Common Diagnostic Challenges in Genitourinary Mesenchymal Tumors: A Practical Approach.

Mesenchymal neoplasms within the genitourinary tract include a wide spectrum of tumors, ranging from benign to malignant, and tumors of uncertain malignant potential. Except for stromal tumors of the prostate, which originate from the specific prostatic stroma, these neoplasms generally resemble their counterparts in other body sites. The rarity of these neoplasms and the limitation associated with small biopsy samples present unique diagnostic challenges for pathologists. Accurate diagnosis is paramount, as it significantly influences prognosis and guides management and treatment strategies. This review addresses common diagnostic scenarios, discusses key differential diagnoses, and sheds light on potential diagnostic pitfalls.

High sensitivity ctDNA assays in genitourinary malignancies: current evidence and future directions.

In the recent decade, analysis of circulating tumor DNA (ctDNA) has improved cancer care by allowing for rapid detection of actionable molecular targets. A new generation of circulating DNA tests is now becoming available commercially. These tests are characterized by a superior limit of detection of 0.01% vaF or better, allowing for the detection of radiologically occult molecular residual disease (MRD). MRD tests have the potential to revolutionize neoadjuvant and adjuvant treatment. In addition, these tests can be used as tumor markers to assess disease response. We reviewed the current evidence for the use of high-sensitivity MRD assays with particular focus on the genitourinary tumors. Multiple studies have now been reported in urothelial, renal, and recently testicular carcinoma. We find that the sensitivity varies across tumor types in the adjuvant setting and may reach a high of 100% in urothelial cancer. Specificity in tumor-informed MRD appears to be preserved across tumor types (98%-100%). Several trials are now prospectively validating MRD testing in biomarker integral studies, mainly in urothelial carcinoma.

The roles of tertiary lymphoid structures in genitourinary cancers: molecular mechanisms, therapeutic strategies, and clinical applications.

The presence of tertiary lymphoid structures (TLSs) associated with distinct treatment efficacy and clinical prognosis has been identified in various cancer types. However, the mechanistic roles and clinical implications of TLSs in genitourinary (GU) cancers remain incompletely explored. Despite their potential role as predictive markers described in numerous studies, it is essential to comprehensively evaluate the characteristics of TLSs, including drivers of formation, structural foundation, cellular compositions, maturation stages, molecular features, and specific functionality to maximize their positive impacts on tumor-specific immunity. The unique contributions of these structures to cancer progression and biology have fueled interest in these structures as mediators of antitumor immunity. Emerging data are trying to explore the effects of therapeutic interventions targeting TLSs. Therefore, a better understanding of the molecular and phenotypic heterogeneity of TLSs may facilitate the development of TLSs-targeting therapeutic strategies to obtain optimal clinical benefits for GU cancers in the setting of immunotherapy. In this review, the authors focus on the phenotypic and functional heterogeneity of TLSs in cancer progression, current therapeutic interventions targeting TLSs and the clinical implications and therapeutic potential of TLSs in GU cancers.

Final Results From a Phase I Trial and Expansion Cohorts of Cabozantinib and Nivolumab Alone or With Ipilimumab for Advanced/Metastatic Genitourinary Tumors.

PURPOSE: Cabozantinib and nivolumab (CaboNivo) alone or with ipilimumab (CaboNivoIpi) have shown promising efficacy and safety in patients with metastatic urothelial carcinoma (mUC), metastatic renal cell carcinoma (mRCC), and rare genitourinary (GU) tumors in a dose-escalation phase I study. We report the final data analysis of the safety, overall response rate (ORR), progression-free survival (PFS), and overall survival (OS) of the phase I patients and seven expansion cohorts. METHODS: This is an investigator-initiated, multicenter, phase I trial. CaboNivo doublet expansion cohorts included (1) mUC, (2) mRCC, and (3) adenocarcinoma of the bladder/urachal; CaboNivoIpi triplet expansion cohorts included (1) mUC, (2) mRCC, (3) penile cancer, and (4) squamous cell carcinoma of the bladder and other rare GU tumors (ClinicalTrials.gov identifier: NCT02496208). RESULTS: The study enrolled 120 patients treated with CaboNivo (n = 64) or CaboNivoIpi (n = 56), with a median follow-up of 49.2 months. In 108 evaluable patients (CaboNivo n = 59; CaboNivoIpi n = 49), the ORR was 38% (complete response rate 11%) and the median duration of response was 20 months. The ORR was 42.4% for mUC, 62.5% for mRCC (n = 16), 85.7% for squamous cell carcinoma of the bladder (n = 7), 44.4% for penile cancer (n = 9), and 50.0% for renal medullary carcinoma (n = 2). Grade ≥ 3 treatment-related adverse events occurred in 84% of CaboNivo patients and 80% of CaboNivoIpi patients. CONCLUSION: CaboNivo and CaboNivoIpi demonstrated clinical activity and safety in patients with multiple GU malignancies, especially clear cell RCC, urothelial carcinoma, and rare GU tumors such as squamous cell carcinoma of the bladder, small cell carcinoma of the bladder, adenocarcinoma of the bladder, renal medullary carcinoma, and penile cancer.

Current Status and Challenges in Rare Genitourinary Cancer Research and Future Directions.

PURPOSE OF REVIEW: In contemporary urological practice, managing rare genitourinary (GU) malignancies presents significant challenges, necessitating a comprehensive understanding of their unique characteristics and tailored treatment approaches. RECENT FINDINGS: Rare GU malignancies, whether per se, variants of common histologies, or common tumors in uncommon locations, often lack widely available clinical guidelines. Consequently, treatment decisions are frequently based on empirical evidence, risking suboptimal outcomes. However, recent advances in molecular profiling, targeted therapies, and immunotherapy offer promising avenues for improving management strategies and patient outcomes. This review provides a comprehensive overview of some rare GU malignancies encountered in clinical practice, including their distinct pathological features, current management approaches, and ongoing research directions. Understanding the complexities of these rare tumors and implementing multidisciplinary treatment strategies are essential for optimizing patient care and improving survival outcomes.

The combination of immune checkpoint inhibitors and antibody-drug conjugates in the treatment of urogenital tumors: a review insights from phase 2 and 3 studies.

With the high incidence of urogenital tumors worldwide, urinary system tumors are among the top 10 most common tumors in men, with prostate cancer ranking first and bladder cancer fourth. Patients with resistant urogenital tumors often have poor prognosis. In recent years, researchers have discovered numerous specific cancer antigens, which has led to the development of several new anti-cancer drugs. Using protein analysis techniques, researchers developed immune checkpoint inhibitors (ICIs) and antibody-conjugated drugs (ADCs) for the treatment of advanced urogenital tumors. However, tumor resistance often leads to the failure of monotherapy. Therefore, clinical trials of the combination of ICIs and ADCs have been carried out in numerous centers around the world. This article reviewed phase 2 and 3 clinical studies of ICIs, ADCs, and their combination in the treatment of urogenital tumors to highlight safe and effective methods for selecting individualized therapeutic strategies for patients. ICIs activate the immune system, whereas ADCs link monoclonal antibodies to toxins, which can achieve a synergistic effect when the two drugs are combined. This synergistic effect provides multiple advantages for the treatment of urogenital tumors.

Impact of implementing the first edition of the Paris system for reporting: A systematic review and meta-analysis.

Urine cytology is a noninvasive, widely used diagnostic tool for screening and surveillance of genitourinary tract neoplasms. However, the absence of unified terminology and clear objective morphological criteria limits the clinical benefit of urine cytology. The Paris System for Reporting Urine Cytology (TPS) was developed with the goal of standardizing reporting and improving urine cytology performance in detecting high-grade malignancy (HGM). We aimed to evaluate potential effects of TPS on improving urine cytology diagnostic performance and clinical utility by conducting a systematic review and meta-analysis. We searched six electronic databases to identify cross-sectional and cohort studies written in English assessing the accuracy of urine cytology in detecting genitourinary tract malignancies of patients under surveillance or with clinical suspicion of malignancy from January 2004 to December 2022. We extracted relevant data from eligible studies to calculate relative distribution of cytology diagnostic categories; ratio of atypical to HGM cytology diagnosis; and risk of HGM (ROHGM) and HGM likelihood ratio (HGM-LR) associated with cytology diagnostic categories. We used a generalized linear mixed model with logit transformation to combine proportions and multilevel mixed-effect logistic regression to pool diagnostic accuracy measurements. We performed meta-regression to evaluate any significant difference between TPS and non-TPS cohorts. We included 64 studies for 99,796 combined total cytology samples, across 31 TPS and 49 non-TPS cohorts. Pooled relative distribution [95% confidence interval (CI)] of negative for high-grade urothelial carcinoma (NHGUC)/negative for malignancy (NM); atypical urothelial cells (AUC); suspicious for high-grade urothelial carcinoma (SHGUC)/suspicious for malignancy (SM); low-grade urothelial neoplasm (LGUN); and HGM categories among satisfactory cytology cases were 83.8% (80.3%-86.9%), 8.0% (6.0%-10.6%), 2.2% (1.4%-3.3%), 0.01% (0.0%-0.1%), and 4.2% (3.2%-5.5%) in TPS versus 80.8% (76.8-2.7%), 11.3% (8.6%-14.7%), 1.8% (1.2%-2.7%), 0.01% (0.0%-0.1%), and 3.3% (2.5%-4.3%) in non-TPS cohorts. Adopting TPS classification resulted in a significant increase in the frequency of NHGUC and a reduction in AUC cytology diagnoses, respectively. The AUC/HGM ratio in TPS cohort was 2.0, which showed a statistically significant difference from the atypical/HGM ratio of 4.1 in non-TPS cohort (p-value: 0.01). Moreover, the summary rate (95% CI) of LGUN called AUC on cytology significantly decreased to 20.8% (14.9%-28.3%) in the TPS compared with 34.1% (26.4%-42.8%) in non-TPS cohorts. The pooled ROHGM (95% CI) was 20.4% (6.2%-50.0%) in nondiagnostic (NDX), 15.5% (9.6%-24.2%) in NHGUC, 40.2% (30.9%-50.2%) in AUC, 80.8% (72.9%-86.8%) in SHGUC, 15.1% (5.7%-34.3%) in LGUN, and 91.4% (87.3%-94.3%) in HGM categories in TPS studies. NHGUC, AUC, SHGUC, and HGM categories were associated with HGM-LR (95% CI) of 0.2 (0.1-0.3), 0.9 (0.6-1.3), 6.9 (2.4-19.9), and 16.8 (8.3-33.8). Our results suggest that TPS 1.0 has reduced the relative frequency of AUC diagnosis, AUC/HGM ratio, and the frequency of LGUNs diagnosed as AUC on cytology. Adopting this classification has improved the clinical utility of SHGUC and HGM cytology diagnoses in ruling in high-grade lesions. However, an NHGUC diagnosis does not reliably rule out the presence of a high-grade lesion.

Safety and Effectiveness of Irreversible Electroporation in Lymph Node Metastases.

PURPOSE: Demonstrating the safety and efficacy of percutaneous irreversible electroporation (IRE) for the treatment of lymph node metastases. MATERIALS AND METHODS: An IRB-approved, single-center retrospective review was performed on patients with lymph node metastases gastrointestinal, and genitourinary primary cancers. Primary objective safety was evaluated by assessing complications graded according to the Clavien-Dindo Classification, and efficacy was determined by tumor response on follow-up imaging and local progression-free survival (LPFS). Secondary outcome measures were technical success (complete ablation with an adequate ablative margin > 5 mm), length of hospital stay and distant progression-free survival (DPFS). RESULTS: Nineteen patients underwent percutaneous IRE between June 2018 and February 2023 for lymph node metastases, close to critical structures, such as vasculature, bowel, or nerves. The technical success was achieved in all cases. Complications occurred in four patients (21.1%), including two self-limiting grade 1 hematomas, a grade 1 abdominal pain, and grade 2 nerve pain treated with medication. Seventeen patients were hospitalized overnight, one patient stayed two nights and another patient stayed fourteen nights. Median follow-up was 25.5 months. Median time to local progression was 24.1 months (95% CI: 0-52.8) with 1-, 2-, and 5-year LPFS of 57.9%, 57.9% and 20.7%, respectively. Median time to distant progression was 4.3 months (95% CI: 0.3-8.3) with 1-, 2-, and 5-year DPFS of 31.6%, 13.2% and 13.2%, respectively. CONCLUSION: IRE is a safe and effective minimally-invasive treatment for lymph node metastases in locations, where temperature dependent ablation may be contraindicated. Care should be taken when employing IRE near nerves.

Development and validation of nomograms to predict survival of neuroendocrine carcinoma in genitourinary system: A population-based retrospective study.

Neuroendocrine carcinoma (NEC) is a rare yet potentially perilous neoplasm. The objective of this study was to develop prognostic models for the survival of NEC patients in the genitourinary system and subsequently validate these models. A total of 7125 neuroendocrine neoplasm (NEN) patients were extracted. Comparison of survival in patients with different types of NEN before and after propensity score-matching (PSM). A total of 3057 patients with NEC, whose information was complete, were extracted. The NEC influencing factors were chosen through the utilization of the least absolute shrinkage and selection operator regression model (LASSO) and the Fine & Gary model (FGM). Furthermore, nomograms were built. To validate the accuracy of the prediction, the efficiency was verified using bootstrap self-sampling techniques and receiver operating characteristic curves. LASSO and FGM were utilized to construct three models. Confirmation of validation was achieved by conducting analyses of the area under the curve and decision curve. Moreover, the FGS (DSS analysis using FGM) model produced higher net benefits. To maximize the advantages for patients, the FGS model disregarded the influence of additional occurrences. Patients are expected to experience advantages in terms of treatment options and survival assessment through the utilization of these models.

CD34/S100 protein-positive, NTRK1-rearranged infantile fibrosarcoma-like tumors in genitourinary system: two cases expanding the clinicopathologic spectrum and illustrating the diagnostic dilemma.

Infantile fibrosarcoma (IFS) is malignant fibroblastic tumor of infants characterized genetically by ETV6::NTRK3 fusion. Tumors that show morphology indistinguishable from IFS but harbor alternative genetic alterations are uncommon, which have been designated as IFS-like tumors. We report two cases of IFS-like tumors harboring an NTRK1 rearrangement and arsing from genitourinary system. The patients aged 3 and 14 years. One arose in the kidney and one in the paratesticular region. The tumors measured 13 and 3.5 cm in greatest dimension. Both tumors were composed of cellular, mildly atypical, spindle to ovoid cells arranged haphazardly or in intersecting fascicles within a collagenized to myxoid stroma. Mitoses numbered 3 and 5/10 high-power fields. Tumor cells in both neoplasms demonstrated variable co-expression of CD34 and S100 protein, and diffuse and strong cytoplasmic staining for pan-TRK and TrkA. Fluorescence in-situ hybridization demonstrated NTRK1 rearrangement in both tumors. Targeted RNA-sequencing identified CPSF6::NTRK1 fusion and TMP3::NTRK1 fusion. Limited follow-up showed no tumor recurrences or metastases. We expand the clinicopathologic spectrum of IFS-like tumors harboring alternative NTRK1 fusions.

Distinct CT imaging features of new liver metastases from primary genitourinary cancers.

PURPOSE: To apply natural language processing (NLP) to a large volume of structured radiology reports in the investigation of CT imaging features of new liver metastases from primary genitourinary cancers. METHODS: In this retrospective study, a previously reported NLP model was applied to consecutive structured CT reports from 2016 to 2022 to predict those patients with primary genitourinary cancer who developed liver metastasis. Pathology or imaging follow-up served as the reference standard for validating NLP predictions. Subsequently, diagnostic CTs of the identified patients were qualitatively assessed by two radiologists, whereby several imaging features of new liver metastasis were assessed. Proportions of the assessed imaging features were compared between primary genitourinary cancers using the Chi-square or Fisher's exact test. RESULTS: In 112 patients (mean age = 72 years; 83 males), the majority of new liver metastases were hypovascular (73.2%), well defined (76.6%), homogenous (66.9%), and without necrotic/cystic component (73.2%). There was a higher proportion of iso- to hyperdense liver metastases for primary kidney cancer vs other primary genitourinary cancers (42.5% in kidney cancer; 2.3% in ureter/bladder cancer, 8% in prostate cancer, and 0% in testicular cancer; p < 0.05) and a higher proportion of new liver metastases with ill-defined margin for primary prostate cancer vs other primary genitourinary cancers (44.0% in prostate cancer, 15.0% in kidney cancer, 18.6% in ureter/bladder cancer, and 25.0% in testicular cancer; p < 0.05). CONCLUSION: New liver metastases from primary genitourinary cancers tend to be hypovascular and show several distinct imaging features between different primary genitourinary cancers.

Role of Metastasis-Directed Therapy in Genitourinary Cancers.

OPINION STATEMENT: The treatment of oligometastatic genitourinary cancers is a rapidly advancing field with ablative radiotherapy as one of the critical treatment components. The oligometastatic disease state, which can be defined as 1-5 metastatic sites with a controlled primary, represents a distinct clinical state where comprehensive ablative local therapies may provide improved outcomes. Enhanced imaging has increased the number of patients identified with oligometastatic disease. Evidence for improved outcomes with metastasis-directed therapy (MDT) in oligometastatic genitourinary cancers is increasing, and previously published outcome data continues to mature with an increasing body of prospective data to inform the role of MDT in histology-specific settings or in the context of systemic therapy. In select patients, MDT can offer benefits beyond improved local control and allow for time off of systemic therapy, prolonged time until next therapy, or even the hope of cure. However, treatment decisions for locally ablative therapy must be balanced with consideration towards safety. There are exciting advances in technologies to target and adapt treatment in real-time which have expanded options for safer delivery and dose escalation to metastatic targets near critical organs at risk. The role of systemic therapies in conjunction with MDT and incorporation of tumor genetic information to further refine prognostication and treatment decision-making in the oligometastatic setting is actively being investigated. These developments highlight the evolving field of treatment of oligometastatic disease. Future prospective studies combining MDT with enhanced imaging and integrating MDT with evolving systemic therapies will enable the optimal selection of patients most likely to benefit from this "all-or-none" approach and reveal settings in which a combination of therapies could result in synergistic outcomes.

Redefining Rare Genitourinary Cancers: An Initiative Led by the Global Society of Rare Genitourinary Tumors.

Rare cancers account for 20-25% of all cancers diagnosed annually but there is no consensus on the definition of a rare cancer and substantial geographic heterogeneity. The Global Society of Rare Genitourinary Tumors is dedicated to education and research for rare genitourinary tumors.

The Application and Pitfalls of Immunohistochemical Markers in Challenging Diagnosis of Genitourinary Pathology.

CONTEXT.­: The morphologic features of different entities in genitourinary pathology overlap, presenting a diagnostic challenge, especially when diagnostic materials are limited. Immunohistochemical markers are valuable when morphologic features alone are insufficient for definitive diagnosis. The World Health Organization classification of urinary and male genital tumors has been updated for 2022. An updated review of immunohistochemical markers for newly classified genitourinary neoplasms and their differential diagnosis is needed. OBJECTIVE.­: To review immunohistochemical markers used in the diagnosis of genitourinary lesions in the kidney, bladder, prostate, and testis. We particularly emphasized difficult differential diagnosis and pitfalls in immunohistochemistry application and interpretation. New markers and new entities in the 2022 World Health Organization classifications of genitourinary tumors are reviewed. Recommended staining panels for commonly encountered difficult differential diagnoses and potential pitfalls are discussed. DATA SOURCES.­: Review of current literature and our own experience. CONCLUSIONS.­: Immunohistochemistry is a valuable tool in the diagnosis of problematic lesions of the genitourinary tract. However, the immunostains must be carefully interpreted in the context of morphologic findings with a thorough knowledge of pitfalls and limitations.

MicroRNAs for detecting occult genitourinary cancer.

PURPOSE OF REVIEW: Genitourinary (GU) malignancies are a real burden in global health worldwide. Each model has its own clinical challenges, and the early screening and/or detection of occult cancer in follow-up is transversal to all of them. MicroRNAs (miRNAs) have been proposed as minimally invasive liquid biopsy cancer biomarkers, due to their stability and low degradation. RECENT FINDINGS: The different GU tumor models are in different stages concerning miRNAs as biomarkers for cancer detection. Testicular germ cell tumors (TGCTs) already have a specific defined target, miR-371a-3p, that has shown high sensitivity and specificity in different clinical settings, and is now in final stages of preanalytical testing before entering the clinic. The other GU malignancies are in a different stage, with many liquid biopsy studies (both in urine and plasma/serum) being currently performed, but there is not an agreeable miRNA or set of miRNAs that is ready to follow the footsteps of miR-371a-3p in TGCTs. SUMMARY: Further studies with proper molecular characterization of miRNA profiles of GU malignancies and standardization of sampling, biobanking and formal analysis may aid in the advance and choosing of specific target sets to be used for occult cancer detection.

Workflow for Management of Gonadal Neoplasm in 2 Patients with Differences of Sex Development Enrolled in an Experimental Gonadal Tissue Cryopreservation Protocol.

OBJECTIVE: To outline our experimental gonadal tissue cryopreservation (GTC) protocol that does not disrupt the standard of care in medically-indicated gonadectomy for patients with differences of sex development, including highlighting the multidisciplinary collaborative protocol for when neoplasm is discovered in these cases. METHODS: Two patients with complete gonadal dysgenesis who were undergoing medically-indicated prophylactic bilateral gonadectomy elected to pursue GTC. Both were found to have germ cell neoplasia in situ on initial pathologic analysis, requiring recall of the gonadal tissue, which had been cryopreserved. RESULTS: Cryopreserved gonadal tissue was successfully thawed and transferred to pathology for complete analysis. No germ cells were identified in either patient nor were found to have malignancy, so further treatment beyond gonadectomy was not indicated. Pathologic information was communicated to each family, including that long-term GTC was no longer possible. CONCLUSION: Organizational planning and coordination between the clinical care teams, GTC laboratory, and pathology were key to handling these cases with neoplasia. Processes that anticipated the possibility of discovering neoplasia within tissue sent to pathology and the potential need to recall GTC tissue to complete staging included (1) documenting the orientation and anatomical position of tissue processed for GTC, (2) defining parameters in which tissue will be recalled, (3) efficiently thawing and transferring GTC tissue to pathology, and (4) coordinating release of pathology results with verbal communication from the clinician to provide context. GTC is desired by many families and at the time of gonadectomy and is (1) feasible for patients with DSD, and (2) did not inhibit patient care in 2 patients with GCNIS.

Exosomes in Genitourinary Cancers: Emerging Mediators of Drug Resistance and Promising Biomarkers.

Drug resistance presents a major obstacle in the treatment of genitourinary cancers. Exosomes as the medium of intercellular communication serve important biological functions and play essential roles in pathological processes, including drug response. Through the transfer of bioactive cargoes, exosomes can modulate drug resistance via multiple mechanisms. This review attempts to elucidate the mechanisms of exosomal cargoes with reference to tumor drug resistance, their role in genitourinary cancers, and their potential clinical applications as candidate biomarkers in liquid biopsy.

Clinicopathologic and survival correlates of embryonal rhabdomyosarcoma driven by RAS/RAF mutations.

Embryonal rhabdomyosarcoma (ERMS) is the most common subtype of rhabdomyosarcoma (RMS). Among RMS subtypes, ERMS is associated with a favorable outcome with an overall survival of 70% at 5 years for localized disease. The molecular profile of ERMS is heterogeneous, including mostly point mutations in various genes. Therapeutic strategies have remained relatively consistent irrespective of the molecular abnormalities. In this study, we focus on a homogeneous RAS/RAF mutated ERMS subset and correlate with clinicopathologic findings. Twenty-six cases (16 males and 10 females) were identified from screening 98 ERMS, either by targeted DNA sequencing (MSK-IMPACT) or by Sanger sequencing. Fourteen (54%) cases had NRAS mutations, 6 (23%) had KRAS mutations, 5 (19%) had HRAS mutations, and 1 case (4%) had BRAF mutation. Median age at diagnosis was 8 years (range 1-70) with two-thirds occurring in the children. Tumor sites varied with H&N and GU sites accounting for 62% of cases. RAS isoform hot spot mutations predominated: NRAS p.Q61K (57%), KRAS p.G12D (67%), and HRAS (codons 12, 14, and 61). Additional genetic abnormalities were identified in 85% of the RAS-mutated cases. At last follow-up, 29% of patients died of disease and 23% were alive with disease. The 3-year and 5-year survival rates were 75% and 61% respectively. In conclusion, RAS mutations occur in 27% of ERMS, with NRAS mutations encompassing half of the cases. Overall RAS-mutant RMS does not correlate with age or site, but most tumors show an undifferentiated and spindle cell morphology.