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Oncocytic renal neoplasms are a major source of diagnostic challenge in genitourinary pathology; however, they are typically nonaggressive in general, raising the question of whether distinguishing different subtypes, including emerging entities, is necessary. Emerging entities recently described include eosinophilic solid and cystic renal cell carcinoma (ESC RCC), low-grade oncocytic tumor (LOT), eosinophilic vacuolated tumor (EVT), and papillary renal neoplasm with reverse polarity (PRNRP). A survey was shared among 65 urologic pathologists using SurveyMonkey.com (Survey Monkey, Santa Clara, CA, USA). De-identified and anonymized respondent data were analyzed. Sixty-three participants completed the survey and contributed to the study. Participants were from Asia (n = 21; 35%), North America (n = 31; 52%), Europe (n = 6; 10%), and Australia (n = 2; 3%). Half encounter oncocytic renal neoplasms that are difficult to classify monthly or more frequently. Most (70%) indicated that there is enough evidence to consider ESC RCC as a distinct entity now, whereas there was less certainty for LOT (27%), EVT (29%), and PRNRP (37%). However, when combining the responses for sufficient evidence currently and likely in the future, LOT and EVT yielded > 70% and > 60% for PRNRP. Most (60%) would not render an outright diagnosis of oncocytoma on needle core biopsy. There was a dichotomy in the routine use of immunohistochemistry (IHC) in the evaluation of oncocytoma (yes = 52%; no = 48%). The most utilized IHC markers included keratin 7 and 20, KIT, AMACR, PAX8, CA9, melan A, succinate dehydrogenase (SDH)B, and fumarate hydratase (FH). Genetic techniques used included TSC1/TSC2/MTOR (67%) or TFE3 (74%) genes and pathways; however, the majority reported using these very rarely. Only 40% have encountered low-grade oncocytic renal neoplasms that are deficient for FH. Increasing experience with the spectrum of oncocytic renal neoplasms will likely yield further insights into the most appropriate work-up, classification, and clinical management for these entities., Competing Interests: Declarations Conflict of interest The authors declare no competing interests., (© 2024. The Author(s).)

High-grade prostatic intraepithelial neoplasia (HGPIN) is a well-characterised precursor lesion in prostate cancer. The term atypical intraductal proliferations (AIP) describes lesions with features that are far too atypical to be considered HGPIN, yet insufficient to be diagnosed as intraductal carcinoma of the prostate (IDCP). Here, a panel of biomarkers was assessed to provide insights into the biological relationship between IDCP, HGPIN, and AIP and their relevance to current clinicopathological recommendations. Tissue samples from 86 patients with prostate cancer were assessed by routine haematoxylin and eosin staining and immunohistochemistry (IHC) with a biomarker panel (Appl1/Sortilin/Syndecan-1) and a PIN4 cocktail (34βE12+P63/P504S). Appl1 strongly labelled atypical secretory cells, effectively visualising intraductal lesions. Sortilin labelling was moderate-to-strong in > 70% of cases, while Syndecan-1 was moderate-to-strong in micropapillary HGPIN/AIP lesions (83% cases) versus flat/tufting HGPIN (≤ 20% cases). Distinct biomarker labelling patterns for atypical intraductal lesions of the prostate were observed, including early atypical changes (flat/tufting HGPIN) and more advanced atypical changes (micropapillary HGPIN/AIP). Furthermore, the biomarker panel may be used as a tool to overcome the diagnostic uncertainty surrounding AIP by supporting a definitive diagnosis of IDCP for such lesions displaying the same biomarker pattern as cribriform IDCP., (© 2023. The Author(s).)

A 5-tier grouping of Gleason scores has recently been proposed. Studies have indicated prognostic heterogeneity within these groups. We assessed prostate cancer-specific mortality (PCSM) and all-cause mortality (ACM) for men diagnosed with Gleason score 3 + 5 = 8, 4 + 4 = 8 and 5 + 3 = 8 acinar adenocarcinoma on needle biopsy in a population-based national cohort. The Prostate Cancer data Base Sweden 5.0 was used for survival analysis with PCSM and ACM at 5 and 10 years as endpoints. Multivariable Cox regression models controlling for socioeconomic factors, stage and primary treatment type were used for PCSM and ACM. Among 199,620 men reported with prostate cancer in 2000-2020, 172,112 were diagnosed on needle biopsy. In 18,281 (11%), there was a Gleason score of 8 in needle biopsies, including a Gleason score of 3 + 5, 4 + 4 and 5 + 3 in 11%, 86% and 2.3%, respectively. The primary treatment was androgen deprivation therapy (55%), deferred treatment (8%), radical prostatectomy (16%) or radical radiotherapy (21%). PCSM in men with Gleason scores of 3 + 5, 4 + 4 and 5 + 3 at 5 years of follow-up was 0.10 (95% CI 0.09-0.12), 0.22 (0.22-0.23) and 0.32 (0.27-0.36), respectively, and at 10 years 0.19 (0.17-0.22), 0.34 (0.33-0.35) and 0.44 (0.39-0.49), respectively. There was a significantly higher PCSM after 5 and 10 years in men with Gleason score 5 + 3 cancers than in those with 4 + 4 and in Gleason score 4 + 4 cancers than in those with 3 + 5. Grouping of Gleason scores will eliminate the prognostic granularity of Gleason scoring, thus diminishing the prognostic significance of this proposed grading system., (© 2024. The Author(s).)

The presence of perineural invasion (PNI) by carcinoma in prostate biopsies has been shown to be associated with poor prognosis. The assessment and quantification of PNI are, however, labor intensive. To aid pathologists in this task, we developed an artificial intelligence (AI) algorithm based on deep neural networks. We collected, digitized, and pixel-wise annotated the PNI findings in each of the approximately 80,000 biopsy cores from the 7406 men who underwent biopsy in a screening trial between 2012 and 2014. In total, 485 biopsy cores showed PNI. We also digitized more than 10% (n = 8318) of the PNI negative biopsy cores. Digitized biopsies from a random selection of 80% of the men were used to build the AI algorithm, while 20% were used to evaluate its performance. For detecting PNI in prostate biopsy cores, the AI had an estimated area under the receiver operating characteristics curve of 0.98 (95% CI 0.97-0.99) based on 106 PNI positive cores and 1652 PNI negative cores in the independent test set. For a pre-specified operating point, this translates to sensitivity of 0.87 and specificity of 0.97. The corresponding positive and negative predictive values were 0.67 and 0.99, respectively. The concordance of the AI with pathologists, measured by mean pairwise Cohen's kappa (0.74), was comparable to inter-pathologist concordance (0.68 to 0.75). The proposed algorithm detects PNI in prostate biopsies with acceptable performance. This could aid pathologists by reducing the number of biopsies that need to be assessed for PNI and by highlighting regions of diagnostic interest., (© 2022. The Author(s).)

Numerous studies have shown a correlation between perineural invasion (PNI) in prostate biopsies and outcome. The reporting of PNI varies widely in the literature. While the interobserver variability of prostate cancer grading has been studied extensively, less is known regarding the reproducibility of PNI. A total of 212 biopsy cores from a population-based screening trial were included in this study (106 with and 106 without PNI according to the original pathology reports). The glass slides were scanned and circulated among four pathologists with a special interest in urological pathology for assessment of PNI. Discordant cases were stained by immunohistochemistry for S-100 protein. PNI was diagnosed by all four observers in 34.0% of cases, while 41.5% were considered to be negative for PNI. In 24.5% of cases, there was a disagreement between the observers. The kappa for interobserver variability was 0.67-0.75 (mean 0.73). The observations from one participant were compared with data from the original reports, and a kappa for intraobserver variability of 0.87 was achieved. Based on immunohistochemical findings among discordant cases, 88.6% had PNI while 11.4% did not. The most common diagnostic pitfall was the presence of bundles of stroma or smooth muscle. It was noted in a few cases that collagenous micronodules could be mistaken for a nerve. The distance between cancer and nerve was another cause of disagreement. Although the results suggest that the reproducibility of PNI may be greater than that of prostate cancer grading, there is still a need for improvement and standardization.

The International Society of Urological Pathology (ISUP) hosts a reference image database supervised by experts with the purpose of establishing an international standard in prostate cancer grading. Here, we aimed to identify areas of grading difficulties and compare the results with those obtained from an artificial intelligence system trained in grading. In a series of 87 needle biopsies of cancers selected to include problematic cases, experts failed to reach a 2/3 consensus in 41.4% (36/87). Among consensus and non-consensus cases, the weighted kappa was 0.77 (range 0.68-0.84) and 0.50 (range 0.40-0.57), respectively. Among the non-consensus cases, four main causes of disagreement were identified: the distinction between Gleason score 3 + 3 with tangential cutting artifacts vs. Gleason score 3 + 4 with poorly formed or fused glands (13 cases), Gleason score 3 + 4 vs. 4 + 3 (7 cases), Gleason score 4 + 3 vs. 4 + 4 (8 cases) and the identification of a small component of Gleason pattern 5 (6 cases). The AI system obtained a weighted kappa value of 0.53 among the non-consensus cases, placing it as the observer with the sixth best reproducibility out of a total of 24. AI may serve as a decision support and decrease inter-observer variability by its ability to make consistent decisions. The grading of these cancer patterns that best predicts outcome and guides treatment warrants further clinical and genetic studies. Results of such investigations should be used to improve calibration of AI systems.

The International Collaboration on Cancer Reporting (ICCR) is a not for profit organisation whose goal is to produce standardised internationally agreed and evidence-based datasets for pathology reporting. With input from pathologists worldwide, the datasets are intended to be uniform and structured. They include all items necessary for an objective and accurate pathology report which enables clinicians to apply the best treatment for the patient. This dataset has had input from a multidisciplinary ICCR expert panel. The rationale for some items being required and others recommended is explained, based on the latest literature. The dataset incorporates data from the World Health Organization (WHO) 2016, and also from the latest (8th edition) TNM staging system of the American Joint Committee on Cancer (AJCC). Fifteen required elements and eight recommended items are described. This dataset provides all the details for a precise and valuable pathology report required for patient management and prognostication. This dataset is intended for worldwide use, and should facilitate the collection of standardised comparable data on bladder carcinoma at an international level.

The International Collaboration on Cancer Reporting (ICCR) was formed in 2011 to harmonise the datasets, protocols and checklists for pathological reporting of various cancers and develop internationally agreed upon, evidence-based datasets. A dataset for prostate cancer in radical prostatectomy specimens was developed in 2011-2012 as part of a pilot project; however, it required substantial revision following the ISUP Consensus Conference on Gleason Grading in 2014, the publication of the World Health Organisation (WHO) Classification of Tumours of the Urinary System and Male Genital Organs in 2016, and the 8th edition of the Tumour-Node-Metastasis (TNM) staging system in late 2016. This article presents the up-to-date, evidence-based ICCR dataset and associated commentary for reporting prostate cancer in radical prostatectomy specimens. PubMed and Google search engines were used to review the published literature on the subject, and the dataset was developed in line with the previously published ICCR framework for the development of cancer datasets. Substantial changes have been incorporated into the second edition of the ICCR prostate cancer (radical prostatectomy) dataset. These include revisions to prostate cancer grading, reporting of intraductal carcinoma of prostate and surgical margins, among others. Up-to-date cancer datasets underpin structured reporting and facilitate the production of consistent and accurate pathological data for patient care as well as comparisons between different cohorts and populations internationally.

Intraductal carcinoma of the prostate gland (IDCP), which is now categorised as a distinct entity by WHO 2016, includes two biologically distinct diseases. IDCP associated with invasive carcinoma (IDCP-inv) generally represents a growth pattern of invasive prostatic adenocarcinoma while the rarely encountered pure IDCP is a precursor of prostate cancer. This review highlights issues that require further discussion and clarification. The diagnostic criterion "nuclear size at least 6 times normal" is ambiguous as "size" could refer to either nuclear area or diameter. If area, then this criterion could be re-defined as nuclear diameter at least three times normal as it is difficult to visually compare area of nuclei. It is also unclear whether IDCP could also include tumours with ductal morphology. There is no consensus whether pure IDCP in needle biopsies should be managed with re-biopsy or radical therapy. A pragmatic approach would be to recommend radical therapy only for extensive pure IDCP that is morphologically unequivocal for high-grade prostate cancer. Active surveillance is not appropriate when low-grade invasive cancer is associated with IDCP, as such patients usually have unsampled high-grade prostatic adenocarcinoma. It is generally recommended that IDCP component of IDCP-inv should be included in tumour extent but not grade. However, there are good arguments in favour of grading IDCP associated with invasive cancer. All historical as well as contemporary Gleason outcome data are based on morphology and would have included an associated IDCP component in the tumour grade. WHO 2016 recommends that IDCP should not be graded, but it is unclear whether this applies to both pure IDCP and IDCP-inv.

Pathology training resources remain scarce in many parts of the world. With rapid economic development comes the need to educate new pathologists to meet the medical care demands. Our aim was to set up a cost-effective system for training and testing the diagnostic skills of pathologists. Pathologists in nine countries in Asia and South America were invited by the International Society of Urological Pathology (ISUP) to participate in a prostate pathology education course combining image-based tests with lectures and on-line tutorials. The tests and tutorials are available free of charge at the ISUP education website www.edu.isupweb.org . A total of 603 pathologists registered on the website. Of these, 224 completed pre- and post-lecture assessments (tests 1 and 2). Replies were classified as correct/acceptable, when a lesion was accurately classified into clinically relevant categories (benign, cancer, high-grade prostatic intraepithelial neoplasia, intraductal carcinoma of the prostate). The rate of correct/acceptable replies increased from 60.7 to 72.3% in Tests 1 and 2, respectively. In Test 1, pathologists from upper middle, lower middle, and low resource countries gave a correct/acceptable diagnosis in 65.8%, 61.0%, and 47.4%, respectively. Their results improved in Test 2 to 76.4%, 72.5%, and 62.8%, respectively. The greatest improvement in diagnostic ability was achieved in pathologists from the low resource group of countries. The use of web-based testing and training, combined with lectures, is an efficient method for improving diagnostic skills of pathologists in low to middle resource countries.

Active surveillance (AS) is an important management option for men with low-risk, clinically localized prostate cancer. The clinical parameters for patient selection and definition of progression for AS protocols are evolving as data from several large cohorts matures. Vital to this process is the critical role pathologic parameters play in identifying appropriate candidates for AS. These findings need to be reproducible and consistently reported by surgical pathologists. This report highlights the importance of accurate pathology reporting as a critical component of these protocols.

Ductal adenocarcinoma of the prostate (DAC) is considered to be an aggressive subtype of prostate cancer with greater risk of progression than acinar adenocarcinoma (AC). It has been debated whether DAC is a distinct subtype or a morphological variant of AC. Our aim was to examine the protein expression of DAC and to compare the results with AC. A tissue microarray was constructed from 60 DAC and 46 AC matched by Gleason score. The slides were stained for 28 immunomarkers (estrogen, progesterone and androgen receptor, prolactin, PSA, prostein, PSMA, PSAP, CDX2, lysozyme, villin, monoclonal CEA, CK7, CK20, HMWCK, p63, p504s, c-myc, EGFR, Ki-67, p16, p21, p27, p53, PTEN, ERG, PAX-2, and PAX-8). HMWCK was positive in 8.5 % of DAC, but negative in all cases of AC (p = 0.045). p16 was positive in 53.3 % of DAC and in 26.1 % of AC (p = 0.005). p53 was positive in 42.4 % of DAC and 26.7 % of AC (p = 0.031). A distinct patchy positivity of CK20 was seen in 23.7 % of DAC, and this pattern was also seen in 9.1 % of AC (p = 0.047). Villin was positive in 3.4 % of DAC while expression was negative in AC. Ki-67 labeling index was significantly higher in DAC than in AC (mean 9.2 % [95 % CI 6.4-12.0] and 2.6 % [1.9-3.4], p < 0.001). While there is some overlap in the immunohistochemical expression of DAC and AC, the differences between these two morphotypes of prostatic carcinoma are consistent with DAC having a more aggressive phenotype than AC.

Treatment options for primary and metastatic renal cancer are increasing. Accurate data from the pathological examination of renal cancer specimens aid clinicians in stratifying patients for surveillance and adjuvant therapies. This review focuses on biomarkers in diagnosis, prognosis and prediction of the biologic behavior of renal tumors which should be recorded in pathology reports and which are under investigation. Special emphasis is given to the use of immunohistochemical markers in differential diagnosis of various renal tumor subtypes. The relevance of cytogenetic and molecular findings is also discussed. The review includes the 2012 International Society for Urological Pathology Consensus conference recommendations.

Streptozotocin-induced tumours in the kidneys of experimental animals have been shown to be histologically similar to human renal cell carcinoma. We report the ultrastructural features of renal tumours induced in 15 mice by a single intravenous bolus of 2.5% streptozotocin administered in a dose of 250 mg streptozotocin/kg mouse body weight. Animals were sacrificed 232-361 days after the administration of streptozotocin. On examination both kidneys from each animal contained 1-4 dysplastic tubules and 1-3 discrete tumours per kidney. Twelve dysplastic proximal convoluted tubules showing varying degrees of epithelial atypia and nine tumours exhibiting either a papillary or solid architecture were examined. Dysplastic epithelial cells and tumours of papillary and solid type exhibited complex cell borders with well-developed junctional complexes. The majority of cells contained surface microvilli, and in some cells microvilli-lined intracytoplasmic lumina were observed. Occasional dysplastic epithelial cells and tumour cells contained double-membrane vesicles 120-200 nm in diameter. These were similar to the intracytoplasmic vesicles characteristic of human chromophobe renal cell carcinoma. Intracytoplasmic collections of glycogen granules and flocculant protein were identified in both dysplastic and neoplastic cells, and where prominent they resulted in compression of cytoplasmic organelles. Coated vesicles were commonly observed. These were free within the cytoplasm and were also seen budding from strands of rough endoplasmic reticulum. The distribution of these vesicles suggested a role in protein transport from the rough endoplasmic reticulum. It is concluded that while streptozotocin-induced renal tumours have some ultrastructural features in common with human chromophobe renal cell carcinoma, the overall ultrastructural morphology differs significantly from that described for the various histological types of human renal cell carcinoma.

Renal tumours were induced in female mice 132 days after intravenous administration of streptozotocin. The tumours exhibited papillary and/or solid architecture with papillary tumours showing no histological evidence of malignancy. Malignant behaviour, manifest as infiltration of adjacent renal tissue and lymphatic infiltration, was noted for tumours with solid architecture. Intermediate architectural forms exhibiting dual papillary and solid architecture were identified. Proliferation kinetics were evaluated by enumeration of silver-staining nucleolar organizer regions and proliferating cell nuclear antigen expression. The results showed a stepwise progress in cell proliferation between histologically normal renal tubule epithelium [untreated animals, mean AgNOR score (MAS) 2.32, mean PCNA index (MPI) 0.53%; treated animals, MAS, 2.44; MPI 0.99%], dysplastic tubule epithelium (MAS, 4.15; MPI 1.65%), papillary tumours (MAS, 5.90; MPI 3.89%) and solid tumours (MAS, 6.94; MPI, 6.80%). Solid tumours as a group were significantly larger than papillary tumours and were associated with a significantly longer mean post-injection survival interval. The findings suggest that at least some solid tumours evolve from tumours exhibiting papillary architecture.