How to cite: Hansel DE. Upper Tract versus Lower Tract: Is There a Biological Difference? Grand Rounds in Urology. December 2025.  Accessed Oct 2026. https://grandroundsinurology.com/upper-tract-versus-lower-tract-is-there-a-biological-difference/

Summary

Donna E. Hansel, MD, PhD, Professor and Division Head of Pathology and Laboratory Medicine, University of Texas MD Anderson Cancer Center, Houston, Texas, examines whether upper tract urothelial carcinoma is biologically distinct from lower tract disease, integrating embryology, pathology challenges, Lynch syndrome associations, and genomic profiling data.

Upper tract tumors pose diagnostic challenges. Biopsies are often small, crushed, and limited in architecture. Muscularis propria is not a continuous structure in the upper tract, complicating substaging. Upgrading occurs in up to 25% and upstaging in up to 38% of cases between biopsy and resection.

Morphologically, upper tract tumors often appear less pleomorphic and may demonstrate lower-grade features compared with bladder tumors. Lynch-associated tumors show distinct basophilic, pushing growth patterns with prominent lymphocytes and mismatch repair deficiency.

Genomic studies demonstrate substantial overlap between upper and lower tract tumors, including common alterations in FGFR3, TP53, and RTK/RAS pathways. Some analyses suggest higher mutation frequencies or distinct immune infiltration profiles in upper tract disease, though findings vary. Embryologic origins differ between the upper and lower tract urothelium, yet comparative studies reveal greater similarity than expected.

Dr. Hansel highlights that biological differences exist, particularly in hereditary cases and certain genomic patterns, but significant overlap remains. Detection timing, specimen limitations, and tumor evolution may account for perceived distinctions as much as intrinsic biology.

How to cite: Bochner BH, Petrylak, DP, Dreicer, R, et al. “Session 4 Panel Discussion: Radical Surgical Approaches to Bladder Cancer.” December 2025. Accessed Oct 2026. https://grandroundsinurology.com/session-4-panel-discussion-radical-surgical-approaches-to-bladder-cancer/

Summary

This expert panel explores controversial and rapidly evolving questions across non–muscle-invasive and muscle-invasive urothelial cancer, including trial design, immune therapy toxicity, ctDNA-guided (circulating tumor DNA) management, perioperative sequencing, radiation integration, and mechanisms of resistance to antibody-drug conjugates.

The discussion begins with intermediate-risk non–muscle-invasive bladder cancer and whether surveillance is an appropriate control arm in phase III trials. Panelists emphasize the heterogeneity of the intermediate-risk category and note that many patients in real-world practice undergo observation alone. Regulatory requirements now mandate randomized trials rather than single-arm chemoablation studies, with observation accepted as a control in settings lacking a universally applied standard of care.

Debate then shifts to immune checkpoint combinations in non–muscle-invasive disease. Panelists express concern that modest reductions in high-grade non-progressive recurrences do not justify systemic immune toxicity, particularly given the continued effectiveness of Bacillus Calmette-Guérin (BCG) in appropriately selected patients. The need to avoid overtreatment of the majority who respond to BCG is emphasized.

In muscle-invasive disease, ctDNA-guided adjuvant therapy generates substantial discussion. Questions include whether to escalate therapy based on positive ctDNA in the absence of radiographic disease, the binary versus quantitative interpretation of ctDNA results, and the uncertainty regarding lead time and false negatives. Clinical judgment remains central.

The panel also addresses mechanisms of resistance to enfortumab vedotin and antibody-drug conjugates, including payload resistance, linker technology, and human epidermal growth factor receptor 2 expression thresholds. Dual-payload antibody-drug conjugates and improved biomarker selection are highlighted as future directions.

Challenges in integrating Fibroblast Growth Factor Receptor inhibitors, targeted therapies, and radiation strategies are discussed, particularly the logistical barriers to molecular testing and treatment selection in acutely ill patients.

The session underscores the tension between innovation, toxicity, biomarker uncertainty, and the need for better patient selection.

How to cite: Bochner BH. Session 1 Panel Discussion: Pathology, Etiology, and Diagnosis of Urothelial Cancer. Grand Rounds in Urology. December 2025. Accessed Oct 2026. https://grandroundsinurology.com/session-1-panel-discussion-pathology-etiology-and-diagnosis-of-urothelial-cancer/

Summary

A multidisciplinary panel examines the practical implementation of enhanced cystoscopy, the evolving management of carcinoma in situ, and the potential role of artificial intelligence in improving diagnostic precision and clinical trial interpretation.

The panel focuses on real-world adoption of blue light cystoscopy and narrow band imaging in the surveillance and management of non–muscle-invasive bladder cancer. Participants describe variability in practice patterns driven by workflow constraints, cost, equipment availability, and scope platform limitations. Blue light cystoscopy requires pre-procedure intravesical instillation and scheduling adjustments, limiting spontaneous use in busy clinics. Narrow band imaging is easier to toggle during standard cystoscopy, but it is not universally available, particularly as disposable scopes become more common.

Operational challenges, maintenance contracts, and discontinuation of certain flexible blue light platforms further restrict access. Despite these barriers, participants emphasize that enhanced imaging technologies improve visualization of small papillary tumors and carcinoma in situ. The debate centers on whether enhanced cystoscopy should be mandated in clinical trials to standardize detection and reduce variability in the quality of transurethral resection of bladder tumors.

A major theme involves carcinoma in situ heterogeneity. Small focal lesions detected with enhanced imaging may biologically differ from extensive multifocal disease, yet both are categorized similarly in single-arm trials. The panel questions assumptions that all carcinoma in situ represents persistent disease after resection, noting that aggressive resection and fulguration may eliminate visible disease in a subset of patients. Lack of objective quantification methods complicates the assessment of response and the interpretation of therapeutic efficacy.

Participants discuss limitations in histologic sampling of carcinoma in situ and challenges in molecular analysis due to minimal tissue volume. Urinary-based assays and circulating tumor DNA are suggested as potential objective tools. Artificial intelligence–based cystoscopic enhancement, image capture, and three-dimensional mapping may enable quantification of lesion surface area and improve longitudinal assessment of response.

The discussion highlights the need for standardization, objective measurement, and integration of emerging technologies in both clinical practice and trial design.

How to cite: Hansel DE. Gender Disparities in the Diagnosis of Urothelial Carcinoma. Grand Rounds in Urology. December 2025. Accessed Oct 2026. https://grandroundsinurology.com/gender-disparities-in-the-diagnosis-of-urothelial-carcinoma/

Summary

Donna E. Hansel, MD, PhD, Division Head of Pathology and Laboratory Medicine, University of Texas MD Anderson Cancer Center, Houston, Texas, examines persistent gender disparities in urothelial carcinoma, focusing on differences in incidence, stage at diagnosis, histologic subtypes, treatment patterns, and cancer-specific outcomes. Dr. Hansel integrates epidemiologic data, pathology insights, and real-world diagnostic pathways to explain why women experience worse outcomes despite lower disease incidence.

Dr. Hansel begins with an overview of urothelial carcinoma across the urinary tract and emphasizes that bladder cancer accounts for the majority of cases. Although men develop bladder cancer three to four times more often than women, women experience higher cancer-specific mortality. Dr. Hansel underscores that this disparity persists even after adjusting for stage, indicating multifactorial causes beyond delayed detection alone.

Biologic contributors are reviewed, including differences in carcinogen metabolism, detoxifying enzymes, hormonal signaling, and X chromosome–linked genetic alterations. Differential expression of UGT and GSTM1 enzymes, androgen and estrogen receptor signaling, and higher prevalence of KDM6A and STAG2 mutations in women are discussed as potential drivers of susceptibility and disease behavior.

Diagnostic delay is examined in detail. Dr. Hansel notes that women are more frequently treated empirically for urinary tract infection when presenting with hematuria or irritative voiding symptoms, resulting in delayed urology referral and advanced stage at diagnosis. Data demonstrate longer referral times, increased antibiotic exposure, and a higher likelihood of muscle-invasive and node-positive disease at presentation in women.

Histologic and anatomic differences are highlighted, including higher rates of variant histologies in women and anatomic features that may facilitate local invasion and lymphatic spread. Treatment disparities are reviewed, with evidence showing higher perioperative morbidity, longer hospital stays, and worse survival outcomes for women following radical cystectomy and radiation therapy.

Dr. Hansel stresses that gender disparities in urothelial carcinoma arise from intersecting biologic, diagnostic, and systemic factors. Improved awareness, earlier referral, refined staging, and deeper investigation of sex-based biology are emphasized as actionable steps to reduce outcome gaps.

How to cite: Hansel DE. Molecular Changes in Bladder Cancer. Grand Rounds in Urology. December 2025.  Accessed Oct 2026. https://grandroundsinurology.com/molecular-changes-in-bladder-cancer/

Summary

Donna E. Hansel, MD, PhD, Division Head of Pathology and Laboratory Medicine, University of Texas MD Anderson Cancer Center, Houston, Texas, provides a comprehensive overview of the molecular landscape of urothelial carcinoma, emphasizing how genetic alterations, molecular subtypes, and morphologic variants intersect with diagnosis, prognosis, and emerging therapeutic strategies. Dr. Hansel synthesizes decades of molecular pathology research with contemporary clinical relevance.

Dr. Hansel contrasts low-grade papillary and high-grade urothelial carcinomas. Low-grade tumors are characterized by alterations in FGFR3, HRAS, PIK3CA, TERT promoter, and STAG2, whereas high-grade disease exhibits a dominant disruption of cell-cycle and tumor suppressor pathways, including TP53, RB1, CDKN2A loss, ERBB2 amplification, ARID1A, and extensive copy number alterations.

The evolution of molecular classification is reviewed, beginning with TCGA-driven basal and luminal subtypes and progressing to modern consensus classes. While these classifications enhance biologic understanding and inform clinical trials, they remain research tools rather than routine diagnostic categories due to tumor plasticity and treatment-induced phenotypic shifts.

Targetable alterations are discussed in depth, with particular focus on FGFR signaling. Multiple mechanisms of FGFR activation are outlined, including point mutations, fusions, and overexpression. The presentation reviews the development of FGFR inhibitors and highlights mechanisms of resistance, underscoring the need for comprehensive sequencing and the potential future role of monitoring circulating tumor DNA.

Morphologic variants serve as a bridge between histology and molecular alterations. Micropapillary urothelial carcinoma is examined in detail, with emphasis on its aggressive behavior and strong association with ERBB2 amplification. Challenges in HER2 testing methodology, inter-laboratory variability, and implications for antibody–drug conjugate development are discussed. Additional variants, including plasmacytoid urothelial carcinoma, are reviewed, highlighting characteristic E-cadherin mutations and poor clinical outcomes.

Dr. Hansel also discusses carcinoma in situ biomarkers, limitations of immunohistochemical panels, and the expanding role of liquid biopsy. She emphasizes that integrating morphology with molecular profiling remains essential for precision care in bladder cancer.

About the 2025 International Bladder Cancer Update Expert Forum™

The International Bladder Cancer Update (IBCU) Expert Forum™ is a physician-led conference bringing together urologists, urologic oncologists, and other healthcare professionals involved in the treatment and diagnosis of bladder cancer. The conference offers interactive expert lectures, panel discussions, and case presentations offers a dynamic look at the latest advancements and state-of-the-art technologies in the field of bladder cancer management. The 2025 IBCU Expert Forum™ encompassed the management of muscle-invasive, non-muscle invasive, and metastatic bladder cancer; upper-tract disease; as well as giving a specific focus on radical vs bladder sparing surgical approaches.

Donna E. Hansel, MD, PhD, presented “Biomarker Integration for Advanced Urothelial Carcinoma” at the 6th International Bladder Cancer Update on November 20, 2022, in Scottsdale, Arizona.

How to cite: Hansel, Donna E. “Biomarker Integration for Advanced Urothelial Carcinoma” November 2022. Accessed Dec 2022. https://grandroundsinurology.com/biomarker-integration-for-advanced-urothelial-carcinoma/

Biomarker Integration for Advanced Urothelial Carcinoma

Donna E. Hansel, MD, PhD, delves into the critical role of biomarker integration in the management of advanced urothelial carcinoma and underscores the transformative potential of biomarkers in enhancing diagnostic precision, guiding treatment decisions, and improving patient outcomes.

Dr. Hansel defines biomarkers and their significance in oncology, particularly in the context of urothelial carcinoma. Biological molecules found in blood, other body fluids, or tissues indicate a normal or abnormal process, condition, or disease. In advanced urothelial carcinoma, biomarkers can offer insights into the tumor’s genetic and molecular landscape, helping clinicians tailor treatments to each patient’s cancer.

Several key biomarkers have shown promise in urothelial carcinoma, including genetic alterations such as FGFR3 mutations, ERBB2 amplifications, and DNA damage repair gene mutations. Dr. Hansel discusses how these biomarkers can predict responses to targeted therapies and immune checkpoint inhibitors, offering a personalized approach to treatment. For example, patients with FGFR3 mutations may benefit from FGFR inhibitors, while those with high mutational burden might respond better to immune checkpoint blockade.

Dr. Hansel also delves into the methodologies used to detect these biomarkers, including next-generation sequencing (NGS), immunohistochemistry (IHC), and liquid biopsies. She emphasizes the importance of integrating these advanced diagnostic tools into clinical practice to ensure accurate and comprehensive biomarker profiling. The use of liquid biopsies, for instance, allows for non-invasive monitoring of tumor dynamics and treatment response, offering a significant advantage over traditional tissue biopsies.

Dr. Hansel acknowledges the limitations of biomarker integration, such as the variability in biomarker expression, the need for standardized testing protocols, and the economic considerations of widespread biomarker testing. Despite these challenges, she advocates for continued research and collaboration to overcome these barriers and maximize the clinical utility of biomarkers.

About the 6th International Bladder Cancer Update:

The International Bladder Cancer Update (IBCU) is a CME conference focused on the diagnosis and treatment of bladder cancer. The conference offers medical professionals an opportunity to listen to updates from, and interact with, expert international faculty to improve knowledge and determine best treatment practices to improve patient outcomes. IBCU encompasses expert lectures, interactive discussions, a panel roundtable, debates, and case presentations. It is physician-led, multi-supported, and designed for urologists, urologic oncologists, and other healthcare professionals involved in the treatment of bladder cancer.

For further educational activities from this conference, visit our collection page.

Donna E. Hansel, MD, PhD, presented “Pathology of Urothelial Cancers” at the 6th International Bladder Cancer Update on November 19, 2022, in Scottsdale, Arizona.

How to cite: Hansel, Donna E. “Pathology of Urothelial Cancers” November 2022. Accessed Dec 2022. https://grandroundsinurology.com/pathology-of-urothelial-cancers/

Pathology of Urothelial Cancers

Donna E. Hansel, MD, PhD, delivered a compelling presentation on the pathology of urothelial cancers, emphasizing the complexity and heterogeneity of urothelial carcinomas and underscoring the critical need for accurate pathological evaluation in guiding treatment decisions.

She detailed the molecular subtypes of urothelial cancers, explaining their distinct genetic and epigenetic profiles. This classification aids in predicting treatment responses and patient outcomes. Dr. Hansel highlighted the importance of recognizing variant histologies, such as micropapillary, plasmacytoid, and neuroendocrine subtypes, which have unique clinical behaviors and therapeutic implications.

The presentation also covered the role of biomarkers in urothelial cancer, including FGFR3 mutations and PD-L1 expression, which are pivotal in the era of targeted therapies and immunotherapy. Dr. Hansel provided insights into the latest advancements in diagnostic techniques, such as next-generation sequencing and liquid biopsies, which are enhancing the precision of urothelial cancer diagnosis and monitoring.  

About the 6th International Bladder Cancer Update:

The International Bladder Cancer Update (IBCU) is a CME conference focused on the diagnosis and treatment of bladder cancer. The conference offers medical professionals an opportunity to listen to updates from, and interact with, expert international faculty to improve knowledge and determine best treatment practices to improve patient outcomes. IBCU encompasses expert lectures, interactive discussions, a panel roundtable, debates, and case presentations. It is physician-led, multi-supported, and designed for urologists, urologic oncologists, and other healthcare professionals involved in the treatment of bladder cancer.

For further educational activities from this conference, visit our collection page.

Donna E. Hansel, MD, PhD, presented “What Should I Do About Micropapillae? Do I Treat it Differently than Standard?” at the 6th International Bladder Cancer Update on November 20, 2022, in Scottsdale, Arizona.

How to cite: Hansel, Donna E. “What Should I Do About Micropapillae? Do I Treat it Differently than Standard?” November 2022. Accessed Oct 2026. https://grandroundsinurology.com/what-should-i-do-about-micropapillae-do-i-treat-it-differently-than-standard/

What Should I Do About Micropapillae? Do I Treat it Differently than Standard? – Summary

Donna E. Hansel, MD, PhD, identifies the histopathological features that set micropapillary bladder cancer apart. This variant, though relatively rare, poses significant challenges due to its aggressive behavior and distinct morphological traits. She explains that micropapillary bladder cancer often exhibits a propensity for early invasion into the muscularis propria and a higher likelihood of lymphovascular invasion, factors that contribute to its aggressive clinical course.

Given these characteristics, Dr. Hansel underscores the necessity of a more vigilant and aggressive treatment strategy compared to standard urothelial carcinoma. She discusses the pivotal role of accurate staging and early detection, advocating for comprehensive diagnostic evaluations including advanced imaging techniques and cystoscopy. Her presentation highlights the critical importance of recognizing micropapillary features in biopsy specimens to guide appropriate therapeutic decisions.

Treatment paradigms for micropapillary bladder cancer, as outlined by Dr. Hansel, diverge significantly from those for standard bladder cancer. She emphasizes that immediate radical cystectomy often emerges as the preferred treatment modality due to the high risk of progression and metastasis associated with micropapillary histology. Dr. Hansel provides compelling evidence from recent studies that support this aggressive surgical approach, aiming to improve patient outcomes.

In addition to surgical intervention, Dr. Hansel explores the potential benefits of neoadjuvant chemotherapy, stressing its role in downstaging the tumor and addressing micrometastatic disease. She also considers the prospects of adjuvant therapies post-cystectomy, particularly in high-risk patients, to mitigate recurrence rates and enhance long-term survival.

About the 6th International Bladder Cancer Update:

The International Bladder Cancer Update (IBCU) is a CME conference focused on the diagnosis and treatment of bladder cancer. The conference offers medical professionals an opportunity to listen to updates from, and interact with, expert international faculty to improve knowledge and determine best treatment practices to improve patient outcomes. IBCU encompasses expert lectures, interactive discussions, a panel roundtable, debates, and case presentations. It is physician-led, multi-supported, and designed for urologists, urologic oncologists, and other healthcare professionals involved in the treatment of bladder cancer.

For further educational activities from this conference, visit our collection page.

Donna E. Hansel, MD, PhD, presented “UTUC Is it Biologically Distinct” at the 6th International Bladder Cancer Update on November 20, 2022, in Scottsdale, Arizona.

How to cite: Hansel, Donna E. “UTUC Is it Biologically Distinct.” November 2022. Accessed Dec 2022. https://grandroundsinurology.com/utuc-is-it-biologically-distinct/

UTUC Is it Biologically Distinct – Summary

Donna E. Hansel, MD, PhD, discusses the challenges presented by upper tract urothelial carcinoma (UTUC) due to its distinct biological characteristics compared to bladder urothelial carcinoma. Hansel delves into the molecular and genetic mutations, such as those in the FGFR3 and TP53 genes, that define UTUC, that guide therapeutic decisions.

Hansel explores the potential of targeted therapies and immunotherapies that specifically address the genetic aberrations prevalent in UTUC. The presentation also covers the role of comprehensive genomic profiling in identifying actionable mutations and guiding personalized treatment strategies. Further, Hansel examines the impact of anatomical location on the clinical management of UTUC. 

About the 6th International Bladder Cancer Update:

The International Bladder Cancer Update (IBCU) is a CME conference focused on the diagnosis and treatment of bladder cancer. The conference offers medical professionals an opportunity to listen to updates from, and interact with, expert international faculty to improve knowledge and determine best treatment practices to improve patient outcomes. IBCU encompasses expert lectures, interactive discussions, a panel roundtable, debates, and case presentations. It is physician-led, multi-supported, and designed for urologists, urologic oncologists, and other healthcare professionals involved in the treatment of bladder cancer.

For further educational activities from this conference, visit our collection page.