Gallium-68–Labeled Prostate-Specific Membrane Antigen–11 PET/CT of Prostate and Nonprostate Cancers

Abstract

OBJECTIVE.

The purpose of this study is to provide a concise summary of the current experience with ⁶⁸Ga-labeled prostate-specific membrane antigen (PSMA)–11 imaging of prostate and nonprostate malignancies and benign conditions.

CONCLUSION.

PSMA is overexpressed in prostate cancer and in the neovasculature of many other malignancies. The relevance of PSMA as a biologic target, coupled with advances in the design, synthesis, and evaluation of PSMA-based radionuclides for imaging and therapy, is anticipated to play a major role in patient care.

PSMA, also known as folate hydrolase I or glutamate carboxypeptidase II, is a type II, 750– amino acid, 110to 120-kDa transmembrane protein expressed in the secretory cells of the prostate epithelium and a few other normal tissues. There have been reports of several PSMA-based ligands, including ⁸⁹Zr- and ⁶⁴Cu-labeled anti–PSMA antibody and antibody fragments, ⁶⁴Cu-labeled aptamers, and ¹¹C-, ¹⁸F-, ⁶⁸Ga-, ⁶⁴Cu-, ⁴⁴Sc-, and ⁸⁶Y-labeled low-molecular-weight inhibitors of PSMA. Recent strides in the synthesis of small-molecule inhibitors of PSMA, consisting of glutamate-urea-lysine moieties targeting the extracellular epitope of PSMA in association with constitutive cell internalization of PSMA, have provided unprecedented prospects for PSMA-targeted radionuclide imaging and treatment (i.e., theranostics) [1]. Most imaging studies have reported on ⁶⁸Ga-PSMA-11 (otherwise known as HBED-CC). This article summarizes current published studies of ⁶⁸Ga-PSMA-11 PET/CT evaluation of prostate and nonprostate malignancies as well as a few benign conditions.

Normal Uptake and Uptake in Benign Lesions

Recognition of PSMA uptake also in benign lesions can further improve its documented excellent accuracy. Normal ⁶⁸Ga-PSMA-11 uptake is seen in the following structures, with descending avidity: kidneys (eight times the level of hepatic uptake), sub-mandibular glands, parotid glands (three times the level of hepatic uptake), descending duodenum, lacrimal glands, spleen, descending colon, Waldeyer ring in the neck, vocal cords, liver, and rectum [2]. Table 1 lists reported ⁶⁸Ga-PSMA-11–avid benign and malignant entities.

TABLE 1:

Gallium-68–Labeled Prostate-Specific Membrane Antigen–11–Avid Benign and Malignant Conditions Reported in the Literature

Region	Benign Conditions	Malignant Conditions
Abdominal	Adrenals or adrenal adenoma, diverticulosis [101], and hepatic hemangioma	Adrenocortical cancer, bladder cancer [102], colon cancer, gastrointestinal stromal tumor, hepatocellular carcinoma, hepatocellular cholangiocarcinoma, neuroendocrine tumor (pancreatic, paraganglioma, or prostate), prostate cancer, renal cell carcinoma (clear cell, papillary, or chromophobe), and urothelial cancer
Bone	Fibrous dysplasia, fracture, osteoid osteoma, osteoarthritis, Paget disease, polycythemia rubra vera, Schmorl node, and vertebral hemangioma	Multiple myeloma, plasmacytoma, and osteosarcoma
Head and neck	Parathyroid adenoma [103] and follicularthyroid adenoma	Adenoid cystic carcinoma, squamous cell carcinoma of the tongue, and thyroid cancer (papillary, anaplastic, Hurthle cell [angioinvasive follicular, follicuiar, or medullary]) [104]
Muscular, cutaneous, and vascular	Angiolipoma [105], intramuscular myxoma, neurofibromatosis, subcutaneous hemangioma, and synovitis	Hemangiopericytoma, liposarcoma, and melanoma
CNS	Meningioma [106], neurocysticercosis [107], and subacute braininfarcts	Atypical meningioma, glioma (grades 2,3, and 4), and primary CNS lymphoma
Peripheral nervous system	Neurofibromatosis, peripheral nerve sheath tumor, schwannoma, and sympathetic ganglia
Systemic	Amyloidosis [108], sarcoidosis, and tuberculosis [109]	Lymphoma (diffuse large B cell, follicular, or small cleaved B cell follicular)
Thorax	Anthracosilicosis, bronchiectasis, gynecomastia [110], lung infection or pneumonia [111], lung atelectasis, inflammation related to pleural plaques, middle lobe syndrome, and stromal hyperplasia of the breast	Breast cancer (ductal, lobular, or neuroendocrine), gastroesophageal junction, lung adenocarcinoma, and thymoma (types AB, B2, and C) [112]

Selected ⁶⁸Ga-PSMA-11–avid benign conditions are summarized in Table 2. In benign entities, most ⁶⁸Ga-PSMA-11 uptake is low intensity or nonfocal, with notable exceptions (e.g., cutaneous, vertebral, and hepatic hemangiomas) exhibiting prominent uptake [3, 4]. Increased uptake of ⁶⁸Ga-PSMA-11 is seen in acute and chronic inflammation [3], such as synovitis [2]. Gallium-68–labeled PSMA-11 uptake can be seen in the cervical, celiac, and sacral ganglia of the sympathetic trunk as well as an associated small amount of soft tissue on CT, and this can be mistaken for lymph node metastases [5, 6]. Anatomic and biochemical correlation can help with differentiation [3, 7].

TABLE 2:

Gallium-68–Labeled Prostate-Specific Membrane Antigen (PSMA)–11–Avid Benign Conditions

Region and Condition	Finding(s)
Abdominal
Normal adrenal [113] or adrenal adenoma [114]	Low-to-moderate uptake
Hepatic hemangioma	Tracer uptake greater than sliver; MRI findings characteristic of condition
Bone
Fibrous dysplasia	Low-grade uptake
Fracture	In ribs [115], vertebral bodies [116], distal radius [117], and sacral insufficiency fracture [118]; low-to-moderate uptake
Osteoid osteoma [119]	Low-grade uptake
Paget disease [120–123]	Moderate uptake at sites typical for Paget disease
Schmorl node [124]	Focal moderate uptake
Vertebral hemangioma [125]	Focal low-to-moderate uptake
Muscular, cutaneous, and vascular
Intramuscular myxoma [126]	Low-grade uptake
Subcutaneous hemangioma	May or may not be avid
CNS
Meningioma	Mild uptake
Neurocysticercosis	Mild tracer uptake in the enhancing areas of the periphery of cysts; rare; typical features on correlative imaging
Subacute brain infarcts	Mild tracer uptake, both cerebellar [127] and cortical [128]
Peripheral nervous system
Neurofibromatosis	Mild-to-moderate uptake in multiple cutaneous lesions
Peripheral nerve sheath tumor	Mild-to-moderate uptake
Schwannoma[129,130]	Moderate uptake; may mimic pelvic nodes
Sympathetic ganglia	Faint uptake in 98.5% of patients; fainttracer uptake in stellate ganglia; may mimic nodal metastasis
Systemic
Amyloidosis	Symmetric intense uptake in seminal vesicles mimicking locally invasive prostate cancer, resulting in upstaging
Sarcoidosis [131–134]	Moderate uptake in nodes and organs
Thorax
Anthracosis [135], anthracosilicosis [136]	Moderately avid hilar and mediastinal nodes
Lung opacities and bronchiectasis	Opacities and bronchiectasis with airway wall thickening with moderate PSMA uptake
Middle lobe syndrome	Mild tracer uptake

A molecular imaging PSMA expression scoring system for standardized reporting of PSMA-ligand PET has been proposed [7] and can be used to describe no ⁶⁸Ga-PSMA-11 uptake (with a score of 0 denoting uptake less than that of blood pool), low uptake (with a score of 1 denoting uptake equal to or greater than that of blood pool but less than that of the liver), intermediate uptake (with a score of 2 denoting uptake equal to or greater than that of liver but less than that of the parotid gland), or high uptake (with a score of 3 denoting uptake equal to or greater than that of the parotid gland) of ⁶⁸Ga-PSMA-11. Although potentially useful, such a scoring system is not incorporated into most of the current literature.

Prostate Cancer

PSMA is highly upregulated in prostate cancer (PC) [8]. Recent studies have shown that PSMA cleavage of vitamin B9 (folic acid) stimulates oncogenic signaling through glutamate receptors with downstream activation of the PI3K-Akt-mTOR signaling pathway [9]. Many studies have generally shown superior diagnostic performance of PSMA-based radiotracers over other relevant radiotracers in the clinical settings of intermediate- to high-risk primary cancer, biochemical recurrence after definitive therapy, delineation of the extent of metastatic disease, and patient eligibility for PSMA-targeted radioligand therapy [10, 11].

Detection of Primary Prostate Cancer and Initial Staging

Accumulation of ⁶⁸Ga-PSMA-11 in PC is based on PSMA overexpression. The maximum standardized uptake value (SUV_max) is higher with PSMA expression of greater than 50% on immunohistochemical staining [12] and with a Gleason score greater than 7 or a prostate-specific antigen (PSA) level of 10 ng/mL or greater [13]. This suggests that PSMA PET may be able to provide unique information to guide biopsy to the most genomically aggressive (i.e., index) lesion in multifocal primary PC [14]. When compared with the use of histopathologic findings from prostatectomy, a higher sensitivity for detection of the index lesion (81.1%) was reported for PSMA PET than for multiparametric MRI (64.8%), with a specificity of approximately 83.5% reported for both modalities [15].

In a retrospective investigation of 78 men with PC who were stratified on the basis of D’Amico risk criteria, PSMA PET/CT changed the staging for 56.4% of patients [16]. Figure 1 shows staging of PC with ⁶⁸Ga-PSMA–avid bone metastases that are not seen on CT. A meta-analysis of ⁶⁸Ga-PSMA-11 with histopathologic correlation showed that sensitivity and specificity for the detection of nodal disease at prostatectomy were 74% and 96%, respectively, whereas biochemical recurrence had a positive predictive value of 99% and detection rates of 63% (PSA level, < 2.0 ng/mL) and 94% (PSA level, > 2.0 ng/mL) [17].

Fig. 1—

53-year-old man with newly diagnosed prostate cancer who underwent imaging for staging purposes.

A and B, Gallium-68–labeled prostate-specific membrane antigen–11 PET/CT fusion (A) and CT

(B) images show pelvic bone and nodal metastases (arrows). Note bone lesion in sacrum with no obvious changes on CT image.

PSMA PET may be useful in planning radiation therapy with a focal dose boost to the index lesion within the prostate gland [18]. In a post hoc analysis of an intention-to-treat cohort of 73 patients with localized PC (15% with intermediate-risk PC, 45% with high-risk PC, and 30% with very-high-risk PC), ⁶⁸Ga-PSMA-11 had a major impact on intended definitive radiation therapy planning for 16.5% of the patients [19]. Similarly, another study showed that without the information provided by ⁶⁸Ga-PSMA-11 PET, up to 35.7% of lymph nodes would have not been included in the clinical radiation volume delineated by the Radiation Therapy Oncology Group consensus [20].

Biochemical Recurrence

Many studies have shown the utility and competitive advantage of PSMA compared with other relevant radiopharmaceuticals and conventional imaging for the evaluation of biochemical recurrence of PC after definitive primary treatment [21–24]. Delayed imaging performed up to 3 hours after injection of the radiopharmaceutical may reveal additional lesions, especially in patients with low serum PSA levels [25]. A prospective study of 332 patients with PSA levels of 0.2–2 ng/mL reported detection rates of 13.5% for those with persistent detectable PSA after radical prostatectomy, 44.9% for those with a first-time decrease in the PSA level after therapy, and 41.6% for those with an increase in the PSA level after salvage or hormonal therapy [26]. Figure 2 shows PSMA-avid PC in biochemical recurrence (PSA level, 2.2 ng/mL). In one study in which patients had a very low PSA level (< 0.5 ng/mL), the detection rate with PSMA PET was 34.4%, allowing a change in the intended treatment of 30.2% of patients [27]. The detection rate of ⁶⁸Ga-PSMA-11 PET/CT is positively associated with PSA levels and use of ongoing androgen deprivation therapy (ADT), and it may be correlated with a shorter time to doubling of the PSA level (< 6 months) [28, 29]. In a systematic review and meta-analysis, detection rates in biochemical recurrence were 42%, 58%, 76%, and 95% for the PSA level categories of 0–0.2, 0.2–1, 1–2, and > 2 ng/mL, respectively [30].

Fig. 2—

80-year-old man with prostate cancer who had completed radiotherapy and androgen deprivation therapy 3 years before presenting with increasing prostate-specific antigen levels (from 0.8 to 2.2 ng/mL over 8 months).

A, Gallium-68–labeled prostate-specific membrane antigen–11 PET/CT fusion image shows tracer-avid recurrence (arrow) in left lobe of prostate.

B, CT image shows no obvious abnormality.

In 270 patients with a PSA level of less than 1.0 ng/mL, there was a major impact on salvage radiotherapy planning for 19% of patients [31]. Moreover, a negative or fossa-confined positive PSMA PET finding in patients with whose PSA level returned to a low level (0.05–1.0 ng/mL; defined as PSA relapse) after radical prostatectomy is predictive of high treatment response to salvage radiotherapy [32]. A systematic review and meta-analysis of 15 studies (involving 1163 patients) reported that the pooled proportion of management changes was 54% (95% CI, 47–60%) [33]. Gallium-68–labeled PSMA-11 PET imaging of PSA relapse after definitive primary therapy may also be useful in identifying oligometastatic disease amenable to focal radiotherapy or resection with reported improvement in biochemical progression-free survival [34, 35].

Metastatic Disease

PSMA PET/CT is useful in determining the extent of osseous metastatic disease and may be more advantageous than ^99mTc-based bone scintigraphy and whole-body DWI [36, 37], although ¹⁸F-NaF PET combined with ⁶⁸Ga-PSMA-11 PET may be best for restaging before initiation or modification of therapy [38]. Although background normal bone activity is lower on ⁶⁸Ga-PSMA-11 PET and the target-to-background ratio is higher on ¹⁸F-NaF PET, osteolytic lesions show higher activity than osteoblastic lesions with both radiotracers [38].

Preclinical and pilot human studies have shown that short-duration (4-week) ADT can increase PSMA expression in metastatic lesions, with 59% more lesions imaged with ⁶⁸Ga-PSMA-11 [39], reminiscent of the flare phenomenon that can be observed with bone scintigraphy after ADT administration. In contrast, continuous long-term ADT use (median duration, 230 days) by patients with castration-susceptible PC was associated with detection of 55% fewer lesions on imaging with ⁶⁸Ga-PSMA-11 (when assessed before and after the patient received ADT), with a decrease in tracer uptake seen in most lesions [40].

Treatment Response Assessment

Regarding treatment response evaluation with ⁶⁸Ga-PSMA-11 PET/CT, one study compared Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST), PET Response Evaluation Criteria in Solid Tumors (PERCIST), European Organization for Research and Treatment of Cancer (EORTC), and MD Anderson Cancer Center (MDA) criteria in 88 men with metastatic PC who were undergoing therapy [41]. Molecular criteria performed better than morphologic criteria in assessing the response to treatment in patients with metastatic PC and an increased PSA level. Figure 3 shows new PSMA-avid bone metastases not evident on CT. Preliminary results also show that ⁶⁸Ga-PSMA-11 PET/CT may be useful in assessing the response to docetaxel chemotherapy [42]. However, additional prospective studies involving a large cohort of patients are needed to decipher the potential utility of ⁶⁸Ga-PSMA-11 PET/CT in the clinical setting of treatment response evaluation and to improve our understanding of how various therapies affect PSMA expression.

Fig. 3—

76-year-old man with history of prostate cancer who was receiving antiandrogen therapy with enzalutamide.

A and B, Gallium-68–labeled prostate-specific membrane antigen (PSMA)–11 PET/CT fusion (A) and CT (B) images obtained at baseline show no pelvic, bone, or nodal metastases.

C and D, Gallium-68–labeled PSMA-11 PET/CT fusion (C) and CT (D) images were acquired at follow-up 5 months after images shown in A and B and reveal new ⁶⁸Ga-PSMA-11–avid nodal and bone metastases (arrows, C) but no new abnormalities on CT (D). These findings indicate progression of disease that is only evident on ⁶⁸Ga-PSMA-11 PET/CT.

Prostate-Specific Membrane Antigen Radioligand Therapy

A major use of ⁶⁸Ga-PSMA-11 PET is in the identification of patients with metastatic disease who may be eligible for targeted treatment with ¹⁷⁷Lu-, ²²⁵Ac-, or ²¹³Bi-PSMA radioligand therapy [1]. Most current experience is with the beta particle emitting ¹⁷⁷Lu-PSMA-617. PSMA radioligand therapy is not curative, and proper patient selection is important (e.g., no or a low number of non– PSMA-expressing metastases, sufficient marrow reserve, and kidney function). A number of studies have shown remarkable PSA responses (a decrease of > 50% in the PSA level in 50% of patients) in heavily pretreated patients with relatively mild and manageable toxicity [43].

A recent single-arm, single-center, Australian phase 2 trial reported the outcome for 30 patients with metastatic castration-resistant PC who received up to four cycles of IV ¹⁷⁷Lu-PSMA-617 (7 × 5 GBq per cycle) at six weekly intervals. The primary endpoints were PSA response, as based on the Prostate Cancer Clinical Trial Working Group criteria, which defined response as a decrease in the PSA level of more than 50% from baseline, and toxicity, as based on Common Terminology Criteria for Adverse Events. Most patients (approximately 80%) had received prior chemotherapy or antiandrogen therapy with either abiraterone acetate or enzalutamide. A decrease in the PSA level of 50% or more was observed in 57% of all 30 patients, and an objective response in nodal or visceral disease was reported in 82% of 17 patients with measurable disease. Adverse events included grade 1 xerostomia (in 87% of patients), transient nausea (in 50%), and grade 3 or 4 thrombocytopenia (in 13%) [44]. An international, prospective, open-label, multicenter, randomized phase 3 study of ¹⁷⁷Lu-PSMA-617 in the treatment of patients with progressive PSMA-positive metastatic castration-resistant PC (VISION trial, NCT identifier 03511664 on ClinicalTrials.gov), which compares the use of up to six cycles of 7.4 GBq of ¹⁷⁷Lu-PSMA-617 every 6 weeks combined with best supportive care or best standard of care with the use of best supportive care or best standard of care only, is currently underway. Another trial by the Australian and New Zealand Urogenital and Prostate Cancer Trial Group is also engaged in an open-label, randomized, stratified, two-arm, multicenter, phase 2 trial, with the goal of determining the activity and safety of ¹⁷⁷Lu-PSMA-617 versus cabazitaxel in men with progressive metastatic castration-resistant PC (TheraP trial, NCT identifier 03392428 on ClinicalTrials.gov).

Nonprostate Cancer Malignancies

Many nonprostate ⁶⁸Ga-PSMA-11–avid malignancies have been reported in the literature, although most studies are case reports of incidental findings in which ⁶⁸Ga-PSMA-11 PET/CT was performed for identification of suspected PC [45], PC staging, biochemical recurrence, and suspected metastases. Gallium-68–labeled PSMA-11 PET/CT evaluation of 764 patients with known PC revealed findings atypical for PC in 6.4%, including a histologically proven avid synchronous primary cancer in 0.7%, a benign condition in 3.1%, and atypical presentations of PC in 1% [46]. Figures 4 and 5 show selected ⁶⁸Ga-PSMA– avid benign conditions.

Fig. 4—

Uptake of ⁶⁸Ga-labeled prostate-specific membrane antigen (PSMA)–11 on PET/CT images of three patients with benign conditions. (Courtesy of Sohi JS [Northern California PET Imaging Center, Sacramento, CA] and Bengel FM and Derlin T [Hannover Medical School, Hannover, Germany])

A, 72-year-old man who underwent ⁶⁸Ga-PSMA-11 PET/CT for restaging of prostate cancer (PC) after completing ¹⁷⁷Lu-PSMA therapy. PET/CT image shows uptake in ganglion (arrow).

B, 83-year-old man with biochemical recurrence of PC and radiopharmaceutical-avid atelectasis. Gallium-68–labeled PSMA-11 PET/CT image shows tracer uptake in pulmonary atelectasis consistent with known uptake in inflammation (arrow).

Fig. 5—

76-year-old man with known Paget disease with biochemical recurrence of prostate cancer imaged with ⁶⁸Ga-labeled prostate-specific membrane antigen (PSMA)–11 PET/CT. (Courtesy of Sohi JS [Northern California PET Imaging Center, Sacramento, CA] and Bengel FM and Derlin T [Hannover Medical School, Hannover, Germany])

A, CT image from PET/CT shows osteoblastic cortical thickening in left humerus (arrow), which can be seen with Paget disease.

B, Gallium-68–labeled PSMA-11 fusion PET/CT image shows radiopharmaceutical uptake in area of CT changes (arrow) suggestive of Paget disease.

C, Gallium-68–labeled PSMA-11 PET/CT maximum-intensity-projection image shows patchy extensive radiopharmaceutical distribution in left humerus (arrow) typical for Paget disease. H = head.

Complementary patterns of ⁶⁸Ga-PSMA-11 and ¹⁸F-FDG can be seen in lung cancer, renal cancer, and well-differentiated hepatocellular carcinoma (HCC) [47]. PSMA uptake has been reported in HCC that was not ¹⁸F-choline avid [48]. Several small published case studies of ⁶⁸Ga-PSMA-11–avid nonprostate malignancies, each of which included six to 45 patients, are highlighted in Table 3. They include prospective and retrospective studies of adenoid cystic, breast, hepatocellular, lung, and renal cancers, in addition to gliomas. In patients with glioma, ⁶⁸Ga-PSMA uptake is not dependent on grade and is seen in treatment-naive patients as well as in those with residual disease and disease recurrence [49, 50]. Selected case reports are discussed later in this article, with a more exhaustive list presented in Table 1.

TABLE 3:

Studies of Nonprostate ⁶⁸Ga-Labeled Prostate-Specific Membrane Antigen (PSMA)–11–Avid Malignant Conditions

Region and Malignancy [Reference]	Study Details	Objective	Findings
Abdominal
HCC [53]	Prospective, 7 patients	Comparing uptake of PSMA vs FDG in patients with HCC (6 who were treatment naive and 1 who underwent TACE)	68Ga-PSMA-11 and FDG have complementary uptake. A total of 100% of HCCs (both well-differentiated and moderately differentiated HCCs) were visualized using both tracers. Two of 6 patients had HCC upstaged on 68Ga-PSMA imaging (36 of 37 patients with malignant lesions vs 10 of 37 with FDG-avid HCC and 8 of 37 avid for both). 68Ga-PSMA-avid lesions showed intense intratumoral microvessel staining for PSMA. Uptake greaterthan hepatic activity was considered abnormal.
RCC [69]	Retrospective, 8 patients	Staging and therapeutic response with comparison with FDG	68Ga-PSMA-11 imaging visualizes metastases, recurrence, and response to treatment. FDG and PSMA show a flip-flop pattern of uptake. Radiotherapy response takes longer to be visualized with PSMA compared with FDG.
RCC [67]	Retrospective, 6 patients	Staging	Primary RCC may show mild uptake, less-than-normal renal cortical avidity for clear cell and papillary RCC, and markedly diminished PSMA uptake in chromophobe RCC. All metastases were in clear cell RCC and were PSMA avid. Subcentimeter lung metastases were not avid, possibly because of size.
Head and neck
Adenoid cystic carcinoma [137]	Retrospective, 9 patients	Analyze expression of PSMA and visualization on 68Ga-PSMA-11 imaging	All patients were 68Ga-PSMA-11 avid (with variable uptake) and received accurately guided management. Variable PSMA expression was seen in all specimens. One patient underwent 177Lu-PSM A-617 therapy described as encouraging. One case of known recurrence was not detected, with FDG indicating that 68Ga-PSMA-11 may be at least as good as FDG or better for detection of recurrent tumor or metastatic disease.
Metastatic DTC [81]	Prospective, 10 patients	Assess PSMA expression in patients with metastatic DTC	Metastatic DTC sites can be 68Ga-PSMA-11 avid. Those that are PSMA positive could be candidates for 177Lu-PSMA-617 therapy. 68Ga-PSMA-11 detected 30 of 32 total lesions, with iodine uptake seen in the two non-PSMA-avid lesions.
Metastatic DTC [104]	6 patients	Evaluate the role of 68Ga-PSMA-11 in the detection of metastatic DTC (in comparison with FDG)	PSMA might be suitable for staging metastatic DTC. Patients with positive findings on PSMA imaging could be candidates for l77Lu-PSMA-617 therapy. In 3 of 6 patients, PSMA imaging detected more lesions than did FDG imaging. 68Ga-PSMA-11 is more avid for follicular thyroid cancer and is markedly less avid in papillary and oncocytic-DTC, with the SUVmax increasing with increasing serum thyroglobulin levels.
CNS
Glioma[50]	Prospective, 15 patients	10 Patients had suspected glioma recurrence on MRI, 2 had SOLs, and 3 had glioma restaged immediately after surgery	High target-to-background ratio. Nine of 10 patients had biopsy-proven recurrence that was 68Ga-PSMA avid, and the patient who did not have 68Ga-PSM A-avid recurrence was stable on follow-up. PSMA uptake is not dependent on the grade of the glioma. Both SOL lesions (grade 4 gliomas) were 68Ga-PSMA avid. 68Ga-PSMA-avid residual disease was seen in postoperative glioblastoma multiforme. Two 68Ga-PSMA scans that showed negative findings (for suspected recurrence and for postsurgical assessment) had negative findings on follow-up.
Glioma [49] Thorax	10 patients	MRI-positive gliomas (5 with suspected recurrence) and 5 SOLs underwent FDG and 68Ga-PSMA-11 imaging	Higher target-to-background ratio for 68Ga-PSMA (12.9) compared with FDG (0.96). Glioma recurrence in 4 patients was better seen on PSMA imaging, whereas lesion with negative findings was stable on follow-up MRI. Glioma (grade 4) and atypical meningioma are better seen with 68Ga-PSMA (vs FDG) imaging, whereas primary CNS lymphoma is more FDG avid but has a bettertarget-to-background ratio with 68Ga-PSMA.
Breast cancer [96]	Prospective, 19 patients	Uptake in patients with breast carcinoma	Imaged primary tumors, local recurrence, and metastases. Metastases are more avid than the primary lesion. Flip-flop uptake seen with FDG.
Lung cancer [109]	Retrospective, 45 patients	Differentiating lung nodules > 7 mm in patients with prostate cancer	Excluded stable solitary lesions and those with fat or calcifications (signs of benignancy). No significant difference in SUVmax between lung cancer and prostate cancer metastases, both irregular and spiculated on CT, although only metastases were smooth or lobulated. PSMA expression was detected in the tumor-associated neovasculature in all non-small lung cancer specimens.

Note—HCC = hepatocellular carcinoma, TACE = transarterial chemoembolization, RCC = renal cell carcinoma, DTC = differentiated thyroid cancer, SOLs = space-occupying lesions, SUV_max = maximum standardized uptake value.

Abdominal Malignancies

Adrenal Carcinoma

In a patient with adrenocortical cancer who underwent adrenalectomy, ⁶⁸Ga-PSMA-11 accurately imaged metastatic pulmonary nodules, although they were better seen on concurrent FDG [51].

Colorectal Cancer

It has been reported that 84.6% of the colorectal cancer neovascular endothelium has high PSMA expression [52]. However, colorectal primary tumors and metastases (neck and thoracic nodes, lungs, and liver) may or may not have significant PSMA uptake [52–54]. PSMA-avid colorectal malignancies and metastases exhibited uptake greater than hepatic uptake, although the metastases were less avid than the primary cancer.

Gastrointestinal Stromal Tumor

Case reports have shown biopsy-proven PSMA-avid gastrointestinal stromal tumor (GIST) with uptake greater than [55] and less than [56, 57] hepatic levels of uptake. Lesions include centrally photopenic abdominal masses, partially calcified abdominal masses, and lesions in the soft tissue of the gastric wall [57]. PSMA expression has been reported in 12.6% of GISTs, with strong expression observed in 1% [56]. PSMA uptake may be caused by neoangiogenesis [57].

Hepatocellular Carcinoma

A total of 95% of cases of HCC in the tumor vasculature reportedly stained positive for PSMA [45]. Imaging with ⁶⁸Ga-PSMA-11 showed more HCC than did imaging with FDG [58] or ¹⁸F-choline [48], corresponding to contrast enhancement on CT (Fig. 6). Uptake with FDG, however, corresponded to nonenhancing areas [58].

Fig. 6—

Hepatocellular carcinoma. (Adapted with permission from research originally published in JNM. Kesler M, Levine C, Hershkovitz D, et al. ⁶⁸Ga-PSMA is a novel PET-CT tracer for imaging of hepatocellular carcinoma: a prospective pilot study.

A–C, CT image (A), ⁶⁸Ga-labeled prostate-specific membrane antigen (PSMA)–11 PET/CT image (B), and ¹⁸F-FDG PET/CT image (C). CT image (A) shows arterially enhancing hepatocellular carcinoma (arrow) and left portal vein tumor thrombus (arrowhead) with increased uptake of ⁶⁸Ga-PSMA-11 (B) in both areas but no significant ¹⁸F-FDG uptake (C).

Neuroendocrine Tumor

Uptake of ⁶⁸Ga-PSMA-11 by pancreatic neuroendocrine tumor has been reported as faint [59] and peripheral, with higher uptake noted with ⁶⁸Ga-DOTANOC [59]. Gallium-68–labeled PSMA-11 uptake has also been reported for urinary bladder paraganglioma [60]. Of interest, ⁶⁸Ga-DOTANOC–avid PC with neuroendocrine differentiation may have variable FDG and ⁶⁸Ga-PSMA-11 uptake, with both negative [61, 62] and positive uptake reported [63]. However, more lesions were noted with ⁶⁸Ga-DOTANOC and FDG imaging compared with ⁶⁸Ga-PSMA-11 imaging [61].

Pheochromocytoma

Intense ⁶⁸Ga-PSMA-11 and ⁶⁸Ga-DOTANOC uptake was described in clinically diagnosed pheochromocytoma [64].

Renal Cancer

PSMA is highly expressed in renal cell carcinoma (RCC) neovasculature [65, 66]. Higher grade, advanced stage, metastatic, and lethal clear cell RCCs correspond to higher PSMA expression in tumor vessels [65]. Gallium-68–labeled PSMA-11 provides no benefit for imaging primary RCC [65], with uptake less than normal renal cortical avidity [66] in clear cell and papillary RCC and with markedly diminished ⁶⁸Ga-PSMA-11 uptake in chromophobe RCC [67].

Gallium-68–labeled PSMA-11 PET/CT has a reported sensitivity of 92.11% for detecting RCC metastases, compared with 68.6% for CT [65]. RCC metastases [68] may show a flip-flop pattern for ⁶⁸Ga-PSMA-11 and FDG (Fig. 7), with lesions solely imaged or better imaged with one tracer versus the other [69]. Recurrent metastases of clear cell RCC may be intensely ⁶⁸Ga-PSMA-11 avid [70] or may show little or no uptake [69].

Fig. 7—

60-year-old man who initially underwent left nephrectomy and left lung lower lobectomy for synchronous presentation of solitary metastasis of Fuhrman grade 3 clear cell carcinoma. (Adapted with permission from Siva S, Callahan J, Pryor D, Martin J, Lawrentschuk N, Hofman MS. Utility of ⁶⁸Ga prostate specific membrane antigen positron emission tomography in diagnosis and response assessment of recurrent renal cell carcinoma.

A and B, Fluorine-18–labeled FDG PET image (A) and ⁶⁸Ga-labeled prostate-specific membrane antigen (PSMA)–11 PET image (B), obtained 18 months after nephrectomy and lobectomy, show left adrenal metastasis (arrows) that was mildly FDG avid (A) and intensely ⁶⁸Ga-PSMA-11 avid (B).

Gallium-68–labeled PSMA-11 PET/CT shows response earlier than morphologic changes are shown on CT or MRI [69]. With RCC response to radiotherapy, FDG uptake normalizes in 3–4 months, compared with 6–12 months for PSMA, although the significance of this finding is uncertain [65].

Urothelial Carcinoma

Gallium-68–labeled PSMA-11 PET/CT showed supraclavicular metastasis from urothelial carcinoma with synchronous PC and an increasing PSA level [71].

Bone Cancer

Multiple myeloma—

Intense bony uptake is associated with active multiple myeloma and its family of diseases, whether or not there are coexisting osteolytic changes on CT [72–74]. PSMA overexpression may be caused by tumor angiogenic properties of myeloma-related abnormalities.

Osteosarcoma—

PSMA expression is seen in osteosarcoma but not in fibrous dysplasia [75]. Intense ⁶⁸Ga-PSMA-11 uptake (i.e., greater than hepatic uptake) is seen in the transformation of fibrous dysplasia to osteosarcoma, and mild uptake (i.e., less than hepatic uptake) has been reported with fibrous dysplasia [76].

Head and Neck Cancer

Adenoid Cystic Carcinoma

Most studies of head and neck cancers with this radiopharmaceutical are case reports related to adenoid cystic carcinoma. A case report of juvenile nasal angiofibroma is included here because of the aggressive nature and high uptake of the angiofibroma [77]. Gallium-68–labeled PSMA-11–avid thymoma [78], basaloid thymic carcinoma [79], and squamous cell carcinoma of the tongue [46, 80] have been reported (Fig. 8).

Fig. 8—

55-year-old man with incidental ⁶⁸Ga-labeled prostate-specific membrane antigen (PSMA)–11–avid squamous cell carcinoma. (Adapted with permission from research originally published in JNM. Osman MM, Iravani A, Hicks RJ, Hofman MS. Detection of synchronous primary malignancies with ⁶⁸Ga-labeled prostate-specific membrane antigen PET/CT in patients with prostate cancer: frequency in 764 patients.

A and B, Gallium-68–labeled PSMA-11 PET/CT images show incidental abnormal uptake in squamous cell carcinoma of right tonsillar pillar (arrow, A) and also in ipsilateral mildly enlarged level II neck node (arrow, B).

Thyroid Cancer

Uptake of ⁶⁸Ga-PSMA-11 is seen in iodine-avid and iodine scintigraphy–negative differentiated thyroid cancers (Fig. 9), revealing more lesions than FDG [81, 82]. Recurrent papillary thyroid cancer with an elevated thyroglobulin level not avid for iodine or FDG was avid for ⁶⁸Ga-PSMA-11 [83], although not all papillary thyroid cancer is ⁶⁸Ga-PSMA-11 avid [84]. Uptake of ⁶⁸Ga-PSMA-11 was also reported in thyroid cancer in patients with elevated thyroglobulin levels and negative results of iodine scintigraphy [81–83] as well as in anaplastic thyroid cancer [85], Hürthle cell carcinoma, and follicular adenomas [86–89].

Fig. 9—

72-year-old man with prostate cancer. (Adapted with permission from research originally published in JNM. Sager S, Vatankulu B, Uslu L, Sönmezoglu K. Incidental detection of follicular thyroid carcinoma in ⁶⁸Ga-PSMA PET/CT imaging.

A and B, Gallium-68–labeled prostate-specific membrane antigen (PSMA)–11 PET/CT fusion (A) and CT (B) images show ⁶⁸Ga-PSMA-11–avid malignant thyroid nodule (arrows). On CT, there is lobulated heterogeneous nodule. On PET, nodule has small area of central necrosis with peripheral abnormal increased uptake.

Muscular, Cutaneous, and Vascular Cancer Hemangiopericytoma

Imaging with ⁶⁸Ga-PSMA-11 showed several avid sites of hemangiopericytoma, whereas FDG was not avid for most of these lesions, including the site of local recurrence [90].

Liposarcoma

Levels of PSMA uptake in well-differentiated liposarcoma have been reported to be lower than those in hepatic uptake and blood pool activity [2, 91].

Melanoma

Uptake of ⁶⁸Ga-PSMA-11 has been reported in nodal metastases from melanoma, at levels either less than [92] or greater than [93] hepatic levels of uptake, with corresponding FDG uptake noted in both instances. PSMA expression was found in the neovasculature but not in tumor cells [92].

Systemic Cancer (Lymphoma)

A good ⁶⁸Ga-PSMA-11 target-to-background ratio was noted in primary CNS lymphoma [49], with uptake also seen in diffuse large B-cell lymphoma [46]. Low-level PSMA uptake was noted in follicular lymphoma [94, 95].

Thorax

Breast

Breast cancer metastases have been reported as more avid than the primary lesion or local recurrence, although not all lesions are avid for PSMA [96], corresponding to reported PSMA expression patterns in tumor cells and neovasculature [8]. Concordance of FDG and PSMA uptake has been reported [97].

Lung

Intense ⁶⁸Ga-PSMA-11 uptake (at levels greater than hepatic uptake) was seen in FDG-negative, highly differentiated lung adenocarcinoma [47]. Mild to moderately ⁶⁸Ga-PSMA-11–avid metastatic lung adenocarcinoma (Fig. 10) has also been reported both in patients who are treatment naive [84, 98] and in those who have recurrent disease [99].

Fig. 10—

69-year-old man with prostate cancer. Axial PET/CT fusion image shows focal ⁶⁸Ga-labeled prostate-specific membrane antigen–11 uptake (arrow) in incidentally detected spiculated right-sided lung nodule found to be synchronous lung adenocarcinoma. (Adapted with permission from research originally published in JNM. Osman MM, Iravani A, Hicks RJ, Hofman MS. Detection of synchronous primary malignancies with ⁶⁸Ga-labeled prostate-specific membrane antigen PET/CT in patients with prostate cancer: frequency in 764 patients.

Conclusion

Gallium-68–labeled PSMA-11 is useful for imaging evaluation of prostate and non-prostate malignancies and other benign conditions. The uptake of ⁶⁸Ga-PSMA-11 in nonprostate malignancies raises the possibility of therapy with ¹⁷⁷Lu-PSMA-617 similar to that undergoing evaluation for PC treatment in current trials [69, 100]. Histologic or other relevant ancillary information may be important if PSMA-avid findings are not typical for PC [53]. The use of PSMA-targeted imaging and therapy is expected to grow dramatically in the coming years.