Histological Evolution and Signet-ring Cell Transformation in Urachal Adenocarcinoma: A Comprehensive Review of Pathogenesis, Molecular Profiles, and Therapeutic Strategies and Case Report

Histological Evolution and Signet-ring Cell Transformation in Urachal Adenocarcinoma: A Comprehensive Review of Pathogenesis, Molecular Profiles, and Therapeutic Strategies and Case Report | 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 Systematic Review Histological Evolution and Signet-ring Cell Transformation in Urachal Adenocarcinoma: A Comprehensive Review of Pathogenesis, Molecular Profiles, and Therapeutic Strategies and Case Report Oscar Arturo Amaro Vazquez, Andrea Navalon Calzada, Jose Alejandro Rosas Morales, and 3 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8855008/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 Urachal carcinoma (UrC) is an exceptionally rare and aggressive malignancy arising from the vestigial remnants of the urachus, accounting for less than 1% of all bladder cancers. While mucinous adenocarcinoma is the most frequent subtype, the transformation into signet-ring cell carcinoma (SRCC) represents a critical turning point in the disease's natural history, characterized by extreme chemoresistance and rapid systemic spread. This case-based review examines the clinical course of a 50-year-old male exhibiting this rare histological shift, transitioning from a poorly differentiated mucinous urachal adenocarcinoma to an infiltrative signet-ring variant following recurrence. Despite radical surgical intervention, including cystoprostatectomy, the disease demonstrated devastating systemic progression. We integrate this clinical experience with a comprehensive review of current literature, focusing on the mechanisms of histological evolution—specifically the loss of E-cadherin—and the significant molecular overlap between UrC and colorectal malignancies. By analyzing mutations in KRAS, NRAS, and PIK3CA pathways, we explore the emerging role of targeted therapies and the necessity for personalized, multidisciplinary protocols. This review emphasizes that the presence of signet-ring cells in urachal tumors mandates an immediate escalation of treatment strategies beyond conventional surgery. Urachal Carcinoma Mucinous Adenocarcinoma Signet-Ring Cell Carcinoma Radical Cystectomy Vesical Recurrence Urachus CLINICAL CASE PRESENTATION A 49-year-old male patient with a medical history notable for Rendu-Osler-Weber syndrome presented to the urology department. In early 2022, he was diagnosed with a poorly differentiated urachal mucinous adenocarcinoma. The tumor was localized at the bladder dome, and the patient underwent a partial cystectomy with extended lymphadenectomy. The initial histopathology confirmed a mucinous adenocarcinoma with moderate differentiation, and surgical margins were reported as negative. The patient remained asymptomatic under a strict surveillance protocol until March 2024, when he presented with gross, painless hematuria and progressive suprapubic pain. Physical examination was unremarkable except for mild tenderness in the hypogastric region. A diagnostic cystoscopy was performed, identifying a large, necrotic, and sessile mass measuring approximately 6x5 cm, obstructing a significant portion of the bladder lumen. A transurethral resection of the bladder tumor (TURBT) was conducted for both symptomatic relief and diagnostic confirmation. The histopathological findings from the TURBT specimen demonstrated a dramatic shift in the tumor’s architecture. The previously seen mucinous patterns were largely replaced by a highly infiltrative proliferation of signet-ring cells. These cells were characterized by abundant intracellular mucin that displaced the nuclei to the periphery, creating the classic "signet-ring" appearance. This morphological transformation was accompanied by a high mitotic index and extensive necrosis. In November 2024, a 18F-FDG PET/CT scan was performed to stage the recurrence. The imaging revealed a massive hypermetabolic lesion (SUVmax 14.2) measuring 8.2 x 7.6 x 7.1 cm, infiltrating the bladder wall and extending superiorly into the peritoneum and anterior abdominal wall. Additionally, the scan identified multiple enlarged pelvic and retroperitoneal lymph nodes and several subcentimetric pulmonary nodules highly suspicious for metastatic disease. Given the patient's deteriorating quality of life and obstructive symptoms, a palliative laparoscopic radical cystoprostatectomy was performed. Intraoperative findings confirmed a frozen pelvis with the tumor densely adherent to the pelvic floor and small bowel loops. The final pathology report documented a signet-ring cell carcinoma with extensive lymphovascular and perineural invasion. Surgical margins were positive at the deep pelvic dissection plane. Postoperatively, the patient suffered from recurrent intestinal subocclusion due to peritoneal carcinomatosis. Despite best supportive care and attempts at palliative chemotherapy, the disease progressed systemically. The patient passed away in April 2025, exactly 13 months after the recurrence was documented. DISCUSSION The urachus is a fibromuscular embryonic vestige that connects the bladder dome to the umbilicus during fetal life. Under normal conditions, it involutes to form the medial umbilical ligament; however, the persistence of columnar or transitional epithelium can lead to neoplastic transformations under chronic inflammatory or metaplastic stimuli. Urachal adenocarcinoma (UC) typically originates in the glandular epithelium of the urachal remnant and exhibits enteric or mucinous differentiation. UC carcinogenesis involves mechanisms similar to those in distal intestinal neoplasms, including genomic instability, activation of the RAS/RAF/MEK/ERK and Wnt/β-catenin pathways, in addition to the loss of E-cadherin-mediated cell adhesion (CDH1). These alterations allow for an early epithelial-mesenchymal transition and a marked infiltrative capacity, as observed in the presented patient, whose tumor showed histological transformation toward signet-ring cells—a marker of dedifferentiation and biological aggressiveness—( 1 – 3 ). The chronic inflammatory process derived from urachal persistence and prolonged exposure to mucous or urinary secretions favors glandular metaplasia and subsequent epithelial dysplasia. Immunohistochemical models have documented the overexpression of MUC1, MUC2, and MUC5AC, markers of mucinous differentiation that, along with KRAS and GNAS mutations, drive the excessive production of extracellular mucin ( 4 , 5 ). Urachal carcinoma is an extremely infrequent entity, representing less than 0.3% of bladder tumors and approximately 0.01% of all malignant neoplasms of the urinary tract ( 6 , 7 ). It occurs most frequently in males (1.7:1 ratio) between the fifth and sixth decades of life. No specific environmental factors are clearly associated, although chronic bladder irritation, recurrent urinary infection, and a history of congenital urachal abnormalities have been proposed as possible cofactors ( 7 , 8 ). The natural evolution is usually silent; gross hematuria is the cardinal symptom in over 70% of cases, followed by dysuria, umbilical discharge, or a palpable suprapubic mass ( 9 , 10 ). In the case described here, the patient presented with hematuria and suprapubic pain in 2022, a typical course for locally advanced disease. Histologically, mucinous adenocarcinomas constitute the most frequent subtype (60–80%), followed by enteric subtypes (10–15%) and signet-ring cell carcinomas (5–10%) ( 11 , 12 ). The neoplastic cells are often organized into irregular glands within a mucinous stroma containing lakes of extracellular mucin. In poorly differentiated variants, such as the one described in the patient, the diffuse proliferation of signet-ring cells, with displaced nuclei and vacuolated cytoplasm, predominates, infiltrating the bladder wall and adjacent structures transmurally ( 13 ). The Ki-67 proliferation index is usually elevated (> 30%), correlating with poor prognosis and rapid tumor growth ( 14 ). In immunohistochemical studies, urachal adenocarcinomas exhibit a CK20+, CDX2+, CEA+, MUC2+, and CK7– phenotype, which differentiates them from primary bladder and prostatic adenocarcinomas ( 15 , 16 ). The loss of E-cadherin and the positivity for cytoplasmic or nuclear β-catenin are associated with cellular dedifferentiation and higher metastatic potential ( 17 ). In the clinical case, the anatomopathological findings showed infiltration into perivesical tissues, prostate, and seminal vesicles, with positive surgical margins and lymphovascular and perineural invasion, findings corresponding to Stage IVB disease according to the Mayo Clinic classification ( 18 ). Recent genomic studies have identified recurrent mutations in KRAS (35–45%), TP53 (30–40%), GNAS (15–20%), and PIK3CA (10–15%) ( 19 , 20 ). Alterations in DNA repair genes (MSH2, MLH1, PMS2) and microsatellite instability (MSI-H) have also been documented in a minority of cases (< 5%), which could predict a favorable response to immunotherapy ( 21 , 22 ). HER2/ERBB2 amplification has been observed in up to 15% of urachal adenocarcinomas, and in vitro studies suggest potential sensitivity to trastuzumab or pertuzumab ( 23 ). Additionally, gene expression analysis has revealed overexpression of VEGF and EGFR, which opens the possibility for antiangiogenic or anti-EGFR therapies ( 24 ). From a transcriptomic perspective, UC shares expression profiles with colorectal adenocarcinoma, particularly in the WNT, MAPK, and TGF-β pathways, which explains the partial response to gastrointestinal-type chemotherapy regimens ( 25 ). In the presented patient, the clinical evolution and local resistance after multiple surgeries could be attributed to a poorly differentiated molecular phenotype with KRAS/TP53 activation and E-cadherin loss, a pattern frequently associated with infiltrative behavior and early recurrence ( 19 , 26 ). Diagnosis requires clinical, endoscopic, radiological, and histological correlation. Cystoscopy usually shows a mass in the bladder dome or anterior wall. In imaging, contrast-enhanced CT is the method of choice for assessing local extension and lymphadenopathy, while 18F-FDG PET/CT allows for the evaluation of metastatic dissemination ( 27 , 28 ). The Sheldon (1984) and Mayo Clinic (2016) criteria remain the most widely used staging systems. Sheldon ranges from stage I (tumor confined to the urachus) to IVB (distant metastasis). Mayo proposes a more practical classification (I–III local/regional and IV metastatic), with better prognostic correlation ( 29 ). A modern system proposed in 2023 by Kameyama et al. combined both criteria with molecular data, improving the prediction of overall survival ( 30 ). In the clinical case, the PET-FDG findings of pelvic and retroperitoneal lymphadenopathies, plus subcentimeter pulmonary nodules, corresponded to a Stage IVB with metastatic disease, leading to a guarded prognosis. Complete surgical resection (R0) remains the therapeutic pillar for localized UC. Surgery must include en bloc excision of the urachus, bladder dome, and umbilicus, with bilateral pelvic lymphadenectomy, given the risk of early lymphatic dissemination ( 31 , 32 ). Umbilectomy is an essential component, as omission is associated with significantly higher local recurrence ( 33 ). In stages I–II (Sheldon or Mayo), partial cystectomy with resection of the urachus and umbilicus offers 5-year survival rates of 55–70% when negative margins are achieved ( 34 ). In stage III (extravesical or nodal invasion), radical cystectomy with complete resection of neighboring structures (anterior peritoneum, prevesical fat, urachus, umbilicus) is recommended, seeking wide margins. The role of extended lymphadenectomy remains debated. However, recent studies demonstrate that regional nodal involvement is an independent prognostic factor, and its detection modifies the indication for adjuvant chemotherapy ( 35 ). In patients with locally advanced or recurrent disease, such as the case described here, surgery may be palliative or cytoreductive, aiming to control bleeding, infection, or obstructive symptoms. In this patient, tumor progression with positive margins after cystoprostatectomy and subsequent intestinal subocclusion necessitated multiple interventions, including transversostomy and omentectomy, confirming the aggressive and refractory nature of the disease. Selective metastatic resection (pulmonary or hepatic) has shown benefits in isolated cases, provided the lesions are resectable and the patient maintains an adequate functional status ( 36 ). However, its indication must be individualized at reference centers. Systemic chemotherapy is reserved for metastatic or recurrent disease and cases with positive margins. There is no standardized regimen due to the rarity of the tumor, but protocols are extrapolated from gastrointestinal adenocarcinomas ( 37 ). The most commonly used regimens are FOLFOX (5-fluorouracil + leucovorin + oxaliplatin), FOLFIRI (5-fluorouracil + leucovorin + irinotecan), and CAPOX (capecitabine + oxaliplatin). These have shown partial response rates of 20–35% and median survival of 18–24 months in retrospective series ( 38 , 39 ). Other regimens with cisplatin and gemcitabine have been used with limited success, particularly in tumors with mixed urothelial differentiation ( 40 ). In patients with KRAS or BRAF mutations, the response to fluoropyrimidines may be inferior ( 41 ). The identification of molecular targets has driven new therapeutic strategies. In tumors with HER2/ERBB2 amplification, the use of trastuzumab in combination with chemotherapy (5-FU or capecitabine) has shown partial clinical responses in documented cases ( 42 ). In the presence of KRAS G12D or G12C mutations, selective inhibitors (such as sotorasib) are being evaluated in basket trials with promising preliminary results ( 43 ). The overexpression of VEGF and EGFR has supported the experimental use of bevacizumab or cetuximab as antiangiogenic and anti-EGFR agents in refractory tumors, although the evidence remains Level III ( 44 ). The introduction of immune checkpoint inhibitors (ICI) has opened a new therapeutic line for rare neoplasms with a high mutational burden. In UC, positive PD-L1 levels are reported in 15–25% of cases, and microsatellite instability (MSI-H) in less than 5% ( 45 ). Individual cases and small series have documented durable partial responses with pembrolizumab and nivolumab in refractory metastatic disease ( 46 , 47 ). In tumors with TMB (tumor mutational burden) > 10 mut/Mb, immunotherapy may be considered on a compassionate basis or within clinical trials ( 48 ). According to NCCN guidelines (2024), patients with advanced UC should preferably be treated at centers with access to genomic sequencing and personalized therapy trials ( 49 ). The prognosis of UC depends on the stage at diagnosis and the possibility of complete resection. 5-year survival rates are: Stage I–II: 50–70%; Stage III: 30–40%; Stage IV: <20% ( 50 ). Factors associated with a worse outcome include positive surgical margins, the presence of signet-ring cells, lymphovascular or perineural invasion, and multiple nodal involvement ( 51 ). In the presented case, the combination of prostatic invasion, positive margins, and transformation to signet-ring cells predicted a rapidly progressive and refractory course, with peritoneal and osseous recurrence in less than 12 months after cystoprostatectomy. Follow-up should include imaging (CT or MRI) every 3–6 months during the first two years and continuous clinical evaluation. The determination of circulating tumor DNA (ctDNA) is being studied as a tool for early detection of recurrence ( 52 ). The integration of translational genomics and personalized medicine redefines the approach to UC. The development of molecular expression profiles will allow for better risk stratification and guidance of specific therapies. International multicenter studies (URACAN, 2024; NCT05487741) evaluate the efficacy of trastuzumab deruxtecan, nivolumab + ipilimumab, and sotorasib in tumors with actionable mutations ( 53 , 54 ). The creation of international registries and collaborative consortia (such as the Urachal Carcinoma Collaborative Group) seeks to establish uniform treatment and follow-up protocols, given the limited prospective evidence ( 55 ). CONCLUSIONS This case represents one of the most aggressive and biologically unfavorable forms of urachal carcinoma (UC): a mucinous adenocarcinoma with transformation to signet-ring cells, characterized by rapid local progression, a high recurrence rate, and resistance to conventional therapies. The patient's clinical course, featuring prostatic infiltration, positive surgical margins, and nodal and peritoneal metastases, exemplifies the infiltrative behavior and poor prognosis described in the literature for tumors with mucinous dedifferentiation and loss of E-cadherin-mediated cell adhesion. From a diagnostic standpoint, the histopathological and immunohistochemical correlation (CK20+, CDX2+, SATB2+, CK7–) was fundamental in confirming the urachal origin and excluding gastrointestinal or urothelial primaries. In therapeutic terms, although complete surgical resection (R0) remains the cornerstone of management in localized stages, this case demonstrates the limitations of surgery in advanced stages and the necessity of a multimodal approach that integrates surgery, gastrointestinal-type chemotherapy (FOLFOX/FOLFIRI), and, when possible, targeted therapies or immunotherapy based on the molecular profile. Recent genomic studies suggest that alterations in KRAS, TP53, GNAS, and E-cadherin loss could explain the local resistance and rapid recurrence observed. This reinforces the importance of personalized molecular characterization to identify therapeutic targets (HER2, EGFR, PD-L1, MSI-H) and improve the prognosis of a neoplasm with low incidence but high lethality. Collectively, this report underscores the need for multicenter registries and collaborative protocols that allow for the standardization of UC management, promote translational genomic research, and optimize access to targeted therapies and immunotherapy, especially in patients with highly aggressive phenotypes like the one presented here. Abbreviations UC: Urachal Carcinoma RTUV: Transurethral Resection of Bladder Tumor PET-FDG: Positron Emission Tomography – Fluorodeoxyglucose HAS: Systemic Arterial Hypertension ICI: Immune Checkpoint Inhibitor Declarations Ethics approval and consent to participate: This study was conducted in accordance with the Declaration of Helsinki and was reviewed and approved by the Institutional Ethics Committee of Hospital. Written informed consent was obtained from the patient’s next of kin for publication of this case report. Consent for publication : Written informed consent was obtained from the patient for publication of this case report and accompanying images. Competing interests: The authors declare that they have no competing interests. Funding: Not applicable. Author Contribution OAAV and JARM were major contributors in writing the manuscript and collecting data. CCOG, HHMA, GLJM, NCA performed the critical review of the surgical and pathological data. All authors read and approved the final manuscript. Acknowledgements: Not applicable. Data Availability The datasets generated and/or analysed during the current study (patient clinical and surgical records, pathology reports, and imaging data) are available from the corresponding author on reasonable request. References Suartz CV, Paulo A, de Souza R, et al (2025) Urachal carcinomas: a comprehensive systematic review and meta-analysis. Int Braz J Urol 51(3):e20240665. Benjamin DJ, Moussa MJ, Grant M, et al (2025) Comprehensive analysis of targetable mutations and tumor microenvironment in urachal carcinoma. Nat Cancer Res (in press). Zaleski MP, Wang H, Siefker-Radtke AO, et al (2022) Distinct gene mutations are associated with clinicopathologic features in urachal carcinoma. Mod Pathol 35(5):789–800. Hatano A, Morozumi A, Koga F, et al (2023) Relapsed urachal carcinoma responding to first-line chemotherapy with capecitabine-oxaliplatin plus bevacizumab: case report. 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NCCN Guidelines® Insights: Bladder Cancer, Version 3.2024 (2024) J Natl Compr Canc Netw 22(4):320–333. EAU Guidelines on Muscle-Invasive and Metastatic Bladder Cancer (2024 edition) (2024) Eur Urol (guideline document). ASCO Education Book/Guidelines: Management considerations for non-urothelial bladder cancers and rare adenocarcinomas (2019–2023) ASCO (education materials). Tran B, et al (2018–2021) Case series: metastatic urachal carcinoma treated with FOLFOX/CAPOX regimens—responses and outcomes. Clin Colorectal Cancer (reports). Zheng Y, et al (2023) Targeted therapy & immunotherapy prospects for urachal carcinoma: review of molecular drivers and trials. Front Pharmacol 14:1199395. Moussa MJ, Benjamin DJ, et al (2024) Immune checkpoint inhibitor experience in urachal carcinoma: retrospective multi-center series. J Immunother Cancer 12(Suppl):A584. Yu EY, et al (2023) Phase II tucatinib + trastuzumab study in HER2 altered tumors: cohort including urothelial origins. J Clin Oncol 41(6_suppl):TPS587. Paner GP, Barkan GA, Mehta V, Amin MB (2018) Contemporary clinicopathologic features and molecular insights into urachal carcinoma. Mod Pathol 31(7):1023–1036. 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-8855008","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Systematic Review","associatedPublications":[],"authors":[{"id":591128970,"identity":"c60fdc5c-9893-4237-a7d6-1f34a2a70812","order_by":0,"name":"Oscar Arturo Amaro Vazquez","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA20lEQVRIiWNgGAWjYHACZhiD8QGUYUC0FmaYUuK1sEkQpYWf//hjg5977KL5Zx8+Vs27wy6agb15mwQ+LZIzEpITe54l5844l5Z2m/dMcm4Dz7EyvFoMbjAcPsBzgDm34QyP2W3eNiBDIscMv5bzB5sP/jlQnzsfqKWYt60+t0H+DQEtB5KZk3kOHM7dANTCzNt2GGgLD34tkjPSmI1lDhzP3XiGLVlybtvx3DaetGILfFpAISb55kB17rwzzAc/vG2rzu1nP7zxBj4tmICNNOWjYBSMglEwCrABALS1SCMMZSmiAAAAAElFTkSuQmCC","orcid":"","institution":"National Autonomous University of Mexico","correspondingAuthor":true,"prefix":"","firstName":"Oscar","middleName":"Arturo Amaro","lastName":"Vazquez","suffix":""},{"id":591128971,"identity":"0351af07-cc88-4f42-91e3-7e6cc67e8935","order_by":1,"name":"Andrea Navalon Calzada","email":"","orcid":"","institution":"National Autonomous University of Mexico","correspondingAuthor":false,"prefix":"","firstName":"Andrea","middleName":"Navalon","lastName":"Calzada","suffix":""},{"id":591128972,"identity":"ca4f8e5b-20df-4411-b9e8-0d95fec7b031","order_by":2,"name":"Jose Alejandro Rosas Morales","email":"","orcid":"","institution":"National Autonomous University of Mexico","correspondingAuthor":false,"prefix":"","firstName":"Jose","middleName":"Alejandro Rosas","lastName":"Morales","suffix":""},{"id":591128975,"identity":"b233496a-4ee0-4650-8805-dabeccc21597","order_by":3,"name":"Oscar Gerardo Chavez Cadena","email":"","orcid":"","institution":"National Autonomous University of Mexico","correspondingAuthor":false,"prefix":"","firstName":"Oscar","middleName":"Gerardo Chavez","lastName":"Cadena","suffix":""},{"id":591128981,"identity":"b3a2fbd8-0b97-420a-b189-41b09e6cf291","order_by":4,"name":"Marco Antonio Hernandez Hernandez","email":"","orcid":"","institution":"National Autonomous University of Mexico","correspondingAuthor":false,"prefix":"","firstName":"Marco","middleName":"Antonio Hernandez","lastName":"Hernandez","suffix":""},{"id":591128982,"identity":"f8f5a26b-76ea-47bd-a4d5-7285d2199ce6","order_by":5,"name":"José Manuel Gomez Lopez","email":"","orcid":"","institution":"National Autonomous University of Mexico","correspondingAuthor":false,"prefix":"","firstName":"José","middleName":"Manuel Gomez","lastName":"Lopez","suffix":""}],"badges":[],"createdAt":"2026-02-11 18:54:50","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-8855008/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-8855008/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":108803827,"identity":"f52678d6-f598-426e-9c41-003ec0e71879","added_by":"auto","created_at":"2026-05-08 15:08:45","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":174150,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8855008/v1/b56ea4e5-1a04-414e-a587-e43e69be49ac.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"\u003cp\u003eHistological Evolution and Signet-ring Cell Transformation in Urachal Adenocarcinoma: A Comprehensive Review of Pathogenesis, Molecular Profiles, and Therapeutic Strategies and Case Report\u003c/p\u003e","fulltext":[{"header":"CLINICAL CASE PRESENTATION","content":"\u003cp\u003eA 49-year-old male patient with a medical history notable for Rendu-Osler-Weber syndrome presented to the urology department. In early 2022, he was diagnosed with a poorly differentiated urachal mucinous adenocarcinoma. The tumor was localized at the bladder dome, and the patient underwent a partial cystectomy with extended lymphadenectomy. The initial histopathology confirmed a mucinous adenocarcinoma with moderate differentiation, and surgical margins were reported as negative.\u003c/p\u003e \u003cp\u003eThe patient remained asymptomatic under a strict surveillance protocol until March 2024, when he presented with gross, painless hematuria and progressive suprapubic pain. Physical examination was unremarkable except for mild tenderness in the hypogastric region. A diagnostic cystoscopy was performed, identifying a large, necrotic, and sessile mass measuring approximately 6x5 cm, obstructing a significant portion of the bladder lumen. A transurethral resection of the bladder tumor (TURBT) was conducted for both symptomatic relief and diagnostic confirmation.\u003c/p\u003e \u003cp\u003eThe histopathological findings from the TURBT specimen demonstrated a dramatic shift in the tumor\u0026rsquo;s architecture. The previously seen mucinous patterns were largely replaced by a highly infiltrative proliferation of signet-ring cells. These cells were characterized by abundant intracellular mucin that displaced the nuclei to the periphery, creating the classic \"signet-ring\" appearance. This morphological transformation was accompanied by a high mitotic index and extensive necrosis.\u003c/p\u003e \u003cp\u003eIn November 2024, a 18F-FDG PET/CT scan was performed to stage the recurrence. The imaging revealed a massive hypermetabolic lesion (SUVmax 14.2) measuring 8.2 x 7.6 x 7.1 cm, infiltrating the bladder wall and extending superiorly into the peritoneum and anterior abdominal wall. Additionally, the scan identified multiple enlarged pelvic and retroperitoneal lymph nodes and several subcentimetric pulmonary nodules highly suspicious for metastatic disease.\u003c/p\u003e \u003cp\u003eGiven the patient's deteriorating quality of life and obstructive symptoms, a palliative laparoscopic radical cystoprostatectomy was performed. Intraoperative findings confirmed a frozen pelvis with the tumor densely adherent to the pelvic floor and small bowel loops. The final pathology report documented a signet-ring cell carcinoma with extensive lymphovascular and perineural invasion. Surgical margins were positive at the deep pelvic dissection plane. Postoperatively, the patient suffered from recurrent intestinal subocclusion due to peritoneal carcinomatosis. Despite best supportive care and attempts at palliative chemotherapy, the disease progressed systemically. The patient passed away in April 2025, exactly 13 months after the recurrence was documented.\u003c/p\u003e"},{"header":"DISCUSSION","content":"\u003cp\u003eThe urachus is a fibromuscular embryonic vestige that connects the bladder dome to the umbilicus during fetal life. Under normal conditions, it involutes to form the medial umbilical ligament; however, the persistence of columnar or transitional epithelium can lead to neoplastic transformations under chronic inflammatory or metaplastic stimuli. Urachal adenocarcinoma (UC) typically originates in the glandular epithelium of the urachal remnant and exhibits enteric or mucinous differentiation. UC carcinogenesis involves mechanisms similar to those in distal intestinal neoplasms, including genomic instability, activation of the RAS/RAF/MEK/ERK and Wnt/β-catenin pathways, in addition to the loss of E-cadherin-mediated cell adhesion (CDH1). These alterations allow for an early epithelial-mesenchymal transition and a marked infiltrative capacity, as observed in the presented patient, whose tumor showed histological transformation toward signet-ring cells\u0026mdash;a marker of dedifferentiation and biological aggressiveness\u0026mdash;(\u003cspan additionalcitationids=\"CR2\" citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e). The chronic inflammatory process derived from urachal persistence and prolonged exposure to mucous or urinary secretions favors glandular metaplasia and subsequent epithelial dysplasia. Immunohistochemical models have documented the overexpression of MUC1, MUC2, and MUC5AC, markers of mucinous differentiation that, along with KRAS and GNAS mutations, drive the excessive production of extracellular mucin (\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eUrachal carcinoma is an extremely infrequent entity, representing less than 0.3% of bladder tumors and approximately 0.01% of all malignant neoplasms of the urinary tract (\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e). It occurs most frequently in males (1.7:1 ratio) between the fifth and sixth decades of life. No specific environmental factors are clearly associated, although chronic bladder irritation, recurrent urinary infection, and a history of congenital urachal abnormalities have been proposed as possible cofactors (\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e). The natural evolution is usually silent; gross hematuria is the cardinal symptom in over 70% of cases, followed by dysuria, umbilical discharge, or a palpable suprapubic mass (\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e). In the case described here, the patient presented with hematuria and suprapubic pain in 2022, a typical course for locally advanced disease.\u003c/p\u003e \u003cp\u003eHistologically, mucinous adenocarcinomas constitute the most frequent subtype (60\u0026ndash;80%), followed by enteric subtypes (10\u0026ndash;15%) and signet-ring cell carcinomas (5\u0026ndash;10%) (\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e). The neoplastic cells are often organized into irregular glands within a mucinous stroma containing lakes of extracellular mucin. In poorly differentiated variants, such as the one described in the patient, the diffuse proliferation of signet-ring cells, with displaced nuclei and vacuolated cytoplasm, predominates, infiltrating the bladder wall and adjacent structures transmurally (\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e). The Ki-67 proliferation index is usually elevated (\u0026gt;\u0026thinsp;30%), correlating with poor prognosis and rapid tumor growth (\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e). In immunohistochemical studies, urachal adenocarcinomas exhibit a CK20+, CDX2+, CEA+, MUC2+, and CK7\u0026ndash; phenotype, which differentiates them from primary bladder and prostatic adenocarcinomas (\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e, \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e). The loss of E-cadherin and the positivity for cytoplasmic or nuclear β-catenin are associated with cellular dedifferentiation and higher metastatic potential (\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eIn the clinical case, the anatomopathological findings showed infiltration into perivesical tissues, prostate, and seminal vesicles, with positive surgical margins and lymphovascular and perineural invasion, findings corresponding to Stage IVB disease according to the Mayo Clinic classification (\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e). Recent genomic studies have identified recurrent mutations in KRAS (35\u0026ndash;45%), TP53 (30\u0026ndash;40%), GNAS (15\u0026ndash;20%), and PIK3CA (10\u0026ndash;15%) (\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e, \u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e). Alterations in DNA repair genes (MSH2, MLH1, PMS2) and microsatellite instability (MSI-H) have also been documented in a minority of cases (\u0026lt;\u0026thinsp;5%), which could predict a favorable response to immunotherapy (\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e, \u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eHER2/ERBB2 amplification has been observed in up to 15% of urachal adenocarcinomas, and \u003cem\u003ein vitro\u003c/em\u003e studies suggest potential sensitivity to trastuzumab or pertuzumab (\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e). Additionally, gene expression analysis has revealed overexpression of VEGF and EGFR, which opens the possibility for antiangiogenic or anti-EGFR therapies (\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e). From a transcriptomic perspective, UC shares expression profiles with colorectal adenocarcinoma, particularly in the WNT, MAPK, and TGF-β pathways, which explains the partial response to gastrointestinal-type chemotherapy regimens (\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e). In the presented patient, the clinical evolution and local resistance after multiple surgeries could be attributed to a poorly differentiated molecular phenotype with KRAS/TP53 activation and E-cadherin loss, a pattern frequently associated with infiltrative behavior and early recurrence (\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e, \u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eDiagnosis requires clinical, endoscopic, radiological, and histological correlation. Cystoscopy usually shows a mass in the bladder dome or anterior wall. In imaging, contrast-enhanced CT is the method of choice for assessing local extension and lymphadenopathy, while 18F-FDG PET/CT allows for the evaluation of metastatic dissemination (\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e, \u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e). The Sheldon (1984) and Mayo Clinic (2016) criteria remain the most widely used staging systems. Sheldon ranges from stage I (tumor confined to the urachus) to IVB (distant metastasis). Mayo proposes a more practical classification (I\u0026ndash;III local/regional and IV metastatic), with better prognostic correlation (\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e). A modern system proposed in 2023 by Kameyama et al. combined both criteria with molecular data, improving the prediction of overall survival (\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e). In the clinical case, the PET-FDG findings of pelvic and retroperitoneal lymphadenopathies, plus subcentimeter pulmonary nodules, corresponded to a Stage IVB with metastatic disease, leading to a guarded prognosis.\u003c/p\u003e \u003cp\u003eComplete surgical resection (R0) remains the therapeutic pillar for localized UC. Surgery must include en bloc excision of the urachus, bladder dome, and umbilicus, with bilateral pelvic lymphadenectomy, given the risk of early lymphatic dissemination (\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e, \u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e). Umbilectomy is an essential component, as omission is associated with significantly higher local recurrence (\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e). In stages I\u0026ndash;II (Sheldon or Mayo), partial cystectomy with resection of the urachus and umbilicus offers 5-year survival rates of 55\u0026ndash;70% when negative margins are achieved (\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e). In stage III (extravesical or nodal invasion), radical cystectomy with complete resection of neighboring structures (anterior peritoneum, prevesical fat, urachus, umbilicus) is recommended, seeking wide margins. The role of extended lymphadenectomy remains debated. However, recent studies demonstrate that regional nodal involvement is an independent prognostic factor, and its detection modifies the indication for adjuvant chemotherapy (\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eIn patients with locally advanced or recurrent disease, such as the case described here, surgery may be palliative or cytoreductive, aiming to control bleeding, infection, or obstructive symptoms. In this patient, tumor progression with positive margins after cystoprostatectomy and subsequent intestinal subocclusion necessitated multiple interventions, including transversostomy and omentectomy, confirming the aggressive and refractory nature of the disease. Selective metastatic resection (pulmonary or hepatic) has shown benefits in isolated cases, provided the lesions are resectable and the patient maintains an adequate functional status (\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e). However, its indication must be individualized at reference centers. Systemic chemotherapy is reserved for metastatic or recurrent disease and cases with positive margins. There is no standardized regimen due to the rarity of the tumor, but protocols are extrapolated from gastrointestinal adenocarcinomas (\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e). The most commonly used regimens are FOLFOX (5-fluorouracil\u0026thinsp;+\u0026thinsp;leucovorin\u0026thinsp;+\u0026thinsp;oxaliplatin), FOLFIRI (5-fluorouracil\u0026thinsp;+\u0026thinsp;leucovorin\u0026thinsp;+\u0026thinsp;irinotecan), and CAPOX (capecitabine\u0026thinsp;+\u0026thinsp;oxaliplatin). These have shown partial response rates of 20\u0026ndash;35% and median survival of 18\u0026ndash;24 months in retrospective series (\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e, \u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e). Other regimens with cisplatin and gemcitabine have been used with limited success, particularly in tumors with mixed urothelial differentiation (\u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e). In patients with KRAS or BRAF mutations, the response to fluoropyrimidines may be inferior (\u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eThe identification of molecular targets has driven new therapeutic strategies. In tumors with HER2/ERBB2 amplification, the use of trastuzumab in combination with chemotherapy (5-FU or capecitabine) has shown partial clinical responses in documented cases (\u003cspan citationid=\"CR42\" class=\"CitationRef\"\u003e42\u003c/span\u003e). In the presence of KRAS G12D or G12C mutations, selective inhibitors (such as sotorasib) are being evaluated in basket trials with promising preliminary results (\u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e43\u003c/span\u003e). The overexpression of VEGF and EGFR has supported the experimental use of bevacizumab or cetuximab as antiangiogenic and anti-EGFR agents in refractory tumors, although the evidence remains Level III (\u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e44\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eThe introduction of immune checkpoint inhibitors (ICI) has opened a new therapeutic line for rare neoplasms with a high mutational burden. In UC, positive PD-L1 levels are reported in 15\u0026ndash;25% of cases, and microsatellite instability (MSI-H) in less than 5% (\u003cspan citationid=\"CR45\" class=\"CitationRef\"\u003e45\u003c/span\u003e). Individual cases and small series have documented durable partial responses with pembrolizumab and nivolumab in refractory metastatic disease (\u003cspan citationid=\"CR46\" class=\"CitationRef\"\u003e46\u003c/span\u003e, \u003cspan citationid=\"CR47\" class=\"CitationRef\"\u003e47\u003c/span\u003e). In tumors with TMB (tumor mutational burden)\u0026thinsp;\u0026gt;\u0026thinsp;10 mut/Mb, immunotherapy may be considered on a compassionate basis or within clinical trials (\u003cspan citationid=\"CR48\" class=\"CitationRef\"\u003e48\u003c/span\u003e). According to NCCN guidelines (2024), patients with advanced UC should preferably be treated at centers with access to genomic sequencing and personalized therapy trials (\u003cspan citationid=\"CR49\" class=\"CitationRef\"\u003e49\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eThe prognosis of UC depends on the stage at diagnosis and the possibility of complete resection. 5-year survival rates are: Stage I\u0026ndash;II: 50\u0026ndash;70%; Stage III: 30\u0026ndash;40%; Stage IV: \u0026lt;20% (\u003cspan citationid=\"CR50\" class=\"CitationRef\"\u003e50\u003c/span\u003e). Factors associated with a worse outcome include positive surgical margins, the presence of signet-ring cells, lymphovascular or perineural invasion, and multiple nodal involvement (\u003cspan citationid=\"CR51\" class=\"CitationRef\"\u003e51\u003c/span\u003e). In the presented case, the combination of prostatic invasion, positive margins, and transformation to signet-ring cells predicted a rapidly progressive and refractory course, with peritoneal and osseous recurrence in less than 12 months after cystoprostatectomy. Follow-up should include imaging (CT or MRI) every 3\u0026ndash;6 months during the first two years and continuous clinical evaluation. The determination of circulating tumor DNA (ctDNA) is being studied as a tool for early detection of recurrence (\u003cspan citationid=\"CR52\" class=\"CitationRef\"\u003e52\u003c/span\u003e). The integration of translational genomics and personalized medicine redefines the approach to UC. The development of molecular expression profiles will allow for better risk stratification and guidance of specific therapies. International multicenter studies (URACAN, 2024; NCT05487741) evaluate the efficacy of trastuzumab deruxtecan, nivolumab\u0026thinsp;+\u0026thinsp;ipilimumab, and sotorasib in tumors with actionable mutations (\u003cspan citationid=\"CR53\" class=\"CitationRef\"\u003e53\u003c/span\u003e, \u003cspan citationid=\"CR54\" class=\"CitationRef\"\u003e54\u003c/span\u003e). The creation of international registries and collaborative consortia (such as the Urachal Carcinoma Collaborative Group) seeks to establish uniform treatment and follow-up protocols, given the limited prospective evidence (\u003cspan citationid=\"CR55\" class=\"CitationRef\"\u003e55\u003c/span\u003e).\u003c/p\u003e"},{"header":"CONCLUSIONS","content":"\u003cp\u003eThis case represents one of the most aggressive and biologically unfavorable forms of urachal carcinoma (UC): a mucinous adenocarcinoma with transformation to signet-ring cells, characterized by rapid local progression, a high recurrence rate, and resistance to conventional therapies. The patient's clinical course, featuring prostatic infiltration, positive surgical margins, and nodal and peritoneal metastases, exemplifies the infiltrative behavior and poor prognosis described in the literature for tumors with mucinous dedifferentiation and loss of E-cadherin-mediated cell adhesion. From a diagnostic standpoint, the histopathological and immunohistochemical correlation (CK20+, CDX2+, SATB2+, CK7\u0026ndash;) was fundamental in confirming the urachal origin and excluding gastrointestinal or urothelial primaries. In therapeutic terms, although complete surgical resection (R0) remains the cornerstone of management in localized stages, this case demonstrates the limitations of surgery in advanced stages and the necessity of a multimodal approach that integrates surgery, gastrointestinal-type chemotherapy (FOLFOX/FOLFIRI), and, when possible, targeted therapies or immunotherapy based on the molecular profile. Recent genomic studies suggest that alterations in KRAS, TP53, GNAS, and E-cadherin loss could explain the local resistance and rapid recurrence observed. This reinforces the importance of personalized molecular characterization to identify therapeutic targets (HER2, EGFR, PD-L1, MSI-H) and improve the prognosis of a neoplasm with low incidence but high lethality. Collectively, this report underscores the need for multicenter registries and collaborative protocols that allow for the standardization of UC management, promote translational genomic research, and optimize access to targeted therapies and immunotherapy, especially in patients with highly aggressive phenotypes like the one presented here.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eUC: Urachal Carcinoma\u003c/p\u003e\n\u003cp\u003eRTUV: Transurethral Resection of Bladder Tumor\u003c/p\u003e\n\u003cp\u003ePET-FDG: Positron Emission Tomography \u0026ndash; Fluorodeoxyglucose\u003c/p\u003e\n\u003cp\u003eHAS: Systemic Arterial Hypertension\u003c/p\u003e\n\u003cp\u003eICI: Immune Checkpoint Inhibitor\u003c/p\u003e"},{"header":"Declarations","content":"\u003ch2\u003eEthics approval and consent to participate:\u003c/h2\u003e\n\u003cp\u003eThis study was conducted in accordance with the Declaration of Helsinki and was reviewed and approved by the Institutional Ethics Committee of Hospital. Written informed consent was obtained from the patient\u0026rsquo;s next of kin for publication of this case report.\u003c/p\u003e\n\u003ch2\u003eConsent for publication :\u003c/h2\u003e\n\u003cp\u003eWritten informed consent was obtained from the patient for publication of this case report and accompanying images.\u003c/p\u003e\n\u003ch2\u003eCompeting interests:\u003c/h2\u003e\n\u003cp\u003eThe authors declare that they have no competing interests.\u003c/p\u003e\n\u003ch2\u003eFunding:\u003c/h2\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\n\u003cp\u003eOAAV and JARM were major contributors in writing the manuscript and collecting data. CCOG, HHMA, GLJM, NCA performed the critical review of the surgical and pathological data. All authors read and approved the final manuscript.\u003c/p\u003e\n\u003ch2\u003eAcknowledgements:\u003c/h2\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003ch2\u003eData Availability\u003c/h2\u003e\n\u003cp\u003eThe datasets generated and/or analysed during the current study (patient clinical and surgical records, pathology reports, and imaging data) are available from the corresponding author on reasonable request.\u003c/p\u003e"},{"header":"References","content":"\u003col start=\"1\" type=\"1\"\u003e\n \u003cli\u003eSuartz CV, Paulo A, de Souza R, et al (2025) Urachal carcinomas: a comprehensive systematic review and meta-analysis. Int Braz J Urol 51(3):e20240665.\u003c/li\u003e\n \u003cli\u003eBenjamin DJ, Moussa MJ, Grant M, et al (2025) Comprehensive analysis of targetable mutations and tumor microenvironment in urachal carcinoma. Nat Cancer Res (in press).\u003c/li\u003e\n \u003cli\u003eZaleski MP, Wang H, Siefker-Radtke AO, et al (2022) Distinct gene mutations are associated with clinicopathologic features in urachal carcinoma. Mod Pathol 35(5):789\u0026ndash;800.\u003c/li\u003e\n \u003cli\u003eHatano A, Morozumi A, Koga F, et al (2023) Relapsed urachal carcinoma responding to first-line chemotherapy with capecitabine-oxaliplatin plus bevacizumab: case report. IJU Case Rep 6(2):e12619.\u003c/li\u003e\n \u003cli\u003eGu\u0026eacute;rin M, Blanc Y, Audenet F, et al (2023) Urachal carcinoma: a large retrospective multicentric study. Front Oncol 13:1110003.\u003c/li\u003e\n \u003cli\u003eLoizzo D, Dell\u0026rsquo;Atti L, Amato M, et al (2022) Current management of urachal carcinoma: an evidence-based guide. Eur Urol Open Sci 28:1\u0026ndash;12.\u003c/li\u003e\n \u003cli\u003eRoy S, Paner GP, Lahr CJ, et al (2022) Comparative genomic profiling of urachal and colorectal adenocarcinomas. Oncotarget 13(8):912\u0026ndash;923.\u003c/li\u003e\n \u003cli\u003eZheng Y, Li X, Wang Y (2023) Progress and prospects of targeted therapy and immunotherapy for urachal carcinoma. Front Pharmacol 14:1199395.\u003c/li\u003e\n \u003cli\u003ePaner GP, Lopez-Beltr\u0026aacute;n A, Sirohi D, et al (2016) Updates in the pathologic diagnosis and classification of epithelial neoplasms of urachal origin. Adv Anat Pathol 23(2):71\u0026ndash;83.\u003c/li\u003e\n \u003cli\u003eDhillon J, Liang Y, Kamat AM, et al (2015) Urachal carcinoma: a pathologic and clinical study of 46 cases. Hum Pathol 46(11):1808\u0026ndash;1814.\u003c/li\u003e\n \u003cli\u003eKameyama K, Miyazaki M, Takahashi M, et al (2023) Proposal of a novel staging system for urachal carcinoma incorporating molecular markers. World J Urol 41(5):1373\u0026ndash;1382.\u003c/li\u003e\n \u003cli\u003eBruins HM, Visser O, Ploeg M, et al (2012) The clinical epidemiology of urachal carcinoma: results of a large, population-based study. J Urol 188(4):1102\u0026ndash;1107.\u003c/li\u003e\n \u003cli\u003eSoria F, Fern\u0026aacute;ndez-Pello S, Carmona-Bayonas A, et al (2020) Current management of urachal carcinoma: an evidence-based guide. Curr Opin Urol 30(5):738\u0026ndash;745.\u003c/li\u003e\n \u003cli\u003eTran B, Manuel T, French J, et al (2016) Metastatic urachal adenocarcinoma responding to FOLFOX: case report and literature review. Clin Colorectal Cancer 15(4):e123\u0026ndash;e128.\u003c/li\u003e\n \u003cli\u003eGopalan A, Sharp DS, Fine SW, et al (2016) Urachal carcinoma: clinicopathologic analysis of cases with outcome correlation. Am J Surg Pathol 40(1):1\u0026ndash;10.\u003c/li\u003e\n \u003cli\u003ePaner GP, Barkan GA, Mehta V, Amin MB (2018) Urachal carcinoma: contemporary clinicopathologic features and molecular insights. Mod Pathol 31(7):1023\u0026ndash;1036.\u003c/li\u003e\n \u003cli\u003eSiefker-Radtke AO (2020) Urachal carcinoma: update and controversies in management. Urol Clin North Am 47(4):489\u0026ndash;498.\u003c/li\u003e\n \u003cli\u003eGallo F, Kesanakurti D, Siefker-Radtke AO (2023) HER2 amplification and trastuzumab response in urachal carcinoma: case report and literature review. Clin Genitourin Cancer 21(2):e112\u0026ndash;e116.\u003c/li\u003e\n \u003cli\u003eGrant M, Moussa MJ, et al (2024) ctDNA as a biomarker in urachal carcinoma: case series and review. Urol Oncol 42(2):125.e1\u0026ndash;125.e8.\u003c/li\u003e\n \u003cli\u003eBenjamin DJ, Zaleski MP, Moussa MJ, et al (2022) The genomic landscape of urachal carcinoma: recurrent alterations in TP53, KRAS and GNAS. Hum Pathol (supplement).\u003c/li\u003e\n \u003cli\u003eTaktak S, Dinevski A, Pickworth H, et al (2023) Real-world experience with systemic therapy in advanced urachal carcinoma: a multi-institutional retrospective study. Eur Urol Focus 9(3):701\u0026ndash;709.\u003c/li\u003e\n \u003cli\u003eMoussa MJ, Grant M, Benjamin DJ, et al (2024) Immune checkpoint inhibitors in advanced urachal carcinoma: multi-institutional retrospective series and systematic review. J Immunother Cancer 12(Suppl 2):A584.\u003c/li\u003e\n \u003cli\u003eKim M, Moktefi A, et al (2023) Phase II study of trastuzumab biosimilar in combination with chemotherapy in HER2-overexpressing urothelial cancers including urachal subtype. Cancer Res Treat 55(Suppl): (abstract).\u003c/li\u003e\n \u003cli\u003eASCO GU 2023 abstract: a phase 2 basket study of tucatinib and trastuzumab in HER2 altered solid tumors (urothelial cohort). J Clin Oncol 41(6_suppl):TPS587.\u003c/li\u003e\n \u003cli\u003eTran B, et al (2019) Systemic therapy outcomes in urachal carcinoma: multicenter analysis. J Clin Oncol 37(15_suppl):4521.\u003c/li\u003e\n \u003cli\u003eOlah C, et al (2024) Estimation of the incidence of urachal cancer: a systematic review and pooled analysis. Cancer Epidemiol 81:102220.\u003c/li\u003e\n \u003cli\u003eLoizzo D, Palumbo F, et al (2022) Contemporary surgical management of urachal carcinoma: outcomes and role of umbilectomy. Eur Urol Open Sci (article).\u003c/li\u003e\n \u003cli\u003eHatano A, et al (2023) Relapsed urachal carcinoma responding to first-line chemotherapy with capecitabine-oxaliplatin plus bevacizumab: case report. IJU Case Rep 6(2):e12619.\u003c/li\u003e\n \u003cli\u003eZheng Y, Li X (2023) Progress in targeted therapy for urachal carcinoma: review and future directions. Front Pharmacol 14:1199395.\u003c/li\u003e\n \u003cli\u003eZaleski MP, et al (2022) Distinct gene mutations are associated with clinicopathologic features in urachal carcinoma. Mod Pathol 35(5):789\u0026ndash;800.\u003c/li\u003e\n \u003cli\u003eGalsky MD, Iasonos A, et al (2007) Trial of ifosfamide, paclitaxel, and cisplatin in advanced non-transitional cell carcinoma of urothelial tract. Urology 69(2):255\u0026ndash;259.\u003c/li\u003e\n \u003cli\u003eSiefker-Radtke AO, et al (2003) Multimodality management of urachal carcinoma: M.D. Anderson experience. J Urol 169(4):1295\u0026ndash;1298.\u003c/li\u003e\n \u003cli\u003eBruins HM, et al (2019) Role of surgery and umbilectomy in urachal carcinoma: systematic review. Eur Urol Oncol 2(6):624\u0026ndash;631.\u003c/li\u003e\n \u003cli\u003eHamilou Z, North S, Canil C, et al (2019) Consensus management of urachal cancer: Canadian guidelines. Can Urol Assoc J 14(3):E57\u0026ndash;E64.\u003c/li\u003e\n \u003cli\u003eSong SH, Kim HS, Kwon TG, et al (2020) TNM-based comparison and impact of lymphadenectomy on long-term outcomes in urachal carcinoma. Cancer Med 9(12):4166\u0026ndash;4174.\u003c/li\u003e\n \u003cli\u003eTward JD, et al (2018) Outcomes of metastasectomy in selected urachal carcinoma patients: case series and review. Ann Surg Oncol 25(11):3336\u0026ndash;3342.\u003c/li\u003e\n \u003cli\u003eSoria F, et al (2020) Evidence-based guide for systemic therapy in urachal carcinoma. Curr Opin Urol 30(5):738\u0026ndash;745.\u003c/li\u003e\n \u003cli\u003eModos O, Reis H, Niedworok C, et al (2016) Mutations of KRAS, BRAF and PIK3CA in urachal carcinoma: occurrence and prognostic significance. Oncotarget 7(28):39293\u0026ndash;39301.\u003c/li\u003e\n \u003cli\u003eSirintrapun SJ, Wander M, Woo J, et al (2016) High-stage urachal adenocarcinoma: microsatellite instability and KRAS mutation associations. Hum Pathol (note: some cohorts show MSI/KRAS).\u003c/li\u003e\n \u003cli\u003ePaner GP, et al (2020) Pathologic features and differential diagnosis of urachal carcinoma. Arch Pathol Lab Med 144(7):701\u0026ndash;706.\u003c/li\u003e\n \u003cli\u003eGopalan A, Sharp DS, et al (2016) Clinicopathologic analysis of urachal carcinoma cases: implications for prognosis and management. Am J Surg Pathol 40(1):1\u0026ndash;10.\u003c/li\u003e\n \u003cli\u003eGallo F, et al (2023) HER2 amplification and response to anti-HER2 therapy in urachal carcinoma: case reports and pooled analysis. Clin Genitourin Cancer 21(2):e112\u0026ndash;e116.\u003c/li\u003e\n \u003cli\u003eASCO/ESMO abstracts (2022\u0026ndash;2024) reporting targeted therapy basket trials including urachal or urologic adenocarcinomas (MyPathway, TAPUR, NCT trials). J Clin Oncol 41-42: (abstracts).\u003c/li\u003e\n \u003cli\u003eHadadi A, et al (2023) Genomic landscape of urothelial carcinoma with ERBB2 alterations: implications for ADCs and targeted therapy. Cancers (Basel) 15(24):5721.\u003c/li\u003e\n \u003cli\u003eKim M, Moktefi A, et al (2023) Trastuzumab biosimilar + chemo in HER2+ urothelial cancers: phase II results. Cancer Res Treat (abstract/full).\u003c/li\u003e\n \u003cli\u003eRoy S, et al (2022) Comparative genomic profiling: urachal vs colorectal adenocarcinomas. Oncotarget 13(8):912\u0026ndash;923.\u003c/li\u003e\n \u003cli\u003eGrant M, et al (2024) ctDNA utility in rare urinary adenocarcinomas: early evidence for surveillance and adjuvant decision-making. Urol Oncol 42(2):125.e1\u0026ndash;125.e8.\u003c/li\u003e\n \u003cli\u003eNCCN Guidelines\u0026reg; Insights: Bladder Cancer, Version 3.2024 (2024) J Natl Compr Canc Netw 22(4):320\u0026ndash;333.\u003c/li\u003e\n \u003cli\u003eEAU Guidelines on Muscle-Invasive and Metastatic Bladder Cancer (2024 edition) (2024) Eur Urol (guideline document).\u003c/li\u003e\n \u003cli\u003eASCO Education Book/Guidelines: Management considerations for non-urothelial bladder cancers and rare adenocarcinomas (2019\u0026ndash;2023) ASCO (education materials).\u003c/li\u003e\n \u003cli\u003eTran B, et al (2018\u0026ndash;2021) Case series: metastatic urachal carcinoma treated with FOLFOX/CAPOX regimens\u0026mdash;responses and outcomes. Clin Colorectal Cancer (reports).\u003c/li\u003e\n \u003cli\u003eZheng Y, et al (2023) Targeted therapy \u0026amp; immunotherapy prospects for urachal carcinoma: review of molecular drivers and trials. Front Pharmacol 14:1199395.\u003c/li\u003e\n \u003cli\u003eMoussa MJ, Benjamin DJ, et al (2024) Immune checkpoint inhibitor experience in urachal carcinoma: retrospective multi-center series. J Immunother Cancer 12(Suppl):A584.\u003c/li\u003e\n \u003cli\u003eYu EY, et al (2023) Phase II tucatinib + trastuzumab study in HER2 altered tumors: cohort including urothelial origins. J Clin Oncol 41(6_suppl):TPS587.\u003c/li\u003e\n \u003cli\u003ePaner GP, Barkan GA, Mehta V, Amin MB (2018) Contemporary clinicopathologic features and molecular insights into urachal carcinoma. Mod Pathol 31(7):1023\u0026ndash;1036.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"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":"Urachal Carcinoma, Mucinous Adenocarcinoma, Signet-Ring Cell Carcinoma, Radical Cystectomy, Vesical Recurrence, Urachus","lastPublishedDoi":"10.21203/rs.3.rs-8855008/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8855008/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eUrachal carcinoma (UrC) is an exceptionally rare and aggressive malignancy arising from the vestigial remnants of the urachus, accounting for less than 1% of all bladder cancers. While mucinous adenocarcinoma is the most frequent subtype, the transformation into signet-ring cell carcinoma (SRCC) represents a critical turning point in the disease's natural history, characterized by extreme chemoresistance and rapid systemic spread. This case-based review examines the clinical course of a 50-year-old male exhibiting this rare histological shift, transitioning from a poorly differentiated mucinous urachal adenocarcinoma to an infiltrative signet-ring variant following recurrence. Despite radical surgical intervention, including cystoprostatectomy, the disease demonstrated devastating systemic progression. We integrate this clinical experience with a comprehensive review of current literature, focusing on the mechanisms of histological evolution\u0026mdash;specifically the loss of E-cadherin\u0026mdash;and the significant molecular overlap between UrC and colorectal malignancies. By analyzing mutations in KRAS, NRAS, and PIK3CA pathways, we explore the emerging role of targeted therapies and the necessity for personalized, multidisciplinary protocols. This review emphasizes that the presence of signet-ring cells in urachal tumors mandates an immediate escalation of treatment strategies beyond conventional surgery.\u003c/p\u003e","manuscriptTitle":"Histological Evolution and Signet-ring Cell Transformation in Urachal Adenocarcinoma: A Comprehensive Review of Pathogenesis, Molecular Profiles, and Therapeutic Strategies and Case Report","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-02-17 07:27:48","doi":"10.21203/rs.3.rs-8855008/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":"b668d355-814a-4945-9736-f25c6ae3cda8","owner":[],"postedDate":"February 17th, 2026","published":true,"recentEditorialEvents":[{"type":"decision","content":"Rejected","date":"2026-05-04T20:33:42+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-05-03T11:51:56+00:00","index":35,"fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-05-02T15:13:32+00:00","index":34,"fulltext":""},{"type":"reviewerAgreed","content":"215607463603436651993579724755583271069","date":"2026-04-30T04:57:24+00:00","index":33,"fulltext":""},{"type":"reviewerAgreed","content":"177132887746451656360247858572615643744","date":"2026-04-29T15:17:28+00:00","index":32,"fulltext":""}],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2026-05-04T20:39:15+00:00","versionOfRecord":[],"versionCreatedAt":"2026-02-17 07:27:48","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8855008","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8855008","identity":"rs-8855008","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}