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The Genitourinary Pathology Society (GUPS) reviewed recent advances in renal neoplasia, particularly post-2016 World Health Organization (WHO) classification, to provide an update on existing entities, including diagnostic criteria, molecular correlates, and updated nomenclature. Key prognostic features for clear cell renal cell carcinoma (RCC) remain WHO/ISUP grade, AJCC/pTNM stage, coagulative necrosis, and rhabdoid and sarcomatoid differentiation. Accrual of subclonal genetic alterations in clear cell RCC including SETD2, PBRM1, BAP1, loss of chromosome 14q and 9p are associated with variable prognosis, patterns of metastasis, and vulnerability to therapies. Recent National Comprehensive Cancer Network (NCCN) guidelines increasingly adopt immunotherapeutic agents in advanced RCC, including RCC with rhabdoid and sarcomatoid changes. Papillary RCC subtyping is no longer recommended, as WHO/ISUP grade and tumor architecture better predict outcome. New papillary RCC variants/patterns include biphasic, solid, Warthin-like, and papillary renal neoplasm with reverse polarity. For tumors with 'borderline' features between oncocytoma and chromophobe RCC, a term "oncocytic renal neoplasm of low malignant potential, not further classified" is proposed. Clear cell papillary RCC may warrant reclassification as a tumor of low malignant potential. Tubulocystic RCC should only be diagnosed when morphologically pure. MiTF family translocation RCCs exhibit varied morphologic patterns and fusion partners. TFEB-amplified RCC occurs in older patients and is associated with more aggressive behavior. Acquired cystic disease (ACD) RCC-like cysts are likely precursors of ACD-RCC. The diagnosis of renal medullary carcinoma requires a negative SMARCB1 (INI-1) expression and sickle cell trait/disease. Mucinous tubular and spindle cell carcinoma (MTSCC) can be distinguished from papillary RCC with overlapping morphology by losses of chromosomes 1, 4, 6, 8, 9, 13, 14, 15, and 22. MTSCC with adverse histologic features shows frequent CDKN2A/2B (9p) deletions. BRAF mutations unify the metanephric family of tumors. The term "fumarate hydratase deficient RCC" ("FH-deficient RCC") is preferred over "hereditary leiomyomatosis and RCC syndrome-associated RCC". A low threshold for FH, 2SC, and SDHB immunohistochemistry is recommended in difficult to classify RCCs, particularly those with eosinophilic morphology, occurring in younger patients. Current evidence does not support existence of a unique tumor subtype occurring after chemotherapy/radiation in early childhood.

BACKGROUND Urinary cytology is a noninvasive and cost-effective diagnostic and surveillance test in the clinical management of urothelial carcinoma (UC). The Paris System for Reporting Urinary Cytology (TPS), published in 2016, introduced definite diagnostic criteria aimed at improving performance in detecting high-grade UC (HGUC) and decreasing the indeterminate (atypical) diagnosis. METHODS The authors retrospectively reviewed and compared urinary cytology diagnoses reported between January 2013 and December 2014 (pre-TPS, 7658 cases) and between May 2016 and April 2018 (post-TPS, 20,026 cases) to assess the influence of TPS in their practice. The time in between was used as a learning period. Follow-up information and correlation with the UroVysion fluorescence in situ hybridization test were obtained when available. RESULTS Urinary cytology diagnoses pre-TPS included negative for UC (NUC) (n = 5293; 69.2%), atypical urothelial cells (AUC) (n = 2227; 29%), and suspicious/positive for HGUC (SHGUC/HGUC) (n = 138; 1.8%). Diagnoses post-TPS included negative for HGUC (NHGUC) (n = 18,507; 92.4%), AUC (n = 1237; 6.2%), and SHGUC/HGUC (n = 282; 1.4%). Comparing the pre-TPS and post-TPS periods, AUC diagnoses decreased from 29% to 6.2% (P < .00001), and the specificity and positive predictive value of AUC to detect HGUC significantly improved from 49% to 86% (P < .00001) and from 9% to 39% (P = .002), respectively. The correlation of an AUC diagnosis with a positive UroVysion test improved from 17% to 38% (P < .00001), whereas overall use of the UroVysion test was decreased. CONCLUSIONS Implementation of TPS resulted in a significant reduction in AUC diagnoses that had a superior correlation with a subsequent biopsy and a UroVysion test, resulting in potential reductions in test use and medical cost.

Trophoblastic differentiation (including choriocarcinoma) arising in urothelial carcinoma has been described in numerous case reports, but never in a single series. We present a series of these tumors, describing the morphologic spectrum, applying traditional and novel immunohistochemical stains, and characterizing clinical follow-up. We identified 16 cases, arising predominantly in the bladder (N=14), but also the ureter (N=1) and prostatic urethra (N=1). Six of our cases (38%) contained invasive urothelial carcinoma with admixed syncytiotrophoblasts, 8 cases (50%) consisted of invasive urothelial carcinoma with choriocarcinoma, 1 case (6%) showed urothelial carcinoma in situ with associated choriocarcinoma, and 1 case (6%) consisted of pure choriocarcinoma. Other subtypes of variant morphology were seen in 5 of our cases (31%) and included squamous, glandular, lipoid, chordoid/myxoid, and sarcomatoid features. Given the limited specificity of human chorionic gonadotropin immunohistochemistry, we also studied the expression of a novel specific trophoblastic marker, hydroxyl-δ-5-steroid dehydrogenase, as well as Sal-like protein 4. Human chorionic gonadotropin expression was seen in nearly all cases (93%) but was often not limited to the trophoblastic component, staining the urothelial component also in 85% of the cases. Expression of hydroxyl-δ-5-steroid dehydrogenase was more sensitive and more specific, staining 100% of the cases and limited to trophoblasts in all but 1 case. Sal-like protein 4 expression was variable, staining trophoblast in only 50% of cases and staining the urothelial carcinoma component in 43% of those positive cases. Most of our tumors presented at a high stage and were associated with poor clinical outcomes, with at least muscle-invasive disease (pT2) in 10 of the 14 bladder tumors (71%), periureteric fat invasion in the ureter tumor (pT3), distant metastases in 7 of 16 cases (44%) and death of disease in 3 of the 15 patients with follow-up (20%). Our study describes a series of urothelial carcinomas with trophoblastic differentiation, demonstrating the morphologic spectrum of this entity, its frequent association with other subtypes of variant morphology, its characteristic immunoprofile, and its aggressive clinical behavior.

The Genitourinary Pathology Society (GUPS) undertook a critical review of the recent advances in bladder cancer focusing on important topics of high interest for the practicing surgical pathologist and urologist. This review represents the second of 2 manuscripts ensuing from this effort. Herein, we address the effective reporting of bladder cancer, focusing particularly on newly published data since the last 2016 World Health Organization (WHO) classification. In addition, this review focuses on the importance of reporting bladder cancer with divergent differentiation and variant (subtypes of urothelial carcinoma) histologies and the potential impact on patient care. We provide new recommendations for reporting pT1 staging in diagnostic pathology. Furthermore, we explore molecular evolution and classification, emphasizing aspects that impact the understanding of important concepts relevant to reporting and management of patients.

Radiation dose intensification improves outcome in men with high-risk prostate cancer (HR-PCa). A prospective trial was conducted to determine safety, feasibility, and maximal tolerated dose of multilevel magnetic resonance imaging (MRI)-based 5-fraction SABR in patients with HR-PCa.This phase I clinical trial enrolled patients with HR-PCa with grade group ≥4, prostate-specific antigen (PSA) ≥20 ng/mL, or radiographic ≥T3, and well-defined prostatic lesions on multiparametric MRI (mpMRI) into 4 dose-escalation cohorts. The initial cohort received 47.5 Gy to the prostate, 50 Gy to mpMRI-defined intraprostatic lesion(s), and 22.5 Gy to pelvic lymph nodes in 5 fractions. Radiation doses were escalated for pelvic nodes to 25 Gy and mpMRI lesion(s) to 52.5 Gy and then 55 Gy. Escalation was performed sequentially according to rule-based trial design with 7 to 15 patients per cohort and a 90-day observation period. All men received peri-rectal hydrogel spacer, intraprostatic fiducial placement, and 2 years of androgen deprivation. The primary endpoint was maximal tolerated dose according to a 90-day acute dose-limiting toxicity (DLT) rate33%. DLT was defined as National Cancer Institute Common Toxicity Criteria for Adverse Events ≥grade 3 treatment-related toxicity. Secondary outcomes included acute and delayed gastrointestinal (GI)/genitourinary (GU) toxicity graded with Common Toxicity Criteria for Adverse Events.Fifty-five of the 62 enrolled patients were included in the analysis. Dose was escalated through all 4 cohorts without observing any DLTs. Median overall follow-up was 18 months, with a median follow-up of 42, 24, 12, and 7.5 months for cohorts 1 to 4 respectively. Acute and late grade 2 GU toxicities were 25% and 20%, while GI were 13% and 7%, respectively. Late grade 3 GU and GI toxicities were 2% and 0%, respectively.SABR dose for HR-PCa was safely escalated with multilevel dose painting of 47.5 Gy to prostate, 55 Gy to mpMRI-defined intraprostatic lesions, and 25 Gy to pelvic nodal region in 5 fractions. Longer and ongoing follow-up will be required to assess late toxicity.

BACKGROUND The loss of PTEN tumor suppressor gene is one of the most common somatic genetic aberrations in prostate cancer (PCa) and is frequently associated with high-risk disease. Deletion or mutation of at least one PTEN allele has been reported to occur in 20% to 40% of localized PCa and up to 60% of metastases. The goal of this study was to determine if somatic alteration detected by PTEN immunohistochemical loss of expression is associated with specific histologic features. METHODS Two hundred sixty prostate core needle biopsies with PCa were assessed for PTEN loss using an analytically validated immunohistochemical assay. Blinded to PTEN status, each tumor was assessed for the Grade Group (GG) and the presence or absence of nine epithelial features. Presence of stromogenic PCa was also assessed and defined as grade 3 reactive tumor stroma as previously described: the presence of carcinoma associated stromal response with epithelial to stroma ratio of greater than 50% reactive stroma. RESULTS Eight-eight (34%) cases exhibited PTEN loss while 172 (66%) had intact PTEN. PTEN loss was significantly (P

Purpose: To survey urologic clinicians regarding interpretation of and practice patterns in relation to emerging aspects of prostate cancer grading, including quantification of high-grade disease, cribriform/intraductal carcinoma, and impact of magnetic resonance imaging-targeted needle biopsy. Materials and methods: The Genitourinary Pathology Society distributed a survey to urology and urologic oncology-focused societies and hospital departments. Eight hundred and thirty four responses were collected and analyzed using descriptive statistics. Results: Eighty percent of survey participants use quantity of Gleason pattern 4 on needle biopsy for clinical decisions, less frequently with higher Grade Groups. Fifty percent interpret "tertiary" grade as a minor/< 5% component. Seventy percent of respondents would prefer per core grading as well as a global/overall score per set of biopsies, but 70% would consider highest Gleason score in any single core as the grade for management. Seventy five percent utilize Grade Group terminology in patient discussions. For 45%, cribriform pattern would affect management, while for 70% the presence of intraductal carcinoma would preclude active surveillance. Conclusion: This survey of practice patterns in relationship to prostate cancer grading highlights similarities and differences between contemporary pathology reporting and its clinical application. As utilization of Gleason pattern 4 quantification, minor tertiary pattern, cribriform/intraductal carcinoma, and the incorporation of magnetic resonance imaging-based strategies evolve, these findings may serve as a basis for more nuanced communication and guide research efforts involving pathologists and clinicians. (C) 2020 Elsevier Inc. All rights reserved.

The Genitourinary Pathology Society (GUPS) undertook a critical review of the recent advances in renal neoplasia, particularly focusing on the newly accumulated evidence post-2016 World Health Organization (WHO) classification. In the era of evolving histo-molecular classification of renal neoplasia, morphology is still key. However, entities (or groups of entities) are increasingly characterized by specific molecular features, often associated either with recognizable, specific morphologies or constellations of morphologies and corresponding immunohistochemical profiles. The correct diagnosis has clinical implications leading to better prognosis, potential clinical management with targeted therapies, may identify hereditary or syndromic associations, which may necessitate appropriate genetic testing. We hope that this undertaking will further facilitate the identification of these entities in practice. We also hope that this update will bring more clarity regarding the evolving classification of renal neoplasia and will further reduce the category of "unclassifiable renal carcinomas/tumors". We propose three categories of novel entities: (1) "Novel entity", validated by multiple independent studies; (2) "Emerging entity", good compelling data available from at least two or more independent studies, but additional validation is needed; and (3) "Provisional entity", limited data available from one or two studies, with more work required to validate them. For some entities initially described using different names, we propose new terminologies, to facilitate their recognition and to avoid further diagnostic dilemmas. Following these criteria, we propose as novel entities: eosinophilic solid and cystic renal cell carcinoma (ESC RCC), renal cell carcinoma with fibromyomatous stroma (RCC FMS) (formerly RCC with leiomyomatous or smooth muscle stroma), and anaplastic lymphoma kinase rearrangement-associated renal cell carcinoma (ALK-RCC). Emerging entities include: eosinophilic vacuolated tumor (EVT) and thyroid-like follicular renal cell carcinoma (TLFRCC). Finally, as provisional entities, we propose low-grade oncocytic tumor (LOT), atrophic kidney-like lesion (AKLL), and biphasic hyalinizing psammomatous renal cell carcinoma (BHP RCC).

PURPOSE: To determine and compare rates of grade group (GG) discrepancies between different targeted biopsy techniques (in-bore vs fusion) after propensity score weighting using whole-mount radical prostatectomy (RP) histopathologic analysis as the reference standard. MATERIALS AND METHODS: This retrospective study evaluated men who underwent targeted (fusion or in-bore) biopsy between April 2017 and January 2019 followed by prostatectomy. The primary endpoint of the study was a change in GG from biopsy to RP at a patient level. For downgrade and upgrade analysis, men with biopsy GG1 (downgrade not possible) and GG5 (upgrade not possible) were excluded, respectively. GG upgrade, downgrade, and concordance rates of each targeting approach were compared using propensity score weighting and logistic regression with inverse probability of treatment weighting. Significance level was set at .05. Index lesion GG on RP specimen served as the reference standard. RESULTS: A total of 191 men (90 in the in-bore [mean age, 63 years ± 7 (standard deviation)] and 101 in the fusion biopsy group [mean age, 65 years ± 7]) were eligible and included. Fewer GG upgrades were noted in the in-bore biopsy group (14%; 12 of 85) compared with the fusion plus systematic biopsy group (30%; 28 of 93) (P = .012). The incidence of GG downgrade in the in-bore group (25%; 21 of 84) was higher than in the fusion group (17%; 16 of 93); however, the difference was not statistically significant (P = .2). Of the 77 men misclassified by both biopsy techniques, the majority (56%, n = 43) had a change in GG of 2 to 3 or 3 to 2. CONCLUSION: Superior sampling accuracy with MRI-guided in-bore biopsies offers a lower incidence of GG upgrades compared with MRI–transrectal US fusion biopsies upon RP. Keywords: Biopsy/Needle Aspiration, MR-Imaging, Oncology, Pathology, Prostate Supplemental material is available for this article. © RSNA, 2021

Context.— Controversies and uncertainty persist in prostate cancer grading. Objective.— To update grading recommendations. Data Sources.— Critical review of the literature along with pathology and clinician surveys. Conclusions.— Percent Gleason pattern 4 (%GP4) is as follows: (1) report %GP4 in needle biopsy with Grade Groups (GrGp) 2 and 3, and in needle biopsy on other parts (jars) of lower grade in cases with at least 1 part showing Gleason score (GS) 4 + 4 = 8; and (2) report %GP4: less than 5% or less than 10% and 10% increments thereafter. Tertiary grade patterns are as follows: (1) replace “tertiary grade pattern” in radical prostatectomy (RP) with “minor tertiary pattern 5 (TP5),” and only use in RP with GrGp 2 or 3 with less than 5% Gleason pattern 5; and (2) minor TP5 is noted along with the GS, with the GrGp based on the GS. Global score and magnetic resonance imaging (MRI)-targeted biopsies are as follows: (1) when multiple undesignated cores are taken from a single MRI-targeted lesion, an overall grade for that lesion is given as if all the involved cores were one long core; and (2) if providing a global score, when different scores are found in the standard and the MRI-targeted biopsy, give a single global score (factoring both the systematic standard and the MRI-targeted positive cores). Grade Groups are as follows: (1) Grade Groups (GrGp) is the terminology adopted by major world organizations; and (2) retain GS 3 + 5 = 8 in GrGp 4. Cribriform carcinoma is as follows: (1) report the presence or absence of cribriform glands in biopsy and RP with Gleason pattern 4 carcinoma. Intraductal carcinoma (IDC-P) is as follows: (1) report IDC-P in biopsy and RP; (2) use criteria based on dense cribriform glands (>50% of the gland is composed of epithelium relative to luminal spaces) and/or solid nests and/or marked pleomorphism/necrosis; (3) it is not necessary to perform basal cell immunostains on biopsy and RP to identify IDC-P if the results would not change the overall (highest) GS/GrGp part per case; (4) do not include IDC-P in determining the final GS/GrGp on biopsy and/or RP; and (5) “atypical intraductal proliferation (AIP)” is preferred for an intraductal proliferation of prostatic secretory cells which shows a greater degree of architectural complexity and/or cytological atypia than typical high-grade prostatic intraepithelial neoplasia, yet falling short of the strict diagnostic threshold for IDC-P. Molecular testing is as follows: (1) Ki67 is not ready for routine clinical use; (2) additional studies of active surveillance cohorts are needed to establish the utility of PTEN in this setting; and (3) dedicated studies of RNA-based assays in active surveillance populations are needed to substantiate the utility of these expensive tests in this setting. Artificial intelligence and novel grading schema are as follows: (1) incorporating reactive stromal grade, percent GP4, minor tertiary GP5, and cribriform/intraductal carcinoma are not ready for adoption in current practice.

Intraductal carcinoma of the prostate (IDC-P) has been recently recognized by the World Health Organization classification of prostatic tumors as a distinct entity, most often occurring concurrently with invasive prostatic adenocarcinoma (PCa). Whether documented admixed with PCa or in its rare pure form, numerous studies associate this entity with clinical aggressiveness. Despite increasing clinical experience and requirement of IDC-P documentation in protocols for synoptic reporting, the specifics of its potential contribution to assessment of grade group (GG) and cancer quantitation of PCa in both needle biopsies (NBx) and radical prostatectomy (RP) specimens remain unclear. Moreover, there are no standard guidelines for incorporating basal cell marker immunohistochemistry (IHC) in the diagnosis of IDC-P, either alone or as part of a cocktail with AMACR/racemase. An online survey containing 26 questions regarding diagnosis, reporting practices, and IHC resource utilization, focusing on IDC-P, was undertaken by 42 genitourinary subspecialists from 9 countries. The degree of agreement or disagreement regarding approaches to individual questions was classified as significant majority (>75%), majority (51% to 75%), minority (26% to 50%) and significant minority (≤25%). IDC-P with or without invasive cancer is considered a contraindication for active surveillance by the significant majority (95%) of respondents, although a majority (66%) also agreed that the clinical significance/behavior of IDC-P on NBx or RP with PCa required further study. The majority do not upgrade PCa based on comedonecrosis seen only in the intraductal component in NBx (62%) or RP (69%) specimens. Similarly, recognizable IDC-P with GG1 PCa was not a factor in upgrading in NBx (78%) or RP (71%) specimens. The majority (60%) of respondents include readily recognizable IDC-P in assessment of linear extent of PCa at NBx. A significant majority (78%) would use IHC to confirm or exclude intraductal carcinoma if other biopsies showed no PCa, while 60% would use it to confirm IDC-P with invasive PCa in NBx if it would change the overall GG assignment. Nearly half (48%, a minority) would use IHC to confirm IDC-P for accurate Gleason pattern 4 quantitation. A majority (57%) report the percentage of IDC-P when present, in RP specimens. When obvious Gleason pattern 4 or 5 PCa is present in RP or NBx, IHC is rarely to almost never used to confirm the presence of IDC-P by the significant majority (88% and 90%, respectively). Most genitourinary pathologists consider IDC-P to be an adverse prognostic feature independent of the PCa grade, although recommendations for standardization are needed to guide reporting of IDC-P vis a vis tumor quantitation and final GG assessment. The use of IHC varies widely and is performed for a multitude of indications, although it is used most frequently in scenarios where confirmation of IDC-P would impact the GG assigned. Further study and best practices recommendations are needed to provide guidance with regards to the most appropriate indications for IHC use in scenarios regarding IDC-P.

Aims Intraductal proliferations of the prostate with more complexity and/or cytological atypia than high-grade prostate intra-epithelial neoplasia (HGPIN), but falling short of intraductal carcinoma (IDC-P), are described as 'atypical intraductal proliferation' (AIP). When present in needle biopsy (NBX) without IDC-P, the clinical significance is not known. Methods and results Sixty-two NBX cases were diagnosed as AIP over 7 years with estimated incidence of 1%. AIP was characterised by loose cribriform architecture (90%) or non-cribriform architecture exhibiting significant nuclear atypia that fell short of IDC-P. Fifty patients had concomitant PCa (20% grade group (GG) 1, 48% GG2, 14% GG3, 8% GG4 and 10% GG 5), and 12 had AIP alone. Of 40 patients who were candidates for no therapy (AIP alone) or active surveillance (AIP with GG1 or GG2 PCa without cribriform pattern 4), 20 had subsequent follow-up pathology [seven NBXs and 13 radical prostatectomy (RP)]. Of the 12 AIP only patients, six had a subsequent biopsy diagnosis of: benign prostate (two), IDC-P with PCa (one) and PCa (three). One or more adverse pathological features at subsequent RP were present in 93% of patients with AIP and GG1 or GG2 PCa, defined as: GG ≥ 3 (15%), IDC-P (77%), cribriform Gleason pattern 4 (69%), pT3a (77%) or pT3b (8%). Conclusions AIP in NBX may be a marker of unsampled IDC-P and/or other adverse pathological features in suspected low- to intermediate-risk PCa. AIP should be considered distinct from HGPIN for risk assessment and warrant consideration for further work-up to detect unsampled high-risk PCa.

Since its initial description in 1966 by Dr Donald Gleason, Gleason grading has become the cornerstone in the management of prostate cancer (PCa). With widespread use of Prostate Specific Antigen (PSA) screening and needle core biopsy, the diagnosis and management of PCa have dramatically evolved. In addition, better understanding of the morphological spectrum of prostate cancer and its clinical significance have prompted the refinement of the grading criteria and reporting guidelines commensurate to contemporary practice. The modification of the Gleason grading system implemented by the International Society of Urological Pathology in 2005 and subsequent revision in 2014 has profoundly impacted how PCa is graded and managed. This review aims to provide a concise update on the refinement of the histological criteria for various Gleason patterns and problem areas of Gleason grading, and provide recommendations on how to improve the grading reproducibility. The new proposal to group Gleason scores into clinically meaningful "grade groups" will also be discussed. Finally, we will discuss how magnetic resonance imaging (MRI)-targeted biopsy and emerging genetic markers may help improve the Gleason grading accuracy and risk stratification currently based on clinicopathological parameters.

In an adult man without significant prostatic hyperplasia, the prostate gland is shaped like an inverted cone and weighs 30–40 g. It is located within the pelvis, with its base proximally at the bladder neck and its apex distally at the urogenital diaphragm. It lies anterior to the rectum, with the urethra running through its center and serving as an important reference landmark. Therefore, the prostate is amenable to transrectal needle biopsy and transurethral resection. Anatomically, it comprises three zones with different volume, histology, and disease preference.

Spindle cell lesions of the prostate are encountered infrequently in clinical practice but represent a broad spectrum of diagnostically challenging lesions with varying clinical significance. The spindle cell lesions encompass both primary and secondary processes. A subset of these lesions is thought to be derived from the hormone-responsive stroma of the prostate gland, including stromal hyperplasia, stromal tumors of uncertain malignant potential (STUMP), and prostate stromal sarcoma (PSS). The utility of ancillary studies, including immunohistochemistry, is often limited, and the diagnosis relies on careful morphological evaluation.

Immunohistochemistry has been widely used in the workup of difficult prostate biopsies [1, 2]. It is used in two clinical settings: to distinguish prostate cancer from benign lesions that mimic cancer and to distinguish poorly differentiated prostate cancer from other malignant tumors that can occasionally involve the prostate, including urothelial carcinoma and colonic adenocarcinoma (see Table 4.1). Immunohistochemistry, as an adjunct to histological examination, has had significant impact on the prostate biopsy evaluation. In the case of limited cancer or histological variants with deceptively bland morphology, immunohistochemistry is an indispensible part of the workup [2]. Use of immunohistochemistry has also significantly reduced the incidence of prostate biopsies with atypical diagnosis to establish a definitive diagnosis [3–5].

The diagnosis of prostate carcinoma, especially when present in a limited amount in biopsy, is often challenging because numerous benign conditions have architectural and cytological features overlapping with and mimicking carcinoma [1]. These mimics include various anatomic structures, inflammatory and reactive conditions, and pathophysiological conditions, including atrophy, hyperplasia, and metaplasia. Many of these lesions are readily recognized and separated from malignancy but some may cause potential diagnostic difficulties. A useful approach to classifying benign mimics is based on major growth patterns of prostate carcinoma outlined in the Gleason grading system. This approach provides a conceptual framework for considering differential diagnoses. Three major growth patterns are encountered: small gland pattern mimicking Gleason score 4–6 carcinomas; large gland/cribriform growth pattern mimicking Gleason score 7–8 carcinomas; and fused glands/solid growth/single cells pattern mimicking Gleason score 8–10 carcinomas. Most benign lesions mimic small gland (acinar) adenocarcinoma.

Diagnosis of prostate cancer is based primarily on its light microscopic morphological features. Previous chapters have already discussed in detail the morphological criteria for diagnosis of prostate cancer and distinction from other cancer mimickers. Many flowcharts, algorithms, and tables are used to illustrate the steps in the diagnosis and differential diagnosis. This chapter serves as a quick reference for working-up prostate biopsies with various morphological patterns. It will discuss succinctly the morphological patterns that are commonly seen in prostate biopsies and focus on morphological features and immunohistochemical markers most important for decision-making steps during the evaluation of a particular pattern.

The diagnostic term “atypical glands suspicious for cancer (ATYP),” or “atypical small acinar proliferation (ASAP),” describes a small focus of prostate glands that exhibits architectural and cytological atypia and is suspicious for, yet falls short of, the diagnostic threshold for prostate cancer. It is not a distinct biological entity; rather, it encompasses a range of lesions of varying clinical significance, including under-sampled cancer, high-grade prostatic intraepithelial neoplasia (HGPIN), benign lesions that mimic cancer, and benign prostate glands with reactive atypia. An ATYP diagnosis in prostate needle biopsy is considered a risk factor for finding prostate cancer in subsequent biopsies. Such risk ranges from 27% to 47%, with an average of 42%, in recent studies. National Comprehensive Cancer Network (NCCN) recommends patients with ATYP on initial biopsies for additional biomarker testing, such as free PSA %, prostate health index (PHI) or 4Kscore, and imaging studies, to assess the risk of high-grade cancer and consider repeated biopsy with relative increased sampling of the site of the atypical diagnosis.

With widespread prostate-specific antigen (PSA) screening, an increasing number of patients are diagnosed with limited, or small focus of, prostate carcinoma on prostate biopsies. Many of these patients were found to have clinically insignificant disease on radical prostatectomy. Pathologists, nevertheless, still need to evaluate prostate biopsies with due diligence and diagnose cancer that meet the accepted diagnostic criteria for several reasons. First, many patients have clinically significant disease even after a biopsy diagnosis of limited cancer and currently, there is no reliable way to predict which patient may have clinically significant disease. Second, the current medico-legal environment demands that pathologists render accurate diagnoses on prostate biopsies according to the standard of care.

Intraductal carcinoma of the prostate (IDC-P) is an intraglandular/ductal neoplastic proliferation of prostatic glandular epithelial cells that is characterized by marked expansion of glandular architecture and nuclear atypia that often exceeds than seen in invasive carcinoma. It has been long recognized that some “invasive” prostatic carcinomas had residual basal cells on H&E staining or basal cell immunostains. McNeal and Yemoto first reported that it represented an aggressive form of acinar carcinoma. The concept of IDC-P has evolved significantly since then to culminate in recognizing it as a distinct entity in the 2016 WHO blue book.

Histologic variants of prostate acinar adenocarcinoma, ductal adenocarcinoma, neuroendocrine tumors, and other carcinomas account for 5–10% of prostate carcinomas and frequently are associated with ordinary acinar prostate adenocarcinoma. The morphologic spectrum of histologic variants of acinar adenocarcinoma ranges from tumors often resembling benign conditions, such as foamy and pseudohyperplastic carcinoma, to highly aggressive forms, such as sarcomatoid carcinoma. These histologic variants of acinar adenocarcinoma, ductal adenocarcinoma, neuroendocrine tumors, and other carcinomas often differ from acinar carcinoma in clinical, immunophenotypic, ultrastructural, or genetic features. Some of this histologic spectrum also differ in prognosis and may necessitate a different therapeutic approach. This chapter outlines important clinical and pathologic characteristics of histologic variants of acinar adenocarcinoma, ductal adenocarcinoma, neuroendocrine tumors, and other carcinomas.

The primary goal of prostate needle biopsy is to diagnose prostate cancer (PCa). Biopsy evaluation also provides a significant quantity of important data, including histological type, Gleason score, and tumor volume and extent, which are all critical for clinicians to prognosticate and manage patients. In keeping with the current trend of standardization of surgical pathology reports [1–3], several pathology organizations periodically issue recommendations for the reporting of prostate cancer in needle biopsy specimens [4]. The information that must be included in prostate biopsy reports is understandably in flux as our understanding of the pathological and molecular characteristics of prostate cancer expands, and diagnosis and treatment of prostate cancer continue to evolve. In addition, the prostate biopsy report should be written in a way that facilitates effective communications between pathologists and clinicians.

The clinicopathological characteristics of newly diagnosed prostate cancer have significantly changed due to widespread prostate-specific antigen (PSA) screening after its introduction in the late 1980s. The most remarkable change has been “stage migration” toward smaller volume disease at a younger age. The diagnosis of prostate cancer now is mostly triggered by an elevated or rising PSA rather than an abnormal digital rectal examination, resulting in a significant increase in the percentage of nonpalpable cancers (stage T1C) between 1988 and 1996 from 10% to 73%. With this trend, the prostate biopsy application and sampling techniques have also rapidly evolved. In 1989, the transrectal ultrasound (TRUS)-guided sextant prostate biopsy was introduced and rapidly became the standard over directed biopsies of hypoechoic lesions and palpable nodules. In recent years, it has become increasingly evident that sextant biopsies could miss a significant number (up to 30%) of cancers because only a small percentage of prostates has a tumor distribution detectable with the paramedian template utilized by the sextant approach. Furthermore, sextant protocol tends to undersample certain areas of the prostate, such as “anterior horns” and the lateral aspects of the peripheral zone, where majority of prostate cancer arises. Recent studies suggested moving the biopsies more laterally to better sample the lateral aspects and anterior horns of the peripheral zones. This recommendation was supported by the zonal anatomy of the prostate as well as the origin of the tumor. Because approximately 80% of prostate cancers originate in the peripheral zone, extended biopsy templates that more extensively sample this region could improve the cancer detection rate.

Prostate lesions can be managed by several surgical and nonsurgical modalities, including surgical resection and, ablation by physical methods such as cryo- and thermal ablation (see Table 12.1). Treatment can cause significant histological changes in both benign and malignant prostate tissue [1]. Such changes may pose a significant challenge in interpretation, particularly in needle biopsy specimens. In addition, prostate cancer with treatment effect should not be assigned a Gleason grade. History of such treatment, however, is not always provided by clinicians. Therefore, pathologists should be aware of the histological changes associated with treatment in benign and malignant prostate tissue.

Intraductal carcinoma of the prostate and high-grade prostatic intraepithelial neoplasia (PIN) have markedly different implications for patient care but can be difficult to distinguish in needle biopsies. In radical prostatectomies, we demonstrated that PTEN and ERG immunostaining may be helpful to resolve this differential diagnosis. Here, we tested whether these markers are diagnostically useful in the needle biopsy setting. Separate or combined immunostains were applied to biopsies containing morphologically identified intraductal carcinoma, PIN, or borderline intraductal proliferations more concerning than PIN but falling short of morphologic criteria for intraductal carcinoma. Intraductal carcinoma occurring with concurrent invasive tumor showed the highest rate of PTEN loss, with 76% (38/50) lacking PTEN and 58% (29/50) expressing ERG. Of biopsies containing isolated intraductal carcinoma, 61% (20/33) showed PTEN loss and 30% (10/33) expressed ERG. Of the borderline intraductal proliferations, 52% (11/21) showed PTEN loss and 27% (4/15) expressed ERG. Of the borderline cases with PTEN loss, 64% (7/11) had carcinoma in a subsequent needle biopsy specimen, compared with 50% (5/10) of PTEN-intact cases. In contrast, none of the PIN cases showed PTEN loss or ERG expression (0/19). On needle biopsy, PTEN loss is common in morphologically identified intraductal carcinoma yet is very rare in high-grade PIN. Borderline intraductal proliferations, especially those with PTEN loss, have a high rate of carcinoma on resampling. If confirmed in larger prospective studies, these results suggest that PTEN and ERG immunostaining may provide a useful ancillary assay to distinguish intraductal carcinoma from high-grade PIN in this setting.

In the above-referenced commentary,1 Murali Varma raises two valid concerns regarding implications for communication from the message of our study2. First, introducing a term ”Atypical Intraductal Proliferation (AIP)” or “low-grade intraductal carcinoma (IDC-P)” for which there are no well-defined morphological cut-offs or criteria and, second, for the risk of overtreatment. In this author's experience which is based on current2 and previous studies,3-6 AIPs represent significant lesions and must be distinguished from HGPIN. Morphologically, the vast majority of AIPs present with cribriform morphology which have been increasingly recognized as significant lesions. This article is protected by copyright. All rights reserved.

Accurate recognition of Gleason pattern 5 (GP5) prostate adenocarcinoma (PCa) on core biopsy (NBX) is critical because it is associated with disease progression and the worst clinical outcome. We evaluated 1557 consecutive and prospectively collected NBXs to determine the frequency of diagnosis, morphologic subpatterns, and their relation to the amount and pattern distribution of GP5 PCa based on the 2005 modified Gleason grading system. Tertiary GP5 was upgraded to a secondary pattern to derive the final Gleason score. GP5 accounted for 6% of all NBXs and 14% of PCa cases. GP5 PCas were associated with high-risk preoperative clinical and biopsy characteristics, regardless of the amount of GP5. Most patients (85%) with % GP5 greater than 5% of PCa had the final Gleason score of 9 to 10, compared with % GP5 of 5% or less of PCa (P < .0001). The morphologic subpatterns of GP5 PCas were as follows: infiltrating cords (96%), single cells (76%), solid sheets (29%), and comedocarcinoma (2%). Infiltrating cords and single-cell patterns frequently coexisted (76%). The GP5 was distributed in a tertiary (66%), followed by secondary (32%) and primary (2%) components of PCa. Infiltrating cords and single cells were the 2 most frequently encountered patterns, specifically when GP5 involved 5% or less of PCa and represented secondary or tertiary component of PCa. GP5 PCa is a relatively frequent presentation in the contemporary NBX practice. Because of its important prognostic and therapeutic implications, pathologists must be aware of its varied morphologic presentations and to the fact that most cases with GP5 represent a tertiary component of PCa.

Background and objective Urothelial carcinoma (UC) demonstrating variant histologic differentiation is associated with poor outcomes, and certain variants exhibit differing therapeutic responses compared with pure conventional UC. Little is known about the awareness and reporting practices of UC with variant histology in community practice. Materials and Methods Patients diagnosed with UC based on an outside pathologic review had their pathology centrally reviewed before instituting therapy. A discordant diagnosis was defined as the presence of variant histologic differentiation not reported by the referring institution. Variant histologic differentiation was quantitated as focal (10%–50%) or extensive (>50%). Results Of 589 transurethral biopsies (TURBTs), 115 (19.5%) UCs demonstrated variant histologic differentiation. Muscle invasion at TURBT and extravesical disease at cystectomy was present in 69% and 52%, respectively. Of 56 patients with at least 1 year follow-up, recurrence-free survival was 56%. The majority (90%) showed a single variant histology, which was extensive in 58% of cases. Squamous differentiation (32%) was the most common variant histology identified, followed by small cell (16%), glandular (13%), micropapillary (12%), nested (8%), sarcomatoid (6%), lymphoepithelial (3%), and plasmacytoid (1%) type. Variant histologic differentiation was not documented by the referring institution in 44% of cases, of which 47% were extensive. Commonly under-recognized patterns included lymphoepithelial (2) and plasmacytoid (1) types (100%), nested (7, 87%), micropapillary (10, 83%), and small cell (7, 44%). Conclusions This study emphasizes the importance of central pathology review in the management of bladder cancer patients and the need for increased awareness of this relatively common phenomenon in UC.

The classification working group of the International Society of Urological Pathology consensus conference on renal neoplasia was in charge of making recommendations regarding additions and changes to the current World Health Organization Classification of Renal Tumors (2004). Members of the group performed an exhaustive literature review, assessed the results of the preconference survey and participated in the consensus conference discussion and polling activities. On the basis of the above inputs, there was consensus that 5 entities should be recognized as new distinct epithelial tumors within the classification system: tubulocystic renal cell carcinoma (RCC), acquired cystic disease-associated RCC, clear cell (tubulo) papillary RCC, the MiT family translocation RCCs (in particular t(6;11) RCC), and hereditary leiomyomatosis RCC syndrome-associated RCC. In addition, there are 3 rare carcinomas that were considered as emerging or provisional new entities: thyroid-like follicular RCC; succinate dehydrogenase B deficiency-associated RCC; and ALK translocation RCC. Further reports of these entities are required to better understand the nature and behavior of these highly unusual tumors. There were a number of new concepts and suggested modifications to the existing World Health Organization 2004 categories. Within the clear cell RCC group, it was agreed upon that multicystic clear cell RCC is best considered as a neoplasm of low malignant potential. There was agreement that subtyping of papillary RCC is of value and that the oncocytic variant of papillary RCC should not be considered as a distinct entity. The hybrid oncocytic chromophobe tumor, which is an indolent tumor that occurs in 3 settings, namely Birt-Hogg-Dubé Syndrome, renal oncocytosis, and as a sporadic neoplasm, was placed, for the time being, within the chromophobe RCC category. Recent advances related to collecting duct carcinoma, renal medullary carcinoma, and mucinous spindle cell and tubular RCC were elucidated. Outside of the epithelial category, advances in our understanding of angiomyolipoma, including the epithelioid and epithelial cystic variants, were considered. In addition, the apparent relationship between cystic nephroma and mixed epithelial and stromal tumor was discussed, with the consensus that these tumors form a spectrum of neoplasia. Finally, it was thought that the synovial sarcoma should be removed from the mixed epithelial and mesenchymal category and placed within the sarcoma group. The new classification is to be referred to as the International Society of Urological Pathology Vancouver Classification of Renal Neoplasia.

The International Society of Urologic Pathology 2012 Consensus Conference on renal cancer, through working group 3, focused on the issues of staging and specimen handling of renal tumors. The conference was preceded by an online survey of the International Society of Urologic Pathology members, and the results of this were used to inform the focus of conference discussion. On formal voting a Z65% majority was considered a consensus agreement. For specimen handling it was agreed that with radical nephrectomy specimens the initial cut should be made along the long axis and that both radical and partial nephrectomy specimens should be inked. It was recommended that sampling of renal tumors should follow a general guideline of sampling 1 block/cm with a minimum of 3 blocks (subject to modification as needed in individual cases). When measuring a renal tumor, the length of a renal vein/caval thrombus should not be part of the measurement of the main tumor mass. In cases with multiple tumors, sampling should include at a minimum the 5 largest tumors. There was a consensus that perinephric fat invasion should be determined by examining multiple perpendicular sections of the tumor/perinephric fat interface and by sampling areas suspicious for invasion. Perinephric fat invasion was defined as either the tumor touching the fat or extending as irregular tongues into the perinephric tissue, with or without desmoplasia. It was agreed upon that renal sinus invasion is present when the tumor is in direct contact with the sinus fat or the loose connective tissue of the sinus, clearly beyond the renal parenchyma, or if there is involvement of any endothelium-lined spaces within the renal sinus, regardless of the size. When invasion of the renal sinus is uncertain, it was recommended that at least 3 blocks of the tumor-renal sinus interface should be submitted. If invasion is grossly evident, or obviously not present (small peripheral tumor), it was agreed that only 1 block was needed to confirm the gross impression. Other recommendations were that the renal vein margin be considered positive only when there is adherent tumor visible microscopically at the actual margin. When a specimen is submitted separately as "caval thrombus, "the recommended sampling strategy is to take 2 or more sections to look for the adherent caval wall tissue. It was also recommended that uninvolved renal parenchyma be sampled by including normal parenchyma with tumor and normal parenchyma distant from the tumor. There was consensus that radical nephrectomy specimens should be examined for the purpose of identifying lymph nodes by dissection/palpation of the fat in the hilar area only; however, it was acknowledged that lymph nodes are found in

The International Society of Urological Pathology 2012 Consensus Conference made recommendations regarding classification, prognostic factors, staging, and immunohistochemical and molecular assessment of adult renal tumors. Issues relating to prognostic factors were coordinated by a workgroup who identified tumor morphotype, sarcomatoid/rhabdoid differentiation, tumor necrosis, grading, and microvascular invasion as potential prognostic parameters. There was consensus that the main morphotypes of renal cell carcinoma (RCC) were of prognostic significance, that subtyping of papillary RCC (types 1 and 2) provided additional prognostic information, and that clear cell tubulopapillary RCC was associated with a more favorable outcome. For tumors showing sarcomatoid or rhabdoid differentiation, there was consensus that a minimum proportion of tumor was not required for diagnostic purposes. It was also agreed upon that the underlying subtype of carcinoma should be reported. For sarcomatoid carcinoma, it was further agreed upon that if the underlying carcinoma subtype was absent the tumor should be classified as a grade 4 unclassified carcinoma with a sarcomatoid component. Tumor necrosis was considered to have prognostic significance, with assessment based on macroscopic and microscopic examination of the tumor. It was recommended that for clear cell RCC the amount of necrosis should be quantified. There was consensus that nucleolar prominence defined grades 1 to 3 of clear cell and papillary RCCs, whereas extreme nuclear pleomorphism or sarcomatoid and/or rhabdoid differentiation defined grade 4 tumors. It was agreed upon that chromophobe RCC should not be graded. There was consensus that microvascular invasion should not be included as a staging criterion for RCC.

Aims Patients who have undergone prostate radiation are at increased risk for developing urothelial carcinoma. Radiation changes can cause significant cytological atypia in benign prostate glands that may mimic pagetoid spread of urothelial carcinoma. GATA3 is a common marker for differentiating prostatic adenocarcinoma from urothelial carcinoma. The aim of this study was to investigate the expression of GATA3 in the epithelium of irradiated benign and malignant prostate tissue. Methods and results We performed a retrospective review of prostate cases with radiation atypia. GATA3 staining was performed on benign prostate tissue with and without radiation atypia, as well as on residual/recurrent prostatic adenocarcinoma after radiation therapy. PIN4 immunohistochemical (IHC) staining was performed on prostate tissue with radiation atypia to confirm the presence of both basal and luminal cells. We identified 31 cases with benign prostate glands containing radiation atypia. The average time between treatment with radiation therapy and the surgical procedure was 10 years (range 5-20 years). PIN4 IHC staining confirmed the presence of basal and luminal cells in benign prostate glands with radiation atypia. Thirty-one of 31 (100%) cases of benign prostate tissue with radiation atypia showed staining for GATA3 in both basal and luminal cells. Eight of eight (100%) cases of benign prostate glands without radiation atypia and no inflammatory changes showed GATA3 positivity limited to basal cells. GATA3 was negative in 12/12 (100%) cases of prostatic adenocarcinoma after radiation therapy. Conclusion Benign prostate glands with radiation atypia show diffuse positivity for GATA3. This staining pattern, along with the cytological atypia resulting from radiation, can mimic urothelial carcinoma.

Activation of the EGF receptors EGFR (ErbB1) and HER2 (ErbB2) drives the progression of multiple cancer types through complex mechanisms that are still not fully understood. In this study, we report that HER2 expression is elevated in bone metastases of prostate cancer independently of gene amplification. An examination of HER2 and NF-κB receptor (RANK) coexpression revealed increased levels of both proteins in aggressive prostate tumors and metastatic deposits. Inhibiting HER2 expression in bone tumor xenografts reduced proliferation and RANK expression while maintaining EGFR expression. In examining the role of EGFR in tumor-initiating cells (TIC), we found that EGFR expression was required for primary and secondary sphere formation of prostate cancer cells. EGFR expression was also observed in circulating tumor cells (CTC) during prostate cancer metastasis. Dual inhibition of HER2 and EGFR resulted in significant inhibition of tumor xenograft growth, further supporting the significance of these receptors in prostate cancer progression. Overall, our results indicate that EGFR promotes survival of prostate TIC and CTC that metastasize to bone, whereas HER2 supports the growth of prostate cancer cells once they are established at metastatic sites. Cancer Res; 77(1); 74–85. ©2016 AACR.

This article provides comprehensive review of benign diseases and neoplastic conditions of the penis. It describes and provides representative images of clinical, key pathologic features and ancillary techniques to aid in differential diagnoses. It examines these diseases from the epidemiologic standpoint, looks at environmental and genetic factors, and outlines the new histologic entities for penile neoplasms with distinct outcomes and clinical behavior that have been proposed in recent years.

As hypoxia is believed to play an important role in the development and progression of prostate cancer, we evaluated whether 18F-labeled fluoroazomycin arabinoside (18F-FAZA) would be useful to identify tumor hypoxia in resectable prostate cancer. Positron emission tomography (PET)/CT was performed on 14 patients with untreated localized primary prostate cancer 3 h post-injection of approximately 390 MBq of 18F-FAZA using forced diuresis to decrease radioactivity in the urinary bladder. Anatomical trans-pelvic coil and pre- and post-contrast 1.5 T MRI with endorectal coil were performed on the same day. Patients underwent radical prostatectomy and ex vivo 3 T MRI of the prostatectomy specimen within 14 days following in vivo imaging. Imaging results were verified by whole mount histopathology plus tissue microarray (TMA) immunohistochemical (IHC) analysis for carbonic anhydrase IX (CAIX) and hypoxia-inducible factor 1α (HIF-1α). Registration of in vivo imaging with histology was achieved using mutual information software and performing ex vivo MRI of the prostatectomy specimen and whole mount sectioning with block face photography as intermediate steps. Whole mount histology identified 43 tumor nodules, 19 of them larger than 1 ml as determined on coregistered volumes featuring 18F-FAZA, MRI, and histological 3-D image information. None of these lesions was found to be positive for CAIX or visualized by 18F-FAZA PET/CT while IHC for HIF-1α showed variable staining of tumor tissues. Accordingly, no correlation was found between 18F-FAZA uptake and Gleason scores. Our data based on 18F-FAZA PET/CT and CAIX IHC do not support the presence of clinically relevant hypoxia in localized primary prostate cancer including high-grade disease. Activation of HIF-1α may be independent of tissue hypoxia in primary prostate cancer.

Rationale and Objectives Positron emission tomography (PET) is actively investigated to aid in target volume definition for radiation therapy. The objectives of this study were to apply an automatic computer algorithm to compute target volumes and to validate the algorithm using histologic data from real human prostate cancer. Materials and Methods Various modalities for prostate imaging were performed. In vivo imaging included T2 3-T magnetic resonance imaging and 11C-choline PET. Ex vivo imaging included 3-T magnetic resonance imaging, histology, and block face photos of the prostate specimen. A novel registration method based on mutual information and thin-plate splines was applied to all modalities. Once PET is registered with histology, a voxel-by-voxel comparison between PET and histology is possible. A thresholding technique based on various fractions of the maximum standardized uptake value in the tumor was applied, and the respective computed threshold volume on PET was compared with histologic truth. Results Sixteen patients whose primary tumor volumes ranged from 1.2 to 12.6 cm3 were tested. PET has low spatial resolution, so only tumors > 4 cm3 were considered. Four cases met this criterion. A threshold value of 60% of the 11C-choline maximum standardized uptake value resulted in the highest volume overlap between threshold volume on PET and histology. Medial axis distances between threshold volume on PET and histology showed a mean error of 7.7 ± 5.2 mm. Conclusions This is a proof-of-concept study demonstrating for the first time that histology-guided thresholding on PET can delineate tumor volumes in real human prostate cancer.

Purpose: Fusion of the TMPRSS2 prostate-specific gene with the ERG transcription factor is a putatively oncogenic gene rearrangement that is commonly found in prostate cancer tissue from men undergoing prostatectomy. However, the prevalence of the fusion was less common in samples of transurethral resection of the prostate from a Swedish cohort of patients with incidental prostate cancer followed by watchful waiting, raising the question as to whether the high prevalence in prostatectomy specimens reflects selection bias. We sought to determine the prevalence of TMPRSS2-ERG gene fusion among prostate-specific antigen–screened men undergoing prostate biopsy in the United States. Experimental Design: We studied 140 prostate biopsies from the same number of patients for TMPRSS2-ERG fusion status with a fluorescent in situ hybridization assay. One hundred and thirty-four samples (100 cancer and 34 benign) were assessable. Results: ERG gene rearrangement was detected in 46% of prostate biopsies that were found to have prostate cancer and in 0% of benign prostate biopsies (P < 0.0001). Evaluation of morphologic features showed that cribriform growth, blue-tinged mucin, macronucleoli, and collagenous micronodules were significantly more frequent in TMPRSS2-ERG fusion–positive prostate cancer biopsies than gene fusion–negative prostate cancer biopsies (P ≤ 0.04). No significant association with Gleason score was detected. In addition, non-Caucasian patients were less likely to have positive fusion status (P = 0.02). Conclusions: This is the first prospective North American multicenter study to characterize TMPRSS2-ERG prostate cancer prevalence in a cohort of patients undergoing needle biopsy irrespective of whether or not they subsequently undergo prostatectomy. Our results show that this gene rearrangement is common among North American men who have prostate cancer on biopsy, is absent in benign prostate biopsy, and is associated with specific morphologic features. These findings indicate a need for prospective studies to evaluate the relationship of TMPRSS2-ERG rearrangement with clinical course of screening-detected prostate cancer in North American men, and a need for the development of noninvasive screening tests to detect TMPRSS2-ERG rearrangement.

The clinical under staging of T1 bladder cancer potentially delays therapy and undermines survival. In this study we evaluated clinicopathological features to aid in the identification of patients with clinical T1 bladder cancer at risk for under staging.We identified patients diagnosed with clinical T1 bladder cancer who underwent cystectomy within 4 months. Muscularis propria was present and uninvolved in initial biopsies or patients had a re-staging biopsy with muscle [corrected] present. Under staging was defined as pT2 or greater, N+ or M+ disease at radical cystectomy. A logistic regression multivariable model was used for the risk of under staging. Overall survival was assessed using the Kaplan-Meier method.Of 95 patients 26 (27%) had under staged disease. Median followup was 24 months. Compared to accurately staged cases under staged cases were more likely to have muscularis mucosae invasion (54% vs 19%, p = 0.001), mixed histology (42% vs 17%, p = 0.02) and urethral involvement (31% vs 10%, p = 0.03). In a multivariable model muscularis mucosae invasion increased the odds of under staging 9-fold (95% CI 1.5-54.5, p = 0.01). The cumulative association of these risk factors increased the odds of under staging 20-fold (95% CI 1.8-217, p = 0.0029). Median overall survival (years) was lower in patients with under staged disease (1.4 vs 10.6, p0.001), those with muscularis mucosae invasion (2.2 vs 6.5, p = 0.04) and those with urethral involvement (25th percentile 0.8 vs 2.0, p = 0.01).Under staging adversely impacts survival. Muscularis mucosae invasion, urethral involvement and mixed histology cumulatively increase the risk of under staging, and may be valuable in counseling patients regarding early, aggressive intervention.

To better represent the Gleason score of radical prostatectomy, the International Society of Urologic Pathologists Consensus Committee recommends assigning individual Gleason scores to prostate cancer cores submitted in separate containers and/or multiple cores in the same container with site identifiers. However, scenarios where multiple cores are submitted in the same container without site identifiers or labeled "left/right" are common. To assess this scenario, we analyzed 110 extended biopsies containing different Gleason scores with corresponding radical prostatectomy for clinically significant grade differences. Because cores are individually labeled and submitted at our institution, we simulated a scenario of multiple intact cores with different Gleason scores in the same container(s) by analyzing as if submitted in containers labeled "left/right." For each biopsy, a Global (all positive cores averaged as 1 long positive core), Worst, and Largest tumor volume Gleason score was determined and compared with grade of radical prostatectomy using kappa statistics. Biopsies containing core(s) with 3+4 and other core(s) 3+3 were excluded because in this situation, both Global and Worst Gleason score will be always 3+4. The following scenarios were considered clinically significant upgrading: biopsy Gleason score 6 / 3+4 to radical prostatectomy 4+3; biopsy 7 to radical prostatectomy 8-10; biopsy 7 to radical prostatectomy 7 with tertiary Gleason pattern 5. Overall, 51 cases met inclusion criteria. Biopsy Worst Gleason score had the best correlation with radical prostatectomy (kappa agreement of 0.37). Clinically significant upgrading at radical prostatectomy was least with Worst (4%) and highest with Global Gleason score (37%). Upgrading and downgrading were noted in 14% and 8%, respectively, of 59 cases containing core(s) with a Gleason score of 3+4 and other core(s) 3+3, suggesting that any amount of higher Gleason pattern should be recorded. When multiple intact cores are submitted in the same container without specific identifiers, individual cores with cancer should be graded and/or the Worst Gleason score should be recorded.

BACKGROUND. Focal targeted therapy has been proposed as a potential treatment for localized prostate cancer in an attempt to reduce morbidity. However, these modalities rely heavily on accurate tumor localization to achieve total tumor ablation. In the current study, we sought to examine the ability of contemporary extended pattern prostate biopsy to predict the location of tumors. METHODS. A total of 281 men with prostate cancer detected via a standardized extended pattern biopsy template with at least 12 cores and who subsequently underwent radical prostatectomy were evaluated. Tumor location on biopsy, stratified by laterality and by site (apex vs mid-base prostate), was compared with corresponding locations on the prostatectomy specimen. Generalized estimating equation models were developed to assess the effects of clinical variables on pathologic agreement between biopsy and prostatectomy specimens. RESULTS. Of the 281 prostate biopsies, the positive predictive value (PPV) of right and left needle biopsy was high at 97.3% and 96.7%, respectively. However, the negative predictive value (NPV) was low at 24.7% and 31.3%, respectively. When more specific locations were considered, the NPV improved at the apex. However, this came at a cost to the PPV. Tumor focality on prostatectomy specimen was the only clinical feature found to be significantly and consistently related to pathologic agreement. CONCLUSIONS. Contemporary extended pattern prostate biopsy, although able to diagnose cancers, fails to provide reliable localization of tumors to specific areas of the prostate. Focal therapy, which relies heavily on localization, should only be performed with this caveat in mind. Cancer 2008;113:1559-65. � 2008 American Cancer Society.

BACKGROUND Prostate cancer (PCa) frequently metastasizes to the bone and induces osteoblastic lesions. We previously demonstrated through over-expression of the Wnt inhibitor dickkopf-1 (DKK-1) that Wnts contribute to the osteoblastic component of PCa osseous lesions in vivo. METHODS To test the clinical significance of DKK-1 expression during PCa progression, tissue microarrays were stained for DKK-1 protein by immunohistochemistry. RESULTS DKK-1 expression index (EI) was found to increase in PIN and primary lesions compared to non-neoplastic tissue (106 ± 10 vs. 19 ± 6, respectively, where the EI is the product of the percent expression and staining intensity). DKK-1 expression was also found to be higher in all PCa metastatic lesions (56 ± 21 EI) compared to non-neoplastic tissues but was significantly decreased versus primary PCa lesions (P

Rationale and Objectives Registration enables quantitative spatial correlation of features from different imaging modalities. Our objective is to register in vivo imaging with histologic sections of the human prostate so that histologic truth can be correlated with in vivo imaging features. Materials and Methods In vivo imaging of the prostate included T2-weighted anatomic and diffusion weighted 3-T magnetic resonance imaging (MRI) as well as 11 C-choline positron emission tomography (PET). In addition, ex vivo 3-T MRI of the prostate specimen, histology, and associated block face photos of the prostate specimen were obtained. A standard registration method based on mutual information (MI) and thin-plate spline (TPS) was applied. Registration among in vivo imaging modalities is well established; however, accurate registration involving histology is difficult. Our approach breaks up the difficult direct registration of histology and in vivo imaging into achievable subregistration tasks involving intermediate ex vivo modalities like block face photography and specimen MRI. Results of subregistration tasks are combined to compute the intended, final registration between in vivo imaging and histology. Results The methodology was applied to two patients and found to be clinically feasible. Overall registered anatomic MRI, diffusion MRI, and 11 C-choline PET aligned well with histology qualitatively for both patients. There is no ground truth of registration accuracy as the scans are real patient scans. An indirect validation of the registration accuracy has been proposed comparing tumor boundary markings found in diffusion MRI and histologic sections. Registration errors for two patients between diffusion MRI and histology were 3.74 and 2.26 mm. Conclusion This proof of concept paper demonstrates a method based on intrinsic image information content for successfully registering in vivo imaging of the human prostate with its post-resection histology, which does not require the use of extrinsic fiducial markers. The methodology successfully mapped histology onto the in vivo imaging space, allowing the observation of how well different in vivo imaging features correspond to histologic truth. The methodology is therefore the basis for a systematic comparison of in vivo imaging for staging of human prostate cancer.

Purpose: More than 1,300,000 prostate needle biopsies are done annually in the United States with up to 16% incidence of isolated high-grade prostatic intraepithelial neoplasia (HGPIN). HGPIN has low predictive value for identifying prostate cancer on subsequent needle biopsies in prostate-specific antigen–screened populations. In contemporary series, prostate cancer is detected in ∼20% of repeat biopsies following a diagnosis of HGPIN. Further, discrete histologic subtypes of HGPIN with clinical implication in management have not been characterized. The TMPRSS2-ERG gene fusion that has recently been described in prostate cancer has also been shown to occur in a subset of HGPIN. This may have significant clinical implications given that TMPRSS2-ERG fusion prostate cancer is associated with a more aggressive clinical course. Experimental Design: In this study, we assessed a series of HGPIN lesions and paired prostate cancer for the presence of TMPRSS2-ERG gene fusion. Results: Fusion-positive HGPIN was observed in 16% of the 143 number of lesions, and in all instances, the matching cancer shared the same fusion pattern. Sixty percent of TMPRSS2-ERG fusion prostate cancer had fusion-negative HGPIN. Conclusions: Given the more aggressive nature of TMPRSS2-ERG prostate cancer, the findings of this study raise the possibility that gene fusion-positive HGPIN lesions are harbingers of more aggressive disease. To date, pathologic, molecular, and clinical variables do not help stratify which men with HGPIN are at increased risk for a cancer diagnosis. Our results suggest that the detection of isolated TMPRSS2-ERG fusion HGPIN would improve the positive predictive value of finding TMPRSS2-ERG fusion prostate cancer in subsequent biopsies.

There is no consensus regarding the role of intraoperative pathological consultation during kidney cancer surgery. Accordingly intraoperative pathological consultation use is susceptible to variation based on nonclinical factors. We explored this hypothesis by evaluating national trends in the use of intraoperative pathological consultation during radical or partial nephrectomy with time, across regions, and by patient and provider characteristics.Using linked Surveillance, Epidemiology and End Results-Medicare data we identified a cohort of patients who underwent partial or radical nephrectomy from 1991 to 2002. In each case we ascertained corresponding Medicare claims for gross and/or frozen section intraoperative pathological consultation. We assessed variations in the use of intraoperative pathological consultation by year of treatment and geographic region as well as by patient and provider characteristics.We identified 7,507 cases treated with partial (600 or 8.0%) or radical (6,907 or 92.0%) nephrectomy from 1991 through 2002. Of cases treated with radical nephrectomy 744 (10.8%) and 843 (12.2%) received gross and frozen section intraoperative pathological consultation, respectively. Of cases treated with partial nephrectomy 67 (11.2%) had an intraoperative gross consultation and 323 (53.8%) had a frozen section evaluation. Use of intraoperative pathological consultation (gross or frozen section) during partial and radical nephrectomy varied based on patient demographics, United States Census region, and Surveillance, Epidemiology and End Results registry (p0.05). Intraoperative pathological consultation during radical nephrectomy differed by year of treatment (p0.05). Intraoperative pathological consultation use also varied based on provider characteristics (p0.05).Intraoperative pathological consultation use during kidney cancer surgery varies with time, across geographic regions and based on patient demographics and broadly defined provider characteristics. These data provide context for future studies seeking to refine the use of intraoperative pathological consultation in this clinical setting.

Purpose: To determine if perineural invasion (PNI) should be included in addition to prostate-specific antigen (PSA), biopsy Gleason score, and clinical T-stage for risk-stratification of patients with localized prostate cancer. Methods and Materials: We analyzed prostatectomy findings for 1550 patients, from a prospectively collected institutional database, to determine whether PNI was a significant predictor for upgrading of Gleason score or pathologic T3 disease after patients were stratified into low-, intermediate-, and high-risk groups (on the basis of PSA, biopsy Gleason score, and clinical T-stage). Results: For the overall population, PNI was associated with a significantly increased frequency of upgrading and of pathologic T3 disease. After stratification, PNI was still associated with significantly increased odds of pathologic T3 disease within each risk group. In particular, for low-risk patients, there was a markedly increased risk of extraprostatic extension (23% vs. 7%), comparable to that of intermediate-risk patients. Among high-risk patients, PNI was associated with an increased risk of seminal vesicle invasion and lymph node involvement. Furthermore, over 80% of high-risk patients with PNI were noted to have an indication for postoperative radiation. Conclusions: Perineural invasion may be useful for risk-stratification of prostate cancer. Our data suggest that low-risk patients with PNI on biopsy may benefit from treatment typically reserved for those with intermediate-risk disease. In addition, men with high-risk disease and PNI, who are contemplating surgery, should be informed of the high likelihood of having an indication for postoperative radiation therapy.

OBJECTIVES To study the evolution of surgical margins in robotic prostatectomy (DVP), to ascertain the surgical volume necessary to provide quality cancer care. METHODS Clinicopathologic data on consecutive DVP patients were abstracted from our institutional database. The primary outcome evaluated was the presence of any positive surgical margin. Surgeon DVP volume was the unit of exposure. A logistic model was fit to measure the association of volume and margin status, adjusting for patient differences. RESULTS Between November 2001 and August 2005, 193 consecutive patients underwent DVP. Disease and patient characteristics were similar across the levels of surgeon volume. Overall, surgical margins did not dramatically decline over time (first 15 cases, 26% versus cases 81 and beyond, 22%; P = 0.82). However, extensive margins were largely eliminated (first 15 cases, 12% versus cases 81 and beyond, 2%; P = 0.05). After adjusting for preoperative patient differences, the odds of any positive margin among those treated by a surgeon in the highest-volume group was 0.99 (95% confidence interval 0.36 to 2.72) compared with those treated during a surgeon's first 15 cases. CONCLUSIONS Although extensive surgical margins decline with increasing volume, overall positive margin rates after DVP respond slowly. It seems that cumulative surgeon volume beyond that which can be obtained in the typical urology practice may be needed to obtain ideal margin rates with this new technology.

Context The incidence of syphilis is on the rise, particularly in male patients who are human immunodeficiency virus (HIV) positive, and men who have sex with men. Objective To describe 4 cases of primary syphilis presenting in the anal canal to increase awareness of its presentation and morphology in this location, as the diagnosis can be easily overlooked clinically and by the pathologist. Design Clinical presentation, hematoxylin-eosin–stained sections, and Treponema pallidum immunohistochemical staining were reviewed in detail in all 4 cases. Results Three patients presented with anal canal ulcers; one presented with an ulcerated anal mass. All 4 patients were male, of whom 2 were HIV positive. Syphilis was clinically suspected in only 1 case; in 2 cases, confirmatory evaluation and treatment were prompted by pathologic diagnosis. In the fourth case, syphilis was diagnosed serologically at time of biopsy; however, the patient had an anal mass, and malignancy was clinically suspected. All 4 cases had bandlike chronic plasma cell–rich inflammation at the squamous epithelium and lamina propria junction; 2 cases had poorly formed granulomas. One case had concomitant rectal biopsy specimens with proctitis. Treponema pallidum immunohistochemistry highlighted homing of organisms in a perivascular pattern and at the junction of squamous epithelium and lamina propria. Conclusions Syphilis should be considered in the differential diagnosis of anal canal ulcers, anorectal inflammatory masses, and proctitis. Detailed knowledge of clinical history and recognition of the characteristic pattern of inflammation by the pathologist is important. Treponema pallidum immunohistochemical staining can help avoid a missed diagnosis of syphilis, which, if left unrecognized, can progress to late-stage disease with serious complications.