asian Working Group for Sarcopenia's skeletal muscle mass index criteria were used to classify the participants into the low and high skeletal muscle mass index groups. The patient characteristics of the two groups were compared. The primary and secondary outcome measures were independent walking and walking speed, respectively. RESULTS: In total, 174 participants were included. There were no significant differences in the length of hospital stay, rehabilitation volume, or functional independence measure score at discharge between the males and females. Multivariate logistic regression analysis revealed that independent walking was independently associated with the skeletal muscle mass index on admission. The SMI, as an explanatory variable, was independently associated with the comfortable and fastest walking speeds. Faster walking was associated with higher skeletal muscle mass indexes on admission for both males and females. CONCLUSIONS: A low skeletal muscle mass index negatively influences walking function improvement in patients with stroke. A strategy aimed at increasing skeletal muscle mass can have beneficial effects on walking function in patients with stroke.

Cytoplasmic PTEN protein loss distinguishes intraductal carcinoma of the prostate from high-grade prostatic intraepithelial neoplasia.

Intraductal carcinoma of the prostate is a marker of aggressive disease. However, intraductal carcinoma exists on a morphologic continuum with high-grade prostatic intraepithelial neoplasia (PIN) and distinguishing intraductal carcinoma from PIN is a common diagnostic dilemma with significant clinical implications. We evaluated whether immunostains for PTEN and ERG can sensitively identify intraductal carcinoma and accurately distinguish it from high-grade PIN. A combined immunostain for PTEN, ERG, p63 and CK903 was developed and validated. Radical prostatectomy specimens with lesions meeting criteria for intraductal carcinoma (n=45), intraductal cribriform proliferations falling short of intraductal carcinoma (n=15), and PIN lesions (n=39) were retrospectively identified and assessed for PTEN and ERG. Cytoplasmic PTEN loss was identified in 84% (38/45) of the intraductal carcinoma and 100% (15/15) of intraductal cribriform proliferation cases. In contrast, cytoplasmic PTEN loss was never observed in PIN (0/39; P<0.0001). Of the 53 cases of intraductal carcinoma or intraductal cribriform proliferation with cytoplasmic PTEN loss, it was homogeneously lost in 42 cases (79%). Weak, focal nuclear positivity for PTEN was retained in 31 of these 42 cases (74%). ERG expression was identified in 58% (26/45) of intraductal carcinoma and 67% (10/15) of intraductal cribriform proliferations compared with 13% (5/39) of PIN. Concordance between the PTEN/ERG status of the intraductal carcinoma lesions and the concurrent invasive carcinoma was high (>95% and P<0.0001 for each), and substantially less for PIN and the concurrent invasive tumor (83% for PTEN and 67% for ERG; P=NS for each). Cytoplasmic PTEN loss occurs in the majority of intraductal carcinoma and intraductal cribriform proliferation cases. Cytoplasmic PTEN loss was never observed in PIN (100% specificity). Our study identifies PTEN loss as a potentially useful marker to distinguish intraductal carcinoma from PIN and provides a plausible molecular explanation for why intraductal carcinoma is associated with poor prognosis.

Global levels of H3K27me3 track with differentiation in vivo and are deregulated by MYC in prostate cancer.

Cancer cells and stem cells share a number of biological characteristics including abundant amounts of decondensed chromatin. However, the molecular correlates and the factors involved in altering chromatin structure in cancer cells are not well known. Here, we report that less differentiated stem-like cells in the basal compartment of human and mouse prostate contain lower levels of the polycomb heterochromatin marker H3K27me3 than more differentiated luminal cells. This link to differentiated normal cells is also found in a number of other human and rodent tissues characterized by hierarchical differentiation. In addition to MYC's traditional role as a gene-specific transcription factor, recent studies indicate that MYC also affects global chromatin structure where it is required to maintain "open" or active chromatin. We now demonstrate that in both MYC-driven prostate cancers in mice and human prostate cancers, global levels of H3K27me3 are reduced in prostatic intraepithelial neoplasia and invasive adenocarcinoma lesions. Moreover, decreased levels of H3K27me3 correlate with increased markers of disease aggressiveness (eg, Gleason score and pathological stage). In vitro, experimentally forced reductions in MYC levels result in increased global levels of H3K27me3. These findings suggest that increased levels of decondensed chromatin in both normal progenitor cells and cancer cells are associated with global loss of H3K27me3, which is linked to MYC overexpression.