Focused Submission of Tissue for Radical Prostatectomy Following Multiparametric Magnetic Resonance Imaging/Ultrasound Fusion-Targeted Biopsy.

Prostate cancer can be difficult to appreciate grossly and therefore partial sampling of the gland can lead to incorrect grading, staging, or margin status. However, submitting the entire prostate is more time consuming and costly. We investigated the use of magnetic resonance imaging/ultrasound-targeted biopsy for the selective submission of prostatectomy specimens. We performed a retrospective review for patients with cancer on targeted prostate biopsy who underwent subsequent radical prostatectomy. Prostatectomy specimens were submitted in their entirety and assessed for Grade Group, extraprostatic extension (EPE), margins, and number of blocks. For Targeted-Grossing (TG) assessment, apex margin, bladder neck margin, seminal vesicles, and vas deferens sections were included. For the remainder of the prostate, only sections from areas shown to be positive for cancer on targeted biopsy were included in the analysis. With total tissue submission, EPE was found in 39/81 (48.1%) cases and positive margins in 19/81 (23.5%) cases. The TG method required significantly fewer blocks: 15.8 ± 5.9 versus 44.9 ± 11.9 (P < .0001). The TG method would have diagnosed the correct stage in 73/81 (90.1%) cases, Grade Group in 74/81 (91.4%) cases, and margin status in 79/81 (97.5%) cases. EPE was missed completely by the TG method in 7 cases (P = .008), of which 5/7 (71.4%) had focal EPE. There was no significant difference in stage (P = .24), Grade Group (P = .95), or margin status (P = .16) between the 2 methods. Grossing utilizing selective tissue submission from areas found to be positive for prostate cancer on magnetic resonance imaging/ultrasound-targeted prostate biopsy remains inferior to complete submission of tissue for radical prostatectomy specimens.

Morphology, p16, HPV, and outcomes in squamous cell carcinoma of the penis: a multi-institutional study.

Our objective was to evaluate the pathologic features and clinical outcomes in cases of invasive penile squamous cell carcinoma (SCC) and the association with p16 immunohistochemistry (IHC) and human papilloma virus (HPV) in situ hybridization (ISH). A retrospective multi-institutional database search was conducted for invasive SCC of the penis diagnosed between 2007 and 2018 that had undergone surgical resection. Pathologic features, p16 IHC, and HPV ISH were investigated with clinical outcomes. A total of 102 patients were included in the study. The average age was 63 ±â€¯13.3 years. Based on histology, 46% of tumors displayed an HPV-related subtype, whereas p16 was positive in 52% of all cases. Tumor histology correlated well with p16 positivity (P < .001), and p16 IHC accurately predicted the presence of HPV in 25/26 (96%) cases. On multivariate analysis, perineural invasion was associated with local disease recurrence (P = .02), whereas lymphovascular invasion was associated with progression to metastatic disease (P = .002) and increased overall mortality (P = .02). Urethral involvement was also associated with increased overall mortality (P = .02). In addition, HPV-related tumors based on histologic features correlated with lower rates of metastatic disease (P = .007). HPV is a common cause of penile SCC and can be diagnosed by tumor histology and confirmed by overexpression of p16 on IHC. The presence of lymphovascular invasion, perineural invasion, and urethral involvement are poor prognostic indicators, whereas HPV-related tumors based on histology may have lower risk for metastatic disease.

Active Surveillance of Small Renal Masses.

Most renal masses in the United States are incidentally detected via abdominal imaging. This has led to an increase in the incidence of small renal masses (≤4 cm). Active surveillance is, an oncologically safe option in slow growing and indolent tumors in other organs and has recently become more widely studied in small renal masses. For selected patients, particularly those who harbor significant comorbidities, active surveillance is a safe option for small renal masses. Renal biopsy may be helpful in the decision making process, but remains an optional component for the active surveillance of small renal masses.

Histologic findings associated with false-positive multiparametric magnetic resonance imaging performed for prostate cancer detection.

Magnetic resonance imaging (MRI)/ultrasound fusion-targeted biopsy (TB) has been shown to more accurately identify higher-grade prostate cancers compared with standard-of-care systematic sextant prostate biopsy (SB). However, occasional false-positive imaging findings occur. We investigated the histologic findings associated with false-positive prostate MRI findings. A retrospective review was performed on our surgical pathology database from 2014 to 2017 selecting patients with no cancer detected on TB with concurrent SB after at least 1 prior benign SB session. Histologic features evaluated included percentage of core involvement by chronic inflammation, percentage of core composed of stroma, percentage of glands involved by atrophy, and presence of the following features: acute or granulomatous inflammation, stromal nodular hyperplasia, adenosis, squamous metaplasia, basal cell hyperplasia, and presence of skeletal muscle. Histologic findings were compared between TB and concurrent SB. We identified 544 patients who underwent TB. Of these, 41 patients, including 62 targeted lesions, met criteria. Compared with SB tissue, the mean percentage of stroma was increased in TB (P = .02). Basal cell hyperplasia was also found to be more common on TB (P = .02). Both high percentage of stroma (P = .046) and presence of basal cell hyperplasia (P = .038) were independent predictors on multivariate analysis. The combination of high chronic inflammation, high stroma, acute inflammation, and basal cell hyperplasia was associated with TB (P = .001). Atrophic glands and chronic inflammation showed a positive correlation (r = 0.67, P = .003), which was especially seen in high prostate imaging reporting and data system lesions. Specific benign histologic entities are associated with false-positive findings on prostate MRI.

PTEN and ERG detection in multiparametric magnetic resonance imaging/ultrasound fusion targeted prostate biopsy compared to systematic biopsy.

Multiparametric magnetic resonance imaging (MRI)/ultrasound fusion targeted prostate biopsy has been shown to outperform systematic biopsy in the detection of clinically significant prostate cancer. Aside from tumor grade, tumor biomarkers such as phosphatase and tensin homolog (PTEN) and ETS-related gene (ERG) have prognostic significance in prostate cancer and may help direct management of patients with low-grade tumors. Our objective was to compare the detection of PTEN and ERG expression in MRI-targeted versus systematic prostate biopsies. We compared immunohistochemical expression for PTEN and ERG on prostate biopsy cores from patients with Grade Group (GG) 1 or GG2 prostate cancer who had undergone systematic biopsy with concurrent targeted biopsy. Fifty-three cases had both systematic and MRI-targeted prostate tissue available for staining for PTEN; and 52 cases, for ERG. ERG positivity was seen in 37/52 (71.2%) cases, and PTEN loss was seen in 15/53 (28.3%) cases. The detection of ERG expression was not significantly different between MRI-targeted and systematic biopsy (P = .4). Targeted biopsy was superior to systematic biopsy in the detection of PTEN loss (P = .02). MRI-targeted cores detected 14/15 (93.3%) cases of PTEN loss compared to 7/15 (46.7%) cases detected by systematic cores. Most cases with PTEN loss showed heterogeneous expression in both systematic and targeted cores. In 14/15 (93.3%) cases with PTEN loss, GG was the same between targeted and systematic biopsy. Targeted biopsy is superior to systematic biopsy in the detection of PTEN loss in GG1 and GG2 tumors. Inclusion of targeted cores may be helpful for evaluation of certain prognostic biomarkers.

Defining the optimal method for reporting prostate cancer grade and tumor extent on magnetic resonance/ultrasound fusion-targeted biopsies.

Magnetic resonance (MR)/ultrasound fusion-targeted biopsy (TB) routinely samples multiple cores from each MR lesion of interest. Pathologists can evaluate the extent of cancer involvement and grade using an individual core (IC) or aggregate (AG) method, which could potentially lead to differences in reporting. We reviewed patients who underwent TB followed by radical prostatectomy (RP). TB cores were evaluated for grade and tumor extent by 2 methods. In the IC method, the grade for each TB lesion was based on the core with the highest Gleason score. Tumor extent for each TB was based on the core with the highest percent of tumor involvement. In the AG method, the tumor from all cores within each TB lesion was aggregated to determine the final composite grade and percentage of tumor involvement. Each method was compared with MR lesional volume, MR lesional density (lesion volume/prostate volume), and RP. Fifty-five patients underwent TB followed by RP. Extent of tumor by the AG method showed a better correlation with target lesion volume (r= 0.27,P= .022) and lesional density (r = 0.32, P = .008) than did the IC method (r= 0.19 [P = .103] andr= 0.22 [P = .062]), respectively. Extent of tumor on TB was associated with extraprostatic extension on RP by the AG method (P= .04), but not by the IC method. This association was significantly higher in patients with a grade group (GG) of 3 or higher (P= .03). A change in cancer grade occurred in 3 patients when comparing methods (2 downgraded GG3 to GG2, 1 downgraded GG4 to GG3 by the AG method). For multiple cores obtained via TB, the AG method better correlates with target lesion volume, lesional density, and extraprostatic extension.

YAP1 and COX2 Coordinately Regulate Urothelial Cancer Stem-like Cells.

Overcoming acquired drug resistance remains a core challenge in the clinical management of human cancer, including in urothelial carcinoma of the bladder (UCB). Cancer stem-like cells (CSC) have been implicated in the emergence of drug resistance but mechanisms and intervention points are not completely understood. Here, we report that the proinflammatory COX2/PGE2 pathway and the YAP1 growth-regulatory pathway cooperate to recruit the stem cell factor SOX2 in expanding and sustaining the accumulation of urothelial CSCs. Mechanistically, COX2/PGE2 signaling induced promoter methylation of let-7, resulting in its downregulation and subsequent SOX2 upregulation. YAP1 induced SOX2 expression more directly by binding its enhancer region. In UCB clinical specimens, positive correlations in the expression of SOX2, COX2, and YAP1 were observed, with coexpression of COX2 and YAP1 particularly commonly observed. Additional investigations suggested that activation of the COX2/PGE2 and YAP1 pathways also promoted acquired resistance to EGFR inhibitors in basal-type UCB. In a mouse xenograft model of UCB, dual inhibition of COX2 and YAP1 elicited a long-lasting therapeutic response by limiting CSC expansion after chemotherapy and EGFR inhibition. Our findings provide a preclinical rationale to target these pathways concurrently with systemic chemotherapy as a strategy to improve the clinical management of UCB.Significance: These findings offer a preclinical rationale to target the COX2 and YAP1 pathways concurrently with systemic chemotherapy to improve the clinical management of UCB, based on evidence that these two pathways expand cancer stem-like cell populations that mediate resistance to chemotherapy. Cancer Res; 78(1); 168-81. ©2017 AACR.

Detection of TERT promoter mutations in primary adenocarcinoma of the urinary bladder.

TERT promoter mutations (TERT-mut) have been detected in 60% to 80% of urothelial carcinomas. A molecular urine-based screening assay for the detection of TERT-mut is currently being pursued by our group and others. A small but significant number of bladder carcinomas are adenocarcinoma. The current study assesses the incidence of TERT-mut in primary adenocarcinomas of urinary bladder. A retrospective search of our institutional pathology records identified 23 cystectomy specimens with a diagnosis of adenocarcinoma (2000-2014). All slides were reviewed by a senior urologic pathologist to confirm tumor type and select a representative formalin-fixed, paraffin-embedded block for mutational analysis. Adequate material for DNA testing was available in 14 cases (7 enteric type and 7 not otherwise specified). TERT-mut sequencing analysis was performed using previously described SafeSeq technique. Overall, 28.5% of primary adenocarcinoma harbored TERT-mut. Interestingly, 57% of nonenteric adenocarcinomas were mutation positive, whereas none of the enteric-type tumors harbored mutations. Similar to urothelial carcinoma, we found a relatively higher rate of TERT-mut among nonenteric-type adenocarcinomas further supporting the potential utility of TERT-mut urine-based screening assay for bladder cancer.