Background/Objectives: Although 90% of prostate cancer (PCa) metastasis occurs in the bone, there are limited studies and rarely available genome-wide profiles at individual sample level for genomic copy number changes in the literature. Methods: We performed Affymetrix SNP 6.0 high-density microarray analysis to generate the genome-wide copy number change profiles for six cases of PCa bone metastases. A common genomic loss was confirmed by fluorescence in situ hybridization (FISH) in paraffin-embedded PCa bone metastasis samples together with primary PCa and benign prostate hyperplasia samples. We overexpressed the candidate miRNA in PCa cell lines and knocked down its target genes by siRNA transfection and investigated the effect on protein expression and cell viability, migration, and invasion abilities, respectively. Protein expression in PCa tissues was analyzed by immunohistochemical staining. Results: We provided high-resolution PCa bone metastasis profiles of six cases and identified potential bone metastasis-specific common genomic alterations, including a 1.6 mb region on 17q11.2, as well as those shared by non-bone metastatic PCa. The common 17q11.2 loss was confirmed by FISH in further 14/21 PCa bone metastasis samples but was only found in 9/151 primary PCa samples. The well-established tumor-suppressing miRNA located within this small genomic region, miR-193a-3p, was downregulated in both bone metastasis and primary PCa cases, leading to overexpression of cyclin D1 and uPA to promote cancer cell migration and invasion. Cyclin D1 was highly expressed in both localized PCa and bone metastasis samples, and the expression was significantly higher in the latter group (p = 0.013). Conclusions: We generated high-resolution copy number change profiles for bone metastasis samples. This led to the identification of a common, small genomic loss and downregulation of miR-193a-3p, which suppresses PCa bone metastasis through inhibition of its target proteins, providing new insight into bone metastasis development.

Prostate cancers with high proliferation rates have shorter survival times but when spread has occurred (metastatic), there is increased sensitivity to hormone therapy with abiraterone.

Tumors resembling conventional, somatic-type malignancies arise infrequently (<10%) in association with malignant, postpubertal-type testicular germ cell tumors, mainly at the metastatic sites (less frequently at primary), and often after treatment. Historically, the pathogenetic framework for these tumors, indeed their current classification and nomenclature under the WHO 5 th Edition, contemplated their arising from (malignant) postpubertal-type teratomatous components undergoing oncogenic changes homologous to conventional somatic malignancies of the relevant tissue lineages. Recent scholarship questions the specificity of their provenance to postpubertal-type teratoma, with strong evidence relating them also to postpubertal-type yolk sac tumor as well. In tandem, molecular studies support a close relationship to their associated postpubertal-type testicular germ cell tumor rather than identifying any of the known molecular drivers of the somatic-type malignancies they resemble. The histologic patterns observed include sarcoma-like tumors, carcinoma-like tumors, primitive-appearing embryonic-type neuroectodermal tumor, nephroblastoma-like tumors, neuroglial-like neoplasms, leukemia-like malignancies, and combined forms incorporating 2 or more of the foregoing. Although greater experience will be required to validate the changing conceptualization of their origin, from a management standpoint when seen at metastatic sites these somatic tumors-like neoplasms may be poorly responsive to cisplatin-based chemotherapy regimens whereas when seen in the primary site they behave favorably. Surgical resection, if feasible, may provide the best chance for sure at metastatic sites.

Inflammatory and nested testicular sex cord tumor (INTSCT) is a recently recognized malignant testicular neoplasm characterized by distinctive morphologic, immunophenotypic, and molecular features, including frequent EWSR1::ATF1 gene fusions. Although prior series have established INTSCT as a distinct entity with aggressive behavior, its full clinicopathologic and molecular spectrum remains incompletely defined.Thirteen previously unreported INTSCT from multiple institutions were analyzed. Clinicopathologic features were reviewed, including clinical presentation, outcome, histologic findings, and immunophenotype. Molecular characterization was performed using RNA sequencing and/or fluorescence in situ hybridization (FISH) for EWSR1 and ATF1 rearrangements.Patients ranged from 22 to 71 years old (median 37). All presented with testicular masses. Among 8 patients with adequate follow-up, 7 developed metastases to retroperitoneal lymph nodes and 2 to lungs. Histologically, tumors consistently exhibited nested architecture, intratumoral and/or peritumoral inflammation, and thick collagenous stroma, with frequent cellular discohesion and vacuolated cytoplasm; one case showed a Leydig cell-like phenotype. Immunohistochemistry demonstrated high rates of inhibin-α, CD30, keratin, EMA, and SF1 expression, with absence of germ cell markers. Molecular studies revealed EWSR1::ATF1 fusion or EWSR1 rearrangement in 12 of 13 tumors.This multi-institutional series corroborates and expands prior observations, confirming INTSCT as a distinctive, aggressive malignant sex cord-stromal tumor with a highly recurrent EWSR1::ATF1 fusion. Awareness of its morphologic spectrum, including features mimicking Leydig cell tumor, is essential to avoid misdiagnosis and ensure appropriate clinical management.

Conflicting practice recommendations regarding the grading of intraductal carcinoma of the prostate (IDCP) from two leading uropathology societies, the Genitourinary Pathology Society (GUPS) and the International Society of Urological Pathology (ISUP), are confusing for both pathologists and treating clinicians. The objectives of this consultation were to clarify unresolved issues regarding IDCP and atypical intraductal proliferation (AIP) terminology, diagnostic criteria, grading, and management implications, as well as to develop uniform reporting guidelines for IDCP and AIP, endorsed by both societies. A 32-member expert panel, composed of five core members, 25 expert urological pathologists, and two expert urologists, employed a modified Delphi process consisting of multiple rounds of consultation and voting. These were supplemented by discussions at the 2025 United States and Canadian Academy of Pathologists Annual Meeting to achieve expert consensus (defined as at least 67% agreement). Consensus was reached on several key issues. IDCP was regarded most commonly as reflecting the retrograde spread of invasive prostate cancer (PCa). IDCP diagnosis should be based on the Guo and Epstein criteria, supported by basal cell immunohistochemistry in cases that are difficult to distinguish from invasive PCa. The term AIP should be used only in equivocal proliferations where IDCP is favoured but the criteria are not fully met, and these should be reported as 'AIP, suspicious for IDCP'. In the presence of invasive PCa, IDCP should generally be incorporated into Gleason grading irrespective of Grade Group (GG). However, a significant minority (30%) favoured excluding IDCP from the Gleason score if the invasive component was solely Gleason pattern (GP) 3. Pure IDCP (not associated with invasive PCa) and AIP, suspicious for IDCP, should not be graded. IDCP should not be incorporated in the grading of invasive PCa when it is spatially distinct from invasive PCa. A second opinion from a senior or dedicated GU pathologist and discussion within a multidisciplinary management setting should be considered, in the rare settings of pure IDCP or GP3 + IDCP (formerly GG1 + IDCP scenario). This joint GUPS-ISUP consultation provides unified recommendations for the diagnosis, terminology, grading, and reporting of IDCP and AIP, and will pave the way for the development of future IDCP/AIP WHO guidelines. Their adoption should reduce interobserver variation, facilitate consistent communication with clinicians, and improve patient management.

Aims Testicular sex cord-stromal tumours (TSCSTs) are rare neoplasms that arise from (or show differentiation to) elements derived from the sex cords or intertubular stroma. The current classification (World Health Organization, 2022) is based almost entirely on morphology, with many tumour types such as granulosa cell tumours being defined based on their resemblance to ovarian counterparts. Recent studies have uncovered new clinicopathological, molecular and biological nuances within this group of tumours, underscoring differences with ovarian homologues.Methods and results Considering the new data, a group of genitourinary pathology experts (Testicular Sex Cord-Stromal Tumour [TESST] group) has proposed a revised 'TESST classification' that incorporates the best available evidence. This classification is structured and hierarchical, composed of the following tiers: (1) group, (2) category, (3) entity and (4) histological pattern. 'Group' refers to the histological compartment a specific tumour belongs to (sex cords, stroma or both), whereas 'category' is defined by the phenotype of the tumour, taking non-neoplastic elements of the ovary and testis as a reference. The third tier, 'entity', refers to neoplasms with shared clinicopathological and/or molecular features that justify classifying them as distinct types. Lastly, 'histological patterns' are recurrent morphological variations within entities that are not linked to distinct clinicopathological or molecular features.Conclusions We propose a classification that will provide a framework to improve current clinical management and guide future research in the field.

To summarise the content and significance of the recently published second edition International Collaboration on Cancer Reporting (ICCR) histopathology dataset for testicular germ cell tumours, covering the Orchiectomy specimen dataset. We highlight key updates from the first editions, including alignment with the 5th edition World Health Organization (WHO) Classification, revised staging criteria, clarified core data elements versus non-core elements and the evidentiary basis underpinning these changes. A review of the ICCR 2nd edition dataset for Orchiectomy specimens of primary testicular tumours was performed, focusing on their development by an international expert committee using a consensus-based approach. Core (required) and non-core (recommended) data elements were identified along with the level of evidence supporting each, following National Health and Medical Research Council (NHMRC) criteria. Changes from the first edition were extracted by comparing dataset content and notes, informed by up-to-date literature through July 2024. The 2nd edition Orchiectomy dataset provides an integrated, harmonised framework for reporting testicular germ cell tumours. The dataset incorporates the WHO 5th Edition Classification of Urinary and Male Genital Tumours. Pathological staging criteria have been updated to align with the 8th edition Union for International Cancer Control (UICC)/American Joint Committee on Cancer (AJCC) tumour-node-metastasis (TNM) definitions. The second edition of this dataset includes changes to align the dataset with the WHO Classification of Tumours, Urinary and Male Genital Tumours, 5th edition, 2022. The ICCR dataset includes the 5th edition Corrigenda, July 2024. It was agreed that this dataset is not suitable for non-germ cell tumours, with the hope that a new dataset, especially for sex-cord stromal tumours, would be developed. The 2nd edition Orchiectomy dataset represents an authoritative, up-to-date standard for pathology reporting of primary testicular germ cell tumours. By incorporating the WHO 5th edition classifications, current TNM staging and the latest evidence on prognostic factors, this dataset facilitates uniform reporting and prognostication. The ICCR dataset underscores core data required for patient management decisions (e.g., adjuvant therapy in Stage I disease, post-chemotherapy management) while providing flexibility through non-core elements for additional useful information. Adoption of this internationally vetted dataset will enhance consistency, assist multidisciplinary treatment planning and align pathology reports with modern consensus guidelines and classifications. The dataset can be used in both high-resource and limited-resource settings without compromising the essential reporting standards.

BACKGROUND:Effective prognostication improves selection of patients with prostate cancer for treatment combinations. We aimed to evaluate whether a previously developed multimodal artificial intelligence (MMAI) algorithm was prognostic in very advanced prostate cancer using data from four phase 3 trials of the STAMPEDE platform protocol. METHODS:We included patients starting androgen-deprivation therapy in the docetaxel, docetaxel plus zoledronic acid, abiraterone, or abiraterone plus enzalutamide trials. Patients were recruited at 112 sites. We combined all standard-of-care control patients (including those allocated to standard of care [SOC-ADT] consisting of testosterone suppression with luteinising hormone-releasing hormone agonists or antagonists, and radiotherapy when indicated), and we combined the rest of the patients into docetaxel-treated or abiraterone-treated groups. Patients had either metastatic disease or were at very high-risk of metastatic disease, determined by node-positivity or, if node-negative, by T stage, serum prostate-specific antigen (PSA) level, and Gleason score. We used the locked ArteraAI Prostate MMAI algorithm that combined these clinical variables, age, and digitised prostate biopsy pathology images. We performed Fine-Gray and Cox regression adjusted for treatment allocation and cumulative incidence analyses at 5 years to evaluate associations with prostate cancer-specific mortality (PCSM) for continuous (per SD increase) and categorical (quartile-Q) scores. The STAMPEDE platform protocol is registered with ClinicalTrials.gov, NCT00268476. FINDINGS:Of 5213 eligible patients recruited from Oct 5, 2005, to March 31, 2016, 3167 were included in this analysis (1575 [49·7%] with non-metastatic disease, 1592 [50·3%] with metastatic disease; median follow-up 6·9 years [IQR 5·9-8·0]) with all datapoints available for score generation. The MMAI algorithm (per SD increase) was strongly associated with PCSM (hazard ratio [HR] 1·40, 95% CI 1·30-1·51, p<0·0001). On ad-hoc inspection, the highest scoring quartile of patients in each disease and treatment allocation group (MMAI Q4; vs the bottom three quartiles, Q1-3) had the highest PCSM risk in both patients with non-metastatic disease (HR 2·12, 1·61-2·81, p<0·0001) and those with metastatic disease (HR 1·62, 1·39-1·88, p<0·0001). MMAI quartile stratification split patients categorised by disease burden into groups with notably different risks of 5-year PCSM: patients with non-metastatic disease that were node-negative could be further stratified by MMAI score quartile Q1-3 (3%, 2-4) versus Q4 (11%, 7-15), those with non-metastatic disease that were node-positive could be stratified by Q1-3 (11%, 8-14) versus Q4 (20%, 13-26), those with metastatic disease with low-volume could be stratified by Q1-3 (27%, 23-31) versus Q4 (43%, 36-51), and those with metastatic disease with high-volume could be stratified by Q1-3 (48%, 44-52) versus Q4 (68%, 62-75). INTERPRETATION:Diagnostic prostate biopsy samples contain prognostic information in patients with, or at high-risk of, radiologically overt metastatic prostate cancer. MMAI algorithm combined with disease burden improves prognostication of advanced prostate cancer. FUNDING:Prostate Cancer UK, UK Medical Research Council, Cancer Research UK, John Black Charitable Foundation, Prostate Cancer Foundation, Sanofi Aventis, Janssen, Astellas, Novartis, Artera.

5001 Background: The STAMPEDE trials showed that adding abiraterone acetate + prednisolone (AAP) ± enzalutamide (ENZ) to standard of care androgen deprivation therapy (SOC) improves metastasis-free survival (MFS) in high-risk non-metastatic (M0) prostate cancer (PCa) patients (pts). However, variable responses & adverse events underscore the need for prognostic & predictive biomarkers. We evaluated performance of a validated MMAI algorithm (ArteraAI Prostate Test v1.2) to identify pts who benefit most from the addition of AAP ± ENZ (ARPI). Methods: High-risk M0 STAMPEDE pts treated with SOC+ARPI (N=555) or SOC (N=781) with sufficient quality H&E biopsy images & clinical data (T stage, age, PSA) were included. MMAI score association with PCa specific mortality (PCSM, primary outcome measure) & distant metastasis (DM) was analyzed using Fine-Gray regression & cumulative incidence curves, with other cause mortality treated as competing risks. MFS was assessed using Cox regression & Kaplan-Meier curves. An optimal cut-point was identified via grid search to maximize ARPI benefit separation across biomarker positive (pos, MMAI in top quartile) & negative (neg) subgroups. Hazard ratios [95% CI] & p values are reported. Results: PCSM median follow-up was 6.0 years (N=1336). Continuous MMAI scores were statistically significantly associated with poorer PCSM (1.65 [1.43-1.90], p<0.001), MFS (1.42 [1.29-1.56], p<0.001) & DM (1.54 [1.36-1.74], p<0.001). Using clinically-established prognostic cut-offs, 89% of pts were MMAI high-risk. The optimal ARPI MMAI cut-point identified 334 biomarker-pos pts who had significantly higher PCSM than biomarker-neg pts. A statistically significant biomarker-treatment interaction for PCSM (p-int=0.04) revealed that biomarker-pos pts treated with ARPI had improved PCSM (0.42 [0.24-0.74], p=0.003), while biomarker-neg pts did not derive a treatment benefit (0.85 [0.56-1.29], p=0.45). Estimated 5-year PCSM was 9% for biomarker-pos pts receiving ARPI vs. 17% with SOC, compared to 4% & 7% for biomarker-neg pts, respectively, with similar results observed in M0N0 pts (Table 1). Conclusions: For the first time, we demonstrate that a validated MMAI algorithm can identify high-risk non-metastatic PCa pts most likely to benefit from the addition of ARPI. Notably we identify a positive biomarker-treatment interaction in the highest MMAI score quartile, which in cases of clinical equipoise could inform clinical decision-making. We highlight MMAI’s potential to optimize treatment decisions & spare biomarker-neg pts from unnecessary therapy & toxicities. Clinical trial information: NCT00268476 . Estimated 5-yr absolute risk reduction from ARPI vs SOC-treated patients by biomarker groups in M0 (M0N0) pts. Biomarker-neg Biomarker-pos PCSM 3% (1%) 8% (9%) MFS 2% (-1%) 17% (16%) DM 5% (3%) 12% (15%)

BACKGROUND:Primary aldosteronism (PA) causes hypertension and is potentially surgically curable when it is caused by a unilateral aldosterone-producing adrenal adenoma (APA). Adrenal vein sampling (AVS) is required to guide surgery, but it is invasive, is technically difficult, and has limited availability. OBJECTIVE:To determine whether the accuracy of post-dexamethasone [11C]metomidate ([11C]MTO) positron emission tomography-computed tomography, a diagnostic test for APAs, is superior or noninferior to the accuracy of AVS in predicting outcomes from unilateral adrenalectomy, and whether [11C]MTO is interchangeable with its longer-half-life analogue, para-chloro-2-[18F]fluoroethyletomidate ([18F]CETO). DESIGN:Prospective within-patient comparison of diagnostic interventions. (ClinicalTrials.gov: NCT02945904). SETTING:Three referral centers. PARTICIPANTS:174 patients with PA desiring surgery if a unilateral source of PA was diagnosed. INTERVENTION:[11C]MTO and AVS in 169 patients, plus [18F]CETO in the final 31. MEASUREMENTS:International consensus criteria for biochemical and clinical success at 6 and 24 months after surgery; κ statistic and Bland-Altman analyses comparing predictions of surgical outcomes by [11C]MTO and [18F]CETO. RESULTS:Eighty-nine of 169 (52.7%), 78 of 169 (46.2%), and 43 of 169 (25.4%) patients were predicted to have unilateral PA by [11C]MTO, AVS, or both, respectively. One hundred of 169 (59.1%) were assigned to adrenalectomy by the multidisciplinary team; primary outcome data were available for 156 of 169. Predictions were most accurate for complete or partial biochemical success ([11C]MTO, 71.3% [95% CI, 61.0% to 80.1%]; AVS, 62.8% [CI, 52.2% to 72.6%]) and least accurate for complete clinical success (home blood pressure <135/85 mm Hg off treatment). The 95% CIs around differences between accuracies crossed zero, excluding superiority for [11C]MTO, but not the prespecified lower bound of -17%, allowing [11C]MTO to be declared noninferior to AVS. [18F]CETO and [11C]MTO agreed in 29 of 31 patients (κ = 0.85 [CI, 0.68 to 1.00]). LIMITATION:The accuracy of [11C]MTO could be assessed only in the surgical group. CONCLUSION:Molecular imaging is an accurate, noninvasive alternative to AVS. PRIMARY FUNDING SOURCE:National Institute for Health and Care Research.

Advanced prostate cancers respond to hormone therapy but outcomes vary and no predictive tests exist for informed treatment selection. To identify novel biomarker-treatment pairings, we examined associations between biological pathways and 14-year survival outcomes of patients randomized in practice-changing phase 3 trials (testing docetaxel or abiraterone). We included transcriptome-wide expression signatures and immunohistochemistry markers (Ki-67 and PTEN) on prostate tumors from 1,523 patients (832 metastatic). Tumor androgen receptor signaling is associated with longer survival, whereas increased proliferation predicted shorter survival. In a pre-specified analysis, the previously identified decipher RNA signature was both prognostic and predicted survival benefit from docetaxel for metastatic cancers (biomarker-docetaxel interaction p = 0.039). Additionally, transcriptome-based classification of PTEN inactivation identified tumors more likely to have PTEN protein loss (p = 4 × 10-37) and metabolically perturbed metastatic cancers that had shorter survival with hormone therapies (p < 0.001) but exhibited docetaxel sensitivity (biomarker-docetaxel interaction p = 0.002). Transcriptome classifiers predict docetaxel benefit and could be clinically implemented for improved patient management.

The diagnosis of sex cord-stromal tumors is challenging. They show a wide spectrum of behaviors and associations with clinically important pathogenic germline variants. In view of recent advances in molecular subtyping and risk factors, we wished to investigate the differences in diagnosis for a range of these tumors using expert genitourinary pathologists with an interest in this area. Forty-four tumors were selected, and 18 pathologists (members of TEsticular Sex cord-Stromal Tumor group) were invited to view the cases online and give a diagnosis. Consensus was taken as 70% agreement. Consensus was achieved in 59% (26/44) cases. However, there were many areas of disagreement, which included variability in the diagnosis of Sertoli cell and Leydig cell tumors, particularly in malignant lesions, and difficulty in the assignation of fibrothecomas or myoid gonadal stromal tumors, as well as variability in the diagnosis of granulosa cell tumors and in the diagnosis of rarer pediatric tumors. Pathologists placed different weights on positivity with some markers, particularly beta-catenin, S100, and SMA. Some pathologists diagnosed novel diagnostic entities, such as inflammatory and nested testicular sex cord tumors, not currently in the World Health Organization classification. Recommendations to assist in the construction of a new classification to achieve more concordance and better treatment of these rare tumors are included.

417 Background: Following relapse from first line chemotherapy, 30-60% of patients with germ cell tumors (GCTs) can be salvaged with further chemotherapy. Oxaliplatin-based therapies may offer reduced toxicity. Methods: Eligible patients with GCTs who progressed following cisplatin-based chemotherapy were recruited into this single-arm, phase II clinical trial (NCT01782339). Participants were recruited from six centers and received four 21-day cycles of: Actinomycin D 1mg/m2, high dose Methotrexate 5-8g/m2 day 1, Paclitaxel 80mg/m2 days 1, 8 and 15, Oxaliplatin 85mg/m2 days 4 and 8 with Pegfilgrastim support. Participants underwent an FDG-PET scan at baseline, prior to cycle 2 and on completion of treatment. The primary endpoint was objective response rate (ORR). Secondary endpoints were progression-free survival (PFS), overall survival (OS) and toxicity. Results: 44 patients received at least one dose of the study medication between November 2012 and February 2020. In this full analysis set (FAS) population, the median age was 38 (range 20-57), with 9 (20%) with seminoma, 23 (52%) non-seminoma and 12 (27%) of other histology. 31 (70%) patients had at least intermediate risk disease by IPFSG risk group criteria (n = 16, 36% intermediate risk, n = 6, 14% high risk, n = 9, 20% very high risk). 39 patients received 2 or more cycles of the treatment regimen and were deemed part of the subgroup of patients in the evaluable population. The ORR of the FAS population was 52.3% and 59.0% in the evaluable population. The metabolic response rate (MRR) was 52.3% in the FAS population and 59.0% in the evaluable population. The median radiological PFS in the FAS population was 17.0 months (95% CI, 5.7 months- not reached, NR) with a radiological PFS rate at two years of 38.7% (95% CI, 22.3%-54.9%). The median combined radiological or tumour marker PFS in the FAS population was 8.3 months (95% CI, 2.6 months-17.4 months) with a combined radiological or tumour marker PFS rate at two years of 28.9% (95% CI, 16.0%-43.1%). At a median follow-up of 26.8 months, the median OS in the FAS population was not reached (95% confidence interval [CI], 17.0 months-NR) with an OS rate at two years of 62.5% (95% CI, 46.1%-75.2%). Toxicity data and correlation between early metabolic response and outcomes will be presented at the meeting. Conclusions: The GAMMA chemotherapy regimen has demonstrated encouraging anti-tumor activity in relapsed GCT, despite recruiting a cohort of patients with relatively unfavorable outcomes. Clinical trial information: NCT01782339.

The 2021 updated International Germ Cell Cancer Collaborative Group classification for seminomatous germ cell tumours confirmed and refined the original classification, introducing the notion that lactate dehydrogenase (LDH) elevation above 2.5 times the upper limit of normal separates the good-risk prognostic group into two distinct subgroups, with clearly inferior survival outcomes for the high-LDH subgroup. Validation of this prognostic factor has understandably opened the question of the optimal management for patients with high-LDH good-risk seminoma. In the absence of prospective evidence, guideline-recommended management options have not changed. However, there is evidence from the testicular cancer community that management trends might have been influenced by the poor prognosis associated with elevated LDH. The Testicular Cancer Guidelines Panel of the European Association of Urology has undertaken a global survey among oncologists and onco-urologists to document management trends and differences. Patient summary Levels of an enzyme called LDH (lactate dehydrogenase) can differ among patients with testicular cancer that has good prognosis. Recent evidence shows worse outcomes for patients with higher LDH. This information should be used to update clinical guidelines and to tailor personalised treatment plans for these patients.