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

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.