A Review of Prostate-Specific Membrane Antigen (PSMA) Positron Emission Tomography (PET) in Renal Cell Carcinoma (RCC)

  • Thomas AhnEmail author
  • Matthew J. Roberts
  • Aous Abduljabar
  • Andre Joshi
  • Marlon Perera
  • Handoo Rhee
  • Simon Wood
  • Ian Vela
Review Article


Metastatic renal cell carcinoma (mRCC) is a disease that portends poor prognosis despite an increasing number of novel systemic treatment options including new targeted therapies and immunotherapy. Ablative intervention directed at oligometastatic RCC has demonstrated survival benefit. Consequently, developing techniques for improved staging of mRCC on contemporary imaging modalities including X-ray computed tomography (CT), magnetic resonance imaging (MRI) and/or bone scan (BS) is a clinical priority. This is relevant for metastatic deposits too small to characterize or lymph nodes within physiological normality. Prostate-specific membrane antigen (PSMA) is a type II transmembrane glycoprotein highly expressed on prostate cancer epithelial cells. Recently, small molecules targeting the PSMA receptor, linked to radioactive isotopes have been developed for use with positron emission tomography (PET). Despite its nomenclature, PSMA has also been found to be expressed in the neovasculature of non-prostate cancers such as renal cell carcinoma (RCC) and hence PSMA PET/CT imaging has been proposed as an alternative staging modality. Preliminary small studies involving the use of PSMA PET/CT imaging in mRCC have been encouraging with evidence of improved staging sensitivity which has directly led to change in management in some cases. Given these early encouraging reports, we performed a comprehensive narrative review on the available evidence, including the scientific basis for PSMA expression in RCC, the role of PSMA PET/CT imaging with potential clinical implications in mRCC, its limitations and future opportunities.

Key words

Positron emission tomography Prostate-specific membrane antigen Gallium Renal cell carcinoma Metastasis 


Funding Information.

This research received no specific grant from any funding agency in public, commercial, or not-for-profit sectors. IV is supported by a Movember Clinician Scientist Award awarded through Prostate Cancer Foundation of Australia’s Research Program.

Compliance with Ethical Standards

Conflict of Interest

All authors declare that there is no conflict of interest.

Human and Animal Rights

This article does not contain any studies with human participants or animals performed by any of the authors.


  1. 1.
    Znaor A, Lortet-Tieulent J, Laversanne MJ et al (2015) International variations and trends in renal cell carcinoma incidence and mortality. Eur Urol 67:519–530CrossRefGoogle Scholar
  2. 2.
    Gupta K, Miller JD, Li JZ, Russell MW, Charbonneau C (2008) Epidemiologic and socioeconomic burden of metastatic renal cell carcinoma (mRCC): a literature review. Cancer Treat Rev 34:193–205CrossRefGoogle Scholar
  3. 3.
    Dabestani S, Thorstenson A, Lindblad P, Harmenberg U, Ljungberg B, Lundstam S (2016) Renal cell carcinoma recurrences and metastases in primary non-metastatic patients: a population-based study. World J Urol 34:1081–1086CrossRefGoogle Scholar
  4. 4.
    Thompson RH, Hill JR, Babayev Y, Cronin A, Kaag M, Kundu S, Bernstein M, Coleman J, Dalbagni G, Touijer K, Russo P (2009) Metastatic renal cell carcinoma risk according to tumor size. J Urol 182:41–45CrossRefGoogle Scholar
  5. 5.
    Capogrosso P, Capitanio U, La Croce G et al (2016) Follow-up after treatment for renal cell carcinoma: the evidence beyond the guidelines. Eur Urol Focus 1:272–281CrossRefGoogle Scholar
  6. 6.
    Pierorazio PM, Johnson MH, Patel HD, Sozio SM, Sharma R, Iyoha E, Bass EB, Allaf ME (2016) Management of Renal Masses and Localized Renal Cancer: systematic review and meta-analysis. J Urol 196:989–999CrossRefGoogle Scholar
  7. 7.
    Pantuck AJ, Zisman A, Belldegrun AS (2001) The changing natural history of renal cell carcinoma. J Urol 166:1611–1623CrossRefGoogle Scholar
  8. 8.
    Escudier B, Pluzanska A, Koralewski P, Ravaud A, Bracarda S, Szczylik C, Chevreau C, Filipek M, Melichar B, Bajetta E, Gorbunova V, Bay JO, Bodrogi I, Jagiello-Gruszfeld A, Moore N (2007) Bevacizumab plus interferon alfa-2a for treatment of metastatic renal cell carcinoma: a randomised, double-blind phase III trial. Lancet 370:2103–2111CrossRefGoogle Scholar
  9. 9.
    Motzer RJ, Russo P (2000) Systemic therapy for renal cell carcinoma. J Urol 163:408–417CrossRefGoogle Scholar
  10. 10.
    Brufau BP, Cerqueda CS, Villalba LB, Izquierdo RS, González BM, Molina CN (2013) Metastatic renal cell carcinoma: radiologic findings and assessment of response to targeted antiangiogenic therapy by using multidetector CT. Radiographics 33:1691–1716CrossRefGoogle Scholar
  11. 11.
    Loh J, Davis ID, Martin JM, Siva S (2014) Extracranial oligometastatic renal cell carcinoma: current management and future directions. Future Oncol 10:761–774CrossRefGoogle Scholar
  12. 12.
    Ghosh A, Heston WD (2004) Tumor target prostate specific membrane antigen (PSMA) and its regulation in prostate cancer. J Cell Biochem 91:528–539CrossRefGoogle Scholar
  13. 13.
    Leek J, Lench N, Maraj B, Bailey A, Carr IM, Andersen S, Cross J, Whelan P, MacLennan K, Meredith DM (1995) Prostate-specific membrane antigen: evidence for the existence of a second related human gene. Br J Cancer 72:583–588CrossRefGoogle Scholar
  14. 14.
    Silver DA, Pellicer I, Fair WR, Heston WD, Cordon-Cardo C (1997) Prostate-specific membrane antigen expression in normal and malignant human tissues. Clin Cancer Res 3:81–85Google Scholar
  15. 15.
    Bostwick DG, Pacelli A, Blute M, Roche P, Murphy GP (1998) Prostate specific membrane antigen expression in prostatic intraepithelial neoplasia and adenocarcinoma: a study of 184 cases. Cancer 82:2256–2261CrossRefGoogle Scholar
  16. 16.
    Perera M, Papa N, Christidis D, Wetherell D, Hofman MS, Murphy DG, Bolton D, Lawrentschuk N (2016) Sensitivity, specificity, and predictors of positive 68Ga-prostate-specific membrane antigen positron emission tomography in advanced prostate cancer: a systematic review and meta-analysis. Eur Urol 70:926–937CrossRefGoogle Scholar
  17. 17.
    Perera M, Murphy D, Lawrentschuk N (2018) Prostate-specific membrane antigen positron emission tomography/computed tomography in locally advanced, recurrent, and metastatic prostate cancer. JAMA Oncol 4:748–749CrossRefGoogle Scholar
  18. 18.
    Kinoshita Y, Kuratsukuri K, Landas S, Imaida K, Rovito PM Jr, Wang CY, Haas GP (2006) Expression of prostate-specific membrane antigen in normal and malignant human tissues. World J Surg 30:628–636CrossRefGoogle Scholar
  19. 19.
    Kirchner J, Schaarschmidt BM, Sawicki LM, Heusch P, Hautzel H, Ermert J, Rabenalt R, Antoch G, Buchbender C (2017) Evaluation of practical interpretation hurdles in 68Ga-PSMA PET/CT in 55 patients: physiological tracer distribution and incidental tracer uptake. Clin Nucl Med 42:e322–e327CrossRefGoogle Scholar
  20. 20.
    Baccala A, Sercia L, Li J, Heston W, Zhou M (2007) Expression of prostate-specific membrane antigen in tumor-associated neovasculature of renal neoplasms. Urology 70:385–390CrossRefGoogle Scholar
  21. 21.
    Chang SS, Reuter VE, Heston WD, Gaudin PB (2001) Metastatic renal cell carcinoma neovasculature expresses prostate-specific membrane antigen. Urology 57:801–805CrossRefGoogle Scholar
  22. 22.
    Cohen D, Zhou M (2005) Molecular genetics of familial renal cell carcinoma syndromes. Clin Lab Med 25:259–277CrossRefGoogle Scholar
  23. 23.
    Spatz S, Tolkach Y, Jung K, Stephan C, Busch J, Ralla B, Rabien A, Feldmann G, Brossart P, Bundschuh RA, Ahmadzadehfar H, Essler M, Toma M, Müller SC, Ellinger J, Hauser S, Kristiansen G (2018) Comprehensive evaluation of prostate specific membrane antigen expression in the vasculature of renal tumors: implications for imaging studies and prognostic role. J Urol 199:370–377CrossRefGoogle Scholar
  24. 24.
    Gorin MA, Rowe SP, Hooper JE, Kates M, Hammers HJ, Szabo Z, Pomper MG, Allaf ME (2017) PSMA-targeted 18F-DCFPyL PET/CT imaging of clear cell renal cell carcinoma: results from a rapid autopsy. Eur Urol 71:145–146CrossRefGoogle Scholar
  25. 25.
    Rhee H, Ng KL, Tse BW et al (2016) Using prostate specific membrane antigen (PSMA) expression in clear cell renal cell carcinoma for imaging advanced disease. Pathology 48:613–616CrossRefGoogle Scholar
  26. 26.
    Rhee H, Blazak J, Tham CM, Ng KL, Shepherd B, Lawson M, Preston J, Vela I, Thomas P, Wood S (2016) Pilot study: use of gallium-68 PSMA PET for detection of metastatic lesions in patients with renal tumour. EJNMMI Res 6:76CrossRefGoogle Scholar
  27. 27.
    Sawicki LM, Buchbender C, Boos J, Giessing M, Ermert J, Antke C, Antoch G, Hautzel H (2017) Diagnostic potential of PET/CT using a 68Ga-labelled prostate-specific membrane antigen ligand in whole-body staging of renal cell carcinoma: initial experience. Eur J Nucl Med Mol Imaging 44:102–107CrossRefGoogle Scholar
  28. 28.
    Al-Ahmadie HA, Olgac S, Gregor PD et al (2008) Expression of prostate-specific membrane antigen in renal cortical tumors. Mod Pathol 21:727–732CrossRefGoogle Scholar
  29. 29.
    Dumas F, Gala JL, Berteau P et al (1999) Molecular expression of PSMA mRNA and protein in primary renal tumors. Int J Cancer 80:799–803CrossRefGoogle Scholar
  30. 30.
    Chang SS, Reuter VE, Heston WD, Bander NH, Grauer LS, Gaudin PB (1999) Five different anti-prostate-specific membrane antigen (PSMA) antibodies confirm PSMA expression in tumor-associated neovasculature. Cancer Res 59:3192–3198Google Scholar
  31. 31.
    Martinez de Llano SR, Delgado-Bolton RC, Jimenez-Vicioso A et al (2007) Meta-analysis of the diagnostic performance of 18F-FDG PET in renal cell carcinoma. Rev Esp Med Nucl 26:19–29CrossRefGoogle Scholar
  32. 32.
    Wang HY, Ding HJ, Chen JH, Chao CH, Lu YY, Lin WY, Kao CH (2012) Meta-analysis of the diagnostic performance of [18F]FDG-PET and PET/CT in renal cell carcinoma. Cancer Imaging 12:464–474CrossRefGoogle Scholar
  33. 33.
    Demirci E, Ocak M, Kabasakal L, Decristoforo C, Talat Z, Halaç M, Kanmaz B (2014) 68Ga-PSMA PET/CT imaging of metastatic clear cell renal cell carcinoma. Eur J Nucl Med Mol Imaging 41:1461–1462CrossRefGoogle Scholar
  34. 34.
    Rowe SP, Gorin MA, Hammers HJ, Som Javadi M, Hawasli H, Szabo Z, Cho SY, Pomper MG, Allaf ME (2015) Imaging of metastatic clear cell renal cell carcinoma with PSMA-targeted 18F-DCFPyL PET/CT. Ann Nucl Med 29:877–882CrossRefGoogle Scholar
  35. 35.
    Rowe SP, Gorin MA, Hammers HJ, Pomper MG, Allaf ME, Javadi MS (2016) Detection of 18F-FDG PET/CT occult lesions with 18F-DCFPyL PET/CT in a patient with metastatic renal cell carcinoma. Clin Nucl Med 41:83–85CrossRefGoogle Scholar
  36. 36.
    Einspieler I, Tauber R, Maurer T, Schwaiger M, Eiber M (2016) 68Ga prostate-specific membrane antigen uptake in renal cell cancer lymph node metastases. Clin Nucl Med 41:e261–e262CrossRefGoogle Scholar
  37. 37.
    Sasikumar A, Joy A, Nanabala R, Unni M, TK P (2016) Complimentary pattern of uptake in 18F-FDG PET/CT and 68Ga-prostate-specific membrane antigen PET/CT in a case of metastatic clear cell renal carcinoma. Clin Nucl Med 41:e517–e519CrossRefGoogle Scholar
  38. 38.
    Siva S, Callahan J, Pryor D, Martin J, Lawrentschuk N, Hofman MS (2017) Utility of (68) Ga prostate specific membrane antigen - positron emission tomography in diagnosis and response assessment of recurrent renal cell carcinoma. J Med Imaging Radiat Oncol 61:372–378CrossRefGoogle Scholar
  39. 39.
    Zacho HD, Nielsen JB, Dettmann K, Haberkorn U, Petersen LJ (2017) Incidental detection of thyroid metastases from renal cell carcinoma using 68Ga-PSMA PET/CT to assess prostate cancer recurrence. Clin Nucl Med 42:221–222CrossRefGoogle Scholar
  40. 40.
    Joshi A, Nicholson C, Rhee H, Gustafson S, Miles K, Vela I (2017) Incidental malignancies identified during staging for prostate cancer with 68Ga prostate-specific membrane antigen HBED-CC positron emission tomography imaging. Urology 104:e3–e4CrossRefGoogle Scholar
  41. 41.
    Yin Y, Campbell SP, Markowski MC, Pierorazio PM, Pomper MG, Allaf ME, Rowe SP, Gorin MA (2018) Inconsistent detection of sites of metastatic non-clear cell renal cell carcinoma with PSMA-targeted [18F] DCFPyL PET/CT. Mol Imaging BiolGoogle Scholar
  42. 42.
    Corfield J, Perera M, Bolton D, Lawrentschuk N (2018) 68Ga-prostate specific membrane antigen (PSMA) positron emission tomography (PET) for primary staging of high-risk prostate cancer: a systematic review. World J Urol 36:519–527CrossRefGoogle Scholar
  43. 43.
    Udovicich C, Perera M, Hofman MS, Siva S, del Rio A, Murphy DG, Lawrentschuk N (2017) 68Ga-prostate-specific membrane antigen-positron emission tomography/computed tomography in advanced prostate cancer: current state and future trends. Prostate Int 5:125–129CrossRefGoogle Scholar
  44. 44.
    Rhee H, Thomas P, Shepherd B, Gustafson S, Vela I, Russell PJ, Nelson C, Chung E, Wood G, Malone G, Wood S, Heathcote P (2016) Prostate specific membrane antigen positron emission tomography may improve the diagnostic accuracy of multiparametric magnetic resonance imaging in localized prostate cancer. J Urol 196:1261–1267CrossRefGoogle Scholar
  45. 45.
    Backhaus P, Noto B, Avramovic N, Grubert LS, Huss S, Bögemann M, Stegger L, Weckesser M, Schäfers M, Rahbar K (2018) Targeting PSMA by radioligands in non-prostate disease-current status and future perspectives. Eur J Nucl Med Mol Imaging 45:860–877CrossRefGoogle Scholar
  46. 46.
    Salas Fragomeni RA, Amir T, Sheikhbahaei S, Harvey SC, Javadi MS, Solnes LB, Kiess AP, Allaf ME, Pomper MG, Gorin MA, Rowe SP (2018) Imaging of nonprostate cancers using PSMA-targeted radiotracers: rationale, current state of the field, and a call to arms. J Nucl Med 59:871–877CrossRefGoogle Scholar
  47. 47.
    Evangelista L, Basso U, Maruzzo M, Novara G (2018) The role of radiolabeled prostate-specific membrane antigen positron emission tomography/computed tomography for the evaluation of renal cancer. Eur Urol Focus S2405–4569(18)30223–30232.
  48. 48.
    Hangaard L, Jochumsen MR, Vendelbo MH, Bouchelouche K (2017) Metastases from colorectal cancer avid on 68Ga-PSMA PET/CT. Clin Nucl Med 42:532–533CrossRefGoogle Scholar
  49. 49.
    Roy SG, Parida GK, Tripathy S, Singhal A, Tripathi M, Bal C (2017) In vivo demonstration of PSMA expression in adenocarcinoma urinary bladder using 68Ga-PSMA 11 PET/CT. Clin Nucl Med 42:542–543Google Scholar
  50. 50.
    Wang HL, Wang SS, Song WH, Pan Y, Yu HP, Si TG, Liu Y, Cui XN, Guo Z (2015) Expression of prostate-specific membrane antigen in lung cancer cells and tumor neovasculature endothelial cells and its clinical significance. PLoS One 10:e0125924CrossRefGoogle Scholar
  51. 51.
    Ardies PJ, Gykiere P, Goethals L, de Mey J, de Geeter F, Everaert H (2017) PSMA uptake in mediastinal sarcoidosis. Clin Nucl Med 42:303–305CrossRefGoogle Scholar
  52. 52.
    Pyka T, Weirich G, Einspieler I, Maurer T, Theisen J, Hatzichristodoulou G, Schwamborn K, Schwaiger M, Eiber M (2016) 68Ga-PSMA-HBED-CC PET for differential diagnosis of suggestive lung lesions in patients with prostate cancer. J Nucl Med 57:367–371CrossRefGoogle Scholar
  53. 53.
    Gordon IO, Tretiakova MS, Noffsinger AE, Hart J, Reuter VE, al-Ahmadie HA (2008) Prostate-specific membrane antigen expression in regeneration and repair. Mod Pathol 21:1421–1427CrossRefGoogle Scholar
  54. 54.
    Motzer RJ, Hutson TE, Tomczak P, Michaelson MD, Bukowski RM, Rixe O, Oudard S, Negrier S, Szczylik C, Kim ST, Chen I, Bycott PW, Baum CM, Figlin RA (2007) Sunitinib versus interferon alfa in metastatic renal-cell carcinoma. N Engl J Med 356:115–124CrossRefGoogle Scholar
  55. 55.
    Sternberg CN, Hawkins RE, Wagstaff J, Salman P, Mardiak J, Barrios CH, Zarba JJ, Gladkov OA, Lee E, Szczylik C, McCann L, Rubin SD, Chen M, Davis ID (2013) A randomised, double-blind phase III study of pazopanib in patients with advanced and/or metastatic renal cell carcinoma: final overall survival results and safety update. Eur J Cancer 49:1287–1296CrossRefGoogle Scholar
  56. 56.
    Choueiri TK, Motzer RJ (2017) Systemic therapy for metastatic renal-cell carcinoma. N Engl J Med 376:354–366CrossRefGoogle Scholar
  57. 57.
    Baum RP, Kulkarni HR, Schuchardt C, Singh A, Wirtz M, Wiessalla S, Schottelius M, Mueller D, Klette I, Wester HJ (2016) 177Lu-labeled prostate-specific membrane antigen radioligand therapy of metastatic castration-resistant prostate cancer: safety and efficacy. J Nucl Med 57:1006–1013CrossRefGoogle Scholar
  58. 58.
    Ahmadzadehfar H, Rahbar K, Kurpig S et al (2015) Early side effects and first results of radioligand therapy with 177Lu-DKFZ-617 PSMA of castrate-resistant metastatic prostate cancer: a two-centre study. EJNMMI Res 5:114Google Scholar
  59. 59.
    National Institute of Health STUDY of PSMA-targeted 18F-DCFPyL PET/CT in the evaluation of patients with renal cell carcinoma. (accessed 4th May 2018)
  60. 60.
    National Institute of Health preliminary evaluation of uptake of [68Ga]P16-093 in Metastatic Prostate and Renal Cancer. (accessed May 4th)

Copyright information

© World Molecular Imaging Society 2019

Authors and Affiliations

  1. 1.Department of UrologyGreenslopes Private HospitalBrisbaneAustralia
  2. 2.Faculty of MedicineThe University of QueenslandBrisbaneAustralia
  3. 3.Department of UrologyPrincess Alexandra HospitalBrisbaneAustralia
  4. 4.Department of UrologyTownsville HospitalBrisbaneAustralia
  5. 5.Centre for Clinical ResearchThe University of QueenslandBrisbaneAustralia
  6. 6.Centre for Kidney Disease ResearchTranslational Research InstituteBrisbaneAustralia
  7. 7.Department of Surgery, Austin HealthThe University of MelbourneParkvilleAustralia
  8. 8.Australian Prostate Cancer Research Center Queensland, Institute of Health and Biomedical InnovationQueensland University of TechnologyBrisbaneAustralia

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