Coexistence of low-grade component predicts better prognosis in patients with primary, solitary high-grade non-muscle invasive bladder cancer

Coexistence of low-grade component predicts better prognosis in patients with primary, solitary high-grade non-muscle invasive bladder cancer | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Coexistence of low-grade component predicts better prognosis in patients with primary, solitary high-grade non-muscle invasive bladder cancer Jiaxiang Ji, Fei Wang, Chin-Hui Lai, Tao Xu, Hao Hu This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-3881585/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background To determine the impact of coexisted low-grade components on the prognosis of high-grade non-muscle-invasive bladder cancer (NMIBC). Method A total of 167 patients with a mean follow-up of 39.32 months underwent transurethral resection of primary, solitary non-muscle invasive bladder tumor between January 2010 and December 2019, including 35 patients with coexisted low-grade components and 132 patients with pure high-grade tumors. All patients underwent adequate intravesical chemotherapy. Result Baseline characteristics were well balanced between patients with pure high-grade tumor and those with coexisted low-grade components. Five-year recurrence-free survival was much worse for pure high-grade tumor compared to high-grade tumor with coexisted low-grade component (50.5% vs 80.0%, p = 0.01). Multivariable cox regression analysis revealed coexisted low-grade components to be an independent risk factor for recurrence (hazard ratio = 2.34, p = 0.02). Other significant contributing factor was T1 stage (hazard ratio = 2.09, p = 0.01). Conclusion Coexistence of low-grade component predicts better prognosis in patients with primary, solitary high-grade non-muscle invasive bladder cancer. Non-muscle invasive bladder cancer high grade coexistence low grade prognosis Figures Figure 1 Background Bladder cancer (BCa), as one of the most prevalent genitourinary malignancies, accounts for an estimated 500 000 new cases and 200 000 deaths annually worldwide( 1 ). About 75% patients are initially diagnosed as non-muscle invasive bladder cancer (NMIBC), i.e., mucosal or submucosal confined disease.( 2 ) In spite of undergoing transurethral resection of the bladder tumor (TURBT) and adjuvant intravesical therapy including chemotherapy or immunotherapy, disease recurrence and progression remain prevalent, which aggravate the burden of health care system and prompt researchers’ widespread attention( 3 ). In 1998, the World Health Organization (WHO) three-tiered WHO system was replaced by a binary low- or high-grade system, which was widely adopted since then( 4 ). Low-grade tumors and high-grade tumors have very different natural histories, consistent with grade being among the most important predictors of prognosis in NMIBC( 5 ). The divergence in biologic behavior for low-grade versus high-grade lesions correlates with the known dual molecular lines of genetic development for these two lesions and supports the concept that high-grade and low-grade cancers may essentially be considered different diseases( 6 , 7 ). Chromosomal alterations caused by oxidative DNA damage create two separate genetic pathways to the development of UC( 8 ). Bladder cancer can be categorized into high- and low-grade tumors ( 2 ). The prognosis and treatment approaches significantly vary between high- and low-grade lesions, particularly in the context of non–muscle-invasive bladder cancer. For individuals diagnosed with low-grade non–muscle-invasive bladder cancer, transurethral resection of the bladder tumor is generally recommended. In contrast, those with high-grade non–muscle-invasive often necessitate more aggressive treatments such as radical cystectomy, systemic chemotherapy, and radiation therapy ( 5 , 6 ). However, low-grade and high-grade component can coexist within the same histologic specimen. According to 2004 classification, low grade with more than 5% high grade component is considered high grade. In our clinical practice, patients with high grade tumors, whether or not with coexisted low-grade lesions, were treated the same with regard to postoperative instillation regimen (mainly intravesical chemotherapy) and follow-up strategy. Under such circumstances, the evidence was rare in this aspect. The goal of our research was to evaluate the impact of coexistent low-grade lesion on the prognosis of high grade NMIBC patients receiving adjuvant intravesical chemotherapy (IC). Through our study, we hope to improve postoperative instillation regimen and follow-up strategy for high-grade NMIBC with concurrent low-grade component. Patients and methods The study was approved by the Ethics Committee of Peking University People’s Hospital. We retrospectively analyzed all patients who transurethral resection of bladder tumor (TURBT) at Peking University People's Hospital between January 2015 to December 2019. Patients diagnosed with primary, solitary non-muscle invasive bladder cancer (NMIBC) and received adequate IC were included. Adequate IC was defined as a minimum of weekly induction for the initial 8 weeks followed by monthly treatments for up to 6 months. The follow-up schedule post-TURBT typically involved assessments every 3 months for the first 2 years, every 6 months for the subsequent 3 years, and annually thereafter. Follow-up protocols adhered to risk stratification based on the EAU guidelines. Exclusion criteria comprised: ( 1 ) individuals with a history of prior TURBT; ( 2 ) those who had received concurrent treatment for upper urinary tract urothelial carcinoma; ( 3 ) patients who had undergone prior or concurrent prostatic surgeries; ( 4 ) patients with incomplete tumor resection or requiring a second-look TURBT; ( 5 ) individuals not receiving single instillation (SI) within 24 hours after TURBT; ( 6 ) individuals with missing data or a notably short follow-up duration. Patients were categorized into two groups: those with pure high grade bladder tumor (pHG) and those with mixed high-grade lesion (mHG, i.e., with coexistent low-grade components). Demographic, clinical and pathological characteristics were recorded, including age, gender, body mass index, smoking history, presence of hypertension or diabetes, pathological grade, tumor stage, number of tumors, and tumor size. Recurrence was identified as the reappearance of bladder tumors regardless of their stage or grade, while progression was defined as advancement in tumor stage or grade. Continuous variables were presented as the median and interquartile range (IQR), while categorical variables were represented as proportions. Comparison of clinicopathological characteristics was carried out with Student's t-test, the Wilcoxon rank test, and the chi-squared test. Survival analyses were conducted using Kaplan-Meier analysis. The relationship between clinicopathological parameters and oncological outcomes was assessed through both univariate and multivariate Cox proportional hazard regression analyses. Multivariate analysis was performed solely for parameters showing P-values of less than 0.1 in univariate analysis. Statistical significance was determined with a P-value of less than 0.05. IBM SPSS Statistics version 25.0 (IBM, Armonk, NY, USA) was utilized for all statistical analyses." Results 1.Baseline characteristics The final cohort included one hundred and sixty-seven patients of primary high-grade NMIBC who received sufficient IC treatment, with a mean follow up of 39.32 months (interquartile range [IQR]: 26.82–61.37 months). Among them, 35 individuals had bladder tumor with coexistent low-grade component (20.9%), and the rest had pure high-grade lesions. The clinicopathological characteristics of these patients are detailed in Table 1 . Seventy-six percent were male. Thirteen percent had T1 disease, while the rest had stage Ta lesion. Overall, the baseline characteristics are well balanced between two groups (p ≥ 0.05). Table 1 Demographic and clinical characteristics of patients. Variable mHG(n = 35) pHG(n = 132) P Value Age 0.58 ≤65yrd 12 52 >65yrd 23 80 Gender Male 27 100 0.86 Female 8 32 Smoking status,n(%) Never 27 97 0.66 Former/Current 8 35 UTUC history 0.18 Yes 0 8 No 35 124 Hypertension,n(%) No 20 82 0.59 Yes 15 50 Diabetes mellitus,n(%) 0.46 No 30 106 Yes 5 26 Tumor size,n(%) ≤3cm 32 126 0.34 >3cm 3 6 Pathological stage,n(%) Ta 32 112 0.131 T1 3 20 Median instillation numbers 15 16 0.542 Recurrence No 28 76 0.01 Yes 7 56 2.Entire cohort survival analysis In the median follow up duration of 39.32 months (interquartile range: 26.82–61.37 months), 7 patients (20.0%) in mHG group and 56 patients (42.4%) in pHG group experienced recurrence. Figure 1 showed Kaplan–Meier curves of recurrence-free survival (RFS) in two groups. The 5-year RFS was higher in mHG group than in pHG group (80.0% vs 50.5%, p = 0.01), as depicted in Fig. 1 . Univariate Cox regression analysis revealed that T1 stage and pHG were all associated with poorer recurrence-free survival, both of which were further confirmed in multivariable cox regression analysis (pHG hazard ratio = 2.34 p = 0.02). Other significant contributing factor was T1 stage lesion (T1 hazard ratio = 2.09 p = 0.01) (Table 2 ). Table 2 Univariate and multivariate Cox proportional hazard regression analysis to identify predictive factors for recurrence-free survival. Variables Univariate Multivariate Hazard ratio p value Hazard ratio p value Age (years) 0.10 ≤ 65yrd Reference >65yrd 0.65 Sex 0.64 Male reference Female 1.08 Smoking status 0.51 Never reference Former/Current 0.81 Hypertension 0.88 No reference Yes 0.96 Diabetes mellitus 0.64 No reference Yes 0.84 Tumor size 0.58 ≤ 3cm reference >3cm 0.67 stage 0.02 0.01 Ta reference reference T1 2.02 2.09 Pathology 0.03 0.02 mHG reference reference pHG 2.34 2.43 UTUC history 0.59 No reference Yes 1.32 Discussion Bladder cancer exhibits heterogenous recurrent rates, and studies investigating its molecular mechanisms of development and progression are limited. Similar to many epithelial cancer variations, bladder cancer typically follows a progression pattern involving precancerous histological and molecular alterations that potentially develop over several decades, i.e., field cancerization( 9 ). The typical progression from hyperplastic changes to dysplasia is frequently observed in bladder cancer, both in clinical practice and animal model, presenting a chance to better understand the development and progression of this cancer( 10 , 11 ). Therefore, a small number of bladder cancer patients were found to harbor both high-grade and low-grade lesions at the same time. For those with multiple tumors with different grade, it could be the result of multiple primary tumors, meaning extensive precancerous areas and multiple neoplasms with different origin, which was widely acknowledged in lunch cancer, also known as multiple primary lung cancer (MPLC)( 12 ). As a result, the stage, grade and prognosis of MPLC should be based on the most advanced one( 13 ). However, for those with solitary lesion, things may be different. The histologic expression of intravesical lesions forms a broad spectrum that can coexist within the same specimen. It is well known that urothelial carcinoma, like other epithelial neoplasm, is a field change disease. Patients with initial low-grade tumors sometimes develop subsequent high-grade tumors, often years after the original tumor. If this was the case, then a certain proportion of patients would present with lesions with coexisted low-grade and high-grade components. Such patients theoretically have better prognosis, as they are at the early stage of high-grade tumor. However, another possibility remains that longer course of disease entails greater risk of micro-metastasis and higher level of field cancerization, which may be the reason why the prognosis of progressive muscle-invasive bladder cancer is worse than primary muscle-invasive bladder cancer( 14 ). According to our research, patients of mHG exhibited better prognosis, as seen with both better recurrence-free survival and progression-free survival, validating mHG as an early phase of pHG. The current study revealed that high-grade urothelial carcinoma with coexisted low-grade component fared better after adequate intravesical chemotherapy with regard to recurrence. These findings are revealing and clinically meaningful. Traditionally, urothelial carcinoma is dichotomously divided into high grade and low grade. The divergence in biologic behavior for low-grade versus high-grade lesions correlates with the known dual molecular lines of genetic development for these two pathways and supports the concept that high-grade and low-grade cancers may essentially be considered different diseases. However, such dichotomy is not all-inclusive. As low-grade and high-grade components are sometimes found to coexist in a single tumor, indicating at least some high-grade lesion may be secondary to low grade tumor. Our study confirms the hypothesis that some high-grade lesion could be due to the progression from low grade disease. Such clarification could further improve risk stratification and follow-up strategy in non-muscle-invasive bladder cancer, especially those of low-grade tumor. The current study revealed that high-grade urothelial carcinoma with coexisted low-grade component exhibited better response to intravesical chemotherapy for NMIBC. This finding is in line with prior hypothesis that such mixture is a sign of transition between low grade and high grade. The current study does come with certain limitations. Firstly, the utilization of a retrospective cohort introduces the potential of unaccounted-for confounding variables. Secondly, given the infrequent occurrence of UTUC, our analysis is constrained by the relatively limited number of UTUC patients in the cohort. Thirdly, treatment variations across different surgeons were not factored in, including differences in UTUC management, the administration of re-Turbt. Lastly, our analysis was confined to patients who received a relatively sufficient amount of intravesical chemotherapy to ensure a consistently treated cohort. However, this could potentially lead to selection bias. In summary, for bladder cancer patients of mHG, the prognosis may diverge from those with pHG lesion. This observation seems particularly significant for those patients troubled by frequent cystectomy follow-up and fear of recurrence. Conclusion The presence of coexisted low-grade component predicted a significant decrease in recurrence rates for primary, solitary high grade urothelial carcinoma. Future in-depth studies are warranted to optimize treatment and follow-up strategy for this subgroup patients. Abbreviations Bca: Bladder cancer (BCa) NMIBC: non-muscle invasive bladder cancer TURBT: transurethral resection of the bladder tumor pHG: pure high grade bladder tumor mHG: mixed high-grade lesion Declarations Ethics approval and consent to participate : Our study was conducted in accordance with the Declaration of Helsinki (as revised in 2013) and was approved by the Institutional Review Board of Peking University People’s Hospital, which waived the requirement of informed consent for this retrospective analysis. Consent for publication : Not applicable. Acknowledgements : Not applicable. Authors’ contributions Jiaxiang Ji and Hao Hu conceived the study concept. Jiaxiang Ji and Fei Wang carried out the study, analyzed the data, and wrote the article. Chin-Hui Lai and Tao Xu provided critical feedback and helped shape the research, analysis, and article. Hao Hu supervised the project. All authors discussed the results and commented on the article. Fei Wang had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. All authors read and approved the final manuscript. Funding : Not applicable Availability of data and materials : The data and materials can be obtained by contacting the corresponding author. Competing interests: No competing financial interests exist. References Richters A, Aben KKH, Kiemeney L. The global burden of urinary bladder cancer: an update. World J Urol. 2020;38(8):1895–904. Kamat AM, Hahn NM, Efstathiou JA, Lerner SP, Malmstrom PU, Choi W, et al. Bladder cancer Lancet. 2016;388(10061):2796–810. Sylvester RJ, van der Meijden AP, Oosterlinck W, Witjes JA, Bouffioux C, Denis L, et al. Predicting recurrence and progression in individual patients with stage Ta T1 bladder cancer using EORTC risk tables: a combined analysis of 2596 patients from seven EORTC trials. Eur Urol. 2006;49(3):466–5. discussion 75 – 7. Epstein JI, Amin MB, Reuter VR, Mostofi FK. The World Health Organization/International Society of Urological Pathology consensus classification of urothelial (transitional cell) neoplasms of the urinary bladder. Bladder Consensus Conference Committee. Am J Surg Pathol. 1998;22(12):1435-48. Budson AE, Droller DB, Dodson CS, Schacter DL, Rugg MD, Holcomb PJ, Daffner KR. Electrophysiological dissociation of picture versus word encoding: the distinctiveness heuristic as a retrieval orientation. J Cogn Neurosci. 2005;17(8):1181–93. Habuchi T, Marberger M, Droller MJ, Hemstreet GP 3rd, Grossman HB, Schalken JA, et al. Prognostic markers for bladder cancer: International Consensus Panel on bladder tumor markers. Urology. 2005;66(6 Suppl 1):64–74. Hasui Y, Osada Y, Kitada S, Nishi S. Significance of invasion to the muscularis mucosae on the progression of superficial bladder cancer. Urology. 1994;43(6):782–6. Richter J, Jiang F, Gorog JP, Sartorius G, Egenter C, Gasser TC, et al. Marked genetic differences between stage pTa and stage pT1 papillary bladder cancer detected by comparative genomic hybridization. Cancer Res. 1997;57(14):2860–4. Hoglund M. Bladder cancer, a two phased disease? Semin Cancer Biol. 2007;17(3):225–32. Oliveira PA, Arantes-Rodrigues R, Vasconcelos-Nobrega C. Animal models of urinary bladder cancer and their application to novel drug discovery. Expert Opin Drug Discov. 2014;9(5):485–503. Bondaruk J, Jaksik R, Wang Z, Cogdell D, Lee S, Chen Y, et al. The origin of bladder cancer from mucosal field effects. iScience. 2022;25(7):104551. Wu SC, Lin ZQ, Xu CW, Koo KS, Huang OL, Xie DQ. Multiple primary lung cancers. Chest. 1987;92(5):892–6. Usuda J, Ichinose S, Ishizumi T, Hayashi H, Ohtani K, Maehara S, et al. Management of multiple primary lung cancer in patients with centrally located early cancer lesions. J Thorac Oncol. 2010;5(1):62–8. Lai S, Liu J, Lai C, Seery S, Hu H, Wang M et al. Prognostic variations between primary and progressive muscle-invasive bladder cancer following radical cystectomy: A novel propensity score-based multicenter cohort study. Int J Surg. 2023. Additional Declarations No competing interests reported. Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-3881585","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":269924460,"identity":"19570703-889d-439a-8dd0-2114d2cb93ed","order_by":0,"name":"Jiaxiang Ji","email":"","orcid":"","institution":"Peking University People's Hospital","correspondingAuthor":false,"prefix":"","firstName":"Jiaxiang","middleName":"","lastName":"Ji","suffix":""},{"id":269924461,"identity":"cb4b8d49-51de-4972-96d4-45408744af08","order_by":1,"name":"Fei Wang","email":"","orcid":"","institution":"Peking University People's Hospital","correspondingAuthor":false,"prefix":"","firstName":"Fei","middleName":"","lastName":"Wang","suffix":""},{"id":269924462,"identity":"7fd8826c-07a0-4243-aba4-855e8119d675","order_by":2,"name":"Chin-Hui Lai","email":"","orcid":"","institution":"Peking University People's Hospital","correspondingAuthor":false,"prefix":"","firstName":"Chin-Hui","middleName":"","lastName":"Lai","suffix":""},{"id":269924463,"identity":"4dd3c367-f4ad-4984-a66d-5dd6ef6e92c0","order_by":3,"name":"Tao Xu","email":"","orcid":"","institution":"Peking University People's Hospital","correspondingAuthor":false,"prefix":"","firstName":"Tao","middleName":"","lastName":"Xu","suffix":""},{"id":269924464,"identity":"c97ec0a1-9cf2-41e5-ae1d-e40b8e7c7448","order_by":4,"name":"Hao Hu","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAvUlEQVRIiWNgGAWjYBACAwYeIFlxgBnM4yFeyxmStTC2HWAgXou5RO7BDx/n3WHXnZHA+OBtG4O8OSEtljPykiVnbnvGbHYjgdlwbhuD4c4GQg67kWMgzbvtMEgLmzRvG0OCwQHCWox/884Ba2H/TawWM2neBogtzMRpOfPGzHLGMaBfzjxslpxzTsJwA0Etx3OMb3youZNsdjz54Ic3ZTbyBG2BgWRg7DQAaQki1QOBHfFKR8EoGAWjYMQBAEMPQZsTCOulAAAAAElFTkSuQmCC","orcid":"","institution":"Peking University People's Hospital","correspondingAuthor":true,"prefix":"","firstName":"Hao","middleName":"","lastName":"Hu","suffix":""}],"badges":[],"createdAt":"2024-01-20 12:59:15","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-3881585/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-3881585/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":50460371,"identity":"4527fa3e-c2d2-4aed-ab4a-231857360135","added_by":"auto","created_at":"2024-01-31 20:33:47","extension":"jpeg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":134448,"visible":true,"origin":"","legend":"\u003cp\u003eKaplan–Meier curves of recurrence-free survival (RFS) for both mHG group and pHG group.\u003c/p\u003e","description":"","filename":"floatimage1.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-3881585/v1/0d721d0f460d616e1c34fd19.jpeg"},{"id":53590240,"identity":"1db74231-cd00-484a-9f66-6c6db5e1fb37","added_by":"auto","created_at":"2024-03-27 19:58:57","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":343310,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-3881585/v1/640eacdf-f24c-4e90-b4fd-6a632e21fb57.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Coexistence of low-grade component predicts better prognosis in patients with primary, solitary high-grade non-muscle invasive bladder cancer","fulltext":[{"header":"Background","content":"\u003cp\u003eBladder cancer (BCa), as one of the most prevalent genitourinary malignancies, accounts for an estimated 500 000 new cases and 200 000 deaths annually worldwide(\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e). About 75% patients are initially diagnosed as non-muscle invasive bladder cancer (NMIBC), i.e., mucosal or submucosal confined disease.(\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e) In spite of undergoing transurethral resection of the bladder tumor (TURBT) and adjuvant intravesical therapy including chemotherapy or immunotherapy, disease recurrence and progression remain prevalent, which aggravate the burden of health care system and prompt researchers\u0026rsquo; widespread attention(\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eIn 1998, the World Health Organization (WHO) three-tiered WHO system was replaced by a binary low- or high-grade system, which was widely adopted since then(\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e). Low-grade tumors and high-grade tumors have very different natural histories, consistent with grade being among the most important predictors of prognosis in NMIBC(\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eThe divergence in biologic behavior for low-grade versus high-grade lesions correlates with the known dual molecular lines of genetic development for these two lesions and supports the concept that high-grade and low-grade cancers may essentially be considered different diseases(\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e). Chromosomal alterations caused by oxidative DNA damage create two separate genetic pathways to the development of UC(\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eBladder cancer can be categorized into high- and low-grade tumors (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e). The prognosis and treatment approaches significantly vary between high- and low-grade lesions, particularly in the context of non\u0026ndash;muscle-invasive bladder cancer. For individuals diagnosed with low-grade non\u0026ndash;muscle-invasive bladder cancer, transurethral resection of the bladder tumor is generally recommended. In contrast, those with high-grade non\u0026ndash;muscle-invasive often necessitate more aggressive treatments such as radical cystectomy, systemic chemotherapy, and radiation therapy (\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e). However, low-grade and high-grade component can coexist within the same histologic specimen. According to 2004 classification, low grade with more than 5% high grade component is considered high grade.\u003c/p\u003e \u003cp\u003eIn our clinical practice, patients with high grade tumors, whether or not with coexisted low-grade lesions, were treated the same with regard to postoperative instillation regimen (mainly intravesical chemotherapy) and follow-up strategy. Under such circumstances, the evidence was rare in this aspect.\u003c/p\u003e \u003cp\u003eThe goal of our research was to evaluate the impact of coexistent low-grade lesion on the prognosis of high grade NMIBC patients receiving adjuvant intravesical chemotherapy (IC). Through our study, we hope to improve postoperative instillation regimen and follow-up strategy for high-grade NMIBC with concurrent low-grade component.\u003c/p\u003e"},{"header":"Patients and methods","content":"\u003cp\u003e The study was approved by the Ethics Committee of Peking University People\u0026rsquo;s Hospital. We retrospectively analyzed all patients who transurethral resection of bladder tumor (TURBT) at Peking University People's Hospital between January 2015 to December 2019. Patients diagnosed with primary, solitary non-muscle invasive bladder cancer (NMIBC) and received adequate IC were included. Adequate IC was defined as a minimum of weekly induction for the initial 8 weeks followed by monthly treatments for up to 6 months. The follow-up schedule post-TURBT typically involved assessments every 3 months for the first 2 years, every 6 months for the subsequent 3 years, and annually thereafter. Follow-up protocols adhered to risk stratification based on the EAU guidelines.\u003c/p\u003e \u003cp\u003eExclusion criteria comprised: (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e) individuals with a history of prior TURBT; (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e) those who had received concurrent treatment for upper urinary tract urothelial carcinoma; (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e) patients who had undergone prior or concurrent prostatic surgeries; (\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e) patients with incomplete tumor resection or requiring a second-look TURBT; (\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e) individuals not receiving single instillation (SI) within 24 hours after TURBT; (\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e) individuals with missing data or a notably short follow-up duration.\u003c/p\u003e \u003cp\u003ePatients were categorized into two groups: those with pure high grade bladder tumor (pHG) and those with mixed high-grade lesion (mHG, i.e., with coexistent low-grade components). Demographic, clinical and pathological characteristics were recorded, including age, gender, body mass index, smoking history, presence of hypertension or diabetes, pathological grade, tumor stage, number of tumors, and tumor size. Recurrence was identified as the reappearance of bladder tumors regardless of their stage or grade, while progression was defined as advancement in tumor stage or grade.\u003c/p\u003e \u003cp\u003eContinuous variables were presented as the median and interquartile range (IQR), while categorical variables were represented as proportions. Comparison of clinicopathological characteristics was carried out with Student's t-test, the Wilcoxon rank test, and the chi-squared test. Survival analyses were conducted using Kaplan-Meier analysis. The relationship between clinicopathological parameters and oncological outcomes was assessed through both univariate and multivariate Cox proportional hazard regression analyses. Multivariate analysis was performed solely for parameters showing P-values of less than 0.1 in univariate analysis. Statistical significance was determined with a P-value of less than 0.05. IBM SPSS Statistics version 25.0 (IBM, Armonk, NY, USA) was utilized for all statistical analyses.\"\u003c/p\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003e1.Baseline characteristics\u003c/h2\u003e \u003cp\u003eThe final cohort included one hundred and sixty-seven patients of primary high-grade NMIBC who received sufficient IC treatment, with a mean follow up of 39.32 months (interquartile range [IQR]: 26.82\u0026ndash;61.37 months). Among them, 35 individuals had bladder tumor with coexistent low-grade component (20.9%), and the rest had pure high-grade lesions. The clinicopathological characteristics of these patients are detailed in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. Seventy-six percent were male. Thirteen percent had T1 disease, while the rest had stage Ta lesion. Overall, the baseline characteristics are well balanced between two groups (p\u0026thinsp;\u0026ge;\u0026thinsp;0.05).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eDemographic and clinical characteristics of patients.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVariable\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003emHG(n\u0026thinsp;=\u0026thinsp;35)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003epHG(n\u0026thinsp;=\u0026thinsp;132)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eP Value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.58\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026le;65yrd\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e52\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026gt;65yrd\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e23\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e80\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGender\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e27\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e100\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.86\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFemale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e32\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSmoking status,n(%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNever\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e27\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e97\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.66\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFormer/Current\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e35\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eUTUC history\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.18\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e35\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e124\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHypertension,n(%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e20\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e82\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.59\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e15\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e50\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDiabetes mellitus,n(%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.46\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e30\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e106\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e26\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTumor size,n(%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026le;3cm\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e32\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e126\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.34\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026gt;3cm\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePathological stage,n(%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTa\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e32\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e112\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.131\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eT1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e20\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMedian instillation numbers\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e15\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e16\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.542\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRecurrence\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e28\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e76\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.01\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e56\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003e2.Entire cohort survival analysis\u003c/h2\u003e \u003cp\u003eIn the median follow up duration of 39.32 months (interquartile range: 26.82\u0026ndash;61.37 months), 7 patients (20.0%) in mHG group and 56 patients (42.4%) in pHG group experienced recurrence. Figure\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e showed Kaplan\u0026ndash;Meier curves of recurrence-free survival (RFS) in two groups. The 5-year RFS was higher in mHG group than in pHG group (80.0% vs 50.5%, p\u0026thinsp;=\u0026thinsp;0.01), as depicted in Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. Univariate Cox regression analysis revealed that T1 stage and pHG were all associated with poorer recurrence-free survival, both of which were further confirmed in multivariable cox regression analysis (pHG hazard ratio\u0026thinsp;=\u0026thinsp;2.34 p\u0026thinsp;=\u0026thinsp;0.02). Other significant contributing factor was T1 stage lesion (T1 hazard ratio\u0026thinsp;=\u0026thinsp;2.09 p\u0026thinsp;=\u0026thinsp;0.01) (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eUnivariate and multivariate Cox proportional hazard regression analysis to identify predictive factors for recurrence-free survival.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eVariables\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003eUnivariate\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e \u003cp\u003eMultivariate\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eHazard ratio\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003ep value\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eHazard ratio\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003ep value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eAge (years)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026le;\u0026thinsp;65yrd\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eReference\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026gt;65yrd\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.65\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eSex\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.64\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ereference\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFemale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.08\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eSmoking status\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.51\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNever\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ereference\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFormer/Current\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.81\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eHypertension\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.88\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ereference\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.96\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eDiabetes mellitus\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.64\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ereference\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.84\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eTumor size\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.58\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026le;\u0026thinsp;3cm\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ereference\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026gt;3cm\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.67\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003estage\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.02\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.01\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTa\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ereference\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003ereference\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eT1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2.02\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2.09\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003ePathology\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.03\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.02\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003emHG\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ereference\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003ereference\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003epHG\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2.34\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2.43\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eUTUC history\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.59\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ereference\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.32\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eBladder cancer exhibits heterogenous recurrent rates, and studies investigating its molecular mechanisms of development and progression are limited. Similar to many epithelial cancer variations, bladder cancer typically follows a progression pattern involving precancerous histological and molecular alterations that potentially develop over several decades, i.e., field cancerization(\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e). The typical progression from hyperplastic changes to dysplasia is frequently observed in bladder cancer, both in clinical practice and animal model, presenting a chance to better understand the development and progression of this cancer(\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e). Therefore, a small number of bladder cancer patients were found to harbor both high-grade and low-grade lesions at the same time. For those with multiple tumors with different grade, it could be the result of multiple primary tumors, meaning extensive precancerous areas and multiple neoplasms with different origin, which was widely acknowledged in lunch cancer, also known as multiple primary lung cancer (MPLC)(\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e). As a result, the stage, grade and prognosis of MPLC should be based on the most advanced one(\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e). However, for those with solitary lesion, things may be different. The histologic expression of intravesical lesions forms a broad spectrum that can coexist within the same specimen.\u003c/p\u003e \u003cp\u003eIt is well known that urothelial carcinoma, like other epithelial neoplasm, is a field change disease. Patients with initial low-grade tumors sometimes develop subsequent high-grade tumors, often years after the original tumor. If this was the case, then a certain proportion of patients would present with lesions with coexisted low-grade and high-grade components.\u003c/p\u003e \u003cp\u003eSuch patients theoretically have better prognosis, as they are at the early stage of high-grade tumor. However, another possibility remains that longer course of disease entails greater risk of micro-metastasis and higher level of field cancerization, which may be the reason why the prognosis of progressive muscle-invasive bladder cancer is worse than primary muscle-invasive bladder cancer(\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eAccording to our research, patients of mHG exhibited better prognosis, as seen with both better recurrence-free survival and progression-free survival, validating mHG as an early phase of pHG.\u003c/p\u003e \u003cp\u003eThe current study revealed that high-grade urothelial carcinoma with coexisted low-grade component fared better after adequate intravesical chemotherapy with regard to recurrence. These findings are revealing and clinically meaningful. Traditionally, urothelial carcinoma is dichotomously divided into high grade and low grade. The divergence in biologic behavior for low-grade versus high-grade lesions correlates with the known dual molecular lines of genetic development for these two pathways and supports the concept that high-grade and low-grade cancers may essentially be considered different diseases. However, such dichotomy is not all-inclusive. As low-grade and high-grade components are sometimes found to coexist in a single tumor, indicating at least some high-grade lesion may be secondary to low grade tumor. Our study confirms the hypothesis that some high-grade lesion could be due to the progression from low grade disease. Such clarification could further improve risk stratification and follow-up strategy in non-muscle-invasive bladder cancer, especially those of low-grade tumor.\u003c/p\u003e \u003cp\u003eThe current study revealed that high-grade urothelial carcinoma with coexisted low-grade component exhibited better response to intravesical chemotherapy for NMIBC. This finding is in line with prior hypothesis that such mixture is a sign of transition between low grade and high grade.\u003c/p\u003e \u003cp\u003eThe current study does come with certain limitations. Firstly, the utilization of a retrospective cohort introduces the potential of unaccounted-for confounding variables. Secondly, given the infrequent occurrence of UTUC, our analysis is constrained by the relatively limited number of UTUC patients in the cohort. Thirdly, treatment variations across different surgeons were not factored in, including differences in UTUC management, the administration of re-Turbt. Lastly, our analysis was confined to patients who received a relatively sufficient amount of intravesical chemotherapy to ensure a consistently treated cohort. However, this could potentially lead to selection bias.\u003c/p\u003e \u003cp\u003eIn summary, for bladder cancer patients of mHG, the prognosis may diverge from those with pHG lesion. This observation seems particularly significant for those patients troubled by frequent cystectomy follow-up and fear of recurrence.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eThe presence of coexisted low-grade component predicted a significant decrease in recurrence rates for primary, solitary high grade urothelial carcinoma. Future in-depth studies are warranted to optimize treatment and follow-up strategy for this subgroup patients.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eBca: Bladder cancer (BCa)\u003c/p\u003e\n\u003cp\u003eNMIBC: non-muscle invasive bladder cancer\u003c/p\u003e\n\u003cp\u003eTURBT: transurethral resection of the bladder tumor\u003c/p\u003e\n\u003cp\u003epHG: pure high grade bladder tumor\u003c/p\u003e\n\u003cp\u003emHG: mixed high-grade lesion\u0026nbsp;\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e:\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eOur study was conducted in accordance with the Declaration of Helsinki (as revised in 2013) and was approved by the Institutional Review Board of Peking University People\u0026rsquo;s Hospital, which waived the requirement of informed consent for this retrospective analysis.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e: Not applicable.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e: Not applicable.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026rsquo; contributions\u003c/strong\u003e Jiaxiang Ji and Hao Hu conceived the study concept. Jiaxiang Ji and Fei Wang carried out the study, analyzed the data, and wrote the article. Chin-Hui Lai and Tao Xu provided critical feedback and helped shape the research, analysis, and article. Hao Hu supervised the project. All authors discussed the results and commented on the article. Fei Wang had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. All authors read and approved the final manuscript.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e: Not applicable\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e: The data and materials can be obtained by contacting the corresponding author.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests:\u003c/strong\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eNo competing financial interests exist.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eRichters A, Aben KKH, Kiemeney L. The global burden of urinary bladder cancer: an update. World J Urol. 2020;38(8):1895\u0026ndash;904.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKamat AM, Hahn NM, Efstathiou JA, Lerner SP, Malmstrom PU, Choi W, et al. Bladder cancer Lancet. 2016;388(10061):2796\u0026ndash;810.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSylvester RJ, van der Meijden AP, Oosterlinck W, Witjes JA, Bouffioux C, Denis L, et al. Predicting recurrence and progression in individual patients with stage Ta T1 bladder cancer using EORTC risk tables: a combined analysis of 2596 patients from seven EORTC trials. Eur Urol. 2006;49(3):466\u0026ndash;5. discussion 75\u0026thinsp;\u0026ndash;\u0026thinsp;7.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eEpstein JI, Amin MB, Reuter VR, Mostofi FK. The World Health Organization/International Society of Urological Pathology consensus classification of urothelial (transitional cell) neoplasms of the urinary bladder. Bladder Consensus Conference Committee. Am J Surg Pathol. 1998;22(12):1435-48.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBudson AE, Droller DB, Dodson CS, Schacter DL, Rugg MD, Holcomb PJ, Daffner KR. Electrophysiological dissociation of picture versus word encoding: the distinctiveness heuristic as a retrieval orientation. J Cogn Neurosci. 2005;17(8):1181\u0026ndash;93.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHabuchi T, Marberger M, Droller MJ, Hemstreet GP 3rd, Grossman HB, Schalken JA, et al. Prognostic markers for bladder cancer: International Consensus Panel on bladder tumor markers. Urology. 2005;66(6 Suppl 1):64\u0026ndash;74.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHasui Y, Osada Y, Kitada S, Nishi S. Significance of invasion to the muscularis mucosae on the progression of superficial bladder cancer. Urology. 1994;43(6):782\u0026ndash;6.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRichter J, Jiang F, Gorog JP, Sartorius G, Egenter C, Gasser TC, et al. Marked genetic differences between stage pTa and stage pT1 papillary bladder cancer detected by comparative genomic hybridization. Cancer Res. 1997;57(14):2860\u0026ndash;4.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHoglund M. Bladder cancer, a two phased disease? Semin Cancer Biol. 2007;17(3):225\u0026ndash;32.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eOliveira PA, Arantes-Rodrigues R, Vasconcelos-Nobrega C. Animal models of urinary bladder cancer and their application to novel drug discovery. Expert Opin Drug Discov. 2014;9(5):485\u0026ndash;503.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBondaruk J, Jaksik R, Wang Z, Cogdell D, Lee S, Chen Y, et al. The origin of bladder cancer from mucosal field effects. iScience. 2022;25(7):104551.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWu SC, Lin ZQ, Xu CW, Koo KS, Huang OL, Xie DQ. Multiple primary lung cancers. Chest. 1987;92(5):892\u0026ndash;6.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eUsuda J, Ichinose S, Ishizumi T, Hayashi H, Ohtani K, Maehara S, et al. Management of multiple primary lung cancer in patients with centrally located early cancer lesions. J Thorac Oncol. 2010;5(1):62\u0026ndash;8.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLai S, Liu J, Lai C, Seery S, Hu H, Wang M et al. Prognostic variations between primary and progressive muscle-invasive bladder cancer following radical cystectomy: A novel propensity score-based multicenter cohort study. Int J Surg. 2023.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Non-muscle invasive bladder cancer, high grade, coexistence, low grade, prognosis","lastPublishedDoi":"10.21203/rs.3.rs-3881585/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-3881585/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eTo determine the impact of coexisted low-grade components on the prognosis of high-grade non-muscle-invasive bladder cancer (NMIBC).\u003c/p\u003e\u003ch2\u003eMethod\u003c/h2\u003e \u003cp\u003eA total of 167 patients with a mean follow-up of 39.32 months underwent transurethral resection of primary, solitary non-muscle invasive bladder tumor between January 2010 and December 2019, including 35 patients with coexisted low-grade components and 132 patients with pure high-grade tumors. All patients underwent adequate intravesical chemotherapy.\u003c/p\u003e\u003ch2\u003eResult\u003c/h2\u003e \u003cp\u003eBaseline characteristics were well balanced between patients with pure high-grade tumor and those with coexisted low-grade components. Five-year recurrence-free survival was much worse for pure high-grade tumor compared to high-grade tumor with coexisted low-grade component (50.5% vs 80.0%, p\u0026thinsp;=\u0026thinsp;0.01). Multivariable cox regression analysis revealed coexisted low-grade components to be an independent risk factor for recurrence (hazard ratio\u0026thinsp;=\u0026thinsp;2.34, p\u0026thinsp;=\u0026thinsp;0.02). Other significant contributing factor was T1 stage (hazard ratio\u0026thinsp;=\u0026thinsp;2.09, p\u0026thinsp;=\u0026thinsp;0.01).\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e \u003cp\u003eCoexistence of low-grade component predicts better prognosis in patients with primary, solitary high-grade non-muscle invasive bladder cancer.\u003c/p\u003e","manuscriptTitle":"Coexistence of low-grade component predicts better prognosis in patients with primary, solitary high-grade non-muscle invasive bladder cancer","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-01-31 20:33:42","doi":"10.21203/rs.3.rs-3881585/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"ce2da211-baa4-4e34-a11e-40f9fdae59b3","owner":[],"postedDate":"January 31st, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2024-03-27T19:50:50+00:00","versionOfRecord":[],"versionCreatedAt":"2024-01-31 20:33:42","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-3881585","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-3881585","identity":"rs-3881585","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}