While most cases of human muscle-invasive bladder cancer (MIBC) are diagnosed as conventional urothelial carcinoma (UC), there is growing recognition of histologic subtypes and divergent differentiation within conventional UC. In this study, 31 dogs with UC (33 slides) were evaluated for histologic subtypes and divergent differentiation, as specified by the recent World Health Organization update on the classification of urinary bladder cancers. Slides were reviewed by a medical uropathologist and 3 board-certified veterinary pathologists and assessed for expression of uroplakin III, vimentin, and E-cadherin. All tumors were classified as UC. Fifteen cases were identified as conventional UC. Among the remainder, 8 displayed glandular differentiation, 4 were classified as sarcomatoid UC, 2 showed squamous differentiation, 1 case was classified as a large nested subtype, and 1 case was classified as a tubular/microcystic subtype. This study found a higher frequency of certain histologic subtypes and divergent differentiation in canine UC, particularly sarcomatoid UC and UC with glandular differentiation, compared to previous reports of both canine UC and human MIBC. The relatively high prevalence of the sarcomatoid UC and UC with glandular differentiation in dogs observed in this study suggests that canine UC may serve as a valuable translational model for evaluating novel therapeutic agents, particularly for these rare and aggressive subtypes in humans.
Abd el-LatifAWattsKEElsonP, et al. The sensitivity of initial transurethral resection or biopsy of bladder tumor(s) for detecting bladder cancer variants on radical cystectomy. J Urol. 2013;189(4):1263–1267.
2.
Alfred WitjesJMax BruinsHCarriónA, et al. European association of urology guidelines on muscle-invasive and metastatic bladder cancer: summary of the 2023 guidelines. Eur Urol. 2024;85(1):17–31.
3.
AllenspachKChevilleJWickhamH.Similar variant histology and immune cell infiltration in canine and human muscle-invasive bladder cancer. Cancer Res. 2023;83:2509.
4.
AlmassiNWhitingKToubajiA, et al. Clinical and genomic characterization of bladder carcinomas with glandular phenotype. JCO Precis Oncol. 2022;6:e2100392.
5.
AmrheinVTrafimowDGreenlandS.Inferential statistics as descriptive statistics: there is no replication crisis if we don’t expect replication. Am Stat. 2019;73(suppl 1):262–270.
6.
BergSD’AndreaDVetterleinMW, et al. Impact of adjuvant chemotherapy in patients with adverse features and variant histology at radical cystectomy for muscle-invasive carcinoma of the bladder: does histologic subtype matter?Cancer. 2019;125(9):1449–1458.
7.
BlackAJBlackPC.Variant histology in bladder cancer: diagnostic and clinical implications. Transl Cancer Res. 2020;9(10):6565–6575.
8.
BrayFLaversanneMSungH, et al. Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2024;74(3):229–263.
9.
BürknerP-C.brms: an R package for Bayesian multilevel models using Stan. J Stat Soft. 2017;80(1):1–28.
10.
Cancer Genome Atlas Research Network. Comprehensive molecular characterization of urothelial bladder carcinoma. Nature. 2014;507(7492):315–322.
11.
ChaudharyKPareekTSharmaA, et al. Lipid-rich variant of urothelial carcinoma: a lethal enigma. BMJ Case Rep. 2021;14(3):e240593.
12.
ChoJHHolleyJL.Squamous cell carcinoma of the bladder in a female associated with multiple bladder stones. BMC Res Notes. 2013;6(1):354.
13.
CompératEAminMBEpsteinJI, et al. The genitourinary pathology society update on classification of variant histologies, T1 substaging, molecular taxonomy, and immunotherapy and PD-L1 testing implications of urothelial cancers. Adv Anat Pathol. 2021;28(4):196–208.
14.
CompératEMcKenneyJKHartmannA, et al. Large nested variant of urothelial carcinoma: a clinicopathological study of 36 cases. Histopathology. 2017;71(5):703–710.
15.
De BrotSRobinsonBScaseT, et al. The dog as an animal model for bladder and urethral urothelial carcinoma: comparative epidemiology and histology. Oncol Lett. 2018;16:1641–1649.
16.
DeukerMMartinTStolzenbachF, et al. Bladder cancer: a comparison between non-urothelial variant histology and urothelial carcinoma across all stages and treatment modalities. Clin Genitourin Cancer. 2021;19(1):60–68.
17.
DhawanDRamos-VaraJAUtturkarSM, et al. Identification of a naturally-occurring canine model for early detection and intervention research in high grade urothelial carcinoma. Front Oncol. 2022;12:1011969.
18.
DiamantopoulosLNKorentzelosDAlevizakosM, et al. Sarcomatoid urothelial carcinoma: a population-based study of clinicopathologic characteristics and survival outcomes. Clin Genitourin Cancer. 2022;20(2):139–147.
19.
GruverAMAminMBLuthringerDJ, et al. Selective immunohistochemical markers to distinguish between metastatic high-grade urothelial carcinoma and primary poorly differentiated invasive squamous cell carcinoma of the lung. 2012;136(11):1339–1346.
20.
GuoCCMajewskiTZhangL, et al. Dysregulation of EMT drives the progression to clinically aggressive sarcomatoid bladder cancer. Cell Rep. 2019;27(6):1781–1793.
21.
HöglundMBernardoCSjödahlG, et al. The Lund taxonomy for bladder cancer classification—from gene expression clustering to cancer cell molecular phenotypes, and back again. J Pathol. 2023;259(4):369–375.
22.
IsmailSKarsentyGChartier KastlerE, et al. Prevalence, management, and prognosis of bladder cancer in patients with neurogenic bladder: a systematic review. Neurourol Urodyn. 2018;37(4):1386–1395.
23.
KamatAMHahnNMEfstathiouJA, et al. Bladder cancer. Lancet. 2016;388(10061):2796–2810.
24.
KamounAde ReynièsAAlloryY, et al. A consensus molecular classification of muscle-invasive bladder cancer. Eur Urol. 2020;77(4):420–433.
25.
KarasavvidouFMitrakasLStratakiM, et al. Poorly differentiated muscle-invasive giant cell tumor of the bladder leads to unfavorable clinical outcome. 2022;2022(4):rjac046.
26.
KhanAQHasanAMirSS, et al. Exploiting transcription factors to target EMT and cancer stem cells for tumor modulation and therapy. Semin Cancer Biol. 2024;100:1–16.
27.
KimSPFrankIChevilleJC, et al. The impact of squamous and glandular differentiation on survival after radical cystectomy for urothelial carcinoma. J Urol. 2012;188(2):405–409.
28.
KnezVMBarrowWLuciaMS, et al. Clear cell urothelial carcinoma of the urinary bladder: a case report and review of the literature. J Med Case Rep. 2014;8(1):275.
29.
KobayashiTOwczarekTBMcKiernanJM, et al. Modelling bladder cancer in mice: opportunities and challenges. Nat Rev Cancer. 2015;15(1):42–54.
30.
KossaïMRadulescuCAdamJ, et al. Plasmacytoid urothelial carcinoma (UC) are luminal tumors with similar CD8+ Tcell density and PD-L1 protein expression on immune cells as compared to conventional UC. Urol Oncol. 2022;40(1):12e1–12e11.
31.
KumarDAdeniranAJ.Clinicopathological review of micropapillary urothelial carcinoma. Curr Oncol Rep. 2022;24(5):603–610.
32.
LeeDBKimJYLeeYH, et al. Clinical outcomes of patients with variant histology of urothelial carcinoma after radical cystectomy. J Urol Oncol. 2023;21(3):249–256.
33.
LinSJ-HKaoC-FWangF-I, et al. Urothelial carcinomas of the urinary bladder with plasmacytoid or rhabdoid features and tendency of epithelial-mesenchymal transition in 3 dogs. Vet Pathol. 2018;55(5):673–677.
34.
LinderBJBoorjianSAChevilleJC, et al. The impact of histological reclassification during pathology re-review—evidence of a Will Rogers effect in bladder cancer?J Urol. 2013;190(5):1692–1697.
35.
LiuLZhangP-YXiaoY, et al. Prognostic factors influencing postoperative survival in patients with neuroendocrine carcinoma of the bladder: a population-based study. Cancer Med. 2025;14(5):e70758.
36.
LoboNShariatSFGuoCC, et al. What is the significance of variant histology in urothelial carcinoma?Eur Urol Focus. 2020;6(4):653–663.
37.
Lopez-BeltranAHenriquesVMontironiR, et al. Variants and new entities of bladder cancer. Histopathology. 2019;74(1):77–96.
MaiKTHakimSWBallCG, et al. Nested and microcystic variants of urothelial carcinoma displaying immunohistochemical features of basal-like urothelial cells: an immunohistochemical and histopathogenetic study. Pathol Int. 2014;64(8):375–381.
40.
ManochaUKardosJSelitskyS, et al. RNA expression profiling of lymphoepithelioma-like carcinoma of the bladder reveals a basal-like molecular subtype. Am J Pathol. 2020;190(1):134–144.
41.
MohantySKLoboAChengL.The 2022 revision of the World Health Organization classification of tumors of the urinary system and male genital organs: advances and challenges. Hum Pathol. 2023;136:123–143.
42.
MonnMFKaimakliotisHZPedrosaJA, et al. Contemporary bladder cancer: variant histology may be a significant driver of disease. Urol Oncol. 2015;33(1):18e15–18e20.
43.
NakagawaRIwamotoHMakinoT, et al. Squamous or glandular differentiation predicts poor prognosis in pT1 urothelial carcinoma. In Vivo. 2022;36(5):2365–2370.
44.
PanerGPAnnaiahCGulmannC, et al. Immunohistochemical evaluation of novel and traditional markers associated with urothelial differentiation in a spectrum of variants of urothelial carcinoma of the urinary bladder. Hum Pathol. 2014;45(7):1473–1482.
45.
PrzybycinCGMcKenneyJKNguyenJK, et al. Urothelial carcinomas with trophoblastic differentiation, including choriocarcinoma: clinicopathologic series of 16 cases. 2020;44(10):1322–1330.
46.
R Core Team. R: A Language and environment for Statical Computing. Vienna: R Foundation for Statistical Computing; 2024.
47.
RaspolliniMRComperatEMLopez-BeltranA, et al. News in the classification of WHO 2022 bladder tumors. Pathologica. 2022;115(1):32–40.
48.
RaspolliniMRSardiIGiuntiL, et al. Plasmacytoid urothelial carcinoma of the urinary bladder: clinicopathologic, immunohistochemical, ultrastructural, and molecular analysis of a case series. Hum Pathol. 2011;42(8):1149–1158.
49.
ReikeMJde JongJJBismarTA, et al. Alignment of molecular subtypes across multiple bladder cancer subtyping classifiers. Urol Oncol. 2024;42(6):177e5–177e14.
50.
RobertsonAGKimJAl-AhmadieH, et al. Comprehensive molecular characterization of muscle-invasive bladder cancer. Cell. 2017;171(3):540–556.
51.
RuanJ-LHsuJ-WBrowningRJ, et al. Mouse models of muscle-invasive bladder cancer: key considerations for clinical translation based on molecular subtypes. Eur Urol Oncol. 2019;2(3):239–247.
52.
SanfrancescoJMcKenneyJKLeivoMZ, et al. Sarcomatoid urothelial carcinoma of the bladder: analysis of 28 cases with emphasis on clinicopathologic features and markers of epithelial-to-mesenchymal transition. Arch Pathol Lab Med. 2016;140(6):543–551.
53.
SangoiARHigginsJPRouseRV, et al. Immunohistochemical comparison of MUC1, CA125, and Her2Neu in invasive micropapillary carcinoma of the urinary tract and typical invasive urothelial carcinoma with retraction artifact. Mod Pathol. 2009;22(5):660–667.
54.
SanguedolceFCormioAZanelliM, et al. Diagnostic workout of glandular malignant lesions of the bladder according to the 5th WHO classification. Crit Rev Clin Lab Sci. 2025;62:301–312.
55.
ShahRBMontgomeryJSMontieJE, et al. Variant (divergent) histologic differentiation in urothelial carcinoma is under-recognized in community practice: impact of mandatory central pathology review at a large referral hospital. Urol Oncol. 2013;31(8):1650–1655.
56.
SiegelRLMillerKDFuchsHE, et al. Cancer statistics, 2021. CA Cancer J Clin. 2021;71(1):7–33.
57.
Smith-TogoboCMprahRYeboahEA, et al. Detection of cytological abnormalities in urothelial cells from individuals previously exposed or currently infected with Schistosoma haematobium. PLoS ONE. 2023;18(3):e0278202.
58.
SommerBCDhawanDRatliffTL, et al. Naturally-occurring canine invasive urothelial carcinoma: a model for emerging therapies. Bladder Cancer. 2018;4(2):149–159.
59.
SuWSuiWChengX, et al. Morphology, immunohistochemistry characteristics, and clinical presentation of microcystic urothelial carcinoma: a series of 10 cases. Diagn Pathol. 2023;18(1):94.
60.
SuiWMatulayJTJamesMB, et al. Micropapillary bladder cancer: insights from the national cancer database. BLC. 2016;2(4):415–423.
61.
SungMWangMMacLennanG, et al. Histogenesis of sarcomatoid urothelial carcinoma of the urinary bladder: evidence for a common clonal origin with divergent differentiation. J Pathol. 2007;211(4):420–430.
62.
TeoMYAl-AhmadieHSeierK, et al. Natural history, response to systemic therapy, and genomic landscape of plasmacytoid urothelial carcinoma. Br J Cancer. 2021;124(7):1214–1221.
TherneauTMGrambschPM.Modeling Survival Data: Extending the Cox Model. New York: Springer; 2000.
65.
TurkerPBostromPJWroclawskiML, et al. Upstaging of urothelial cancer at the time of radical cystectomy: factors associated with upstaging and its effect on outcome. BJU Int. 2012;110(6):804–811.
66.
VeskimäeEEspinosELBruinsHM, et al. What is the prognostic and clinical importance of urothelial and nonurothelial histological variants of bladder cancer in predicting oncological outcomes in patients with muscle-invasive and metastatic bladder cancer? A European association of urology muscle invasive and metastatic bladder cancer guidelines panel systematic review. Eur Urol Oncol. 2019;2(6):625–642.
67.
WangWLiuJLiuL.Development and validation of a prognostic model for predicting overall survival in patients with bladder cancer: a SEER-based study. Front Oncol. 2021;11:692728.
68.
WeiLHutsonAD.A comment on sample size calculations for binomial confidence intervals. J Appl Stat. 2013;40(2):311–319.
69.
WeyererVEcksteinMCompératE, et al. Pure Large Nested Variant of Urothelial Carcinoma (LNUC) is the prototype of an FGFR3 mutated aggressive urothelial carcinoma with luminal-papillary phenotype. Cancers. 2020;12(3):763.
70.
WilliamsonSRZhangSLopez-BeltranA, et al. Lymphoepithelioma-like carcinoma of the urinary bladder: clinicopathologic, immunohistochemical, and molecular features. Am J Surg Pathol. 2011;35(4):474–483.
71.
WongKAbascalFLudwigL, et al. Cross-species oncogenomics offers insight into human muscle-invasive bladder cancer. Genome Biol. 2023;24(1):191.
72.
ZangJShahatiailiACaiM-C, et al. Genomic profiling and immune phenotyping of neuroendocrine bladder cancer. Clin Cancer Res. 2024;30(21):4920–4931.
73.
ZhaiQJBlackJAyalaAG, et al. Histologic variants of infiltrating urothelial carcinoma. Arch Pathol Lab Med. 2007;131(8):1244–1256.
74.
ZhaoGWangCTangY, et al. Glandular differentiation in pT1 urothelial carcinoma of bladder predicts poor prognosis. Sci Rep. 2019;9(1):5323.
75.
ZhuSZhuZMaA-H, et al. Preclinical models for bladder cancer research. Hematol Oncol Clin North Am. 2021;35(3):613–632.
