Patients ask and pathologists answer: ten questions around prostate cancer grading.

Pathologists have closely collaborated with clinicians, mainly urologists, to update the Gleason grading system to reflect the current practice and approach in prostate cancer diagnosis, prognosis, and treatment. This has led to the development of what is called patient advocacy and patient information. Ten common questions asked by patients to pathologists concerning PCa grading and the answers given by the latter are reported.

ALK-rearranged renal cell carcinoma (ALK-RCC): Evaluation of histomorphological and immunohistochemical features by analysis of 276 renal cell carcinoma cases in Turkey.

Anaplastic lymphoma kinase (ALK) rearrangement-associated renal cell carcinoma (ALK-RCC) is characterized by ALK fusion at chromosome 2p23. It has recently been included as a recognized entity with the 5th edition of the WHO classification urinary and male genital tumor. However, our knowledge about ALK-RCC is limited due to the small number of reported cases. In our study, we aimed to contribute the histomorphological and immunohistochemical features of ALK-rearranged renal cell carcinoma cases. We reviewed 276 cases diagnosed as RCC in order to detect ALKRCCs.We used immunohistochemistry to screen ALK rearrangement and then confirmed the ALK rearrangement by fluorescence in situ hybridization (FISH) method. ALK was immunohistochemically positive in 8 of 276 cases. ALK rearrangement was detected by FISH in 3 of 8 cases. These cases were previously diagnosed as clear cell renal cell carcinoma (CRCC), papillary renal cell carcinoma (PRCC), and chromophobe renal cell carcinoma (ChRCC). Their histomorphological findings were diverse, and all three cases exhibited different immunohistochemical findings. Survival of these patients ranged between 6 and 24 months. ALK immunohistochemical findings were also different in each case as perinuclear, weak cytoplasmic, and membranous.ALK RCCs appear to be very rare tumors with heterogeneous histomorphological and immunohistochemical features. Although immunohistochemistry may be useful to detect ALK positivity, genetic evaluation is required to confirm the diagnosis. With identifying ALK-RCCs, ALK inhibitors, which are currently used in the treatment of lung adenocarcinomas, can be used as a targeted therapy option in ALK-RCCs.

Classifying Malignancy in Prostate Glandular Structures from Biopsy Scans with Deep Learning.

Histopathological classification in prostate cancer remains a challenge with high dependence on the expert practitioner. We develop a deep learning (DL) model to identify the most prominent Gleason pattern in a highly curated data cohort and validate it on an independent dataset. The histology images are partitioned in tiles (14,509) and are curated by an expert to identify individual glandular structures with assigned primary Gleason pattern grades. We use transfer learning and fine-tuning approaches to compare several deep neural network architectures that are trained on a corpus of camera images (ImageNet) and tuned with histology examples to be context appropriate for histopathological discrimination with small samples. In our study, the best DL network is able to discriminate cancer grade (GS3/4) from benign with an accuracy of 91%, F1-score of 0.91 and AUC 0.96 in a baseline test (52 patients), while the cancer grade discrimination of the GS3 from GS4 had an accuracy of 68% and AUC of 0.71 (40 patients).

A Rare Case of Urinary Bladder Hamartoma Clinically Mimicking an Urothelial Carcinoma: A Case Report and Review of the Literature.

Urinary bladder hamartoma is a rare benign proliferation with only 14 cases reported in the literature at present. Urinary bladder hamartoma is composed of a disorderly admixture of normal urinary bladder components, essentially represented by glands lined by transitional epithelium and a variable percentage of fibrous stroma, smooth muscle bundles, and adipose tissue. Urinary bladder hamartomas do not exhibit cytological or architectural abnormalities and show no necrosis or increase in mitotic activity. Clinical manifestations are usually represented by lower urinary tract symptoms, more or less frequently paired with gross hematuria. Several pediatric cases of urinary bladder hamartoma have been reported, sometimes with syndromic associations. Transurethral resection has been curative in all cases reported, with no evidence of recurrence. Here we report an additional rare urinary bladder hamartoma, clinically mimicking urothelial carcinoma, providing a review of the literature regarding this unusual entity.

Well-differentiated Papillary Mesothelial Tumour of the Tunica Vaginalis Testis - A Rare Lesion, but one Pathologists Should Know About Two Patient Reports and a Review of the Literature.

Besides malignant mesothelioma, benign mesothelial neoplasms do exist in the tunica vaginalis testis. However, histological criteria remain controversial, thus leading to diagnostic uncertainty and difficulty in their classification according to their biological behavior. In recent years, molecular markers have emerged that aid in the differentiation of benign and malignant mesothelial proliferations throughout the body. Here, we present two middle-aged men with well-differentiated papillary mesothelial tumors and a review of the literature. By now, more than a year after surgery, one patient showed no recurrence of disease after partial or complete orchiectomy without further treatment, for the second no information is available. In conclusion, well-differentiated papillary mesothelial tumors represent rare lesions in the tunica vaginalis testis, but one pathologists should know about to prevent unnecessary treatment and suffering of patients.

Artificial Intelligence for Diagnosis and Gleason Grading of Prostate Cancer in Biopsies-Current Status and Next Steps.

Diagnosis and Gleason grading of prostate cancer in biopsies are critical for the clinical management of men with prostate cancer. Despite this, the high grading variability among pathologists leads to the potential for under- and overtreatment. Artificial intelligence (AI) systems have shown promise in assisting pathologists to perform Gleason grading, which could help address this problem. In this mini-review, we highlight studies reporting on the development of AI systems for cancer detection and Gleason grading, and discuss the progress needed for widespread clinical implementation, as well as anticipated future developments. PATIENT SUMMARY: This mini-review summarizes the evidence relating to the validation of artificial intelligence (AI)-assisted cancer detection and Gleason grading of prostate cancer in biopsies, and highlights the remaining steps required prior to its widespread clinical implementation. We found that, although there is strong evidence to show that AI is able to perform Gleason grading on par with experienced uropathologists, more work is needed to ensure the accuracy of results from AI systems in diverse settings across different patient populations, digitization platforms, and pathology laboratories.

[Interactions between radical prostatovesiculectomy and diagnosis of prostate cancer : A medical-historical inventory on the occasion of 20 years of robot-assisted treatment]. / Wechselwirkungen von radikaler Prostatovesikulektomie und Diagnostik des Prostatakarzinoms : Eine medizinhistorische Bestandsaufnahme anlässlich 20 Jahre robotisch assistierter Therapie.

The question of what came first-in this case the diagnosis of prostate cancer or its therapy-seems absurd at first glance and is reminiscent of the classic metaphor-like problem that preoccupied the Greek writer Plutarch (45-125). Today it is a matter of course that a reliable diagnosis is made before treating a disease, but this must be viewed as inconsistent in medical history. The beginnings of radical prostatectomy for the treatment of prostate cancer, like the first surgical therapies for kidney and bladder tumors, can be located in the pioneering period of organ surgery in the German Empire (1871-1918). The establishment of this procedure in its current form with larger numbers of cases is in turn thanks to the Nestor of American urology, Hugh Hampton Young, who carried out the first perineal prostatovesiculectomy, which from today's perspective can be described as complete. Although the indication has remained largely unchanged since then, this intervention has undergone extensive changes in recent decades. But how has the diagnosis of prostate cancer developed in this period? Of course, much more dynamic. While the procedure prostatovesiculectomy was already established, development of prostate cancer diagnosis began first slowly in the course of the 20th century, then more dynamically. The following article uses medical (historical) original sources to present not only the basics and further developments of the established and, at the same time, subject to constant intervention in urology, but also the essential developments in the environment of neighboring medical disciplines, for example, think of laboratory medicine, radiology, nuclear medicine or rehabilitation medicine, but especially pathology. Incidentally, it was only these developments that created the basis for the correct setting of indications and the identification of alternatives to radical prostatovesiculectomy.

A Subcentimetric Nodule on the Penile Shaft.

Juvenile xanthogranuloma (JXG) is a benign histiocytic disorder usually affecting the head and trunk region of a child. The isolated occurrence of JXG in the penile shaft of a young adult is hitherto unreported. This lesion is amenable to surgical resection although systemic and/or internal visceral involvement can occur. The clinical differential of this solid cystic lesion may include other solid cystic lesions of the penile shaft, namely, epidermal inclusion cyst. A typical yellowish color can aid in the diagnosis though it is not a constant feature. In this article, we discuss a case of isolated penile JXG in a young adult with salient clinical and histopathological differentials.

Multicentric Analytical and Inter-observer Comparability of Four Clinically Developed Programmed Death-ligand 1 Immunohistochemistry Assays in Advanced Clear-cell Renal Cell Carcinoma.

BACKGROUND: Previous studies have suggested increased clinical benefit with inhibition of programmed death-ligand 1 (PD-L1)/programmed death-1 in patients with PD-L1-positive locally advanced/metastatic renal cell carcinoma (RCC). We examined the analytical and inter-observer comparability of PD-L1-positivity across 4 clinically developed immunohistochemistry assays in clear-cell RCC (CCRCC). MATERIALS AND METHODS: Randomly selected archived, formalin-fixed, paraffin-embedded nephrectomy specimens from 201 patients with locally advanced CCRCC were screened using VENTANA SP142. From these, 30 cases were selected based on their tumor-infiltrating immune cell (IC) PD-L1 status (PD-L1-IC-positivity of < 1%, 1%-5%, or > 5%; 10 cases each). These cases were stained for PD-L1 using VENTANA SP142 and SP263, and DAKO 22C3 and 28-8, and scored for PD-L1 expression on IC and tumor cells (TC) by trained readers at 5 sites. RESULTS: Adjusted mean percentages of PD-L1-IC-positivity and PD-L1-TC-positivity varied from 4.0% to 4.9% and from 1.3% to 10.7%, respectively, between assays. Inter-assay differences in PD-L1-IC-positivity were small and non-significant (P = .1938 to .9963); for PD-L1-TC-positivity, significant differences were observed between VENTANA SP142 and the other assays (P ≤ .0001) and between VENTANA SP263 and DAKO 28-8 (P = .0248). Intra-class correlation values showed moderate-to-high inter-reader agreement for each assay for PD-L1-IC-positivity and for 3 assays for PD-L1-TC-positivity. CONCLUSIONS: In this first multicenter analytical comparison study of PD-L1 assays in CCRCC, PD-L1-positivity could be assessed reproducibly using all 4 assays for IC and for 3 of the 4 assays for TC.

PD-L1 expression is an unfavourable prognostic indicator in Asian renal cell carcinomas.

BACKGROUND/AIMS: The programmed cell death receptor 1 (PD-1) checkpoint inhibitor, nivolumab, has been approved for the treatment of metastatic renal cell carcinoma (RCC). However, the understanding of the expression and distribution of PD ligand 1 (PD-L1) in the tumour immune microenvironment and its prognostic role in an Asian cohort is limited. Our group investigated PD-L1 protein expression in a cohort of Asian patients with RCC of mixed ethnicity, using two commercially available antibody clones. METHODS: E1L3N and SP263 anti-PD-L1 clones were used to categorise RCCs of various histological subtypes, diagnosed at our institution between 1995 and 2008, into PD-L1-positive or PD-L1-negative groups, based on a 1% Tumour Proportion Score (TPS) cut-off. RESULTS: In total, 267 (83%) clear cell (cc)RCC and 55 (17%) non-ccRCC cases were studied. Overall PD-L1 protein expression rates for the entire cohort were 13% and 8% for the E1L3N and SP263 clones, respectively. Patients bearing PD-L1-positive tumours experienced significantly decreased disease-free survival (DFS; E1L3N: p=0.01; SP263: p=0.03) but not overall survival, compared with those with PD-L1-negative tumours. Multivariate survival analysis further confirmed the results of the E1L3N clone (HR 1.85, 95% CI 1.10 to 3.13, p=0.02), but not SP263, after adjusting for pathological stage, histological subtype and grade. The addition of PD-L1 (E1L3N) TPS to clinicopathological features significantly increased the prognostic value for DFS (∆LRχ2=5.25; p=0.022), compared with clinicopathological features alone. CONCLUSIONS: PD-L1 protein expression was associated with an unfavourable prognosis in our study cohort. PD-L1 (E1L3N) expression was an independent prognostic indicator of clinical outcome in all RCCs when using a 1% cut-off.

Accuracy of renal tumour biopsy for the diagnosis and subtyping of papillary renal cell carcinoma: analysis of paired biopsy and nephrectomy specimens with focus on discordant cases.

AIMS: Renal tumour biopsy (RTB) is increasingly recognised as a useful diagnostic tool in the management of small renal masses, particularly those that are incidentally found. Intratumoural heterogeneity with respect to morphology, grade and molecular features represents a frequently identified limitation to the use of RTB. While previous studies have evaluated pathological correlation between RTB and nephrectomy, no studies to date have focused specifically on the role of RTB for the diagnosis of papillary renal cell carcinoma (PRCC) and its further subclassification into clinically relevant subtypes. METHODS: This single-institution study evaluated 60 cases of PRCC for concordance between RTB and nephrectomy with respect to diagnosis, grading and subtyping (type 1/type 2). RESULTS: We observed 93% concordance (55 of 59 evaluable cases) between RTB and nephrectomy for the diagnosis of PRCC, although seven tumours (12%) were undergraded on RTB. Subtyping of PRCC on RTB was concordant with nephrectomy in 89% of cases reported as type 1 PRCC on RTB (31/35), but only 40% of cases reported as type 2 PRCC on RTB (4/10). Morphological misclassification of PRCC on RTB was most likely to occur in tumours showing a solid growth pattern. Discordant PRCC subtyping most often occurred in tumours with eosinophilia/oncocytic change. CONCLUSION: There was good concordance between RTB and nephrectomy for the primary diagnosis of PRCC. Although further subtyping of PRCC can aid therapeutic stratification, this can be challenging on RTB and tumours with overlapping or ambiguous features are best reported as PRCC not otherwise specified pending development of more robust methods to facilitate definitive subclassification.

[Comparison of UICC and AJCC 8th edition TNM classifications in uropathology]. / Comparaison des classifications TNM des 8es éditions de l'UICC et de l'AJCC en uropathologie.

The pTNM stage is one of the most important parameters in the handling of tumor patients. The pathologist plays a major role in the determination of the stage. The classifications undergo an evolution according to the state of art. The TNM system is used worldwide and allows to precise the tumor (T) and lymph node stage and the presence of distant metastasis. This system helps to stratify patient groups and determine their prognosis. In 2017, the Union for International Cancer Control (UICC) and the American Joint Committee on Cancer (AJCC) published their 8th edition. Unluckily several differences exist between both classifications. The UICC neglected to make several recommendations according to the International Society of Urological Pathology (ISUP) decisions, which organises the consensus in uropathology.

Intratumoural heterogeneity may hinder precision medicine strategies in patients with clear cell renal cell carcinoma.

Clear cell renal cell carcinoma (ccRCC) is an heterogeneous tumour at architectural, cellular and molecular level, a reason why the 2014 International Society of Urological Pathology consensus recommended wide sampling of RCC masses to include at least 1 block/cm of tumour together with perpendicular sections of the tumour/perinephric fat interface and the tumour/renal sinus interface. Intratumoural molecular heterogeneity may be a limitation at the moment of defining precision medicine strategies based on gene mutation status. This study analyses the presence of any mutation of KRAS, NRAS, BRAF, PIK3CA, ALK, ERBB2, DDR2, MAP2K1, RET and EGFR genes in 20 tissue blocks from a case of ccRCC and its metastasis. We observed the presence of the mutation at pH1047R of PIK3CA gene in five samples of the tumour, while the remaining 15 samples did not show any mutation at PIK3CA or any other investigated gene. There is a great need to develop novel RCC sampling strategies to overcome tumour heterogeneity prior to define precision oncology strategies.

Increased incidence of BK virus viraemia among patients undergoing chronic haemodialysis: a case-control study.

AIMS: Incidence of BK virus (BKV) viraemia, a major risk factor for nephropathy, among patients undergoing chronic haemodialysis remains poorly investigated. This case-control study evaluated the risk of infection by BKV, in addition to hepatitis C virus (HCV) among haemodialysis subjects (n=100), compared with age-matched controls (n=100). METHODS: Subjects' blood plasma samples were subjected to nucleic acid extraction, followed by real-time PCR to evaluate viraemia by BKV and HCV, while sera samples were subjected to ELISA, to identify IgG seropositivity for HCV. RESULTS: Mean age±SD was 47.8±20.4 and 48.9±17.6 years for the haemodialysis and control groups, respectively. BKV and HCV viraemia was observed among 19% versus 8% (OR 2.38, 95% CI 1.09 to 5.18; p=0.023) and 3% versus 0% (p=0.081) of the haemodialysis and control groups, respectively. Mean BK viral load±SD did not vary significantly among the two groups; 914.8±2868 versus 44.30±74.04 copies/mL for the haemodialysis and control groups, respectively (p=0.4041). HCV seropositivity rates were 6% versus 2% (p=0.149), among the haemodialysis and control groups, respectively. CONCLUSIONS: Subjects on haemodialysis may be at increased risk of nephropathy due to increased incidence of BK virus reactivations and may require optimisation of immunosuppressive therapy.

A snake in the grass.

CLINICAL QUESTION: A 77-year-old man presented with haematuria. Cystoscopy revealed a papillary tumour in the trigone region of the bladder. A TURBT was performed. Review the high-quality, interactive digital Aperio slide at http://virtualacp.com/JCPCases/jclinpath-2016-204015 and consider your diagnosis. WHAT IS YOUR DIAGNOSIS?: Urothelial carcinoma pTaUrothelial carcinoma pT1Metastatic carcinomaProstatic adenocarcinomaProstatic polyp.

Intraductal carcinoma of prostate reporting practice: a survey of expert European uropathologists.

BACKGROUND: It is unclear whether the reported variation in the diagnosis of intraductal carcinoma of the prostate (IDC-P) is due to variable interpretation of borderline morphology, use of different diagnostic criteria or both. AIMS: We sought to determine the degree of variation in the diagnostic criteria and reporting rules for IDC-P in prostate biopsies employed by expert uropathologists. METHODS: A questionnaire survey was circulated to 23 expert uropathologists from 11 European countries. RESULTS: Criteria used for diagnosis of IDC-P included solid intraductal growth (100%), dense cribriform (96%), loose cribriform/micropapillary with nuclear size >6× normal (83%) or comedonecrosis (74%) and dilated ducts >2× normal (39%). 'Nuclear size' was interpreted as nuclear area by 74% and nuclear diameter by 21%. Pure IDC-P in needle biopsies was reported by 100% and Gleason graded by 30%. All would perform immunohistochemistry in such cases to rule out invasive cancer. An IDC-P component associated with invasive cancer would be included in the determination of tumour extent and number of cores involved by 74% and 83%, respectively. 52% would include IDC-P component when grading invasive cancer. 48% would perform immunohistochemistry in solid or cribriform nests with comedonecrosis to exclude IDC-P (17% routinely, 30% if the focus appeared to have basal cells on H&E). 48% graded such foci as Gleason pattern 5 even if immunohistochemistry demonstrated the presence of basal cells. CONCLUSIONS: There is a need for more clarity in the definition of some of the diagnostic criteria for IDC-P as well as for greater standardisation of IDC-P reporting.

Differential diagnosis of bladder versus colorectal adenocarcinoma: keratin 7 and GATA3 positivity in nuclear ß-catenin-negative glandular tumours defines adenocarcinoma of the bladder.

AIMS: This study evaluates immunohistochemical markers for the differential diagnosis of primary bladder adenocarcinoma (BAC) from secondarily involving colorectal adenocarcinoma (CAC). Additional staining of putative precursor lesions (cystitis cystica et glandularis (CC) and intestinal metaplasia (IM)) supports insights into metaplastic cell development and aberrant differentiation in tumours. METHODS: Tissue microarray sections of formalin-fixed, paraffin-embedded tissues from clinically verified 11 BAC, 11 CAC, 18 invasive urothelial carcinomas (UCs), 22 normal urothelium samples, 25 CC and 15 IM were stained for keratin 7, 5/6, 5/14 and 20, ß-catenin, e-cadherin, cadherin 17, cdx2, uroplakin II and III, CD10, androgen receptor (AR), S100P, MUC2, MUC5AC and GATA3 expression. Data were analysed using Kruskal-Wallis/Dunn's multiple comparison test and Fisher's exact test. RESULTS: Significant difference (p<0.05) between all three tumour groups was observed for keratin 7 only. Further significant difference between BAC and CAC was found for GATA3 and nuclear ß-catenin staining. BAC-positive/CAC-negative markers without significance were: p63, keratin 5/6, 5/14, uroplakins II/III and AR. CC showed a urothelial phenotype (p63+, GATA3+, S100P+, uroplakin+ in single cells) with initial signs of intestinal differentiation (single cells cdx2+ or cadherin 17+). IM displayed a full intestinal phenotype (p63-, all urothelial markers-, cdx2/MUC2/MUC5AC+, cadherin17+). CONCLUSIONS: Differential diagnosis of BAC and CAC remains difficult, but positive staining for keratin 7 in nuclear ß-catenin-negative tumours argues for BAC. Additional markers like GATA3 and p63 may be added, as positivity in some cases may be helpful. However, for reliable histological diagnosis, knowledge of comprehensive clinical data is still essential.