De novo neuroendocrine transdifferentiation in primary prostate cancer–a phenotype associated with advanced clinico-pathologic features and aggressive outcome

Abstract

Neuroendocrine transdifferentiation of high-grade prostate cancer (PCA-NT) comprises a morphologic and immunophenotypic transition from conventional adenocarcinoma towards high-grade neuroendocrine/small cell carcinoma. This phenomenon is frequently observed post androgen deprivation and/or radiotherapy, but de novo instances are increasingly recognized. Herein, we report a series of de novo PCA-NT focusing on characteristic morphologic, immunophenotypic and clinical features. Treatment naïve PCA-NT were identified. IHC for PSA, NKX3.1, Chromogranin, Synaptophysin, Cyclin D1, RB and Ki67 were performed. Radiology, treatment and follow-up data were reviewed. Sixteen patients were included. Apart from focal areas of high-grade prostate cancer with acinar features (reminiscent of Grade Group 5 disease), extensive areas with sheets of cells with deep amphophilic/basophilic cytoplasm, enlarged, hyperchromatic nuclei with granular chromatin and inconspicuous to prominent nucleoli with high mitotic activity were identified. Immunohistochemistry showed patchy NKX3.1, patchy PSA, variable Synaptophysin and Chromogranin; RB and CyclinD1 showed loss of expression. Ki67 showed high proliferative index, in most cases. Adverse radiologic findings and metastases were documented in most cases. Two patients died of disease. De novo PCA-NT exhibits high-grade nuclei, high mitotic activity, reduced PSA expression with high Ki67 and functional inactivation of RB1 pathway, suggesting transition from androgen-driven to proliferation-driven phenotype. Most cases presented at advanced stage with adverse radiological findings, metastasis at time of diagnosis, and high mortality. In light of their prognostic and therapeutic implications, pathologists may need to maintain a sensitive threshold for performing immunostains–in particular, Ki67 and CyclinD1–when presented with such cases in their day to day clinical practice.

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References

  1. 1.

    Siegel RL, Miller KD, Jemal A. Cancer statistics, 2020. CA Cancer J Clin. 2020;70(1):7–30.

    Article  Google Scholar 

  2. 2.

    Lipianskaya J, Cohen A, Chen C, et al. Androgen-deprivation therapy-induced aggressive prostate cancer with neuroendocrine differentiation. Asian J Androl. 2014;16(4):541–4.

    CAS  Article  Google Scholar 

  3. 3.

    Freschi M, Colombo R, Naspro R, et al. Primary and pure neuroendocrine tumor of the prostate. Eur Urol. 2004;45(2):166–9.

    Article  Google Scholar 

  4. 4.

    Humphrey PA, Moch H, Cubilla A, et al. The 2016 WHO Classification of Tumours of the Urinary System and Male Genital Organs-Part B: Prostate and Bladder Tumours. Eur Urol. 2016;70(1):106–19.

    Article  Google Scholar 

  5. 5.

    Hirano D, Okada Y, Minei S, et al. Neuroendocrine differentiation in hormone refractory prostate cancer following androgen deprivation therapy. Eur Urol. 2004;45(5):586–92.

    CAS  Article  Google Scholar 

  6. 6.

    Beltran H, Hruszkewwycz A, Scher H, et al. The Role of Lineage Plasticity in Prostate Cancer Therapy Resistance. Clin Cancer Res. 2019;25(23):6916–24.

    CAS  PubMed  PubMed Central  Google Scholar 

  7. 7.

    Epstein JI, Egevad L, Amin M, et al. The International Society of Urological Pathology ISUP Consensus Conference on Gleason Grading of Prostatic Carcinoma Definition of Grading Patterns and Proposal for a New Grading System. Am J Surg Pathol. 2016;40(2):244–52.

    Article  Google Scholar 

  8. 8.

    Epstein JI, Zelefsky M, Sjoberg D, et al. A Contemporary Prostate Cancer Grading System: A Validated Alternative to the Gleason Score. Eur Urol. 2016;69(3):428–35.

    Article  Google Scholar 

  9. 9.

    Kryvenko ON, Epstein JI. Prostate Cancer Grading: A Decade After the 2005 Modified Gleason Grading System. Arch Pathol Lab Med. 2016;140(10):1140–52.

    Article  Google Scholar 

  10. 10.

    Buyyounouski MK, Choyke P, McKenney J, et al. Prostate cancer major changes in the American Joint Committee on Cancer eighth edition cancer staging manual. CA Cancer J Clin. 2017;67(3):245–53.

    Article  Google Scholar 

  11. 11.

    Amin MB, Greene F, Edge S, et al. The Eighth Edition AJCC Cancer Staging Manual: Continuing to build a bridge from a population-based to a more “personalized” approach to cancer staging. CA Cancer J Clin. 2017;67(2):93–9.

    Article  Google Scholar 

  12. 12.

    Sun Y, Niu J, Huang J. Neuroendocrine differentiation in prostate cancer. Am J Transl Res. 2009;1(2):148–62.

    CAS  PubMed  PubMed Central  Google Scholar 

  13. 13.

    Huang J, Wu C, SantAgnese P, et al. Function and molecular mechanisms of neuroendocrine cells in prostate cancer. Anal Quant Cytol Histol. 2007;29(3):128–38.

    PubMed  Google Scholar 

  14. 14.

    Beltran H, Tomlins S, Aparicio A, et al. Aggressive variants of castration-resistant prostate cancer. Clin Cancer Res. 2014;20(11):2846–50.

    CAS  Article  Google Scholar 

  15. 15.

    Bluemn EG, Coleman I, Lucsa J, et al. Androgen Receptor Pathway-Independent Prostate Cancer Is Sustained through FGF Signaling. Cancer Cell. 2017;32(4):474-489.e6.

    CAS  Article  Google Scholar 

  16. 16.

    Prendeville S, Al-Bozom I, Comperat E, et al. Prostate carcinoma with amphicrine features: further refining the spectrum of neuroendocrine differentiation in tumours of primary prostatic origin? Histopathology. 2017;71(6):926–33.

    Article  Google Scholar 

  17. 17.

    Bellur S, Van der Kwast T, Mete O. Evolving concepts in prostatic neuroendocrine manifestations: from focal divergent differentiation to amphicrine carcinoma. Hum Pathol. 2019;85:313–27.

    CAS  Article  Google Scholar 

  18. 18.

    Wu C, Wyatt A, Lapuk A, et al. Integrated genome and transcriptome sequencing identifies a novel form of hybrid and aggressive prostate cancer. J Pathol. 2012;227(1):53–61.

    CAS  Article  Google Scholar 

  19. 19.

    Fine SW. Neuroendocrine tumors of the prostate. Mod Pathol. 2018;31(S1):S122-132.

    Article  Google Scholar 

  20. 20.

    Priemer DS, Montironi R, Wang L, et al. Neuroendocrine Tumors of the Prostate: Emerging Insights from Molecular Data and Updates to the 2016 World Health Organization Classification. Endocr Pathol. 2016;27(2):123–35.

    CAS  Article  Google Scholar 

  21. 21.

    Epstein JI, Amin M, Beltran H, et al. Proposed morphologic classification of prostate cancer with neuroendocrine differentiation. Am J Surg Pathol. 2014;38(6):756–67.

    Article  Google Scholar 

  22. 22.

    Terry S, Beltran H. The many faces of neuroendocrine differentiation in prostate cancer progression. Front Oncol. 2014;4:60.

    Article  Google Scholar 

  23. 23.

    Dankert JT, Wiesehofer M, Czyrnik E, et al. The deregulation of miR-17/CCND1 axis during neuroendocrine transdifferentiation of LNCaP prostate cancer cells. PLoS ONE. 2018;13(7):e0200472.

    Article  Google Scholar 

  24. 24.

    Cyrta J, Augspach A, De Filippo M, et al. Role of specialized composition of SWI/SNF complexes in prostate cancer lineage plasticity. Nat Commun. 2020;11:5529.

    Article  Google Scholar 

  25. 25.

    Mu P, Zhang Z, Benelli M, et al. SOX2 promotes lineage plasticity and antiandrogen resistance in TP53- and RB1-deficient prostate cancer. Science. 2017;355(6320):84–8.

    CAS  Article  Google Scholar 

  26. 26.

    Ku SY, Rosario S, Wang Y, et al. Rb1 and Trp53 cooperate to suppress prostate cancer lineage plasticity, metastasis, and antiandrogen resistance. Science. 2017;355(6320):78–83.

    CAS  Article  Google Scholar 

  27. 27.

    Tetu B, Ro J, Ayala A, et al. Small cell carcinoma of the prostate. Part I. A clinicopathologic study of 20 cases. Cancer. 1987;59(10):1803–9.

    CAS  Article  Google Scholar 

  28. 28.

    Aparicio AM, Harzstark A, Corn P, et al. Platinum-based chemotherapy for variant castrate-resistant prostate cancer. Clin Cancer Res. 2013;19(13):3621–30.

    CAS  Article  Google Scholar 

  29. 29.

    Corn PG, Heath E, Zurita A, et al. Cabazitaxel plus carboplatin for the treatment of men with metastatic castration-resistant prostate cancers: a randomised, open-label, phase 1–2 trial. Lancet Oncol. 2019;20(10):1432–43.

    CAS  Article  Google Scholar 

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This research did not receive any specific grant from funding agencies in the public, commercial, or non-for-profit sectors.

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EA—acquisition of data, interpretation of data and writing up the manuscript. ZR, AC, VD, RM, LK, BH, SK, TM, JM, AA, GP, UV, JA, DS—contribution to design, revising it critically for important intellectual content. MD—contribution to design and acquisition of data. AU—Contribution to the concept and design, revising it critically and final approval of the version to be published. RM—Senior author, corresponding author, contribution to the concept and design, final approval of the version to be published.

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Correspondence to Rohit Mehra.

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Conflict of interest

The University of Michigan has been issued a patent on the detection of ETS gene fusions in prostate cancer, on which Rohit Mehra and Arul M. Chinnaiyan are listed as co-inventors. All other authors have no relevant disclosures.

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Abdulfatah, E., Reichert, Z.R., Davenport, M.S. et al. De novo neuroendocrine transdifferentiation in primary prostate cancer–a phenotype associated with advanced clinico-pathologic features and aggressive outcome. Med Oncol 38, 26 (2021). https://doi.org/10.1007/s12032-021-01473-2

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Keywords

  • Prostate cancer
  • Neuroendocrine
  • Transdifferentiation
  • High-grade