Uncovering prostate cancer aggressiveness signal in T2-weighted MRI through a three-reference tissues normalization technique.

Quantitative T2-weighted MRI (T2W) interpretation is impeded by the variability of acquisition-related features, such as field strength, coil type, signal amplification, and pulse sequence parameters. The main purpose of this work is to develop an automated method for prostate T2W intensity normalization. The procedure includes the following: (i) a deep learning-based network utilizing MASK R-CNN for automatic segmentation of three reference tissues: gluteus maximus muscle, femur, and bladder; (ii) fitting a spline function between average intensities in these structures and reference values; and (iii) using the function to transform all T2W intensities. The T2W distributions in the prostate cancer regions of interest (ROIs) and normal appearing prostate tissue (NAT) were compared before and after normalization using Student's t-test. The ROIs' T2W associations with the Gleason Score (GS), Decipher genomic score, and a three-tier prostate cancer risk were evaluated with Spearman's correlation coefficient (rS ). T2W differences in indolent and aggressive prostate cancer lesions were also assessed. The MASK R-CNN was trained with manual contours from 32 patients. The normalization procedure was applied to an independent MRI dataset from 83 patients. T2W differences between ROIs and NAT significantly increased after normalization. T2W intensities in 231 biopsy ROIs were significantly negatively correlated with GS (rS = -0.21, p = 0.001), Decipher (rS = -0.193, p = 0.003), and three-tier risk (rS = -0.235, p < 0.001). The average T2W intensities in the aggressive ROIs were significantly lower than in the indolent ROIs after normalization. In conclusion, the automated triple-reference tissue normalization method significantly improved the discrimination between prostate cancer and normal prostate tissue. In addition, the normalized T2W intensities of cancer exhibited a significant association with tumor aggressiveness. By improving the quantitative utilization of the T2W in the assessment of prostate cancer on MRI, the new normalization method represents an important advance over clinical protocols that do not include sequences for the measurement of T2 relaxation times.

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.

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.

Heterogeneity in Genomic Risk Assessment from Tissue Based Prognostic Signatures Used in the Biopsy Setting and the Impact of Magnetic Resonance Imaging Targeted Biopsy.

PURPOSE: Genomic prognostic signatures are used on prostate biopsy tissue for cancer risk assessment, but tumor heterogeneity and multifocality may be an issue. We evaluated the variability in genomic risk assessment from different biopsy cores within the prostate using 3 prognostic signatures (Decipher, CCP, GPS). MATERIALS AND METHODS: Men in this study came from 2 prospective prostate cancer trials of patients undergoing multiparametric magnetic resonance imaging and magnetic resonance imaging targeted biopsy with genomic profiling of positive biopsy cores. We explored the relationship among tumor grade, magnetic resonance imaging risk and genomic risk for each signature. We evaluated the variability in genomic risk assessment between different biopsy cores and assessed how often magnetic resonance imaging targeted biopsy or the current standard of care (profiling the core with the highest grade) resulted in the highest genomic risk level. RESULTS: In all, 224 positive biopsy cores from 78 men with prostate cancer were profiled. For each signature, higher biopsy grade (p <0.001) and magnetic resonance imaging risk level (p <0.001) were associated with higher genomic scores. Genomic scores from different biopsy cores varied with risk categories changing by 21% to 62% depending on which core or signature was used. Magnetic resonance imaging targeted biopsy and profiling the core with the highest grade resulted in the highest genomic risk level in 72% to 84% and 75% to 87% of cases, respectively, depending on the signature used. CONCLUSIONS: There is variation in genomic risk assessment from different biopsy cores regardless of the signature used. Magnetic resonance imaging directed biopsy or profiling the highest grade core resulted in the highest genomic risk level in most cases.

Safety and efficacy of holmium laser enucleation of prostate as salvage procedure for persistent or recurrent lower urinary tract symptoms secondary to bladder outlet obstruction after prior prostate artery embolization: a match analysis.

PURPOSE: To evaluate safety and efficacy of Holmium laser enucleation of Prostate (HoLEP) for management of persistent or recurrent lower urinary tract symptoms after prior prostate artery embolization (PAE). We also evaluated histopathological changes in prostate after PAE. METHODS: Ten patients who underwent HoLEP after prior PAE were matched according to age, weight of resected prostate tissue, and anticoagulation status in 1:2 ratio with patients who underwent HoLEP without prior PAE by a researcher who was blinded to patient's outcome at the time of matching. Histopathological examination of prostate tissue was performed to look for changes related to prior PAE. Patient's demographics, perioperative parameters, and follow-up data were retrospectively compared. RESULTS: The median interval between PAE and HoLEP was 25 months [IQR 14.5-37.5]. Patients demographic were comparable in both groups. Intra-operatively plane of enucleation were well-maintained in spite of prior PAE. The differences in duration of surgery, enucleation efficiency, hemoglobin drop, duration of catheterization and hospital stay, and complications were statistically insignificant. Incidental prostate cancer was identified in 10% specimens from both groups. Post-PAE prostate specimens demonstrated evidence of remote-healed infarction represented by dense hyalinized paucicellur connective tissue with surrounding squamous metaplasia. There were no statistically significant differences in AUA symptom scores, maximum urine flow rate, post-void residual urine volume, and PSA at 3- and 6-month follow-up between both groups. CONCLUSIONS: Plane of enucleation is well-maintained after prior PAE. Salvage HoLEP is safe and effective after previous PAE and provide outcome comparable with HoLEP as a primary procedure.

Prospective Evaluation of Focal High Intensity Focused Ultrasound for Localized Prostate Cancer.

PURPOSE: We report short-term outcomes of focal high intensity focused ultrasound use for primary treatment of localized prostate cancer. MATERIALS AND METHODS: Single-center prospectively collected data on patients with prostate cancer who underwent primary focal high intensity focused ultrasound from January 2016 to July 2018 were included. All patients underwent a 12-core biopsy with magnetic resonance imaging-ultrasound fusion biopsy depending on the presence of targetable lesions. Any Grade Group was allowed, however only patients with localized disease were included. The primary outcome was oncologic control, defined as negative followup in-field biopsy of treated cancer. Prostate specific antigen, Sexual Health Inventory for Men, International Prostate Symptom Score and Expanded Prostate Cancer Index Composite domain scores were assessed 3-monthly till 12 months. Biopsy was performed at 6 or 12 months for high or low/intermediate risk cancer, respectively. RESULTS: Fifty-two patients with minimum followup of 12 months were included in the study. The majority of patients (67%) had cancer Grade Group 2 or greater. Fifteen patients (28.8%) underwent complete transurethral prostate resection/holmium laser enucleation of prostate procedure for debulking large prostates to avoid postoperative urinary retention. Among 30 (58%) patients who underwent followup biopsies, 25 (83%) had negative in-field biopsy results and 4 (13%) had de-novo positive out-of-field biopsy. Only 5 major complications (all grade III) in 4 patients were noted. Urinary symptoms returned to near baseline questionnaire scores within 3-6 months. Sexual function returned to baseline at 12 months. CONCLUSIONS: Focal high intensity focused ultrasound is a safe and effective treatment for patients with localized clinically significant prostate cancer with acceptable short-term oncologic and functional outcomes. The complications are minimal and patient selection is essential. Short-term oncologic outcomes are promising but longer followup is required to establish long-term oncologic outcomes.

Potential effect of anti-inflammatory drug use on PSA kinetics and subsequent prostate cancer diagnosis: Risk stratification in black and white men with benign prostate biopsy.

BACKGROUND: Rising prostate-specific antigen (PSA) levels are associated with both increased risk of prostate cancer and prostatic inflammation. The confounding effects of inflammation on the utility of PSA kinetics to predict prostate cancer may be partially mitigated by anti-inflammatory drug use. We investigated the influence of anti-inflammatory drug use on the association of PSA kinetics with prostate cancer risk. METHODS: We studied 488 prostate cancer case-control pairs (290 white, 198 African American (AA)) nested in a retrospective cohort of men with a benign prostate biopsy. A series of multivariable models estimated prostate cancer risk associated with PSA velocity (PSAV) at different levels of anti-inflammatory drug use while adjusting for the presence of both clinical and histologic prostatitis. RESULTS: In men with one, two, or three or more courses of anti-inflammatory drug use, for each ng/mL/year increase in PSAV, prostate cancer risk increased 1.21-fold, 1.83-fold, and 1.97-fold, respectively ( P < 0.0001). In controls with histologic prostatitis, anti-inflammatory drug use was associated with a significantly lower PSAV ( P < 0.0001). This association was not observed in men with histologic prostatitis who were subsequently diagnosed with prostate cancer. A positive interaction between anti-inflammatory drug use and PSAV-associated prostate cancer risk was only observed in AA men, as well as a strong positive association between any anti-inflammatory drug use and clinical prostatitis ( P = 0.004). CONCLUSIONS: In men with benign prostate biopsy, accounting for the presence of histologic prostatitis and anti-inflammatory drug use, particularly in AA men, may help distinguish between men with rising PSA because of prostatitis vs undiagnosed cancer.

Mimickers of urothelial neoplasia.

Management of malignant urothelial tumors is often associated with extended costly treatments, some with significant morbidity. Advanced tumors are treated with radical cystectomy with neoadjuvant or adjuvant radiation or chemotherapy. Over and under interpretation of histological findings from biopsies and transurethral resections of urothelial lesions may either incur treatments with significant side effects or miss a possible window of cure, respectively. Herein we reflect our approaches and common diagnostic challenges of urothelial tumors and their mimickers, and highlight the diagnostic pitfalls and key histological and immunohistochemical differentiating features. It is useful to separate mimickers of bladder adenocarcinoma and mimics of urothelial carcinoma as the former can involve the muscularis propria, whereas the latter do not. Glandular mimickers discussed herein include cystitis cystica et glandularis with intestinal (colonic) metaplasia, endocervicosis and endometriosis, and nephrogenic adenoma. Common mimickers of urothelial carcinoma include polypoid cystitis, pseudocarcinomatous urothelial neoplasia, inverted urothelial papilloma, florid proliferation of von Brunn nests, and reactive urothelial metaplasia associated with prostatic infarction. We emphasize where clinical impression and history are important for the correct diagnosis. In some entities assessment of the entire histological picture is critical rather than focusing on isolated findings that out of context may be indistinguishable from cancer.

Improving the evaluation and diagnosis of clinically significant prostate cancer.

PURPOSE OF REVIEW: This chapter describes important changes in the clinical practice and pathological interpretation of prostate cancer (PCa) that stratify PCa into insignificant and significant disease to allow for better patient management and treatment decisions. RECENT FINDINGS: Among the most important changes over the last half a decade has been the change in PCa grading. A new grading system has been developed that is more patient-centric with more accurate stratification according to risk of disease progression. An additional advance is the recent recommendation to report percentage of pattern 4 in Gleason score 7 cancer that may help identify a subset of these men who have relatively insignificant prostate cancer. The definition of significant PCa at prostatectomy has also been extended from a dichotomized classification into a more tiered nuanced approach. Factors involved in classification of significant cancer at prostatectomy include grade, stage along with classification of extraprostatic extension into focal and nonfocal, and tumor volume. Of these variables, tumor volume appears to be least critical as an independent variable. Promising genetic discoveries may also help predict significant cancer, especially in the small subset of lower-grade cancers. SUMMARY: Significant PCa is a spectrum of findings bearing different clinical significance with some nuanced definitions at biopsy and prostatectomy.

Methylation in benign prostate and risk of disease progression in men subsequently diagnosed with prostate cancer.

In DNA from prostate tumors, methylation patterns in gene promoter regions can be a biomarker for disease progression. It remains unclear whether methylation patterns in benign prostate tissue--prior to malignant transformation--may provide similar prognostic information. To determine whether early methylation events predict prostate cancer outcomes, we evaluated histologically benign prostate specimens from 353 men who eventually developed prostate cancer and received "definitive" treatment [radical prostatectomy (58%) or radiation therapy (42%)]. Cases were drawn from a large hospital-based cohort of men with benign prostate biopsy specimens collected between 1990 and 2002. Risk of disease progression associated with methylation was estimated using time-to-event analyses. Average follow-up was over 5 years; biochemical recurrence (BCR) occurred in 91 cases (26%). In White men, methylation of the APC gene was associated with increased risk of BCR, even after adjusting for standard clinical risk factors for prostate cancer progression (adjusted hazard ratio (aHR) = 2.26; 95%CI 1.23-4.16). APC methylation was most strongly associated with a significant increased risk of BCR in White men with low prostate specific antigen at cohort entry (HR = 3.66; 95%CI 1.51-8.85). In additional stratified analyses, we found that methylation of the RARB gene significantly increased risk of BCR in African American cases who demonstrated methylation of at least one of the other four genes under study (HR = 3.80; 95%CI 1.07-13.53). These findings may have implications in the early identification of aggressive prostate cancer as well as reducing unnecessary medical procedures and emotional distress for men who present with markers of indolent disease.

Changes in prostate cancer grading: Including a new patient-centric grading system.

The first structured approach to grade prostate cancer based on the underlying histological architecture was developed by Donald Gleason who in 1966 proposed a morphologic classification of prostate cancer and in 1974 demonstrated its clinical significance based on prostate cancer-specific death. Contemporarily referred to as the Gleason grading system, it has gained worldwide recognition allowing a more individualized approach to patients with prostate cancer. In 2005, the International Society of Urologic Pathology (ISUP) made the first revisions to the grading system. Subsequently, based on the new discoveries in pathologic and clinical aspects of prostate cancer, as well as the changing nature of the prostate cancer in part due to a robust screening, there was a need for experts to re-visit the approach to grade prostate cancer. In November 2014, the ISUP experts and clinical leaders in prostate cancer from 17 countries conducted a consensus conference in Chicago, IL, USA. The consensus conference defined various grade patterns and proposed the adoption of a new grading system of prostate cancer. Herein, we describe the background and rationale for the changes and provide guidelines to their clinical implementation.

Definition of Insignificant Tumor Volume of Gleason Score 3 + 3 = 6 (Grade Group 1) Prostate Cancer at Radical Prostatectomy-Is it Time to Increase the Threshold?

PURPOSE: We investigated the tumor volume of insignificant Gleason score 3 + 3 = 6 (Grade Group 1) prostate cancer with contemporary grading. MATERIALS AND METHODS: We studied 439 consecutive radical prostatectomies with Gleason score 3 + 3 = 6 (Grade Group 1) cancer entirely submitted for histological examination. RESULTS: A total of 407 cases (92.7%) were organ confined (pT2), 17 (3.9%) had a positive margin at the apex (pT2+) and 15 (3.4%) had extraprostatic extension (pT3a). Extraprostatic extension was focal in 10 cases and nonfocal in 5. pT2 and pT3 cases did not differ by age or gland weight. When total tumor volume was less than 0.5 cm3, 6 of 311 tumors (1.9%) had extraprostatic extension and 6 of 311 (1.9%) had tumor at the margin at the apex for a total of 12 significant cancers (3.8%). Tumor volumes between 0.5 and 1.0 and 1.0 and 2.0 cm3 had a similar incidence of significant cancers. Of 108 cases with a tumor volume of 0.5 to 2.0 cm3 5 (4.6%) had extraprostatic extension and 7 (6.5%) had pT2+ at the apex for a total of 12 significant cancers (11.1%). The incidence of significant cancer increased further with tumor volumes greater than 2.0 cm3. CONCLUSIONS: Only 3.8% of less than 0.5 cm3 Gleason score 3 + 3 = 6 (Grade Group 1) cancers had extraprostatic extension or extended apically where surgical removal was not possible. In contrast, 11.1% of 0.5 to 2.0 cm3 cancers had these adverse features and would not have been tumors amenable to active surveillance. Our data indicate that increasing the threshold above 0.5 cm3 is associated with a significantly increased likelihood of extraprostatic extension and positive surgical margins. This should be considered in future studies of the prognostic value of tumor volume and in studies of active surveillance criteria.

Do Black NonHispanic Men Produce Less Prostate Specific Antigen in Benign Prostate Tissue or Cancer Compared to White NonHispanic Men with Gleason Score 6 (Grade Group 1) Prostate Cancer?

PURPOSE: We evaluated prostate specific antigen production by benign prostate tissue and Gleason score 3+3=6 (Grade Group 1) prostate cancer in black and white nonHispanic men. MATERIALS AND METHODS: We used Gleason score 3+3=6 (Grade Group 1) cases to assess prostate specific antigen production by benign prostate tissue in cases with low volume cancer that did not influence prostate specific antigen and in those with high volume cancer in which gland weight did not influence prostate specific antigen. We then created age, prostate specific antigen and prostate weight adjusted cohorts to demonstrate tumor volume per 1 ng/ml prostate specific antigen and 1 µg prostate specific antigen mass. Prostate specific antigen density and prostate specific antigen mass density were used to adjust for prostate weight. RESULTS: Comparison of 58 black and 301 white men with low volume cancer demonstrated equal prostate specific antigen production by benign prostate tissue. Comparison of 30 black and 75 white men with high volume cancer indicated that prostate specific antigen was being driven by cancer volume, with lower prostate specific antigen production in black men. In the cohort of 54 black and 134 white men matched by age, prostate specific antigen and prostate weight, tumor volume per 1 ng/ml prostate specific antigen or 1 µg prostate specific antigen mass adjusted for prostate weight was 25% and 26% higher in black men, respectively. CONCLUSIONS: Benign prostate tissue produces equal amounts of prostate specific antigen in black and white men. Gleason score 3+3=6 (Grade Group 1) prostate cancer produces less prostate specific antigen in black men. These data should be considered for lowering prostate specific antigen and its derivatives in determining biopsy thresholds and for adjusting values for active surveillance criteria in black men.

African-American Men with Gleason Score 3+3=6 Prostate Cancer Produce Less Prostate Specific Antigen than Caucasian Men: A Potential Impact on Active Surveillance.

PURPOSE: We assess the difference in prostate specific antigen production between African-American and Caucasian men with Gleason score 3+3=6 prostate cancer. MATERIALS AND METHODS: We measured tumor volume in 414 consecutive radical prostatectomies from men with National Comprehensive Cancer Network(®) low risk prostate cancer (348 Caucasian, 66 African-American) who had Gleason score 3+3=6 disease at radical prostatectomy. We then compared clinical presentation, pathological findings, prostate specific antigen, prostate specific antigen density and prostate specific antigen mass (an absolute amount of prostate specific antigen in patient's circulation) between African-American and Caucasian men. The t-test and Wilcoxon rank sum were used for comparison of means. RESULTS: African-American and Caucasian men had similar clinical findings based on age, body mass index and prostate specific antigen. There were no statistically significant differences between the dominant tumor nodule volume and total tumor volume (mean 0.712 vs 0.665 cm(3), p=0.695) between African-American and Caucasian men. Prostates were heavier in African-American men (mean 55.4 vs 46.3 gm, p <0.03). Despite the significantly greater weight of benign prostate tissue contributing to prostate specific antigen in African-American men, prostate specific antigen mass was not different from that of Caucasian men (mean 0.55 vs 0.558 µg, p=0.95). Prostate specific antigen density was significantly less in African-American men due to larger prostates (mean 0.09 vs 0.105, p <0.02). CONCLUSIONS: African-American men with Gleason score 3+3=6 prostate cancer produce less prostate specific antigen than Caucasian men. African-American and Caucasian men had equal serum prostate specific antigen and prostate specific antigen mass despite significantly larger prostates in African-American men with all other parameters, particularly total tumor volume, being the same. This finding has practical implications in T1c cases diagnosed with prostate cancer due to prostate specific antigen screening. Lowering the prostate specific antigen density threshold in African-American men may account for this disparity, particularly in selecting patients for active surveillance programs.

Outcome of Gleason 3 + 5 = 8 Prostate Cancer Diagnosed on Needle Biopsy: Prognostic Comparison with Gleason 4 + 4 = 8.

PURPOSE: ISUP (International Society for Urologic Pathology) and WHO adopted prognostic Grade Groups 1 to 5 that simplify prostate cancer grading for prognosis. Grade Group 4 is Gleason score 8 cancer, which is heterogeneous, and it encompasses Gleason score 4 + 4 = 8, 3 + 5 = 8 and 5 + 3 = 8. The comparative prognostic implications of these various Gleason scores had not been studied by urological pathologists after a re-review of slides. MATERIALS AND METHODS: Patients with a highest biopsy Gleason score of 3 + 5 = 8 or 4 + 4 = 8 were included in the study. Controls were cases with a highest Gleason score of 4 + 3 = 7 or 9-10. A total of 423 prostatic biopsy cases accessioned from 2005 to 2013 at 2 institutions were reviewed. Clinicopathological findings and followup (median 33.4 months) were assessed. RESULTS: Among Gleason score 8 cancers the cancer status outcome in 51 men with Gleason score 3 + 5 = 8 was marginally worse than in 114 with Gleason score 4 + 4 = 8 (p = 0.04). This was driven by a persistent nonmetastatic (after radiation/hormone therapy) cancer rate of 37% among Gleason score 3 + 5 = 8 cases vs 24% among Gleason score 4 + 4 = 8 cases. Conversely, cancer specific survival at 36-month followup was 97.8% in 3 + 5 cases vs 92.6% in 4 + 4 cases but this was not significant (p = 0.089). Cancer specific survival in the Gleason score 8 group was dichotomized by the presence of cribriform growth (p = 0.018). All Gleason score categories did not differ in the fraction of biopsy cores positive, clinical presentation or pathological findings, including the frequency of Gleason pattern 5, in 70 patients who underwent prostatectomy. CONCLUSIONS: Using the most current standards of prostate cancer grading the prognosis is not different in Gleason score 3 + 5 = 8 and 4 + 4 = 8 cancers. This justifies including both in Grade Group 4.

Diagnostic pitfalls of infarcted Warthin tumor in frozen section evaluation.

Warthin tumor (WT) is the second most common benign salivary gland neoplasm and has characteristic cytologic and histologic findings. Fine-needle aspiration is a common and useful preoperative diagnostic technique, which sometimes leads to ischemic injury resulting in the infarction of these lesions. Infarcted WT may demonstrate variable gross and histologic alterations that may render the diagnosis challenging, particularly during intraoperative frozen section evaluation. In this study, we collected 11 resection specimens from 9 patients with infarcted WT. Seven patients were men and 2 were women, ranging from 49 to 85 years (mean, 69). All the patients had fine-needle aspiration before the resection. Macroscopically, the tumors were tan-white and contained soft, yellow, exudative material. The histologic findings were variable and included necrosis, ghosts of papillae, squamous metaplasia, cholesterol clefts, foamy macrophages, multinucleated giant cell reaction, necrotizing granulomas, and fibrosis. Each case predominantly demonstrated 1 or 2 of these histomorphologic features. In the permanent sections, additional sampling revealed foci of residual viable WT in 8 cases. Three cases were completely infarcted; however, they all had ghost-like papillae in which the architecture of WT was evident. Infarcted WT may present a diagnostic challenge during intraoperative frozen section evaluation. Associated morphologic alterations may preclude a definitive diagnosis of WT and may mimic malignancy. Awareness of the gross and microscopic features associated with infarcted WT is important, particularly for accurate frozen section evaluation of these salivary gland tumors.

Pathological characteristics of low risk prostate cancer based on totally embedded prostatectomy specimens.

BACKGROUND: Surveillance and focal therapy are increasingly considered for low risk prostate cancer (PC). We describe pathological characteristics of low risk PC at radical prostatectomy in contemporary patients. METHODS: Five-hundred-fifty-two men from 2008 to 2012 with low risk (stage T1c/T2a, PSA ≤ 10 ng/ml, Gleason score ≤6) PC underwent radical prostatectomy. Slides were re-reviewed to grade and stage the tumor, map separate tumor nodules, and calculate their volumes. RESULTS: Ninety-three (16.9%) men had prostatectomy Gleason score 3 + 4 = 7 or higher and were excluded. Five (0.9%) men had no residual carcinoma. Remaining 454 patients composed the study cohort. The median age was 57 years (36-73) and median PSA 4.4 ng/ml (0.4-9.9). Racial distribution was 77.5% Caucasian, 15.5% African American, and 7% other. The median total tumor volume was 0.38 cm(3) (0.003-7.22). Seventy percent of the patients had bilateral tumor and 34% had a tumor nodule >0.5 cm(3) . The index lesion represented 89% (median) of the total tumor volume. Extraprostatic extension and positive margin were present in 5.7% and 9% of cases, respectively. The tumor nodules measuring >0.5 cm(3) were located almost equally between the anterior (53%) and peripheral (47%) gland. The relationship between PSA and total tumor volume was weak (r = 0.13, P = 0.005). The relationship between PSA density and total tumor volume was slightly better (r = 0.26, P < 0.001). CONCLUSIONS: Low risk prostate cancer is generally a low volume disease. Gleason score upgrade is seen in 16.9% of cases at radical prostatectomy. While the index lesion accounts for the bulk of the disease, the cancer is usually multifocal and bilateral. Neither PSA nor PSA density correlates well with the total tumor volume. Prostate size has a significant contribution to PSA level. These factors need to be considered in treatment planning for low risk prostate cancer.

Significance of lymphovascular invasion in organ-confined, node-negative urothelial cancer of the bladder: data from the prospective p53-MVAC trial.

OBJECTIVES: To investigate the association between lymphovascular invasion (LVI) and clinical outcome in organ-confined, node-negative urothelial cancer of the bladder (UCB) in a post hoc analysis of a prospective clinical trial. To explore the effect of adjuvant chemotherapy with methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC) on outcome in the subset of patients whose tumours exhibited LVI. PATIENTS AND METHODS: Surgical and tumour factors were extracted from the operative and pathology reports of 499 patients who had undergone radical cystectomy (RC) for pT1-T2 N0 UCB in the p53-MVAC trial (Southwest Oncology Group 4B951/NCT00005047). The presence or absence of LVI was determined by pathological examination of transurethral resection or RC specimens. Variables were examined in univariate and multivariate Cox proportional hazards models for associations with time to recurrence (TTR) and overall survival (OS). RESULTS: Among 499 patients with a median follow-up of 4.9 years, a subset of 102 (20%) had LVI-positive tumours. Of these, 34 patients had pT1 and 68 had pT2 disease. LVI was significantly associated with TTR with a hazard ratio (HR) of 1.78 [95% confidence interval (CI) 1.15-2.77; number of events (EV) 95; P = 0.01) and with OS with a HR of 2.02 (95% CI 1.31-3.11; EV 98; P = 0.001) after adjustment for pathological stage. Among 27 patients with LVI-positive tumours who were randomised to receive adjuvant chemotherapy, receiving MVAC was not significantly associated with TTR (HR 0.70, 95% CI 0.16-3.17; EV 7; P = 0.65) or with OS (HR 0.45, 95% CI 0.11-1.83; EV 9; P = 0.26). CONCLUSIONS: Our post hoc analysis of the p53-MVAC trial revealed an association between LVI and shorter TTR and OS in patients with pT1-T2N0 disease. The analysis did not show a statistically significant benefit of adjuvant MVAC chemotherapy in patients with LVI, although a possible benefit was not excluded.