Results or findings

1. PSMA transmembrane glycoprotein expression:
   • Significantly higher in prostate cancer (PCa) than in other tissues, including normal prostate [3]
   • Increases with tumor stage and grade, and it is higher in castration-resistant PCa
   • May happen in other cancers or inflammatory and infectious processes due to neovascularization [4]
   • Allow for combining the PSMA molecule with radioligands to identify PCa lesions on PET/CT and deliver targeted radiation therapy to PCa cells [5]

2. PSMA-based radioligands currently approved in the United States and/or Europe:
   • For diagnostic PET/CT: Piflufolastat F¹⁸, Gallium⁶⁸ PSMA-11, and Gallium⁶⁸ PSMA-1007. Awareness of radioligand-specific physiological biodistribution within the abdomen is essential to avoid misinterpretation of false positive lesions (Figure 1) [2].
     

     Fig 1: Two men undergoing PSMA-PET/CT for metastatic assessment of PCa without active focal lesions in the prostate gland. (A) Piflufolastat F18 and (B) Gallium68 PSMA-11 3D PET images show the physiologic biodistribution of the agents, both with high levels of uptake in the kidneys (white *). The bilateral ureters (thick red arrows) and bladder (red *) also show intense uptake due to urinary excretion. Note the increased splenic (thin red arrow)/hepatic (dashed thin red arrow) uptake ratio of Ga68 compared to F18. (B) This patient has a retroperitoneal PSMA-avid metastasis (red arrowhead). Teaching Point: Intrabdominal organs that may show PSMA uptake in a PET/CT as part of the physiologic biodistribution include: the liver (dashed red thin arrow), the spleen (thin red arrow), the kidneys (white *), the ureters (thick red arrows), the bladder (red *) and the urethra, the bowel (empty thick red arrow), and the prostate (thick black arrow). The normal prostate tissue may show low (A) to moderate (B) levels of PSMA uptake.
   • For targeted radioligand therapy: Luthethium¹⁷⁷ PSMA-617; has shown to prolong progression-free survival and overall survival in patients with metastatic PCa when added to standard care [8]. Indications for Lu ¹⁷⁷ PSMA therapy include:
     • Absence of non-PSMA-avid lesions larger than 1 cm on PET/CT (including liver, lung, and lymph nodes) and
     • PSMA uptake greater than the liver in most metastases.

3. PSMA PET/CT in PCa:
   • Interpretation: The level of PSMA uptake is assessed by comparison with other organs or systems, such as the parotid glands, liver parenchyma, and blood pool (Figure 2) [4]
     

     Fig 2: PSMA PET/CT Interpretation based on uptake level. The parotid gland is the organ with the highest physiologic uptake. Therefore, lesions with higher uptake than the parotid glands are considered highly avid. On the other end of the spectrum, lesions with uptake below the level observed within the vascular structures (blood pool) are considered non-avid. PSMA PCa Prostate Cancer
   • Local staging: MRI remains the gold standard and has a higher spatial resolution than PET/CT; PET/CT has a higher contrast resolution than MRI, which may be useful to:
     • Identify primary PSMA-avid PCa (Figure 3), though 5-7% of PCa may be non-PSMA-avid (Figure 4) [1,6]
       

       Fig 3: A 54-year-old man with de novo PCa. Initial Staging. PSA density= 0.54 ng/mL. (A-D) MRI shows bilateral PI-RADS 4 lesions in the peripheral zone of the prostate midgland (arrows), with T2 hypointense signal (A), restricted diffusion (B,D) and hyperenhancement on the left (C). (E,F) On PSMA PET/CT there is intense corresponding uptake (arrowheads). Biopsy confirmed bilateral Gleason 7 PCa. Teaching Point: Both PSMA PET/CT and MRI can detect primary cancers in the prostate gland.
       

       Fig 4: A 68-year-old man with de novo PCa. Initial Staging. PSA = 34.8. (A-D) MRI shows PI-RADS 5 and 4 lesions in the right and left peripheral zone of the prostate apex (respectively, thick and thin arrows), with T2 hypointense signal, marked restricted diffusion, and hyperenhancement. (E, F) PSMA PET/CT shows corresponding areas with less uptake than the adjacent gland on the right and similar on the left (dashed areas). Note the intense focal uptake in the central gland due to urine within the prostatic urethra (arrowhead). Surgical pathology confirmed a neuroendocrine tumor of the prostate. Teaching points: - Around 5-7% of PCa are non-PSMA-avid, including castration-resistant PCa (neuroendocrine or small cell variant), PCa with neuroendocrine differentiation, highly dedifferentiated prostate adenocarcinomas that have lost PSMA expression, or rare PCa subtypes (e.g., sarcomatoid carcinoma, adenoid cystic carcinoma). Hormonal and chemotherapies may downregulate PSMA expression, also resulting in mild or absent PSMA uptake - Beware of the anatomic location of the intraprostatic urethra, which may show focal uptake due to passing urine and should not be mistaken for a focal lesion; multiplanar assessment may be helpful for confirmation
     • Increase diagnostic sensitivity and confidence when MRI findings are subtle (Figure 5) or lack an obvious focal abnormality (Figure 6)
       

       Fig 5: A 60-year-old man with de novo high-risk PCa. Initial Staging. PSA density= 0.17 ng/mL. (A-D) MRI shows a patchy, mildly T2 hypointense area in the right peripheral zone, with mild restricted diffusion and hyperenhancement (arrow). Findings were considered nonspecific and attributed to a sequela of prostatitis given the faint, wedge-shaped, and ill-defined appearance in all sequences, especially T2. (E) On PSMA PET/CT there is intense corresponding uptake (arrowhead). Surgical pathology confirmed Gleason 9 PCa. Teaching point: PSMA PET/CT may increase the sensitivity to identify PCa lesions when MRI findings are subtle or ill-defined and could be attributed to prostatitis.
       

       Fig 6: A 70-year-old man with de novo PCa. Initial Staging. (A-D) MRI images were interpreted as negative (no focal lesion). (E, F) Subsequent PSMA PET/CT showed intense diffuse uptake in the prostate (arrow), most likely representing PCa. Random biopsy samples from all prostate sections were positive for Gleason 7-9 PCa. On retrospective assessment, there is ill-defined T2 hypointense signal involving the prostate transitional zone and peripheral zone with loss of glandular anatomy (A). Although non-focal, DWI and ADC signals also appear diffusely abnormal with restricted diffusion (B, D). Teaching points: - Diffuse PCa involvement of the prostate may be challenging to detect due to the lack of a focal abnormality. - Diffuse low signal on T2-weighted images in a treatment-naïve patient is abnormal and should raise suspicion for diffuse neoplasm or prostatitis. Post-radiation changes to the pelvis or hormonal therapy may result in a similar appearance, though restricted diffusion would be unlikely. - The abnormality on PSMA-PET/CT is obvious and helps increase diagnostic confidence.
     • Help identify extraprostatic extension and MRI-occult prostate deposits (Figure 7) [1,2]
       

       Fig 7: A 77-year-old man on active surveillance for PCa. (A) MRI shows a 2.9 cm T2 hypointense area in the left peripheral zone (PZ) with hyperenhancement (C) (arrows). (B, D) The lesion shows marked restricted diffusion; however, it was incompletely imaged on the DWI and ADC sequences (arrowheads). (A) There is a heterogeneous T2 signal in the region of the left neurovascular bundle (NVB), raising suspicion for involvement (thin arrows). (C) However, the corresponding enhancement is thin and linear and could be attributed to vessels only. (E) PSMA PET/CT shows obvious intense uptake not only in the left PZ (arrow) but also along the NVB (thin arrow), confirming extraprostatic extension (EPE) and NVB involvement. Findings are consistent with a PI-RADS 5 lesion. An additional focus of marked uptake in the left lateral PZ is likely a site of additional MRI-occult PCa (empty arrowhead). Teaching point: Although PSMA PET/CT has a lower spatial resolution than MRI, its higher contrast resolution may increase diagnostic sensitivity and the reader’s confidence to characterize EPE and detect PCa deposits despite their small size.
     • Increase diagnostic accuracy to identify local recurrence after prostatectomy (Figure 8) or radiotherapy (Figure 9); though PSMA PET/CT may be false positive shortly after radiotherapy and should be ideally delayed for 12 months (Figure 10) [4,7]
       

       Fig 8: A 69-year-old man with PCa, with biochemical recurrence after prostatectomy and radiotherapy. (A) MRI shows T2-dark lines with susceptibility artifacts in the bilateral prostatectomy bed (arrows), likely postsurgical material. (B, C) DWI and ADC show corresponding artifacts and distortion (arrows). MRI was interpreted as negative for recurrent PCa. (D) Subsequent PSMA PET/CT showed marked uptake in the right prostatectomy bed (arrowhead), likely representing recurrent PCa. Upon retrospective assessment of MRI dynamic images (E), there was a linear early arterial hyperenhancement in the right surgical bed (thin arrow), which was initially interpreted as scarring given its linear rather than nodular configuration. Teaching points: - Assessing for local tumor recurrence after prostatectomy may be challenging due to imaging distortion and susceptibility artifacts on MRI caused by surgical materials. The most helpful MRI sequence is the subtraction from the early arterial post-contrast phase; early rather than delayed enhancement favors tumor recurrence versus post-surgical scarring. - Although PSMA PET/CT has a lower spatial resolution than MRI, its higher contrast resolution may increase the diagnostic sensitivity and reader’s confidence in characterizing tumor recurrence at the prostatectomy bed.
       

       Fig 9: A 66-year-old man with a remote history of left-sided PCa, with biochemical recurrence 5 years after Intensity Modulated Radiation Therapy (IMRT). (A-D) MRI shows a mild diffuse low T2 signal in the prostate apex without a focal abnormality to suggest recurrent PCa. Note the punctate foci of dark signal in all sequences corresponding to metallic tissue markers (thin arrows) utilized for IMRT. (E) PSMA PET/CT shows a focal area of intense uptake in the right prostate apex (arrow) at a similar level shown on MRI (corresponding hyperdense tissue markers with thin arrows). Biopsy confirmed Gleason 7 Pca. Teaching point: - New PSMA uptake in the prostate in a different location than the treated tumor bed characterizes a new PCa lesion. - PSMA PET/CT may help increase the sensitivity of MRI to detect PCa recurrence and new PCa in the prostate gland in the setting of treatment-related MRI signal abnormality.
       

       Fig 10: A 71-year-old man with non-metastatic Pca is on hormonal therapy. (A-D) MRI shows a focal T2 hypointense signal in the right peripheral zone with early enhancement and focal restricted diffusion (arrows, PI-RADS 4). (E) PSMA PET/CT shows corresponding focal intense uptake (arrow). Note the recently placed metallic tissue markers (thin arrows) as a preparation for Stereotactic Body Radiation Therapy (SBRT). (F) Four months after SBRT there is persistent marked uptake at the primary tumor site (arrow). (G) 22 months after SBRT, PSMA PET/CT shows significantly decreased uptake at the tumor bed, now like other areas in the prostate gland (dashed area). Note the moderate uptake in the rectum due to radiation-induced proctitis (arrowheads). Teaching points: - PSMA PET/CT may show false-positive uptake shortly after radiation therapy to the prostate and mimic a persistent viable tumor. This uptake is expected to resolve within 12 months in cases of successful treatment and should not be misinterpreted as a residual tumor. Persistent PSMA uptake 12 months after SBRT is suspicious for recurrent or residual tumors. - Benign inflammatory processes may show PSMA uptake due to neovascularization.
   • Metastatic assessment:
     • PSMA PET/CT main applications:
       • Detecting metastasis in the initial staging of high- or intermediate-risk PCa [6]
       • Biochemical recurrence or restaging after initial PCa treatment [7]
       • Therapeutic planning for targeted radioligand therapy [5]
     • Metastatic lymphadenopathy:
       • Typical size criterion used in cross-sectional imaging to define lymphadenopathy (equal or greater than 1 cm in short axis) is insufficient to characterize PCa metastasis
       • PSMA PET/CT is highly sensitive in detecting even tiny nodal metastasis (Figure 11)[6]
         

         Fig 11: A 69-year-old man with PCa, with biochemical recurrence after prostatectomy and radiotherapy. (A, B) MR of the pelvis shows small bilateral pelvic lymph nodes (thin arrows), measuring less than 1 cm in the short axis. (C, D) On PSMA PET/CT, a left common iliac node and a tiny left obturator node are markedly PSMA-avid (full arrowheads), most likely representing metastases. A right external iliac node has an uptake-like blood pool (empty arrowhead), and it is unlikely to represent PCa metastasis. Note the intense focal uptake due to passing urine in the left ureter (thick arrow on D). Teaching point: - The size criterion utilized to characterize lymphadenopathy on morphologic imaging (CT or MRI) is insufficient to characterize lymph node metastasis. - PSMA PET/CT is highly sensitive to characterize nodal metastasis even in tiny lymph nodes.
       • PSMA PET/CT can help recognize nodal metastasis involving atypical nodal stations that may require expansion of a typical radiation field or additional surgical exploration for proper treatment (Figure 12)[7]
         

         Fig 12: A 58-year-old man with de novo high-risk PCa. (A, B) MRI of the pelvis shows a mesorectal lymph node measuring 8 mm in the short axis (below the 10 mm size threshold to characterize lymphadenopathy on MRI). Other tiny mesorectal and presacral nodes were present (thin arrows). (C,D) Subsequent PET/CT showed intense PSMA uptake in these lymph nodes, likely representing PCa metastases (thin arrows). Note the intense uptake in the right ureter (thick arrow). Teaching point: - Recognizing nodal metastases involving atypical drainage pathways within the pelvis is helpful for PCa management, as these may require expansion of the radiation field or additional surgical exploration for proper treatment. Prominent but under-threshold atypical nodes on MRI can be further assessed with PSMA PET/CT to rule out metastasis. - The standard size criterion is insufficient to diagnose PCa nodal metastasis. - PSMA-PET is significantly more sensitive than MRI to characterize PCa nodal metastasis.
       • Beware of mimickers of metastatic lymphadenopathy on PSMA PET/CT (Figure 13)
         

         Fig 13: A 77-year-old man with biochemical recurrence of PCa after radical prostatectomy and hormonal therapy. (A, B) PSMA PET/CT shows focal mild PSMA uptake in the right pre-sacral region and bilateral retroperitoneum (thin arrows), slightly above the blood pool. (C, D) There are corresponding tiny soft tissue nodules on CT (thin arrows). This is most likely uptake in celiac and pre-sacral ganglia, given their location and relatively low level of uptake. (A, C) PSMA PET/CT also shows intense bilateral uptake in the pelvis, at the expected location of the bilateral ureters (thick arrows). (E) Coronal PET/CT reconstructions help identify the bilateral ureters coursing through the lateral pelvis (thick arrows) and bladder (*) filled with markedly PSMA-avid content due to urinary excretion. Teaching points: - Neural ganglia may express the PSMA receptor and show physiologic uptake on a PSMA PET/CT. - Neural ganglia uptake may be above the blood pool level but typically measures less than 5 Maximum Standard Unit Values (SUVmax). Identifying the typical location of neural structures within the abdomen helps differentiate neural ganglia uptake from metastatic nodes. - The intense ureteral uptake due to passing urine may mimic pelvic and retroperitoneal nodal metastases on the axial view. Multiplanar assessment is helpful in characterizing the ureteral origin to avoid misinterpretation.
     • Osseous metastasis:
       • Patients with PCa may present with heterogeneous bone marrow on CT and MRI due to: age-related bone density decline, post-radiation fat replacement, and marrow infiltration from treated metastases.
       • PSMA PET/CT shows the metabolic activity of active metastasis even in the presence of heterogeneous bone marrow [8].
       • PSMA PET/CT has higher sensitivity for detecting active osseous metastasis than CT or MRI (Figure 14)[8].
         

         Fig 14: A 77-year-old man with biochemical recurrence of PCa after prostatectomy. (A) Post-contrast MRI of the pelvis with fat saturation shows a heterogeneous bone marrow enhancement in the sacrum and iliac bones, which was not significantly changed compared to the 6-month prior MRI (B). MRI was interpreted as negative for PCa metastasis. (C) Subsequent PSMA PET/CT shows intense focal uptake in the bilateral sacrum (thin arrows). Note intense uptake in the bilateral ureters (thick arrows). (D) On retrospective assessment of the recent MRI, T1 hypointense lesions were identified on the pre-contrast T1 sequence without fat saturation. Teaching points: - PSMA PET/CT is more sensitive than MRI to detect active osseous metastasis of PCa, especially in the setting of bone marrow heterogeneity that may occur in patients with PCa. - Causes for marrow heterogeneity in PCa patients include age-related bone density decline, post-radiation fat replacement, and marrow infiltration from treated metastasis. - Large field-of-view MR images should be performed and assessed for osseous metastasis. - The pre-contrast T1-weighted sequence without fat suppression may facilitate the identification of osseous metastasis by highlighting the contrast between the T1 hypointense PCa metastasis and the surrounding T1 hyperintense (fat-replaced) bone marrow.
     • Visceral Metastasis: Multimodality evaluation including PSMA PET/CT, abdominal CT, and abdominal MRI is essential for optimal assessment:
       • PCa metastases typically show intense PSMA uptake on PET/CT [7]
       • PET/CT may rarely show non- or mildly PSMA-avid metastases in patients with PCa (Figure 15); these may represent dedifferentiated PCa metastases with loss of PSMA receptors, the neuroendocrine transformation of PCa, or unrelated non-prostatic metastatic malignancies [9]
         

         Fig 15: A 75-year-old man with metastatic PCa. PSMA PET/CT was requested for further treatment planning. (A) 3D PSMA PET showed intense focal uptake in the prostate (empty arrow) and multiple retroperitoneal nodes (red arrows) consistent with metastatic PCa. There was also moderately heterogeneous uptake in the liver (arrowhead). (B, C) Corresponding PET/CT axial views showed multiple hypodense hepatic masses, the dominant showing less uptake than other areas in the background parenchyma (black *). (D, E) MRI confirmed multiple solid liver masses with restricted diffusion (arrowheads). A liver mass biopsy revealed an unrelated metastatic neuroendocrine tumor. Teaching point: PET/CT may rarely show non- or mildly PSMA-avid metastases in patients with PCa. These may represent dedifferentiated PCa metastases with loss of PSMA receptors, neuroendocrine transformation of PCa, or unrelated non-prostatic metastatic malignancies.
       • In patients with both PCa and a non-prostatic PSMA-avid neoplasm (Figure 16), comparison with MRI and CT helps to identify disease-specific features that aid in differential diagnosis
         

         Fig 16: A 75-year-old man with metastatic PCa to the bone, in preparation for radioligand therapy. He also had a past medical history of hepatocellular carcinoma (HCC) in the liver, status post cryoablation. PSMA PET/CT (A), post-contrast arterial phase CT (C), and portal venous phase CT (E) show the photopenic non-enhancing ablation zone in segment VIII (thin arrows). A moderately PSMA-avid focus along the margin of the ablation zone corresponds to arterial hyperenhancement without delayed washout along the margin of the ablation zone (arrowheads). (B, D, F) In liver segment VI, there is markedly PSMA-avid observation with arterial hyperenhancement and washout in the portal venous phase. Note the cirrhotic morphology of the liver with lobulated contour (C-E). Given the setting of cirrhosis, history of HCC, and CT features more typical of HCC than PCa metastasis (typically hypovascular), the PSMA-avid lesions most likely represent recurrent HCC rather than PCa metastasis. Teaching points: - Non-prostatic malignancies may express the PSMA receptor and show false positive PSMA uptake on PET/CT performed for PCa evaluation. - Multimodality assessment of the abdomen is essential in the setting of multiple neoplasms to properly characterize disease-specific imaging features that assist in the differential diagnosis.
       • Cross-modality assessment also ensures the clarification of imaging artifacts (Figure 17), or misregistration errors, which could mimic a focal lesion on PSMA PET/CT.
         

         Fig 17: A 60-year-old man with de novo PCa. A liver biopsy was requested due to suspected liver metastasis on PSMA PET/CT. PSA = 4.7 ng/mL. (A) PSMA PET/CT shows a focal area of marked uptake in liver segment IV (arrow) without a CT correlate (B). (C-F) MRI was recommended for further assessment. (C) The lack of hypointense signal on T1 out-of-phase excludes focal fat deposition, which was suspected given the lesion’s periportal location. (D, E) Post-contrast T1 and DWI show no focal abnormality in segment IV. (F) Corresponding enhancement on the hepatobiliary phase confirms the presence of viable hepatocytes, therefore excluding PCa metastasis. Therefore, the biopsy request was declined. Teaching point: Sectorial vascularity or biliary drainage in the liver, as it can happen in segment IV, may cause false positive PSMA uptake and mimic a focal lesion. Multimodality assessment is recommended to avoid unnecessary biopsies.
     • PSMA/PET CT can add special value in evaluating the metabolic activity of tumors after thermal ablation: A completely treated metastasis typically shows photopenia (absence of uptake) on PSMA-PET/CT (Figure 16a), while persistent or recurrent tumors remain PSMA-avid (Figure 18)[8,10].
       

       Fig 18: A 60-year-old man with oligometastatic PCa to the liver. (A, B) PSMA PET/CT and MRI show a focal PSMA-avid lesion in liver segment II consistent with PCa metastasis (thin arrows). (C) Intraprocedural imaging from thermal ablation shows the well-positioned probes with tips along the bilateral aspects of the lesion. (D) Immediate post-procedural imaging shows the ablation zone that encompasses the anatomic location of the metastasis (white *). (E) One year later, contrast-enhanced CT shows a hypodense area at the treated tumor bed with focal calcification (thick arrow), which was smaller compared to the ablation zone (white * in D). This was deemed incompletely assessed without subtraction images but favored treated disease. However, PET/CT (F) showed intense corresponding PSMA uptake (thick arrow), characterizing viable tumor progression that was larger than the initially ablated lesion (thin arrow in A). Teaching point: PSMA/PET CT may be helpful in identifying the tumoral metabolic activity after thermal ablation. A completely treated metastasis shows photopenia (absent uptake) on PSMA-PET/CT, while persistent or recurrent tumors are PSMA-avid.

• • Recognizing pitfalls in PSMA PET/CT is essential to avoid misinterpretation:
    • False-positive uptake:
      • Intraprostatic urethra (Figure 4) and ureter (Figure 13) due to passing urine; multiplanar assessment helps to identify urinary origin
      • Neural ganglia (Figure 13); uptake is usually lower than 5 Maximum Standard Unit Values (SUVmax) and in typical location
      • Imaging artifacts such as sectorial vascularity or biliary drainage in the liver (Figure 17) and misregistration errors; comparing with diagnostic CT or MRI helps rule out a focal lesion
      • Inflammatory (Figure 10) and infectious processes: clinical correlation is key!
      • Non-prostatic PSMA-avid malignancies: lung (adenocarcinomas and squamous cell carcinomas), renal cell carcinoma, gastrointestinal neoplasms, pancreatic adenocarcinoma, salivary gland tumors, hepatocellular carcinoma (Figure 16), thyroid (papillary and follicular) carcinomas, gliomas, breast cancer (notably the triple-negative), and seminomas
    • False-negative uptake (typically requires histopathologic correlation for diagnosis):
      • PCa with neuroendocrine differentiation
      • Dedifferentiated PCa metastases with loss of PSMA receptors
      • Rare PCa subtypes (e.g. sarcomatoid, adenoid cystic)