Morphological imaging methods exhibit considerable limitations: sensitivity ranges between 25% and 54% for detection of local recurrence of prostate cancer by transrectal ultrasonography or computed tomography (CT) and is moderately improved using functional magnetic resonance (MR) imaging techniques (1–3). Gallium-68 prostate-specific membrane antigen (PSMA)-bis [2-hydroxy-5-(carboxyethyl)benzyl] ethylenediamine-diacetic acid (HBED-CC) is a relatively new positron emission tomography (PET) tracer that is increasingly used in the detection of prostatic metastases at staging and in the evaluation of recurrent disease (4–8). Studies suggest that 68-PSMA-ligand PET/CT is fairly sensitive and highly specific in the detection of prostatic metastases even at low prostate-specific antigen levels (7, 9, 10). PSMA is a cell surface protein, with significantly increased expression in prostate cancer cells than in other PSMA-expressing tissues such as kidney, proximal small intestine, and salivary glands (11, 12). Imaging with Gallium-68 PSMA-bis-HBED-CC is based on the fact that it specifically binds to PSMA on the cell membrane of prostatic tumor cells. However, it has been shown that various normal nonprostatic tissues also express PSMA and therefore show PSMA tracer avidity. Some of the PSMA-avid nonprostatic malignancies have also been shown to express PSMA on their cell or in their neovascularity and could be confused with prostatic metastases. The purpose of this review is to illustrate such interpretive pitfalls that one may encounter during reporting by a process of literature review and integrating some of our cases as examples to help avoid misdiagnosis and mismanagement.
A significant number of Gallium-68 PSMA PET/CT are performed at our center (∼12–15/week). A database is maintained within the department that comprises deidentified patient information, information pertaining to primary prostate malignancy, stage-defined findings on PSMA PET/CT, and any unusual PSMA uptake. A retrospective observation and a review of consecutive 1115 PSMA PET/CT studies performed between February 27, 2015, and May 31, 2017 were conducted by the authors of this paper.
PSMA uptake related to prostate carcinoma within the prostate gland, lymph nodes, or metastases was excluded. Any unusual PSMA uptake was documented, described, and followed up. All such cases were then subdivided into the following 4 categories: physiological uptake, benign pathological uptake, nonprostatic neoplastic uptake, and miscellaneous uptake. The images of such cases were downloaded after deidentification via 2 different picture archive and communication system (PACS) software used at our center, that is, general electronics (GE) and MedView PACS. A literature review was performed to identify similar cases reported in the literature and have been cited here.
Tracer Preparation and Imaging Protocol/Technique
Gallium-68 (68Ga3+) is obtained using a Germanium-68/Gallium-68 (68Ge/68Ga) radionuclide generator and used for radiolabeling of PSMA-HBED-CC using automated a radiosynthesizer. The labeling efficiency of the radiopharmaceutical is typically >98%. The tracer dose is dependent on the patient's weight: <60 kg, 61–90 kg, and >90 kg, receiving 200 MBq, 250 MBq, and 300 MBq, respectively, in our department and is administered via an intravenous injection. The PET/CT images from skull vertex to knees are acquired at 30 min post injection on a Phillips Gemini TF 64 slice PET/CT camera (Phillips Medical Systems, Cleveland). A concurrent low-dose CT (120 keV and 60 mAs per section) with dilute oral contrast of the same region is also performed for lesion localization and attenuation correction. Emission data are corrected for attenuation, scatter, and decay and these are processed as per the vendor reconstruction protocol. The PET, low-dose CT, and fused PET/CT images are then sent to the workstation for interpretation.
Result and Discussion
General Distribution of PSMA Uptake in The Body
PSMA is an integral membrane protein of the prostatic epithelium with both intracellular and extracellular domain. It has several enzymatic functions such as glutamate-preferring carboxypeptidase. The effect of these enzymatic functions is not understood; however, it has been shown that PSMA does have an internalization signal that allows internalization of the protein on the cell surface into an endosomal compartment (13). PSMA is expressed in both benign and malignant prostate pathologies and is upregulated following androgen deprivation (14, 15). In addition to the prostate, which shows mild diffuse PSMA uptake, various other normal and pathological tissues also take up PSMA tracer related to immunoexpression of PSMA on their cells (16–18). PSMA is expressed in other cancers as well, more specifically in the neovasculature associated with these cancers (17). The degree of PSMA uptake of these tissues is dependent on the extent of PSMA expression. PSMA uptake is mild in pancreatic head, Waldeyer ring, and fossa of Rosenmüller, and moderate in proximal small bowel, liver, and spleen. Marked PSMA tracer activity is seen in kidneys, salivary glands, lacrimal glands, and vocal cords. Intense uptake in renal pelvis, ureters, and urinary bladder is mostly related to excretion (Figure 1). Although PSMA immunoexpression is also established in the brain, heart, urinary bladder, testis, and endometrial glands, the extent of expression is minimal, and therefore, it does not show significant uptake.
Variable Physiological Uptake
Activity is seen in the normal salivary glands, for example, parotid and submandibular glands, as well as accessory parotid gland that is similar to the main parotid and other salivary glands. The submandibular glands are usually symmetrical in size; however, there may occasionally be asymmetric PSMA activity that may be misinterpreted as lymphadenopathy (Figure 2). Accessory parotid glands are seen in ∼20% of the population; it is located on the masseter muscle, anterior to the main parotid gland and superior to the Stenson duct (19, 20); and it can be either unilateral or bilateral.
Some of the sympathetic chain ganglia have been shown to take up PSMA including celiac and stellate ganglia (21, 22). Celiac ganglion can be identified by CT in ∼96% of male patients. They are located anterior to the diaphragmatic crura, over the anterolateral wall of the aorta bilaterally and just caudal to the origin of the celiac artery. The left celiac ganglion is more often identified than the right (89% vs 67%) (23). They appear as linear multilobulated or discoid-shaped structures (Figure 3, A and B). CT attenuation of Celiac ganglia is same as the adjacent adrenal glands on a non-enhanced CT. Celiac ganglia strongly express PSMA on immunohistochemical analysis (22). The stellate ganglion lies anterior to the neck of the first rib and the C7 transverse process, lateral to the C7/T1 vertebral bodies, and superior to the pleural cupola over the lung apex.
A variable degree of diffuse uptake is occasionally seen in the gall bladder, although the gall bladder does not show significant uptake (Figure 3, C and D). This is likely related to the variability of PSMA expression, and more studies are needed to evaluate other potential causes.
Benign Pathological PSMA Uptake
We encountered foci of PSMA uptake in unusual sites in patients with the magnetic resonance imaging-/biopsy-proven tumor sites in the prostate gland. This may be related to focal prostatitis or areas of benign prostatic hyperplasia as mentioned previously that PSMA is overexpressed to a certain extent in all kinds of prostate pathology, although the degree of expression may be weak. This explains why PSMA may not be suitable in the evaluation of primary tumor.
Mild nonspecific PSMA uptake is not infrequently seen in distant lymph nodes such as axillary or hilar stations in an unusual pattern of metastatic spread, suggestive of reactive etiology (Figure 4). Similar uptake may also be seen in inguinal nodes and may be difficult to entirely exclude metastasis. However, when the uptake is seen in several contiguous lymph node stations, lymphoma or granulomatous disease needs to be considered.
Inflammation and infection may show increased PSMA uptake, thereby mimicking malignancy. We identified PSMA uptake in lung infection/pneumonia, atelectasis, and inflammation related to pleural plaques (asbestos) (Figure 5). Similarly, atherosclerotic arteries show linear diffuse mild PSMA uptake along their walls, which may be related to underlying inflammation.
Diffuse variable PSMA uptake has been reported in Paget disease of the bone (24, 25). Paget disease is a common benign condition in the elderly, affecting ∼10% of the population of age >80 years. The various hypotheses to explain the mechanism of uptake include uptake within the neovasculature of the Pagetoid bone and uptake driven by hyperemia and increased radiotracer delivery. Correlation with CT to look for typical appearance of Pagetoid bone including diffuse sclerosis, thickened cortex, bone expansion, and coarsened trabeculae should suggest the right diagnosis (Figure 6).
Similarly, we identified mild focal uptake at sites of healing fractures (Figure 7, A and B). Degenerative arthritis in the spine or peripheral joints may show mild-to-moderate PSMA activity (Figure 7, C–F). This may be misinterpreted as metastatic disease. On the other hand, a possible underlying metastasis in the subchondral aspect of the joint may be overlooked (Figure 8) in the setting of background degenerative arthritis.
A case of mild diffuse bone marrow PSMA uptake in a patient with known polycythemia rubra vera is shown, which has not been previously reported in the literature to the best of our knowledge (Figure 9). Recently, a case of follicular lymphoma showing avid PSMA uptake has been reported (26).
Nonprostatic Neoplastic Conditions
PSMA uptake in non–small cell lung cancer with PSMA-avid metastases to the thyroid gland (27) was previously reported by our institution (Figure 10, A and B). Other malignant neoplasms that show PSMA activity include gastric/colonic adenocarcinoma (Figure 10, C–F), renal cell cancer (Figure 11, A and B), neuroendocrine tumor (Figure 11, C and D), gliomas, and breast cancers (17, 27–31). An incidental case of biopsy-proven PSMA-avid hepatocellular carcinoma has been reported by our institution recently (Figure 12). The PSMA uptake in the endothelium of tumor neoangiogenesis explains the tracer uptake within the tumor.
Benign tumors such as schwannoma and follicular thyroid adenoma have been reported to exhibit PSMA uptake (33–35). PSMA uptake in the thyroid may be because of a differentiated thyroid cancer (34). Evaluation of any PSMA uptake in the thyroid gland (Figure 13) with fine-needle biopsy and histopathological examination is therefore warranted to confirm the underlying pathology.
Miscellaneous PSMA Uptake
Some variants of prostatic carcinoma such as ductal type and cancer with neuroendocrine differentiation may not show significant uptake owing to variation of PSMA expression (36). Sometimes, while the primary focus may be PSMA-positive, the metastases may be PSMA-negative because of heterogeneity of PSMA expression. This may result in false downstaging of the cancer and administration of incorrect treatment. Tissue biopsy and histopathological assessment of the suspected lesion should, in most cases, provide the right diagnosis.
Densely sclerotic and markedly osteoblastic bone lesions found on the bone scan are often very mildly PSMA-avid, indicating small-volume metastases (Figure 14), while subtly sclerotic bone foci on CT can show moderate-to-marked PSMA uptake without significant osteoblastic activity on bone scan.
Mild, diffuse symmetrical uptake was seen in gynecomastia (Figure 15) and the mechanism is not clear considering immunoexpression is not typically identified in the mammary tissue. Other benign unexpected PSMA uptake was also identified in muscles (Figure 16) and cutaneous lesions. Mild PSMA uptake has been noted in atelectasis (Figure 17). Care should be taken to not miss adjacent lung parenchyma, rib, or vertebral body metastases.
Particular attention needs to be given to the areas adjacent to high physiological PSMA activity, which may be easily overlooked. This can occur particularly around the urinary bladder (Figure 18).
As 68Ga-PSMA-ligand PET/CT becomes a more widely used tool in the management of prostate cancer, knowledge of normal physiological distribution, variation in physiological distribution, and confounding PSMA uptake in nonprostatic pathologies is essential to optimize interpretation. Failure to recognize these aspects could result in significant false upstaging or false downstaging and consequent implementation of incorrect management. With newer pathologies being continuously identified to take up PSMA tracer, ongoing learning remains essential. Further studies are required to not only understand the mechanism of PSMA tracer uptake in various other tissues but also establish the potential benefit of PSMA tracer in evaluation of nonprostatic cancers such as fluorodeoxyglucose-negative renal cell carcinoma.