Clinical parameters for the prediction of occult lymph node metastasis in patients with negative PSMA-PET.

BACKGROUND: Depending on the risk of LN metastasis ePLND at RP is recommended. As ePLND has potential side effects, and diagnostics have improved substantially, our objective was to evaluate the performance of the Briganti 2019 nomogram in a contemporary cohort with preoperative negative PSMA-PET. METHODS: Patients with intermediate- and high-risk prostate cancer (CaP), undergoing RP and ePND at our center with preoperative negative [68Ga]Ga-PSMA-11 PET were included. The Accuracy of the nomogram was assessed using ROC analysis. The association of clinical parameters with the presence of LN metastasis was assessed using logistic regression. Specimen of prostate and LNs in patients with false negative PSMA-PET were additionally stained for AR and PSMA expression and assessed by IHC. RESULTS: The study included 108 patients, 28% intermediate- and 72% high-risk. Twelve patients harbored occult LN metastasis. Accuracy of the nomogram was 0.62. [68Ga]Ga-PSMA-11 PET showed a NPV of 89%. IHC showed expression of PSMA and AR in the primary and LN metastasis in all patients. On logistic regression analysis only DRE (OR 2.72; 95%CI 1.01-7.35; P = 0.05) and percentage of cores with significant CaP (OR 1.29; 95%CI 1.05-1.60; P = 0.02) showed a significant association with LN metastasis. CONCLUSION: The currently used nomogram is suboptimal in detecting patients with occult LNM. While the cut-off value to perform ePLND can be increased slightly following a negative PSMA-PET scan, more accurate methods of identifying these patients are needed. Whether ePLND can have a therapeutic benefit, as opposed to a diagnostic only, needs to be re-evaluated in the PSMA-PET era.

Metastatic Translocated Renal Cell Carcinoma in a Kidney Transplant Patient - a Case Report and Review of the Literature.

TFEB-altered renal cell carcinomas are rare tumours. Here, we report the exceptional case of such a tumour in the setting of solid organ transplantation and with already metastatic disease at the time of diagnosis. The primary tumour occurred in the native kidney and only focally showed biphasic morphology whereas the metastasis, among others to the transplant kidney, showed nonspecific, albeit different morphology, but both had consistent TFEB translocation. Treatment with the immune checkpoint inhibitor pembrolizumab together with the multi-kinase inhibitor lenvatinib achieved partial response 14 months after diagnosis.

Consecutive Prostate-Specific Membrane Antigen (PSMA) and Antigen Receptor (AR) PET Imaging Shows Positive Correlation with AR and PSMA Protein Expression in Primary Hormone-Naïve Prostate Cancer.

The present study was carried out to investigate whether PET imaging can be used as a potential substitute for immunohistochemical analysis of tumor samples in prostate cancer (PC) patients. Correlation between imaging signals of 2 PET tracers and the corresponding target structures was assessed. The first tracer was [68Ga]Ga-PSMA (prostate-specific membrane antigen)-HBED-CC (N,N'-bis [2-hydroxy-5-(carboxyethyl)benzyl]ethylenediamine-N,N'-diacetic acid) [68Ga]Ga-PSMAHBED-CC ([68Ga]PSMA), which is already implemented in clinical routines. The second tracer was 16ß-[18F]fluoro-5α-dihydrotestosterone (16ß-[18F]FDHT), which binds to the androgen receptor (AR). The AR is particularly interesting in PC, because AR expression status and its shift during therapy might directly influence patient care. Methods: This prospective, explorative clinical study included 10 newly diagnosed PC patients. Each patient underwent [68Ga]PSMA PET/MRI and [18F]FDHT PET/MRI scans before prostatectomy. Cancer SUVs were determined and related to background SUVs. After prostatectomy, tumor tissue was sampled, and AR and prostate-specific membrane antigen (PSMA) expression was determined. AR and PSMA expression was evaluated quantitatively with the open-source bioimage analysis software QuPath and with a 4-tier rating system. Correlation between imaging signals and marker expression was statistically assessed. Results: For [18F]FDHT, the SUVmax/SUVbackground ratio showed a significant, strong correlation (r = 0.72; P = 0.019) with the AR optical density of the correlating tissue sample. The correlation between PSMA optical density and the [68Ga]PSMA SUVmax/SUVbackground ratio was not significant (P = 0.061), yet a positive correlation trend could be observed (r = 0.61). SUVmax/SUVbackground ratios were higher for [68Ga]PSMA (mean ± SD, 34.9 ± 24.8) than for [18F]FDHT (4.8 ± 1.2). In line with these findings, the tumor detection rates were 90% for the [68Ga]PSMA PET scan but only 40% for the [18F]FDHT PET scan. The 4-tier rating of PSMA staining intensity yielded very homogeneous results, with values of 3+ for most subjects (90%). AR staining was rated as 1+ in 2 patients (20%), 2+ in 4 patients (40%), and 3+ in 4 patients (40%). Conclusion: [18F]FDHT PET may be useful for monitoring AR expression and alterations in AR expression during treatment of PC patients. This approach may facilitate early detection of treatment resistance and allows for adaptation of therapy to prevent cancer progression. [18F]FDHT PET is inferior to [68Ga]PSMA PET for primary PC diagnosis, but the correlation between [68Ga]PSMA SUVs and PSMA expression is weaker than that between [18F]FDHT and the AR.

Update on classification of oncocytic neoplasms of the kidney.

PURPOSE OF REVIEW: This review provides a summary of recent developments in classification of renal oncocytic neoplasms that were incorporated in the fifth edition WHO classification of renal tumors, released in 2022. RECENT FINDINGS: Besides the distinct entities of renal oncocytoma and chromophobe renal cell carcinoma, the WHO now acknowledges a heterogeneous group of oncocytic tumors of the kidney that can be reported as 'oncocytic renal neoplasms of low malignant potential'. Case series by multiple institutions have revealed recurrent patterns of morphological features, protein marker expression, and genetic alterations within these neoplasms that may permit further subclassification in the future. SUMMARY: The new classification system provides pathologists with the opportunity to simplify the diagnostic workup and reporting of morphologically equivocal oncocytic neoplasms.

Mitosis domain generalization in histopathology images - The MIDOG challenge.

The density of mitotic figures (MF) within tumor tissue is known to be highly correlated with tumor proliferation and thus is an important marker in tumor grading. Recognition of MF by pathologists is subject to a strong inter-rater bias, limiting its prognostic value. State-of-the-art deep learning methods can support experts but have been observed to strongly deteriorate when applied in a different clinical environment. The variability caused by using different whole slide scanners has been identified as one decisive component in the underlying domain shift. The goal of the MICCAI MIDOG 2021 challenge was the creation of scanner-agnostic MF detection algorithms. The challenge used a training set of 200 cases, split across four scanning systems. As test set, an additional 100 cases split across four scanning systems, including two previously unseen scanners, were provided. In this paper, we evaluate and compare the approaches that were submitted to the challenge and identify methodological factors contributing to better performance. The winning algorithm yielded an F1 score of 0.748 (CI95: 0.704-0.781), exceeding the performance of six experts on the same task.

Update on Flat and Papillary Urothelial Lesions: Genitourinary Pathology Society Consensus Recommendations.

The reporting recommendations on "flat and papillary urothelial neoplasia," published in 2 position articles by the Genitourinary Pathology Society in July 2021, was a collective contribution of 38 multidisciplinary experts aiming to clarify nomenclature, classification of flat and papillary urothelial neoplasia and controversial issues. In this review, we discuss some of these recommendations including nomenclature, practical approaches, and their importance for clinical practice.

Histological patterns, subtypes and aspects of prostate cancer: different aspects, different outcomes.

PURPOSE OF REVIEW: The most common prostatic cancers (PCa) are acinary adenocarcinomas. Histological subtypes have been variably defined. The purpose of this review is to discuss unusual histological patterns and subtypes of acinar adenocarcinoma, as well as other types of PCa and their prognostic and therapeutic relevance. RECENT FINDINGS: The new term 'subtype' for morphologically defined tumor entities replaced the term 'variant' in the new 2022 classification of the WHO to allow for clear terminological distinction from genetic variants. The 2022 WHO classification mentions prostatic intraepithelial neoplasia (PIN)-like carcinoma, signet-cell-like adenocarcinoma, sarcomatoid carcinoma and pleomorphic-giant-cell adenocarcinoma of the prostate as true subtypes of acinary PCa. Other forms of acinary PCa are termed unusual histological patterns and include atrophic, foamy-cell, microcystic, pseudohyperplastic and mucinous patterns. Nonacinar forms of prostate cancer include other glandular PCa, the ductal adenocarcinoma and the treatment-associated neuroendocrine carcinoma, and nonglandular PCa, the adenosquamous carcinoma, the squamous cell carcinoma and the adenoid cystic (basal cell) carcinoma of the prostate. SUMMARY: True subtypes of acinary PCa and other forms of glandular and nonglandular PCa show relevant differences in prognosis and treatment approach compared with classic acinary PCa. The relevance of unusual histological patterns mainly lies in their deceptive benign appearance and the need for pathologists to know about these entities for accurate and timely diagnosis.

A novel molecular signature identifies mixed subtypes in renal cell carcinoma with poor prognosis and independent response to immunotherapy.

BACKGROUND: Renal cell carcinoma (RCC) is a heterogeneous disease comprising histologically defined subtypes. For therapy selection, precise subtype identification and individualized prognosis are mandatory, but currently limited. Our aim was to refine subtyping and outcome prediction across main subtypes, assuming that a tumor is composed of molecular features present in distinct pathological subtypes. METHODS: Individual RCC samples were modeled as linear combination of the main subtypes (clear cell (ccRCC), papillary (pRCC), chromophobe (chRCC)) using computational gene expression deconvolution. The new molecular subtyping was compared with histological classification of RCC using the Cancer Genome Atlas (TCGA) cohort (n = 864; ccRCC: 512; pRCC: 287; chRCC: 65) as well as 92 independent histopathologically well-characterized RCC. Predicted continuous subtypes were correlated to cancer-specific survival (CSS) in the TCGA cohort and validated in 242 independent RCC. Association with treatment-related progression-free survival (PFS) was studied in the JAVELIN Renal 101 (n = 726) and IMmotion151 trials (n = 823). CSS and PFS were analyzed using the Kaplan-Meier and Cox regression analysis. RESULTS: One hundred seventy-four signature genes enabled reference-free molecular classification of individual RCC. We unambiguously assign tumors to either ccRCC, pRCC, or chRCC and uncover molecularly heterogeneous tumors (e.g., with ccRCC and pRCC features), which are at risk of worse outcome. Assigned proportions of molecular subtype-features significantly correlated with CSS (ccRCC (P = 4.1E - 10), pRCC (P = 6.5E - 10), chRCC (P = 8.6E - 06)) in TCGA. Translation into a numerical RCC-R(isk) score enabled prognosis in TCGA (P = 9.5E - 11). Survival modeling based on the RCC-R score compared to pathological categories was significantly improved (P = 3.6E - 11). The RCC-R score was validated in univariate (P = 3.2E - 05; HR = 3.02, 95% CI: 1.8-5.08) and multivariate analyses including clinicopathological factors (P = 0.018; HR = 2.14, 95% CI: 1.14-4.04). Heterogeneous PD-L1-positive RCC determined by molecular subtyping showed increased PFS with checkpoint inhibition versus sunitinib in the JAVELIN Renal 101 (P = 3.3E - 04; HR = 0.52, 95% CI: 0.36 - 0.75) and IMmotion151 trials (P = 0.047; HR = 0.69, 95% CI: 0.48 - 1). The prediction of PFS significantly benefits from classification into heterogeneous and unambiguous subtypes in both cohorts (P = 0.013 and P = 0.032). CONCLUSION: Switching from categorical to continuous subtype classification across most frequent RCC subtypes enables outcome prediction and fosters personalized treatment strategies.

Molecular uropathology and cancer genetics for the urologist: key findings for classification and diagnosis.

PURPOSE OF REVIEW: To highlight the latest changes in prostate cancer (PCa), urothelial carcinoma, upper tract urothelial carcinoma (UTUC) and renal cell carcinoma (RCC) diagnosis and the impact of genetics in this field. RECENT FINDINGS: Breast cancer1/2 mutations start to play a major role in PCa treatment with regard to personalized medicine. In urothelial carcinoma an overlap between histological pathological and molecular findings exists, fibroblast growth factor receptor alteration are starting to play a major role, programmed death-ligand 1 although problematic is still important in the treatment setting. UTUC is rare, but genetically different from urothelial carcinoma. In the development of RCC, different genetic pathways such as Von Hippel-Lindau, but also tuberous sclerosis 1/2 and others play a major role in tumor development. SUMMARY: Over the last years, genetics has become increasingly important role in the diagnosis and the treatment of patients with urological malignancies. The upcoming 5th edition (1) of the WHO still considers conventional surgical pathology as the diagnostic gold standard, but molecular pathology is gaining importance not only for diagnosis, but also in personalized treatment, of prostate, kidney cancer and urothelial carcinomas. Therefore, a close collaboration between surgical urology, pathology and oncology departments is mandatory. In this review, we will discuss the latest evolutions in PCa, urothelial carcinoma, upper urinary tract carcinomas and RCC s in the field of genetics in urology.

Brief update of the new WHO classification for urothelial carcinoma.

PURPOSE OF REVIEW: Six years after the release of the 4th edition of the WHO classification on male and genitourinary tumors in 2016, the upcoming 5th edition will be released in 2022. This review will discuss significant changes in the new WHO classification for urothelial carcinoma. RECENT FINDINGS: Substantial progress has been made during the last 6 years, especially in the molecular definition of bladder cancer, but also in treatment approaches. The authors have incorporated these and other changes relating to surgical pathology and made relevant changes to provide a more logical and consistent structure in separating chapters. SUMMARY: As the WHO bluebook is intended to be used worldwide, the authors believe that the impact of these changes will be considerable.

Nonmuscle-invasive bladder cancer, old problems, new insights.

PURPOSE OF REVIEW: Nonmuscle-invasive bladder cancer (NMIBC) is the most frequent bladder cancer and represents around 75% of bladder cancers. This review will discuss known challenges and recent advances in staging, grading and treatment stratification based on pathology. RECENT FINDINGS: Pathological staging and grading in NMIBC remains challenging and different techniques exist. Substaging has been shown to be of prognostic relevance and to help predict treatment response in patients receiving Bacillus Calmette-Guérin (BCG) therapy, which is the treatment of choice for high-grade NMIBC. Recent advances in molecular classification and artificial intelligence were also able to show promising results in the stratification of patients. SUMMARY: Many challenges in the diagnosis of NMIBC are still unresolved and ask for more prospective research. New technologies, molecular insights and AI will help in the upcoming years to better stratify and manage these patients.

Basal cell carcinoma of the prostate: a case report responding to the FGFR inhibitor pemigatinib and literature review.

PURPOSE OF REVIEW: Due to the limited number of cases, there are no guidelines for basal cell carcinoma (BCC) of the prostate. This review combines an unpublished case report of a 55-year-old patient with BCC with an assessment of the latest literature. RECENT FINDINGS: BCC of the prostate has previously been described in only approximately 140 cases. We describe the diagnostic process, including the uropathological and DNA-sequencing results, which allowed us to start an experimental treatment with pemigatinib. BCC of the prostate is associated with an aggressive biological and clinical behavior, such as recurrence and metastasis. Several immunohistochemical stainings are available to differentiate BCC from adenocarcinoma of the prostate. Based on pathology and results from next-generation sequencing (NGS), patients can be offered targeted therapies. SUMMARY: With the aid of histological work-up and immunostaining, prostatic BCC can be accurately diagnosed. Our patient underwent radical prostatectomy and staged extended lymphadenectomy due to lymph node recurrence. The patient subsequently developed progressive disease and was treated with the FGFR-inhibitor pemigatinib. The patient's liver metastasis significantly responded. The present case confirms the possibility of aggressive behavior of prostatic BCC and highlights the importance of a thorough uropathological and molecular biological analysis with a precision medicine strategy.

Molecular and Pharmacological Bladder Cancer Therapy Screening: Discovery of Clofarabine as a Highly Active Compound.

BACKGROUND: The heterogeneity of bladder cancers (BCs) is a major challenge for the development of novel therapies. However, given the high rates of recurrence and/or treatment failure, the identification of effective therapeutic strategies is an urgent clinical need. OBJECTIVE: We aimed to establish a model system for drug identification/repurposing in order to identify novel therapies for the treatment of BC. DESIGN, SETTING, AND PARTICIPANTS: A collection of commercially available BC cell lines (n = 32) was comprehensively characterized. A panel of 23 cell lines, representing a broad spectrum of BC, was selected to perform a high-throughput drug screen. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Positive hits were defined as compounds giving >50% inhibition in at least one BC cell line. RESULTS AND LIMITATIONS: Amongst >1700 tested chemical compounds, a total of 471 substances exhibited antineoplastic effects. Clofarabine, an antimetabolite drug used as third-line treatment for childhood acute lymphoblastic leukaemia, was amongst the limited number of drugs with inhibitory effects on cell lines of all intrinsic subtypes. We, thus, reassessed the substance and confirmed its inhibitory effects on commercially available cell lines and patient-derived cell cultures representing various disease stages, intrinsic subtypes, and histologic variants. To verify these effects in vivo, a patient-derived cell xenograft model for urothelial carcinoma (UC) was used. Well-tolerated doses of clofarabine induced complete remission in all treated animals (n = 12) suffering from both early- and late-stage disease. We further took advantage of another patient-derived cell xenograft model originating from the rare disease entity sarcomatoid carcinoma (SaC). Similarly to UC xenograft mice, clofarabine induced subcomplete to complete tumour remissions in all treated animals (n = 8). CONCLUSIONS: The potent effects of clofarabine in vitro and in vivo suggest that our findings may be of high clinical relevance. Clinical trials are needed to assess the value of clofarabine in improving BC patient care. PATIENT SUMMARY: We used commercially available cell lines for the identification of novel drugs for the treatment of bladder cancer. We confirmed the effects of one of these drugs, clofarabine, in patient-derived cell lines and two different mouse models, thereby demonstrating a potential clinical relevance of this substance in bladder cancer treatment.

Updated pathology reporting standards for bladder cancer: biopsies, transurethral resections and radical cystectomies.

AIM: Optimal management of bladder cancer requires an accurate, standardised and timely pathological diagnosis, and close communication between surgeons and pathologists. Here, we provide an update on pathology reporting standards of transurethral resections of the bladder and cystectomies. METHODS: We reviewed recent literature, focusing on developments between 2013 and 2021. RESULTS: Published reporting standards developed by pathology organizations have improved diagnosis and treatment. Tumor sub-staging and subtyping has gained increased attention. Lymph nodes continue to be an area of debate, and their staging has seen minor modifications. Several tasks, particularly regarding specimen preparation ("grossing"), are not yet standardized and offer opportunity for improvement. Molecular classification is rapidly evolving, but currently has only limited impact on management. CONCLUSION: Pathological reporting of bladder cancer is continuously evolving and remains challenging in some areas. This review provides an overview of recent major developments, with a particular focus on published reporting standards.

PD-L1 (SP142) testing is concordant between Benchmark Ultra and Bond-III stainers.

BACKGROUND: Atezolizumab is an inhibitor of programmed death-ligand 1 (PD-L1), used to treat advanced or metastatic bladder cancer, and in trials for non-invasive disease. In order to be eligible for treatment, patients require a PD-L1 immune cell score ≥ 5%, using the Ventana SP142 PD-L1 assay. Many laboratories do not have access to the required Ventana Benchmark Ultra stainer, and it is unclear if the assay performs similarly on other stainers. In this study, we compare SP142 assay results between Ventana Benchmark Ultra and Leica Bond-III stainers. METHODS: Serial sections of 90 samples of transurethral bladder resections (comprising 51 pTaHG, 8 pTis, 18 pT1, 10 pT2 tumors) were stained using the SP142 PD-L1 antibody on Ventana Benchmark Ultra and Leica Bond-III stainers, manually scored, and compared using accuracy and Cohen's kappa measures. RESULTS: Both devices yielded highly concordant PD-L1 immune cell scores (accuracy 0.84, Cohen's κ 0.732). Moreover, we found similar tumor cell (TC) PD-L1 scores using both stainers, and a trend towards greater TC scores in pT2 stage samples (p = 0.05). CONCLUSION: This study is the first to compare the SP142 antibody in bladder cancer on two different stainers. Our results indicate that both Benchmark Ultra and Bond-III stainers yield highly concordant results using the SP142 PD-L1 antibody.

Artificial intelligence in prostate histopathology: where are we in 2021?

PURPOSE OF REVIEW: Artificial intelligence has made an entrance into mainstream applications of daily life but the clinical deployment of artificial intelligence-supported histological analysis is still at infancy. Recent years have seen a surge in technological advance regarding the use of artificial intelligence in pathology, in particular in the diagnosis of prostate cancer. RECENT FINDINGS: We review first impressions of how artificial intelligence impacts the clinical performance of pathologists in the analysis of prostate tissue. Several challenges in the deployment of artificial intelligence remain to be overcome. Finally, we discuss how artificial intelligence can help in generating new knowledge that is interpretable by humans. SUMMARY: It is evident that artificial intelligence has the potential to outperform most pathologists in detecting prostate cancer, and does not suffer from inherent interobserver variability. Nonetheless, large clinical validation studies that unequivocally prove the benefit of artificial intelligence support in pathology are necessary. Regardless, artificial intelligence may soon automate and standardize many facets of routine work, including qualitative (i.e. Gleason Grading) and quantitative measures (i.e. portion of Gleason Grades and tumor volume). For the near future, a model where pathologists are enhanced by second-review or real-time artificial intelligence systems appears to be the most promising approach.

Pathological reporting of cystectomy lymph nodes: a retrospective analysis of experience in Paris.

PURPOSE: Pathological evaluation of pelvic lymph node (LN) dissection (PLND) is important for management of cystectomy patients. However, challenges such as unclear interobserver variability of LN counting remain. Here, we assess interobserver variability of LN measures and their clinical utility, with a focus on variant histology. METHODS: We retrieved radical cystectomy cases with PLND between 2010 and 2016 and reevaluated pathological parameters; number of total and metastatic LN, LN density (LND), length of metastatic LN and metastases, extranodal extension (ENE). RESULTS: We report 96 patients: median age of 71a, 34 cases pN+, 36 cases with any extent of variant histology, median follow-up 10 months. Perivesical LN were only rarely identified, but frequently metastatic (4/9). Variant histology (34 cases) frequently exhibited LN metastasis (53% of pN+ cases). Interobserver variance was poor for total LN (kappa = 0.167), excellent for positive LN (0.85) and pN staging (0.96), and mediocre for LND (0.53). ROC analysis suggests that both LND and the sum of LN metastasis length may predict outcome (AUC 0.83 and 0.75, respectively). CONCLUSION: Our study confirms the notion of LND as a prognostic measure, but cautions due to strong interobserver variance of LN counts. The sum length of LN metastases could be a measure that is independent of LN counts. We find that microscopically identified perivesical LN merit particular attention. In summary, our study highlights current challenges in pathological reporting of PLND, confirms previous observations and forms a basis for further studies.

The Genetic Complexity of Prostate Cancer.

Prostate cancer (PCa) is a major concern in public health, with many genetically distinct subsets. Genomic alterations in PCa are extraordinarily complex, and both germline and somatic mutations are of great importance in the development of this tumor. The aim of this review is to provide an overview of genetic changes that can occur in the development of PCa and their role in potential therapeutic approaches. Various pathways and mechanisms proposed to play major roles in PCa are described in detail to provide an overview of current knowledge.