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European Journal of Nuclear Medicine and Molecular Imaging

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12-05-2022 | Prostate Cancer | Original Article

Diverse PSMA expression in primary prostate cancer: reason for negative [⁶⁸Ga]Ga-PSMA PET/CT scans? Immunohistochemical validation in 40 surgical specimens

Authors: Wojciech Cytawa, Stefan Kircher, Hubert Kübler, Rudolf A. Werner, Simon Weber, Philipp Hartrampf, Tomasz Bandurski, Piotr Lass, Wojciech Połom, Marcin Matuszewski, Hans-Jürgen Wester, Constantin Lapa, Andreas Rosenwald, Anna Katharina Seitz, Andreas K. Buck

Published in: European Journal of Nuclear Medicine and Molecular Imaging | Issue 11/2022

Abstract

Purpose

The purpose of this study was to immunohistochemically validate the primary tumor PSMA expression in prostate cancer (PCa) patients imaged with [⁶⁸Ga]Ga-PSMA PET/CT prior to surgery, with special consideration of PET-negative cases.

Methods

The study included 40 men with newly diagnosed treatment-naïve PCa imaged with [⁶⁸Ga]Ga-PSMA I&T PET/CT as part of the diagnostic work-up prior to radical prostatectomy. All primary tumors were routinely stained with H&E. In addition, immunohistochemical staining of PSMA was performed and the immunoreactive score (IRS) was computed as semiquantitative measure. Subsequently, imaging findings were correlated to histopathologic results.

Results

Eighty-three percent (33/40) of patients presented focal uptake of [⁶⁸Ga]Ga-PSMA I&T in the primary tumor in at least one prostate lobe. Among PSMA-PET positive patients, one-third had lymph node metastases (LNM) detected by post-operative histopathology, while in PET negative patients, only 1 out of 7 presented with regional LN involvement; PSMA-avid distant lesions, predominantly in bones, were observed in 15% and 0% of patients, respectively.

The median IRS classification of PSMA expression in tumor tissue was 2 (range, 1–3) both in PSMA-PET positive and negative prostate lobes, with significantly different interquartile range: 2–3 vs. 2–2, respectively (p = 0.03). The median volume of PSMA-PET positive tumors was 5.4 mL (0.2–32.9) as compared to 1.6 mL (0.3–18.3) of PET-negative tumors (p < 0.001). There was a significant but weak correlation between SUV_max and percentage of PSMA-positive tumor cells (r = 0.46, p < 0.001). A total of 35/44 (~80%) lobes were positive in PSMA-PET imaging, when a cut-off percentage of PSMA-positive cells was ≥ 90%, while 19/36 (~53%) lobes with < 90% PSMA-positive cells were PSMA-PET negative.

Conclusion

Positive [⁶⁸Ga]Ga-PSMA I&T PET/CT scan of primary tumor of PCa results from a combination of factors, such as homogeneity and intensity of PSMA expression, tumor volume and grade, with a cutoff value of ≥ 90% PSMA-positive cells strongly determining PET-positivity. Focal accumulation of [⁶⁸Ga]Ga-PSMA in the primary tumor may correlate positively with aggressiveness of prostate cancer, harboring higher risk of regional LN involvement and distant metastatic spread.

Sung H, Ferlay J, Siegel RL, et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2021;71(3):209–49. https://doi.org/10.3322/caac.21660.CrossRefPubMed

Woythal N, Arsenic R, Kempkensteffen C, et al. Immunohistochemical Validation of PSMA expression measured by (68)Ga-PSMA PET/CT in primary prostate cancer. J Nucl Med. 2018;59:238–43. https://doi.org/10.2967/jnumed.117.195172.CrossRefPubMed

Afshar-Oromieh A, Malcher A, Eder M, et al. PET imaging with a [68Ga]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;40:486–95. https://doi.org/10.1007/s00259-012-2298-2.CrossRefPubMed

Corfield J, Perera M, Bolton D, et al. (68)Ga-prostate specific membrane antigen (PSMA) positron emission tomography (PET) for primary staging of high-risk prostate cancer: a systematic review. World J Urol. 2018;36:519–27. https://doi.org/10.1007/s00345-018-2182-1.CrossRefPubMed

Emmett L, Willowson K, Violet J, et al. Lutetium (177) PSMA radionuclide therapy for men with prostate cancer: a review of the current literature and discussion of practical aspects of therapy. J Med Radiat Sci. 2017;64:52–60. https://doi.org/10.1002/jmrs.227.CrossRefPubMedPubMedCentral

Afshar-Oromieh A, Babich JW, Kratochwil C, et al. The rise of PSMA ligands for diagnosis and therapy of prostate cancer. J Nucl Med. 2016;57:79S-89S. https://doi.org/10.2967/jnumed.115.170720.CrossRefPubMed

D’Amico AV, Whittington R, Malkowicz SB, et al. Biochemical outcome after radical prostatectomy, external beam radiation therapy, or interstitial radiation therapy for clinically localized prostate cancer. JAMA. 1998;280:969–74. https://doi.org/10.1001/jama.280.11.969.CrossRefPubMed

Mottet N, Bellmunt J, Bolla M, et al. EAU-ESTRO-SIOG guidelines on prostate cancer. Part 1: Screening, Diagnosis, and Local Treatment with Curative Intent. Eur Urol. 2017;71:618–629. https://doi.org/10.1016/j.eururo.2016.08.003

Cytawa W, Seitz AK, Kircher S, et al. 68Ga-PSMA I&T PET/CT for primary staging of prostate cancer. Eur J Nucl Med Mol Imaging. 2020;47:168–77. https://doi.org/10.1007/s00259-019-04524-z.CrossRefPubMed

10.

Kaemmerer D, Peter L, Lupp A, et al. Molecular imaging with ⁶⁸Ga-SSTR PET/CT and correlation to immunohistochemistry of somatostatin receptors in neuroendocrine tumours. Eur J Nucl Med Mol Imaging. 2011;38:1659–68. https://doi.org/10.1007/s00259-011-1846-5.CrossRefPubMed

11.

Sheikhbahaei S, Afshar-Oromieh A, Eiber M, et al. Pearls and pitfalls in clinical interpretation of prostate-specific membrane antigen (PSMA)-targeted PET imaging. Eur J Nucl Med Mol Imaging. 2017;44:2117–36. https://doi.org/10.1007/s00259-017-3780-7.CrossRefPubMed

12.

Rowe SP, Pienta KJ, Pomper MG, et al. Proposal for a structured reporting system for prostate-specific membrane antigen-targeted PET imaging: PSMA-RADS version 1.0. J Nucl Med. 2018;59:479–485. https://doi.org/10.2967/jnumed.117.195255

13.

Eiber M, Herrmann K, Calais J, et al. Prostate cancer molecular imaging standardized evaluation (PROMISE ): proposed miTNM classification for the interpretation of PSMA-ligand PET/CT. J Nucl Med. 2018;59:469–79. https://doi.org/10.2967/jnumed.117.198119.CrossRefPubMed

14.

Murciano-Goroff YR, Wolfsberger LD, Parekh A, et al. Variability in MRI vs. ultrasound measures of prostate volume and its impact on treatment recommendations for favorable-risk prostate cancer patients: a case series. Radiat Oncol. 2014;9:200. https://doi.org/10.1186/1748-717X-9-200

15.

Soret M, Bacharach SL, Buvat I. Partial-volume effect in PET tumor imaging. J Nucl Med. 2007;48:932–45. https://doi.org/10.2967/jnumed.106.035774.CrossRefPubMed

16.

Perera M, Papa N, Christidis D, et al. 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. 2016;70:926–37. https://doi.org/10.1016/j.eururo.2016.06.021.CrossRefPubMed

17.

Hofman MS, Lawrentschuk N, Francis RJ, et al. Prostate-specific membrane antigen PET-CT in patients with high-risk prostate cancer before curative-intent surgery or radiotherapy (proPSMA): a prospective, randomised, multicentre study. Lancet. 2020;395:1208–16. https://doi.org/10.1016/S0140-6736(20)30314-7.CrossRefPubMed

18.

Hupe MC, Philippi C, Roth D, et al. Expression of prostate-specific membrane antigen (PSMA) on biopsies is an independent risk stratifier of prostate cancer patients at time of initial diagnosis. Front Oncol. 2018;8:623. https://doi.org/10.3389/fonc.2018.00623.CrossRefPubMedPubMedCentral

19.

Hanna B, Ranasinghe W, Lawrentschuk N. Risk stratification and avoiding overtreatment in localized prostate cancer. Curr Opin Urol. 2019;29:612–9. https://doi.org/10.1097/MOU.0000000000000672.CrossRefPubMed

20.

Fendler WP, Schmidt DF, Wenter V et al. 68Ga-PSMA PET/CT detects the location and extent of primary prostate cancer. J Nucl Med. 2016; 57:1720–1725. https://doi.org/10.2967/jnumed.116.172627

21.

Bakht MK, Derecichei I, Li Y et al. Neuroendocrine differentiation of prostate cancer leads to PSMA suppression. Endocr Relat Cancer. 2018; 26:131–146. https://doi.org/10.1530/ERC-18-0226

22.

Mannweiler S, Amersdorfer P, Trajanoski S, et al. Heterogeneity of prostate-specific membrane antigen (PSMA) expression in prostate carcinoma with distant metastasis. Pathol Oncol Res. 2009;15:167–72. https://doi.org/10.1007/s12253-008-9104-2.CrossRefPubMed

23.

Rüschoff JH, Ferraro DA, Muehlematter UJ, et al. What’s behind 68 Ga-PSMA-11 uptake in primary prostate cancer PET? Investigation of histopathological parameters and immunohistochemical PSMA expression patterns. Eur J Nucl Med Mol Imaging. 2021;48:4042–53. https://doi.org/10.1007/s00259-021-05501-1.CrossRefPubMedPubMedCentral

24.

Ferraro DA, Rüschoff JH, Muehlematter UJ et al. Immunohistochemical PSMA expression patterns of primary prostate cancer tissue are associated with the detection rate of biochemical recurrence with 68Ga-PSMA-11-PET. Theranostics. 2020; 10: 6082–6094. https://doi.org/10.7150/thno.44584

Title: Diverse PSMA expression in primary prostate cancer: reason for negative [68Ga]Ga-PSMA PET/CT scans? Immunohistochemical validation in 40 surgical specimens
Authors: Wojciech Cytawa
Stefan Kircher
Hubert Kübler
Rudolf A. Werner
Simon Weber
Philipp Hartrampf
Tomasz Bandurski
Piotr Lass
Wojciech Połom
Marcin Matuszewski
Hans-Jürgen Wester
Constantin Lapa
Andreas Rosenwald
Anna Katharina Seitz
Andreas K. Buck
Publication date: 12-05-2022
Publisher: Springer Berlin Heidelberg
Keywords: Prostate Cancer
Computed Tomography
Computed Tomography
Prostate Cancer
Published in: European Journal of Nuclear Medicine and Molecular Imaging / Issue 11/2022
Print ISSN: 1619-7070
Electronic ISSN: 1619-7089
DOI: https://doi.org/10.1007/s00259-022-05831-8

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Diverse PSMA expression in primary prostate cancer: reason for negative [⁶⁸Ga]Ga-PSMA PET/CT scans? Immunohistochemical validation in 40 surgical specimens

Abstract

Purpose

Methods

Results

Conclusion

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Abstract

Purpose

Methods

Results

Conclusion

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