Immunohistochemical assessment of basal and luminal markers in non-muscle invasive urothelial carcinoma of bladder
The Cancer Genome Atlas project introduced genomic taxonomy of basal and luminal molecular subtypes in muscle invasive bladder cancer. Fewer studies have addressed the molecular classification in non-muscle invasive bladder cancer (NMIBC). Our aim is to assess the applicability of the proposed phenotypic classification for NMIBC. Three TMAs were constructed from 193 TURBT specimens of 60 bladder cancer patients treated at one of the authors’ institutions (1998–2008). Follow-up data on recurrence, grade, or stage progression was obtained. Immunohistochemistry was performed using an automated Ventana System for markers indicative of luminal (GATA3, CK20, ER, Uroplakin II, and HER2/neu) and basal (CK5/6 and CD44) phenotype. Marker expression was evaluated by 3 urologic pathologists. Using unadjusted logistic regression, we found significant association between tumor recurrence at next biopsy and CD44 expression (OR = 2.51, P = 0.03), tumor recurrence at any subsequent biopsy and ER expression (OR = 0.24, P = 0.04), and tumor grade progression at any subsequent biopsy and HER2/neu expression (OR = 0.24, P = 0.04). After adjusting for pathologic stage, we found a significant association between CK5/6 expression and tumor stage progression at either next or any subsequent biopsy (OR = 0.94, P = 0.006; and OR = 0.97, P = 0.02, respectively). Our findings suggest that individual immunohistochemical markers may be of value as prognostic factors in NMIBC.
KeywordsMolecular classification Basal Luminal Immunohistochemistry Urothelial carcinoma Non-muscle invasive bladder cancer
GJN conceived and designed the study and wrote, edited, and reviewed the manuscript. MCRP collected the data and wrote, edited, and reviewed the manuscript. AC and MLE analyzed the data and wrote, edited, and reviewed the manuscript. ACT collected the data and reviewed the manuscript. DT and WB collected the data and reviewed the manuscript. MKR collected samples and clinical data and reviewed the manuscript. RS performed the immunohistochemical analysis and reviewed the manuscript.
This study is supported in part by a grant from The Johns Hopkins Greenberg Bladder Cancer Institute and The Patana Fund of the Brady Urological Institute, Baltimore, MD.
Compliance with ethical standards
Conflict of interest
The authors declare that they have no conflict of interest.
All authors gave final approval for publication. GJN takes full responsibility for the work as a whole, including the study design, access to data, and the decision to submit and publish the manuscript.
The Institutional Review Board approved this study.
- 2.Babjuk M, Bohle A, Burger M, Capoun O, Cohen D, Comperat EM, Hernandez V, Kaasinen E, Palou J, Roupret M, van Rhijn BW, Shariat SF, Soukup V, Sylvester RJ, Zigeuner R (2017) EAU guidelines on non-muscle-invasive urothelial carcinoma of the bladder: update 2016. Eur Urol 71:447–461. https://doi.org/10.1016/j.eururo.2016.05.041 CrossRefPubMedGoogle Scholar
- 3.Rosenberg JE, Hoffman-Censits J, Powles T, van der Heijden MS, Balar AV, Necchi A, Dawson N, O’Donnell PH, Balmanoukian A, Loriot Y, Srinivas S, Retz MM, Grivas P, Joseph RW, Galsky MD, Fleming MT, Petrylak DP, Perez-Gracia JL, Burris HA, Castellano D, Canil C, Bellmunt J, Bajorin D, Nickles D, Bourgon R, Frampton GM, Cui N, Mariathasan S, Abidoye O, Fine GD, Dreicer R (2016) Atezolizumab in patients with locally advanced and metastatic urothelial carcinoma who have progressed following treatment with platinum-based chemotherapy: a single-arm, multicentre, phase 2 trial. Lancet 387:1909–1920. https://doi.org/10.1016/s0140-6736(16)00561-4 CrossRefPubMedGoogle Scholar
- 4.Sharma P, Retz M, Siefker-Radtke A, Baron A, Necchi A, Bedke J, Plimack ER, Vaena D, Grimm MO, Bracarda S, Arranz JA, Pal S, Ohyama C, Saci A, Qu X, Lambert A, Krishnan S, Azrilevich A, Galsky MD (2017) Nivolumab in metastatic urothelial carcinoma after platinum therapy (CheckMate 275): a multicentre, single-arm, phase 2 trial. Lancet Oncol 18:312–322. https://doi.org/10.1016/s1470-2045(17)30065-7 CrossRefPubMedGoogle Scholar
- 5.Sjodahl G, Lovgren K, Lauss M, Patschan O, Gudjonsson S, Chebil G, Aine M, Eriksson P, Mansson W, Lindgren D, Ferno M, Liedberg F, Hoglund M (2013) Toward a molecular pathologic classification of urothelial carcinoma. Am J Pathol 183:681–691. https://doi.org/10.1016/j.ajpath.2013.05.013 CrossRefPubMedGoogle Scholar
- 9.Choi W, Porten S, Kim S, Willis D, Plimack ER, Hoffman-Censits J, Roth B, Cheng T, Tran M, Lee IL, Melquist J, Bondaruk J, Majewski T, Zhang S, Pretzsch S, Baggerly K, Siefker-Radtke A, Czerniak B, Dinney CP, McConkey DJ (2014) Identification of distinct basal and luminal subtypes of muscle-invasive bladder cancer with different sensitivities to frontline chemotherapy. Cancer Cell 25:152–165. https://doi.org/10.1016/j.ccr.2014.01.009 CrossRefPubMedGoogle Scholar
- 10.Robertson AG, Kim J, H A-A, J B, G G, AD C, T H, PW L, KA H, R A, MAA C, EA G, RS K, DA G, SA S, F S-V, DE H, BA C, VE R, X S, B d SC, VS C, KL M, S S, CS P, Y L, LJ K, J Z, C C, AI O, S B, KM L, TM L, CJ W, N S, G G, M M, GB M, DJ MC, Research Network TCGA, JN W, DJ K, SP L (2017) Comprehensive molecular characterization of muscle-invasive bladder cancer. Cell 171:540–556.e525. https://doi.org/10.1016/j.cell.2017.09.007 CrossRefPubMedGoogle Scholar
- 11.Hedegaard J, Lamy P, Nordentoft I, Algaba F, Hoyer S, Ulhoi BP, Vang S, Reinert T, Hermann GG, Mogensen K, Thomsen MBH, Nielsen MM, Marquez M, Segersten U, Aine M, Hoglund M, Birkenkamp-Demtroder K, Fristrup N, Borre M, Hartmann A, Stohr R, Wach S, Keck B, Seitz AK, Nawroth R, Maurer T, Tulic C, Simic T, Junker K, Horstmann M, Harving N, Petersen AC, Calle ML, Steyerberg EW, Beukers W, van Kessel KEM, Jensen JB, Pedersen JS, Malmstrom PU, Malats N, Real FX, Zwarthoff EC, Orntoft TF, Dyrskjot L (2016) Comprehensive transcriptional analysis of early-stage urothelial carcinoma cancer cell. 30:27–42. https://doi.org/10.1016/j.ccell.2016.05.004
- 12.Breyer J, Wirtz RM, Otto W, Erben P, Kriegmair MC, Stoehr R, Eckstein M, Eidt S, Denzinger S, Burger M, Hartmann A, Consortium B (2017) In stage pT1 non-muscle-invasive bladder cancer (NMIBC), high KRT20 and low KRT5 mRNA expression identify the luminal subtype and predict recurrence and survival. Virchows Arch 470:267–274. https://doi.org/10.1007/s00428-017-2064-8 CrossRefPubMedGoogle Scholar
- 13.Wolff AC, Hammond ME, Hicks DG, Dowsett M, McShane LM, Allison KH, Allred DC, Bartlett JM, Bilous M, Fitzgibbons P, Hanna W, Jenkins RB, Mangu PB, Paik S, Perez EA, Press MF, Spears PA, Vance GH, Viale G, Hayes DF (2013) Recommendations for human epidermal growth factor receptor 2 testing in breast cancer: American Society of Clinical Oncology/College of American Pathologists clinical practice guideline update. Journal of clinical oncology : official journal of the American Society of Clinical Oncology 31:3997–4013. https://doi.org/10.1200/jco.2013.50.9984 CrossRefGoogle Scholar
- 15.Raspollini MR, Luque RJ, Menendez CL, Bollito E, Brunelli M, Martignoni G, Montironi R, Cheng L, Blanca A, Baroni G, Minervini A, Lopez-Beltran A (2016) T1 high-grade bladder carcinoma outcome: the role of p16, topoisomerase-IIalpha, survivin, and E-cadherin. Hum Pathol 57:78–84. https://doi.org/10.1016/j.humpath.2016.06.022 CrossRefPubMedGoogle Scholar