False positive PSMA PET for tumor remnants in the irradiated prostate and other interpretation pitfalls in a prospective multi-center trial

Abstract

Purpose: Readers need to be informed about potential pitfalls of [68Ga]Ga-PSMA-11 PET interpretation.

Methods: Here we report [68Ga]Ga-PSMA-11 PET findings discordant with the histopathology/composite reference standard in a recently published prospective trial on 635 patients with biochemically recurrent prostate cancer.

Results: Consensus reads were false positive in 20 regions of 17/217 (8%) patients with lesion validation. Majority of the false positive interpretations (13 of 20, 65%) occurred in the context of suspected prostate (bed) relapse (T) after radiotherapy (n = 11); other false positive findings were noted for prostate bed post prostatectomy (T, n = 2), pelvic nodes (N, n = 2), or extra pelvic lesions (M, n = 5). Major sources of false positive findings were PSMA-expressing residual adenocarcinoma with marked post-radiotherapy treatment effect. False negative interpretation occurred in 8 regions of 6/79 (8%) patients with histopathology validation, including prostate (bed) (n = 5), pelvic nodes (n = 1), and extra pelvic lesions (n = 2). Lesions were missed mostly due to small metastases or adjacent bladder/urine uptake.

Conclusion: [68Ga]Ga-PSMA-11 PET at biochemical recurrence resulted in less than 10% false positive interpretations. Post-radiotherapy prostate uptake was a major source of [68Ga]Ga-PSMA-11 PET false positivity. In few cases, PET correctly detects residual PSMA expression post-radiotherapy, originating however from treated, benign tissue or potentially indolent tumor remnants.

Trial registration number: ClinicalTrials.gov Identifiers: NCT02940262 and NCT03353740.

Keywords: Interpretation; PET; PSMA; Pitfall; Radiotherapy; Recurrence.

Conflict of interest statement

Wolfgang P. Fendler was a consultant for Ipsen, Endocyte, and BTG, and he received personal fees from RadioMedix outside of the submitted work. Jeremie Calais reports consulting activities for Blue Earth Diagnostics, Curium Pharma, GE Healthcare, Janssen Pharmaceuticals, Progenics Pharmaceuticals, Radiomedix, and Telix Pharmaceuticals outside of the submitted work. Matthias Eiber is consultant for ABX and Blue Earth Diagnostics. Johannes Czernin is a founder, board member, and holds equity in Sofie Biosciences and Trethera Therapeutics. Intellectual property patented by the University of California is licensed to Sofie Biosciences and Trethera Therapeutics. Johannes Czernin serves on the medical advisory board of Actinium and is a member of the VISION trial steering committee, a clinical trial sponsored by Endocyte. Thomas Hope is a consultant for GE Healthcare and Ipsen and receives grant support from GE Healthcare. Matthew Rettig is speaker and advisory board member for Janssen and receives research funding from Novartis. No other potential conflicts of interest relevant to this article have been disclosed.

Figures

Fig. 1

70-year-old man post-radiotherapy 10 years prior, who demonstrates focal [68Ga]Ga-PSMA-11 uptake in the right medial prostate (a, circle; b) (PSA 2.6 ng/mL, CT FP 3). Trans-anal ultrasound guided core needle biopsy demonstrated no evidence of viable tumor. The specimen in the region of the focal uptake (SUVmax 9.1) demonstrated marked radiation changes in residual benign glands (d, dotted circle), cancer with treatment effect including balloon cells (e, black arrows), and cells with marked PSMA expression (c and f, black arrows). Adjacent benign glands did not demonstrate PSMA expression (c, black arrow heads)

Fig. 2

74-year-old man post-radiotherapy performed 10 months prior with biochemical recurrence who had focal uptake on the right peripheral zone of the prostate (a, circle) (PSA 7.2 ng/mL, MRI FP 7). Neither T2 weighted imaging (b, arrow), dynamic contrast enhanced (DCE) imaging or diffusion weighted imaging demonstrated a focal lesion to correlate with the focal uptake (SUVmax 12.5) seen on [68Ga]Ga-PSMA-11. Trans-anal ultrasound guided core needle biopsy was obtained from the region of uptake. Pathology demonstrates tumor cells with significant treatment effect (c) and marked PSMA expression (d). There was no evidence of PSMA expression in vasculature

Fig. 3

68-year-old man post-radiotherapy therapy with focal uptake (SUVmax 13.0) noted in the right hilum on [68Ga]Ga-PSMA-11 PET (a and c, circle) (PSA 4.7 ng/mL, MRI FP 8). Single shot fast spin echo (b) does not visualize the lesion highlighting limitations of PET/MRI for characterization of small lung findings. Transbronchial biopsy demonstrates cuboidal epithelium (d) with adjacent prominent glands typical for a bronchogenic cyst.