A multicenter review of histopathology of variants in the context of upper urinary tract urothelial carcinoma and their impact on clinical outcomes

Introduction Similar to bladder cancer, about one third of upper tract urothelial carcinoma (UTUC) present variant histology (VH). We aim to evaluate the incidence, clinical characteristics and the impact on outcomes of VH in UTUC. Methods We consecutively enrolled 77 patients from 2009-2022 treated with radical surgery for UTUC from a secondary and a tertiary referral center. A central pathology review of all specimens was performed by one independent uropathologist for each center. We compared pure UTUC and UTUC with VH and the accuracy of endoscopic biopsy. Descriptive and comparative analysis were used to assess association with clinical characteristics and the Kaplan-Meier estimator to compare outcomes. Results Median follow-up after surgery was 51 months. VH was present in 21/77 (28%) patients and 4/21 (19%) patients had multiple variants. The most frequent VH was squamous 12/21 (57%), followed by glandular 6/21 (29%) and micropapillary 3/21 (14%). Small cell neuroendocrine bladder carcinoma was present in two patients. Nested variant was found in one patient. Muscle invasive tumor (≥pT2) was present in 29/56 (52%) patients with pure UTUC and in 18/21 (86%) patients with VH (p <0.05). Presence of carcinoma in situ was seen in 14/56 (25%) patients with pure UTUC and in 15/21 (71%) with VH (p <0.05). Cumulative 8/56 (14%) with pure UTUC had a non-intravesical recurrence (6 patients with local and 2 distant recurrence) compared to 8/21 (38%) (3 local, 3 nodal, 2 distant) in the subgroup with VH (p <0.05). Opposite effect was noted for bladder recurrence: 60% for pure UTUC vs. 29% for tumors with VH (p <0.05). Review of preoperative endoscopic biopsy did not show the presence of VH in any patients. Differences in outcomes did not reach significance: 3yr-OS 63% vs 42% (p 0.28) and 3yr-CSS 77% vs. 50% (p 0.7). Conclusion Almost a third of UTUC present VH. Presence of VH is related to more aggressive tumor characteristics and associated with unfavorable outcomes. Due to a higher rate of extravesical recurrences in UTUC with VH, Follow-up controls should include cross sectional imaging and cystoscopy. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This study did not receive any funding ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Each patient included in the cohort signed a declaration of consent of the University Hospital of Bern and of the Hospital Center of Biel for the use of biological material and health-related data for medical research was signed by each patient. Data collection is in accordance with the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE). Ethical approval for this study (Ethical Committee N KEKBE 2016-00660) was provided by the Ethical Committee of Canton Bern, Switzerland (Chairperson Professor C. Seiler) on 02 June 2016 and the need for informed consent was waived. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data produced in the present work are contained in the manuscript