Introduction/Aim
68Ga-PSMA PET/CT is increasingly used in the evaluation of prostate cancer (PC), particularly in the detection and localization of disease recurrence. The main aim of the current study is to present physiological variation in distribution of PSMA activity and avidity in various benign and neoplastic conditions, as well as false-negative findings that may be misinterpreted.
Materials and Methods
PSMA represents an excellent biological target for high quality PET imaging of PC. However, PSMA uptake is not prostate-specific and is also expressed in other pathologic conditions. The causes of false-positive and false-negative 68Ga-PSMA PET/CT findings are described. It is important for reporting physicians to recognize these findings.
Results and Discussion
PSMA is expressed in various benign and pathologic conditions. A wide range of malignancies other than PC have been reported to express PSMA as part of tumor neovasculature.
Conclusion
The nonexclusivity of PSMA avidity can potentially pave the way to expand the PSMA theranostic concept outside of PC.
Afshar-Oromieh A., Haberkorn U., Eder M., Eisenhut M., Zechman C.M. [68Ga]Galliumlabelled PSMA ligand as superior PET tracer for the diagnosis of prostate cancer: comparison with 18F-FECH. Eur J Nucl Med Mol Imaging. 2012; 39 (6): 1085–1086. https://doi.org/10.1007/s00259-012-2069-0
Afshar-Oromieh A., Malcher A., Eder M., Eisenhut M., Linhart H.G., Hadaschik B.A. et al. PET imaging with a [Ga-68]gallium-labelled PSMA ligand for the diagnosis of prostate cancer: biodistribution in humans and first evaluation of tumour lesions. Eur J Nucl Med Mol Imaging. 2013; 40: 486-495. https://doi.org/10.1007/s00259-012-2298-2
Afshar-Oromieh A., Zechmann C.M., Malcher A., Eder M., Eisenhut M., Heinz G. et al. Comparison of PET imaging with a (68)Ga-labelled PSMA ligand and (18)F-choline-based PET/CT for the diagnosis of recurrent prostate cancer. Eur J Nucl Med Mol Imaging. 2014; 41:11–20. https://doi.org/10.1007/s00259-013-2525-5
Afshar-Oromieh A., Avtzi E., Giesel FL., Holland-Letz T., Linhart HG., Eder M. et al. The diagnostic value of PET/CT imaging with the (68)Ga-labelled PSMA ligand HBED-CC in the diagnosis of recurrent prostate cancer. Eur J Nucl Med Mol Imaging. 2015; 42: 197–209. https://doi.org/10.1007/s00259-014-2949-6
Afshar-Oromieh A., Holland-Letz T., Giesel F.L., Kratochwil C., Mier W., Haufe S. et al. Diagnostic performance of (68)Ga-PSMA-11 (HBED-CC) PET/CT in patients with recurrent prostate cancer: evaluation in 1007 patients. Eur J Nucl Med Mol Imaging. 2017; 44:1258-1268. https://doi.org/10.1007/s00259-017-3711-7
Afshar-Oromieh A., Sattler L.P., Steiger K., Holland-Letz T., da Cunha ML., Mier W. et al. Tracer uptake in mediastinal and paraaortal thoracic lymph nodes as a potential pitfall in image Update on pitfalls in PSMA-targeted PET interpretation of PSMA ligand PET/CT. Eur J Nucl Med Mol Imaging. 2018, 45:1179-1187. https://doi.org/10.1007/s00259-018-3965-8
Bashir U., Tree A., Mayer E., Levine D., Parker C., Dearnaley D. et al. Impact of Ga-68-PSMA PET/CT on management in prostate cancer patients with very early biochemical recurrence after radical prostatectomy. Eur J Nucl Med Mol Imaging. 2019; 46, 901–907. https://doi.org/10.1007/s00259-018-4249-z
Chakraborty P.S., Tripathi M., Agarwal K.K., Kumar R., Vijay M.K., Bal C. Metastatic poorly differentiated prostatic carcinoma with neuroendocrine differentiation: negative on 68Ga-PSMA PET/CT. Clin Nucl Med. 2015; 40:163-166. https://doi.org/10.1097/rlu.0000000000000594
De Galiza Barbosa F., Queiroz M.A., Nunes R.F., Costa LB., Zaniboni EC., Marin JFG. et al. Nonprostatic diseases on PSMA PET imaging: a spectrum of benign and malignant findings. Cancer Imaging. 2020; 20: 23. https://dx.doi.org/10.1186%2Fs40644-020-00300-7
De Visschere P.J.L., Standaert C., Fu¨tterer J., Villeirs GM., Panebianco V., Walz J. et al. A Systematic Review on the Role of Imaging in Early Recurrent Prostate Cancer. European Association of Urology. 2019; 2: 47-76. https://doi.org/10.1016/j.euo.2018.09.010
Eder M., Neels O., Muller M., Bauder-Wüst U., Remde Y., Schäfer M. et al. Novel preclinical and radiopharmaceutical aspects of [68 Ga]Ga-PSMA-HBED-CC: a new PET tracer for imaging of prostate cancer. Pharmaceuticals (Basel). 2014;7(7): 779–796. https://doi.org/10.3390/ph7070779
Eiber M., Maurer T., Souvatzoglou M., Beer AJ., Ruffani A., Haller B. et al. Evaluation of hybrid 68Ga-PSMA ligand PET/CT in 248 patients with biochemical recurrence after radical prostatectomy. J Nucl Med. 2015; 56 (5): 668–674.https://doi.org/10.2967/jnumed.115.154153
Eiber М., Herrmann K., Calais J., Hadaschik B., Giesel FL , Hartenbach M. et al. Prostate Cancer Molecular Imaging Standardized Evaluation (PROMISE): Proposed miTNM Classification for the Interpretation of PSMA-Ligand PET/CT. J Nucl Med. 2018; 59: 469–478. https://doi.org/10.2967/jnumed.117.198119
Emmett L., van Leeuwen P.J., Nandurkar R, Scheltema M.J., Cusick T., Hruby G.. et al. Treatment outcomes from (68)Ga-PSMA PET/CT-informed salvage radiation treatment in men with rising PSA after radical prostatectomy: prognostic value of a negative PSMA PET. J Nucl Med. 2017.58: 1972-1976. https://doi.org/10.2967/jnumed.117.196683
Evans M.J., Smith-Jones P.M., Wongvipat J., Navarro V., Kim S., Bander N.H. et al. Noninvasive measurement of androgen receptor signaling with a positronemitting radiopharmaceutical that targets prostate-specific membrane antigen. Proc Natl Acad Sci USA. 2011; 108: 9578-9582. https://doi.org/10.1073/pnas.1106383108
Fendler W.P., Schmidt D.F., Wenter V., Thierfelder K.M., Zach C., Stief C. et al. 68Ga-PSMA-HBED-CC PET/CT detects location and extent of primary prostate cancer. J Nucl Med. 2016, 57(11):1720-1725. https://doi.org/10.2967/jnumed.116.172627
Fendler W.P., Eiber M., Beheshti M., Bomanji J., Ceci F., Cho S.et al. (68)Ga-PSMA PET/CT: Joint EANM and SNMMI procedure guideline for prostate cancer imaging: Version 1.0. Eur J Nucl Med Mol Imaging. 2017, 44(6): 1014-1024. https://doi.org/10.1007/s00259-017-3670-z
Fendler W.P., Calais J., Allen-Auerbach M., Bluemel C., Eberhardt N. , Emmett L. et al. 68Ga-PSMA-11 PET/CT Interobserver Agreement for Prostate Cancer Assessments: An International Multicenter Prospective Study. J Nucl Med. 2017; 58: 1617–1623. https://doi.org/10.2967/jnumed.117.190827
Ghosh A., Heston W.D.W. Tumor target prostate specific membrane antigen (PSMA) and its regulation in prostate cancer. J Cell Biochem 2004; 91: 528-539. https://doi.org/10.1002/jcb.10661
Grubmuller B., Baltzer P., D’Andrea D., Korn S., Haug A. R., Hacker M. et al. (68)Ga-PSMA 11 ligand PET imaging in patients with biochemical recurrence after radical prostatectomy—diagnostic performance and impact on therapeutic decision-making. Eur J Nucl Med Mol Imaging. 2018; 45:235–242. https://doi.org/10.1007/s00259-017-3858-2
Hope T.A., Aggarwal R., Chee B., Tao D., Greene K.L., Cooperberg M.R. et al. Impact of (68)Ga-PSMA-11 PET on management in patients with biochemically recurrent prostate cancer. J Nucl Med. 2017; 58:1956–1961. https://doi.org/10.2967/jnumed.117.192476
Hope T.A., Truillet C., Ehman E.C., Afshar-Oromieh A., Aggarwal R., Ryan C.J. et al. 68Ga-PSMA-11 PET imaging of response to androgen receptor inhibition: first human experience. J Nucl Med. 2017; 58(1): 81–84. https://doi.org/10.2967/jnumed.116.181800
Kabasakal L., Demirci E., Ocak M., Akyel R., Nematyazar J., Aygun A. et al. Evaluation of PSMA PET/CT imaging using a 68Ga-HBEDCC ligand in patients with prostate cancer and the value of early pelvic imaging. Nucl Med Commun. 2015; 36: 582–587. https://doi.org/10.1097/mnm.0000000000000290
Kratochwil C., Bruchertseifer F., Giesel F., Weis M., Verburg F.A., Mottaghy F. et al. 225AcPSMA-617 for PSMA-targeted α-radiation therapy of metastatic castration-resistant prostate cancer. J Nucl Med. 2016; 57: 1941-1944. https://doi.org/10.2967/jnumed.116.178673
Kulkarni M., Hughes S., Mallia A., Gibson V., Young J., Aggarwal A.et al. The management impact of 68gallium-tris(hydroxypyridinone) prostate-specific membrane antigen (68Ga-THP-PSMA) PET-CT imaging for high-risk and biochemically recurrent prostate cancer. Eur J Nucl Med Mol Imaging. 2020; 47, 674–686. https://doi.org/10.1007/s00259-019-04643-7
Malik D., Kumar R., Mittal B.R., Singh H., Bhattacharya A., Singh S.K. 68Ga-labeled PSMA uptake in nonprostatic malignancies: Has the time come to remove “PS” from PSMA? Clin Nucl Med. 2018. 43: 529-532. https://doi.org/10.1097/rlu.0000000000002103
Mannweiler S., Amersdorfer P., Trajanoski S.,Terrett J.A., King D., Mehes G. Heterogeneity of prostate-specific membrane antigen (PSMA) expression in prostate carcinoma with distant metastasis. Pathol Oncol Res. 2009; 15: 167-172. https://doi.org/10.1007/s12253-008-9104-2
Maurer T., Gschwend J.E, Rauscher I., Souvatzoglou M., Haller B., Weirich G. et al. Diagnostic efficacy of gallium-PSMA positron emission tomography compared to conventional imaging in lymph node staging of 130 consecutive patients with intermediate to high risk prostate cancer. J Urol. 2016, 195: 1436-1443. https://doi.org/10.1016/j.juro.2015.12.025
Mena Е., Lindenberg L.M., Choyke P.L. New Targets for PET Molecular Imaging of Prostate Cancer. Semin Nucl Med. 2019, 49: 326-336. https://doi.org/10.1053/j.semnuclmed.2019.02.001
Michaud L., Touijer K. Molecular imaging for prostate cancer: Performance analysis of 68Ga-PSMA PET/CT versus choline PET/CT. Actas Urol Esp. 2017; 41: 292-299. https://doi.org/10.1016/j.acuro.2016.09.015
Perera M., Papa N., Roberts M., Williams M., Udovicich C., Vela I. et al. Gallium-68 prostatespecific membrane antigen positron emission tomography in advanced prostate cancerupdated diagnostic utility, sensitivity, specificity, and distribution of prostate-specific membrane antigen-avid lesions: a systematic review and meta-analysis. Eur Urol. 2019; 77(4): 403-417. https://doi.org/10.1016/j.eururo.2019.01.049
Prasad V., Steffen I.G., Diederichs G., Makowski M.R., Wust P., Brenner W. Biodistribution of [(68)Ga]PSMA-HBED-CC in patients with prostate cancer: characterization of uptake in normal organs and tumour lesions. Mol Imaging Biol. 2016, 18: 428-436. https://doi.org/10.1007/s11307-016-0945-x
Shakespeare T.P. Effect of prostate-specific membrane antigen positron emission tomography on the decision-making of radiation oncologists. Radiat Oncol. 2015; 10, 233. https://doi.org/10.1186/s13014-015-0548-8
Sheikhbahaei S., Afshar-Oromieh A., Eiber M., Solnes L.B., Javadi M.S., Ross A.E. et al. Pearls and pitfalls in clinical interpretation of prostatespecific membrane antigen (PSMA)- targeted PET imaging. Eur J Nucl Med Mol Imaging. 2017; 44: 2117-2136. https://doi.org/10.1007/s00259-017-3780-7
Sheikhbahaei S., Werner R.A., Solnes L.B., Pienta K.J., Pomper M.G., Gorin M.A. et al. Prostate-Specific Membrane Antigen (PSMA)-Targeted PET Imaging of Prostate Cancer: An Update on Important Pitfalls. Semin Nucl Med. 2019, 49: 255-270. https://doi.org/10.1053/j.semnuclmed.2019.02.006
Shetty D., Patel D., Le K., Bui C., Mansberg R. Pitfalls in Gallium-68 PSMA PET/CT Interpretation—A Pictorial Review. Tomography. 2018; 4(4): 182-193. https://doi.org/10.18383/j.tom.2018.00021
Siva S., Callahan J., Pryor D., Martin J., Lawrentschuk N., Hofman M.S. Utility of (68) Ga prostate specific membrane antigen e positron emission tomography in diagnosis and response assessment of recurrent renal cell carcinoma. J Med Imaging Radiat Oncol. 2017; 61 (3): 372- 378. https://doi.org/10.1111/1754-9485.12590
Udovicich C., Pererad M., Hofman M., Siva S., Del Rio A., Murphy D.G. et al. 68Ga-prostatespecific membrane antigen-positron emission tomography/computed tomography in advanced prostate cancer: Current state and future trends. J Prostate Int 5. 2017; 125-129. https://dx.doi.org/10.1016%2Fj.prnil.2017.02.003
Van Leeuwen P.J., Stricker P., Hruby G., Kneebone A., Ting F., Thompson B. et al. 68Ga-PSMA has a high detection rate of prostate cancer recurrence outside the prostatic fossa in patients being considered for salvage radiation treatment. BJU Int. 2016, 117: 732-739. https://doi.org/10.1111/bju.13397
Witkowska-Patena E., Mazurek A., Dziuk M. 68Ga-PSMA PET/CT imaging in recurrent prostate cancer: Where are we now? Cent European J Urol. 2017; 70(1): 37-43. https://doi.org/10.5173/ceju.2017.947
Woythal N., Arsenic R., Kempkensteffen C., Miller K., Janssen JK., Huang K. et al. Immunohistochemical Validation of PSMA Expression Measured by 68Ga-PSMA PET/CT in Primary Prostate Cancer. J Nucl Med. 2018; 59:238–243. https://doi.org/10.2967/jnumed.117.195172
Xu K.M., Chen R.C, Schuster D.M, Jani A.B et al. Role of novel imaging in the management of prostate cancer. Urologic Oncology: Seminars and Original Investigations. 2019, 37: 611−618. https://doi.org/10.1016/j.urolonc.2019.04.008
Zacho H.D, Nielsen J.B., Dettmann K., Haberkorn U., Langkilde N.C., Jensen J.B.et al. 68Ga-PSMA PET/CT in Patients With Biochemical Recurrence of Prostate Cancer A Prospective, 2-Center Study. Clin Nucl Med. 2018; 43: 579-585. https://doi.org/10.1097/rlu.0000000000002169
Zamboglou C., Schiller F., Fechter T., Wieser G., Jilg C.A., Chirindel A. et al. Ga-68 HBEDCC-PSMA PET/CT versus histopathology in primary localized prostate cancer: a voxel-wise comparison. Theranostics. 2016; 6: 1619- 1628. https://doi.org/10.7150/thno.15344
Özülker F. Efficacy of early imaging with 68Ga-PSMA I&T in the discrimination of pelvic lesions in prostate cancer patients. Rev Esp Med Nucl Imagen Mol. 2019; 38:100–105. https://doi.org/10.1016/j.remn.2018.06.006