Prostatic adenocarcinoma and urothelial carcinoma typically demonstrate distinct morphologic and immunohistochemical features. However, high-grade prostate and urothelial carcinomas sometimes show significant morphologic and immunohistochemical overlap, which can result in misdiagnosis and mistreatment. This diagnostic dilemma is particularly acute in patients previously treated with radiation and/or hormone therapy for prostate cancer, who later present with high-grade carcinoma in the urinary bladder. To address the diagnostic utility of integrated immunohistochemical and molecular analysis in this setting, we evaluated 25 high-grade carcinomas of the bladder for which morphologic features were deemed indeterminate. Our analysis included immunohistochemistry for urothelial markers (GATA3, p63, uroplakin II), prostate markers (NKX3.1, prostate specific antigen, P501S), androgen receptor (AR) and ERG, along with molecular characterization using capture-based next generation DNA sequencing. Immunohistochemical findings were concordant with the final integrated diagnosis in 21 (84%) cases. However, in three (12%) cases, immunohistochemistry supported a diagnosis of urothelial carcinoma, but molecular analysis identified the correct diagnosis of prostate cancer based on the presence of a TMPRSS2-ERG fusion. One case remained unclassifiable even after this integrated analysis. Notably, in 1 of 21 cases, the presence of a TERT promoter mutation and the absence of a TMPRSS2-ERG fusion would typically favor a diagnosis of urothelial carcinoma, but the aggregate immunohistochemical and molecular findings instead supported a diagnosis of microsatellite unstable prostatic adenocarcinoma with deep deletion of MSH2 and MSH6. Our findings highlight the importance of considering prostatic origin in high-grade carcinoma of the urinary bladder of patients with a history of treated prostate cancer, even when the immunohistochemical findings favor urothelial carcinoma. In a subset of cases, an approach that integrates immunophenotypic and molecular data may help correctly assign site of origin and prevent misdiagnosis that can result from overreliance on any individual immunohistochemical or molecular result.
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Chuang A-Y, DeMarzo AM, Veltri RW, Sharma RB, Bieberich CJ, Epstein JI. Immunohistochemical differentiation of high-grade prostate carcinoma from urothelial carcinoma. Am J Surg Pathol. 2007;31:1246–55.
Epstein JI, Egevad L, Humphrey PA, Montironi R, Members of the ISUP Immunohistochemistry in Diagnostic Urologic Pathology Group. Best practices recommendations in the application of immunohistochemistry in the prostate: report from the International Society of Urologic Pathology consensus conference. Am J Surg Pathol. 2014;38:e6–19.
Chang A, Amin A, Gabrielson E, Illei P, Roden RB, Sharma R, et al. Utility of GATA3 immunohistochemistry in differentiating urothelial carcinoma from prostate adenocarcinoma and squamous cell carcinomas of the uterine cervix, anus, and lung. Am J Surg Pathol. 2012;36:1472–6.
Amin MB, Trpkov K, Lopez-Beltran A, Grignon D, Members of the ISUP Immunohistochemistry in Diagnostic Urologic Pathology Group. Best practices recommendations in the application of immunohistochemistry in the bladder lesions: report from the International Society of Urologic Pathology consensus conference. Am J Surg Pathol. 2014;38:e20–34.
Gordetsky J, Epstein JI. Pseudopapillary features in prostatic adenocarcinoma mimicking urothelial carcinoma: a diagnostic pitfall. Am J Surg Pathol. 2014;38:941–5.
Parwani AV, Kronz JD, Genega EM, Gaudin P, Chang S, Epstein JI. Prostate carcinoma with squamous differentiation: an analysis of 33 cases. Am J Surg Pathol. 2004;28:651–7.
Lotan TL, Gupta NS, Wang W, Toubaji A, Haffner MC, Chaux A, et al. ERG gene rearrangements are common in prostatic small cell carcinomas. Mod Pathol. 2011;24:820–8.
Osunkoya AO, Hansel DE, Sun X, Netto GJ, Epstein JI. Aberrant diffuse expression of p63 in adenocarcinoma of the prostate on needle biopsy and radical prostatectomy: report of 21 cases. Am J Surg Pathol. 2008;32:461–7.
Beltran H, Tomlins S, Aparicio A, Arora V, Rickman D, Ayala G, et al. Aggressive variants of castration-resistant prostate cancer. Clin Cancer Res. 2014;20:2846–50.
Wheeler JA, Zagars GK, Ayala AG. Dedifferentiation of locally recurrent prostate cancer after radiation therapy. Evidence for tumor progression. Cancer. 1993;71:3783–7.
Siders DB, Lee F. Histologic changes of irradiated prostatic carcinoma diagnosed by transrectal ultrasound. Hum Pathol. 1992;23:344–51.
Mazzone E, Mistretta FA, Knipper S, Palumbo C, Tian Z, Pecoraro A, et al. Long-term incidence of secondary bladder and rectal cancer in patients treated with brachytherapy for localized prostate cancer: a large-scale population-based analysis. BJU Int. 2019. https://doi.org/10.1111/bju.14841.
Moschini M, Zaffuto E, Karakiewicz PI, Andrea DD, Foerster B, Abufaraj M, et al. External beam radiotherapy increases the risk of bladder cancer when compared with radical prostatectomy in patients affected by prostate cancer: a population-based analysis. Eur Urol. 2019;75:319–28.
Cancer Genome Atlas Research Network. The molecular taxonomy of primary prostate cancer. Cell. 2015;163:1011–25.
Cancer Genome Atlas Research Network. Comprehensive molecular characterization of urothelial bladder carcinoma. Nature. 2014;507:315–22.
Robertson AG, Kim J, Al-Ahmadie H, Bellmunt J, Guo G, Cherniack AD, et al. Comprehensive molecular characterization of muscle-invasive bladder cancer. Cell. 2017;171:540–5.e25.
Gao J, Aksoy BA, Dogrusoz U, Dresdner G, Gross B, Sumer SO, et al. Integrative analysis of complex cancer genomics and clinical profiles using the cBioPortal. Sci Signal. 2013;6:pl1.
Cerami E, Gao J, Dogrusoz U, Gross BE, Sumer SO, Aksoy BA, et al. The cBio cancer genomics portal: an open platform for exploring multidimensional cancer genomics data. Cancer Disco. 2012;2:401–4.
Killela PJ, Reitman ZJ, Jiao Y, Bettegowda C, Agrawal N, Diaz LA, et al. TERT promoter mutations occur frequently in gliomas and a subset of tumors derived from cells with low rates of self-renewal. Proc Natl Acad Sci USA. 2013;110:6021–6.
Stoehr R, Taubert H, Zinnall U, Giedl J, Gaisa NT, Burger M, et al. Frequency of TERT promoter mutations in prostate cancer. Pathobiology. 2015;82:53–7.
Lara PN, Heilmann AM, Elvin JA, Parikh M, de Vere White R, Gandour-Edwards R, et al. TMPRSS2-ERG fusions unexpectedly identified in men initially diagnosed with nonprostatic malignancies. JCO Precis Oncol. 2017;2017. https://doi.org/10.1200/PO.17.00065.
Alaghehbandan R, Vanecek T, Trpkov K, Comperat E, Kristiansen G, Svajdler M, et al. High-grade adenocarcinoma of the prostate mimicking urothelial carcinoma is negative for TERT mutations. Appl Immunohistochem Mol Morphol. 2019;27:523–8.
Williamson SR, Zhang S, Yao JL, Huang J, Lopez-Beltran A, Shen S, et al. ERG-TMPRSS2 rearrangement is shared by concurrent prostatic adenocarcinoma and prostatic small cell carcinoma and absent in small cell carcinoma of the urinary bladder: evidence supporting monoclonal origin. Mod Pathol. 2011;24:1120–7.
Mannan R, Taylor AS, Spratt DE, Chinnaiyan AM, Montgomery JS, Brown NA, et al. TERT- beyond the territory: Usage of PCR-based TERT promoter assay in defining urothelial carcinoma in a case of long-standing prostatic adenocarcinoma. Pathol Res Pract. 2019;152663.
Joseph NM, Tsokos CG, Umetsu SE, Shain AH, Kelley RK, Onodera C, et al. Genomic profiling of combined hepatocellular-cholangiocarcinoma reveals similar genetics to hepatocellular carcinoma. J Pathol. 2019;248:164–78.
Rausch T, Zichner T, Schlattl A, Stütz AM, Benes V, Korbel JO. DELLY: structural variant discovery by integrated paired-end and split-read analysis. Bioinformatics. 2012;28:i333–9.
Pritchard CC, Morrissey C, Kumar A, Zhang X, Smith C, Coleman I, et al. Complex MSH2 and MSH6 mutations in hypermutated microsatellite unstable advanced prostate cancer. Nat Commun. 2014;5:4988.
Downes MR, Torlakovic EE, Aldaoud N, Zlotta AR, Evans AJ, van der Kwast TH. Diagnostic utility of androgen receptor expression in discriminating poorly differentiated urothelial and prostate carcinoma. J Clin Pathol. 2013;66:779–86.
Tan H-L, Haffner MC, Esopi DM, Vaghasia AM, Giannico GA, Ross HM, et al. Prostate adenocarcinomas aberrantly expressing p63 are molecularly distinct from usual-type prostatic adenocarcinomas. Mod Pathol. 2015;28:446–56.
Miettinen M, McCue PA, Sarlomo-Rikala M, Rys J, Czapiewski P, Wazny K, et al. GATA3: a multispecific but potentially useful marker in surgical pathology: a systematic analysis of 2500 epithelial and nonepithelial tumors. Am J Surg Pathol. 2014;38:13–22.
Mohanty SK, Smith SC, Chang E, Luthringer DJ, Gown AM, Aron M, et al. Evaluation of contemporary prostate and urothelial lineage biomarkers in a consecutive cohort of poorly differentiated bladder neck carcinomas. Am J Clin Pathol. 2014;142:173–83.
Gurel B, Ali TZ, Montgomery EA, Begum S, Hicks J, Goggins M, et al. NKX3.1 as a marker of prostatic origin in metastatic tumors. Am J Surg Pathol. 2010;34:1097–105.
Tyagi A, Chandrasekaran B, Kolluru V, Rai S, Jordan AC, Houda A, et al. Combination of androgen receptor inhibitor and cisplatin, an effective treatment strategy for urothelial carcinoma of the bladder. Urol Oncol. 2019;37:492–502.
Necchi A, Lo Vullo S, Giannatempo P, Raggi D, Perrone F, Nicolai N, et al. Association of androgen receptor expression on tumor cells and PD-L1 expression in muscle-invasive and metastatic urothelial carcinoma: insights for clinical research. Clin Genitourin Cancer. 2018;16:e403–10.
Shah RB. Clinical applications of novel ERG immunohistochemistry in prostate cancer diagnosis and management. Adv Anat Pathol. 2013;20:117–24.
Udager AM, Shi Y, Tomlins SA, Alva A, Siddiqui J, Cao X, et al. Frequent discordance between ERG gene rearrangement and ERG protein expression in a rapid autopsy cohort of patients with lethal, metastatic, castration-resistant prostate cancer. Prostate. 2014;74:1199–208.
Varinot J, Cussenot O, Roupret M, Conort P, Bitker M-O, Chartier-Kastler E, et al. HOXB13 is a sensitive and specific marker of prostate cells, useful in distinguishing between carcinomas of prostatic and urothelial origin. Virchows Arch. 2013;463:803–9.
Krumbholz M, Agaimy A, Stoehr R, Burger M, Wach S, Taubert H, et al. Molecular composition of genomic TMPRSS2-ERG rearrangements in prostate cancer. Dis Markers. 2019;2019:5085373.
Esgueva R, Perner S, LaFargue CJ, Scheble V, Stephan C, Lein M, et al. Prevalence of TMPRSS2–ERG and SLC45A3–ERG gene fusions in a large prostatectomy cohort. Mod Pathol. 2010;23:539–46.
Abida W, Cheng ML, Armenia J, Middha S, Autio KA, Vargas HA, et al. Analysis of the prevalence of microsatellite instability in prostate cancer and response to immune checkpoint blockade. JAMA Oncol. 2019;5:471–8.
This study was funded by the UCSF Department of Pathology Clinical Research Endowment awards granted to EC, KG, and BS. Capture-based next generation sequencing was performed at the UCSF Clinical Cancer Genomics Laboratory.
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Chan, E., Garg, K. & Stohr, B.A. Integrated immunohistochemical and molecular analysis improves diagnosis of high-grade carcinoma in the urinary bladder of patients with prior radiation therapy for prostate cancer. Mod Pathol 33, 1802–1810 (2020). https://doi.org/10.1038/s41379-020-0543-y