Faculty Bibliography

Gastric cancer is a rare long-term complication in gastrocystoplasty. We report 2 cases of gastric adenocarcinoma and review the literature for similar cases. A total of 14 cases are identified. The majority of patients are males, presented with hematuria, and developed cancer at a younger age, more than 10 years after gastrocystoplasty. Long-term follow up information was limited, but 5 patients (36%) died within 5 years of diagnosis. Annual surveillance for malignancy may not be effective due to its rarity. However, symptomatic patients, particularly those 10 years after the surgery, warrant detailed evaluation to rule out neoplastic transformation.

Five years after the last prostatic carcinoma grading consensus conference of the International Society of Urological Pathology (ISUP), accrual of new data and modification of clinical practice require an update of current pathologic grading guidelines. This manuscript summarizes the proceedings of the ISUP consensus meeting for grading of prostatic carcinoma held in September 2019, in Nice, France. Topics brought to consensus included the following: (1) approaches to reporting of Gleason patterns 4 and 5 quantities, and minor/tertiary patterns, (2) an agreement to report the presence of invasive cribriform carcinoma, (3) an agreement to incorporate intraductal carcinoma into grading, and (4) individual versus aggregate grading of systematic and multiparametric magnetic resonance imaging-targeted biopsies. Finally, developments in the field of artificial intelligence in the grading of prostatic carcinoma and future research perspectives were discussed.

Background: Low risk prostate cancers are amenable to active surveillance which can reduce harmful overtreatment of indolent disease. However there is great variability of criteria in urological practice for determination of active surveillance candidacy. The quantity of Gleason pattern 4 is an important prognostic parameter and may influence treatment decisions. A genomic classifier, the Oncotype DX Genomic Prostate Score has been used to predict both clinical risk and tumor aggressiveness in patients diagnosed on biopsy with low risk prostate cancer (Grade group (GG) 1 and 2). This study investigated whether Genomic Prostate Score (GPS) can predict unfavorable disease and correlates with percentage of Gleason pattern 4 in low grade prostate cancer.
Design(s): We searched our surgical pathology database for prostate biopsies with Oncotype DX Genomic Prostate Score reports (2016- 2019). Oncotype Dx was performed on the single core with worst disease (core with longest tumor and/or maximum percentage of pattern 4). Biopsy results including Gleason Score and length of the tumor and percentage of pattern 4 from the core submitted for Oncotype test were recorded. Follow-up repeat biopsy or prostatectomy, if performed, were also retrieved for review of Gleason Score. Oncotype GPS score and related clinical information were analyzed in the study.
Result(s): 306 prostate biopsy cases with Oncotype DX test report were included in the study. Among these cases, 124 cases were originally diagnosed as GG1 (Gleason Score 3 + 3) and 182 cases were GG2 (3 + 4). The average GPS in GG 2 is significantly higher than GG1 (28.52 +/- 11.80 vs 17.88 +/- 9.35, p < 0.0001). Forty cases in GG1 had follow up repeat biopsy or prostatectomy. Twenty cases were upgraded to GG2. Cases with higher GPS score are more likely to upgrade to GG2 (23.10 +/- 10.13 vs 16.55 +/- 8.22, p < 0.05) in follow up repeat biopsy or prostatectomy. In GG1 group, GPS score correlated with the maximum tumor length and tumor percentage (p < 0.01). In GG2, patients with Gleason pattern 4 greater than 30% received higher GPS score than patients with pattern 4 less than 30% (p < 0.05). GPS significantly correlated with percentage of Gleason pattern 4 but not length of pattern 4, length of tumor, PSA level or PSA density.
Conclusion(s): In GG1, Oncotype Dx GPS can predict the likelihood of unfavorable disease at follow up repeat biopsy or prostatectomy. In GG2, GPS score correlated with percentage of pattern 4, supporting its role as an auxiliary tool for clinical risk classification

Background: Recent clinical guidelines for management of prostate adenocarcinoma are aimed at expanding active surveillance (AS) to include men with intermediate-risk (Gleason score 3+4=7) disease on needle biopsy (NB). However, studies reported a large portion of men with Gleason 3+4=7 prostate cancer on biopsy, that harbored adverse surgical pathologic findings. It remains unclear which subset of intermediate-risk patients with Gleason score 7 cancers can be safely treated with AS. In this study we investigate whether the percentage of Gleason pattern 4 in NB with Gleason score 7 cancers is an indicator for stratifying risk.
Design(s): We retrospectively reviewed our electronic record database for patients that underwent core NB over a 6-year period. We included NB with Gleason score 3+3=6 (G336), 3+4=7 with <5% Gleason pattern 4 (G4%<5) and 3+4=7 with 6-49% maximum Gleason pattern 4 (G4%6-49); all cases had corresponding radical prostatectomy (RP) within 6 months of the biopsy. We defined adverse pathology (AP) as any RP with Gleason score equal to or greater than 4+3=7 and/or stage T3 or higher. We compare AP outcomes in final follow-up RP of three NB groups: G336, G4%<5 and G4%6-49.
Result(s): A total of 289 NB with corresponding radical prostatectomies were identified. The breakdown of Gleason groups is shown in Table 1. GS336 has an AP rate of 26.6%, while G4<5% an AP rate of 20%. In comparison, the group of patients with G4%6-49 exhibited a 42% rate of AP (Table 1). A Chi-square test performed comparing AP of G4%<5 and G%6-49 is statistically significant p= .0237 (Figure 1). Conversely, there is no statistical difference between the rate of AP in G4<5% and G336, p= 0.46. G336 and G4%<5 were aggregated into a new group G%0-5 with an AP rate of 25.2% compared to G%6-10 AP rate 39.6%, p= 0.0576 (Figure 2). G4%6-10 and G4%11-49 had comparable rates of AP, 39.6% and 43.1%, respectively (p=0.681). (Table presented)
Conclusion(s): Currently there is a paradigm shift amongst pathologist and the significance of minimal percentage pattern 4 on prostate biopsies. Our current data supports the recent literature publications that <5% maximal Gleason pattern 4 on a single core has a similar rate of adverse pathological outcomes as Gleason score 3+3=6 and can be considered for AS. Although we did not detect a statistical difference between the rate of AP between G4%0-5 and G4%6-10, the data is beginning to approach statistical significance and warrants further risk stratification

Parathyromatosis is a rare but recognized cause of recurrent primary hyperparathyroidism. Initially described in 1975 by Palmer et al.(1), about 40 cases have been described in the literature. Most patients are middle-aged females. A small majority of the cases arise in the context of secondary hyperplasia due to end-stage renal disease.(2) The nature of parathyromatosis is unknown. It may be a low-grade carcinoma, seeding of a prior adenoma, or overgrowths of embryologic rests. Several oncogenes of interest have been identified in parathyroid neoplasms (PRAD1, MEN1, HRPT2, CaSR). (3) A biallelic CDC73/HRPT2 inactivating mutation is known to be present in about 75% of sporadic parathyroid carcinomas and absent in most adenomas. (4) Their possible relationship to parathyromatosis has not been studied. As such, differentiating parathyromatosis from other parathyroid neoplasms is challenging.(5-10) This article is protected by copyright. All rights reserved.

We previously showed that KLF4, a gene highly expressed in murine prostate stem cells, blocks the progression of indolent intraepithelial prostatic lesions into aggressive and rapidly growing tumors. Here, we show that the anti-tumorigenic effect of KLF4 extends to PC3 human prostate cancer cells growing in the bone. We compared KLF4 null cells with cells transduced with a DOX-inducible KLF4 expression system, and find KLF4 function inhibits PC3 growth in monolayer and soft agar cultures. Furthermore, KLF4 null cells proliferate rapidly, forming large, invasive, and osteolytic tumors when injected into mouse femurs, whereas KLF4 re-expression immediately after their intra-femoral inoculation blocks tumor development and preserves a normal bone architecture. KLF4 re-expression in established KLF4 null bone tumors inhibits their osteolytic effects, preventing bone fractures and inducing an osteogenic response with new bone formation. In addition to these profound biological changes, KLF4 also induces a transcriptional shift from an osteolytic program in KLF4 null cells to an osteogenic program. Importantly, bioinformatic analysis shows that genes regulated by KLF4 overlap significantly with those expressed in metastatic prostate cancer patients and in three individual cohorts with bone metastases, strengthening the clinical relevance of the findings in our xenograft model.

CONTEXT.—/UNASSIGNED:Phosphatase and tensin homolog (PTEN) is a promising prognostic and potentially predictive biomarker in prostate cancer. OBJECTIVE.—/UNASSIGNED:To assess the effects of preanalytic variables on an analytically validated and fully automated PTEN immunohistochemistry assay. DESIGN.—/UNASSIGNED:PTEN immunohistochemistry was performed on Ventana immunostaining systems. In benign prostate tissues, immunostaining intensity across variable conditions was assessed by digital image analysis. In prostate tumor tissues, immunostaining was scored visually. RESULTS.—/UNASSIGNED:Delay of fixation for 4 hours or longer at room temperature or 48 hours or longer at 4°C and duration of formalin fixation did not significantly alter immunostaining intensity. Intensity of staining was highest in 10% formalin compared with other fixatives. Tumor tissues with PTEN loss processed using protocols from 11 academic institutions were all evaluable and scored identically. PTEN immunostaining of needle biopsies where tissue blocks had been stored for less than 10 years was more frequently scored as nonevaluable compared with blocks that had been stored for 10 years or longer. This effect was less evident for radical prostatectomy specimens, where low rates of nonevaluable staining were seen for 23 years or more of storage. Storage of unstained slides for 5 years at room temperature prior to immunostaining resulted in equivalent scoring compared with freshly cut slides. Machine-to-machine variability assessed across 3 Ventana platforms and 2 institutions was negligible in 12 tumors, and platform-to-platform variability was also minor comparing Ventana and Leica instruments across 77 tumors (κ = 0.926). CONCLUSIONS.—/UNASSIGNED:Automated PTEN immunostaining is robust to most preanalytic variables in the prostate and may be performed on prostate tumor tissues subjected to a wide range of preanalytic conditions. These data may help guide assay development if PTEN becomes a key predictive biomarker.

CONTEXT/BACKGROUND:- In Gleason score GS (7) prostate cancers, the quantity of Gleason pattern 4 (GP 4) is an important prognostic factor and influences treatment decisions. Magnetic resonance imaging (MRI)-targeted biopsy has been increasingly used in clinical practice. OBJECTIVE:- To investigate whether MRI-targeted biopsy may detect GS 7 prostate cancer with greater GP 4 quantity, and whether it improves biopsy/radical prostatectomy GS concordance. DESIGN/METHODS:- A total of 243 paired standard and MRI-targeted biopsies with cancer in either standard or targeted or both were studied, 65 of which had subsequent radical prostatectomy. The biopsy findings, including GS and tumor volume, were correlated with the radical prostatectomy findings. RESULTS:- More prostate cancers detected by MRI-targeted biopsy were GS 7 or higher. Mean GP 4 percentage in GS 7 cancers was 31.0% ± 29.3% by MRI-targeted biopsy versus 25.1% ± 29.5% by standard biopsy. A total of 122 of 218 (56.0%) and 96 of 217 (44.2%) prostate cancers diagnosed on targeted biopsy and standard biopsy, respectively, had a GP 4 of 10% or greater ( P = .01). Gleason upgrading was seen in 12 of 59 cases (20.3%) from MRI-targeted biopsy and in 24 of 57 cases (42.1%) from standard biopsy ( P = .01). Gleason upgrading correlated with the biopsy cancer volume inversely and GP 4 of 30% or less in standard biopsy. Such correlation was not found in MRI-targeted biopsy. CONCLUSIONS:- Magnetic resonance imaging-targeted biopsy may detect more aggressive prostate cancers and reduce the risk of Gleason upgrading in radical prostatectomy. This study supports a potential role for MRI-targeted biopsy in the workup of prostate cancer and inclusion of percentage of GP 4 in the prostate biopsy reports.