Original Research| Volume 148, P440-450, May 2021

Download started.


Ductal variant prostate carcinoma is associated with a significantly shorter metastasis-free survival

Published:March 05, 2021DOI:


      • Ductal adenocarcinoma of the prostate is more clinically aggressive than acinar adenocarcinoma.
      • Ductal adenocarcinoma has shorter time to metastasis.
      • This is the first large non-registry–based study to use metastasis-free survival as an end-point.
      • RB1 loss may be a key molecular driver in clinical difference.



      Ductal adenocarcinoma is an uncommon prostate cancer variant. Previous studies suggest that ductal variant histology may be associated with worse clinical outcomes, but these are difficult to interpret. To address this, we performed an international, multi-institutional study to describe the characteristics of ductal adenocarcinoma, particularly focussing on the effect of presence of ductal variant cancer on metastasis-free survival.


      Patients with ductal variant histology from two institutional databases who underwent radical prostatectomies were identified and compared with an independent acinar adenocarcinoma cohort. After propensity score matching, the effect of the presence of ductal adenocarcinoma on time to biochemical recurrence, initiation of salvage therapy and the development of metastatic disease was determined. Deep whole-exome sequencing was performed for selected cases (n = 8).


      A total of 202 ductal adenocarcinoma and 2037 acinar adenocarcinoma cases were analysed. Survival analysis after matching demonstrated that patients with ductal variant histology had shorter salvage-free survival (8.1 versus 22.0 months, p = 0.03) and metastasis-free survival (6.7 versus 78.6 months, p < 0.0001). Ductal variant histology was consistently associated with RB1 loss, as well as copy number gains in TAP1, SLC4A2 and EHHADH.


      The presence of any ductal variant adenocarcinoma at the time of prostatectomy portends a worse clinical outcome than pure acinar cancers, with significantly shorter times to initiation of salvage therapies and the onset of metastatic disease. These features appear to be driven by uncoupling of chromosomal duplication from cell division, resulting in widespread copy number aberration with specific gain of genes implicated in treatment resistance.


      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'


      Subscribe to European Journal of Cancer
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • International Agency for Research on Cancer
        Pathology and genetics of tumours of the urinary system and male genital organs.
        IARC, 2004
        • Amin A.
        • Epstein J.I.
        Pathologic stage of prostatic ductal adenocarcinoma at radical prostatectomy: effect of percentage of the ductal component and associated grade of acinar adenocarcinoma.
        Am J Surg Pathol. 2011; 35: 615-619
        • Packiam V.T.
        • Patel S.G.
        • Pariser J.J.
        • Richards K.A.
        • Weiner A.B.
        • Paner G.P.
        • et al.
        Contemporary population-based comparison of localized ductal adenocarcinoma and high-risk acinar adenocarcinoma of the prostate.
        Urology. 2015; 86: 777-782
        • Humphrey P.A.
        Histological variants of prostatic carcinoma and their significance.
        Histopathology. 2012; 60: 59-74
        • Young B.W.
        • Lagios M.D.
        Endometrial (papillary) carcinoma of the prostatic utricle--response to orchiectomy. A case report.
        Cancer. 1973; 32: 1293-1300
        • Christensen W.N.
        • Steinberg G.
        • Walsh P.C.
        • Epstein J.I.
        Prostatic duct adenocarcinoma. Findings at radical prostatectomy.
        Cancer. 1991; 67: 2118-2124
        • Seipel A.H.
        • Wiklund F.
        • Wiklund N.P.
        • Egevad L.
        Histopathological features of ductal adenocarcinoma of the prostate in 1,051 radical prostatectomy specimens.
        Virchows Arch. 2013; 462: 429-436
        • Jang W.S.
        • Shin S.-J.
        • Yoon C.Y.
        • Kim M.S.
        • Kang D.H.
        • Kang Y.J.
        • et al.
        Prognostic significance of the proportion of ductal component in ductal adenocarcinoma of the prostate.
        J Urol. 2017; 197: 1048-1053
        • Orihuela E.
        • Green J.M.
        Ductal prostate cancer: contemporary management and outcomes.
        Urol Oncol. 2008; 26: 368-371
        • Wu Y.-P.
        • Chen S.-H.
        • Wang S.-T.
        • Li X.-D.
        • Cai H.
        • Lin Y.-Z.
        • et al.
        Prognostic values of clinicopathological characteristics and survival outcomes in prostate infiltrating ductal carcinoma: a population-based study.
        Oncotarget. 2017; 8: 29048-29055
        • Meeks J.J.
        • Zhao L.C.
        • Cashy J.
        • Kundu S.
        Incidence and outcomes of ductal carcinoma of the prostate in the USA: analysis of data from the Surveillance, Epidemiology, and End Results program.
        BJU Int. 2012; 109: 831-834
        • Tarján M.
        • Lenngren A.
        • Hellberg D.
        • Tot T.
        Immunohistochemical verification of ductal differentiation in prostate cancer.
        APMIS. 2012; 120: 510-518
        • Morgan T.M.
        • Welty C.J.
        • Vakar-Lopez F.
        • Lin D.W.
        • Wright J.L.
        Ductal adenocarcinoma of the prostate: increased mortality risk and decreased serum prostate specific antigen.
        J Urol. 2010; 184: 2303-2307
        • Chow K.
        • Mangiola S.
        • Vazirani J.
        • Peters J.S.
        • Costello A.J.
        • Hovens C.M.
        • et al.
        Obesity suppresses tumor attributable PSA, affecting risk categorization.
        Endocr Relat Canc. 2018; 25: 561-568
        • Chow K.
        • Herrera P.
        • Stuchbery R.
        • Peters J.S.
        • Costello A.J.
        • Hovens C.M.
        • et al.
        Late biochemical recurrence after radical prostatectomy is associated with a slower rate of progression.
        BJU Int. 2019; 123: 976-984
        • Moch H.
        • Humphrey P.A.
        • Ulbright T.M.
        • Reuter V.E.
        WHO classification of tumours of the urinary system and male genital organs.
        in: World Health Organization classification of tumours. vol. 8. International Agency for Research on Cancer (IARC), Lyon2016: 400
        • Seipel A.H.
        • Delahunt B.
        • Samaratunga H.
        • Amin M.
        • Barton J.
        • Berney D.M.
        • et al.
        Diagnostic criteria for ductal adenocarcinoma of the prostate: interobserver variability among 20 expert uropathologists.
        Histopathology. 2014; 65: 216-227
        • Eisenhauer E.A.
        • Therasse P.
        • Bogaerts J.
        • Schwartz L.H.
        • Sargent D.
        • Ford R.
        • et al.
        New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1).
        Eur J Canc. 2009; 45: 228-247
        • Bedő J.
        BioShake: a Haskell EDSL for bioinformatics workflows.
        PeerJ. 2019; 7e7223
        • Armenia J.
        • Wankowicz S.A.M.
        • Liu D.
        • Gao J.
        • Kundra R.
        • Reznik E.
        • et al.
        The long tail of oncogenic drivers in prostate cancer.
        Nat Genet. 2018; 50: 645-651
        • Cancer Genome Atlas Research Network
        The molecular taxonomy of primary prostate cancer.
        Cell. 2015; 163: 1011-1025
        • Robinson D.
        • Van Allen E.M.
        • Wu Y.-M.
        • Schultz N.
        • Lonigro R.J.
        • Mosquera J.-M.
        • et al.
        Integrative clinical genomics of advanced prostate cancer.
        Cell. 2015; 161: 1215-1228
        • Xie W.
        • Regan M.M.
        • Buyse M.
        • Halabi S.
        • Kantoff P.W.
        • Sartor O.
        • et al.
        Metastasis-free survival is a strong surrogate of overall survival in localized prostate cancer.
        J Clin Oncol. 2017; 35: 3097-3104
        • Spahn M.
        Re: metastasis-free survival is a strong surrogate of overall survival in localized prostate cancer.
        Eur Urol. 2018; 73: 141-142
        • WU Shipley
        • Seiferheld W.
        • Lukka H.R.
        • Major P.P.
        • Heney N.M.
        • Grignon D.J.
        • et al.
        Radiation with or without antiandrogen therapy in recurrent prostate cancer.
        N Engl J Med. 2017; 376: 417-428
        • Gillard M.
        • Lack J.
        • Pontier A.
        • Gandla D.
        • Hatcher D.
        • Sowalsky A.G.
        • et al.
        Integrative genomic analysis of coincident cancer foci implicates CTNNB1 and PTEN alterations in ductal prostate cancer.
        Eur Urol Focus. 2019; 5: 433-442
        • Dyson N.J.
        RB1: a prototype tumor suppressor and an enigma.
        Genes Dev. 2016; 30: 1492-1502
        • Hamid A.A.
        • Gray K.P.
        • Shaw G.
        • MacConaill L.E.
        • Evan C.
        • Bernard B.
        • et al.
        Compound genomic alterations of TP53, PTEN, and RB1 tumor suppressors in localized and metastatic prostate cancer.
        Eur Urol. 2019; 76: 89-97
        • Nava Rodrigues D.
        • Casiraghi N.
        • Romanel A.
        • Crespo M.
        • Miranda S.
        • Rescigno P.
        • et al.
        RB1 heterogeneity in advanced metastatic castration-resistant prostate cancer.
        Clin Canc Res. 2019; 25: 687-697
        • Seipel A.H.
        • Samaratunga H.
        • Delahunt B.
        • Wiklund P.
        • Clements M.
        • Egevad L.
        Immunohistochemistry of ductal adenocarcinoma of the prostate and adenocarcinomas of non-prostatic origin: a comparative study.
        APMIS. 2016; 124: 263-270
        • Jardel P.
        • Debiais C.
        • Godet J.
        • Irani J.
        • Fromont G.
        Ductal carcinoma of the prostate shows a different immunophenotype from high grade acinar cancer.
        Histopathology. 2013; 63: 57-63
        • Morais C.L.
        • Herawi M.
        • Toubaji A.
        • Albadine R.
        • Hicks J.
        • Netto G.J.
        • et al.
        PTEN loss and ERG protein expression are infrequent in prostatic ductal adenocarcinomas and concurrent acinar carcinomas.
        Prostate. 2015; 75: 1610-1619
        • Corcoran N.M.
        • Clarkson M.J.
        • Stuchbery R.
        • Hovens C.M.
        Molecular pathways: targeting DNA repair pathway defects enriched in metastasis.
        Clin Canc Res. 2016; 22: 3132-3137
        • Schweizer M.T.
        • Antonarakis E.S.
        • Bismar T.A.
        • Guedes L.B.
        • Cheng H.H.
        • Tretiakova M.S.
        • et al.
        Genomic characterization of prostatic ductal adenocarcinoma identifies a high prevalence of DNA repair gene mutations.
        JCO Precis Oncol. 2019; 3
        • Isaacsson Velho P.
        • Silberstein J.L.
        • Markowski M.C.
        • Luo J.
        • Lotan T.L.
        • Isaacs W.B.
        • et al.
        Intraductal/ductal histology and lymphovascular invasion are associated with germline DNA-repair gene mutations in prostate cancer.
        Prostate. 2018; 78: 401-407
        • Xu M.
        • Li L.
        • Liu Z.
        • Jiao Z.
        • Xu P.
        • Kong X.
        • et al.
        ABCB2 (TAP1) as the downstream target of SHH signaling enhances pancreatic ductal adenocarcinoma drug resistance.
        Canc Lett. 2013; 333: 152-158
        • Zhang L.-J.
        • Lu R.
        • Song Y.-N.
        • Zhu J.-Y.
        • Xia W.
        • Zhang M.
        • et al.
        Knockdown of anion exchanger 2 suppressed the growth of ovarian cancer cells via mTOR/p70S6K1 signaling.
        Sci Rep. 2017; 7: 6362
        • He J.
        • Zhao H.
        • Deng D.
        • Wang Y.
        • Zhang X.
        • Zhao H.
        • et al.
        Screening of significant biomarkers related with prognosis of liver cancer by lncRNA-associated ceRNAs analysis.
        J Cell Physiol. 2019;
        • Lawrence M.G.
        • Porter L.H.
        • Clouston D.
        • Murphy D.G.
        • Frydenberg M.
        • Taylor R.A.
        • et al.
        Knowing what's growing: why ductal and intraductal prostate cancer matter.
        Sci Transl Med. 2020; 12
        • Porter L.H.
        • Lawrence M.G.
        • Ilic D.
        • Clouston D.
        • Bolton D.M.
        • Frydenberg M.
        • et al.
        Systematic review links the prevalence of intraductal carcinoma of the prostate to prostate cancer risk categories.
        Eur Urol. 2017; 72: 492-495

      Linked Article