PSMA PET has fundamentally changed how prostate cancer is seen, staged, and treated, but as with any powerful tool, it demands interpretation with a clear eye and a humble mind. In a recent conversation among clinicians, Dr. Ghesani walked through the normal biodistribution of PSMA-targeted tracers, the patterns that can look alarming but are simply the body doing its ordinary work. These tracers are taken up not only by prostate cancer cells but by healthy tissues that naturally express PSMA, including the salivary glands, liver, spleen, and kidneys. From there, the tracer is cleared through the urinary tract and the bowel, which means activity routinely appears along the ureters, in the bladder, and in the intestines. The duodenum, in particular, often shows more pronounced uptake than the rest of the bowel, a finding that might strike a new reader as suspicious but is entirely expected. Dr. Ghesani stressed why knowing this distribution matters clinically, especially for patients being considered for lutetium-177 PSMA therapy. Because that therapy uses a radioactive molecule designed to bind to the same PSMA protein, the normal organs that light up on a diagnostic scan are the same organs that will receive radiation during treatment. Understanding where the tracer goes in a healthy body is therefore not an academic detail; it is central to planning therapy, estimating absorbed dose, and anticipating side effects. A patient may experience dry mouth because the salivary glands are exposed, or renal and bladder irritation because the kidneys and urinary tract are clearing the radioactivity. When a physician reads a PSMA PET scan with this biological map in mind, it transforms the image from a simple game of spotting “hot spots” into something far more powerful: an understanding of where the target lives, how the body handles it, and what a therapy aimed at that target might touch along the way.
Early in the adoption of PSMA PET, many readers were tripped up by a particularly subtle pattern: physiologic uptake in ganglia. Dr. Yonover recalled that, in the early days of his experience, what appeared to be small suspicious lymph nodes were actually normal autonomic ganglia picking up the tracer as part of their everyday biology. Before readers grew familiar with this pattern, these ganglia produced false positives that could have led to unnecessary additional testing or changes in management. The lesson, he explained, is that PSMA PET does not show cancer directly; it shows PSMA expression, which is a biologic feature. Many prostate cancer cells express PSMA at high levels, which is precisely why the scan is so sensitive. But PSMA is not exclusive to cancer, and it is not universally expressed by every cancer cell. Some normal tissues express it, and some advanced or aggressive prostate cancers lose expression of PSMA as they dedifferentiate, becoming essentially invisible on these scans. This is a crucial nuance for clinicians to internalize. A patient with a rapidly progressing, poorly differentiated tumor may have a PSMA PET scan that is relatively quiet or even negative, not because there is no disease, but because the disease no longer produces the protein the scan is looking for. As Dr. Yonover put it, a scan is a reflection of biology, not a final verdict. It can tell you with remarkable precision where PSMA-expressing cells are living, but it cannot tell you what has stopped expressing the target. Understanding both sides of that equation keeps interpretation honest and prevents over-reliance on a single image.
Dr. Mendel echoed that sentiment from his own experience, noting that even now, outside readers occasionally mistake ureteral activity for a suspicious lymph node. Because the kidneys excrete the tracer, the ureters become natural highways of radioactivity. On an axial slice, a ureter cut crosswise can look like a small hot focus nestled next to the iliac vessels or along the pelvic sidewall, exactly where a surgeon would look for metastatic lymph nodes. It is an easy trap, especially if the reading physician is working quickly or relying on old habits. Dr. Mendel’s advice was direct and practical: clinicians managing patients with prostate cancer should not depend solely on the written report. They should pull up the images themselves, scroll through the slices, and look at the anatomy alongside the report. There is no substitute for a moment of direct visual inspection, particularly when treatment decisions hinge on whether a finding is real or an artifact of physiology. This principle was reinforced by his recollection of discovering unexpected high-grade lesions on PSMA PET in patients who had previously been managed with active surveillance. These were not patients who were obviously deteriorating; they were being followed conservatively, and the scan uncovered disease that was far more aggressive than anyone expected. That kind of finding changes everything. It validates the expanding use of PSMA PET and suggests that as more clinical experience accumulates, the indications for this imaging will only continue to broaden. What was once reserved for biochemically recurrent disease is becoming relevant earlier in the disease course, and perhaps even in watchful waiting populations, where it can separate the truly indolent from the silently dangerous.
Dr. Yonover made an even stronger argument for expanding the role of PSMA PET, particularly in the surgical setting. In his view, PSMA PET should now be considered standard imaging before prostatectomy, even for men with favorable intermediate-risk disease who are appropriate candidates for surgery. The reason is not to find small tumors within the prostate; the gland and its pathology are already known. The reason is to avoid operating on men who have occult distant or nodal disease—disease that would render a prostatectomy futile in terms of cure. Without a PSMA PET scan, a surgeon may go into the operating room with every intention of removing the cancer and may perform a beautiful operation, only to learn later that the cancer had already escaped, that the surgery was never going to be curative. That is a devastating conversation to have with a patient, and it is avoidable. Dr. Yonover argued that staging with PSMA PET before prostatectomy gives patients and surgeons an opportunity to make decisions based on information rather than hope. If the scan reveals a small pelvic node or a distant bone lesion, the surgical plan may be abandoned in favor of systemic therapy or radiation, or perhaps a directed biopsy could change the stage and treatment approach entirely. It is not about more imaging for its own sake; it is about matching treatment intensity to the true extent of disease. A favorable intermediate-risk prostate cancer may still be curable with surgery, but only if it is truly organ-confined. The scan is the insurance policy that helps ensure the operation is not doomed from the start.
Dr. Ghesani added valuable technical nuance to the discussion, helping address the very pitfalls his colleagues had described. On the subject of physiologic ganglion uptake, he explained that asymmetry and intensity are not reliable indicators of disease on their own. Some readers might look at a ganglion that is brighter on one side than the other and worry that it represents malignancy. But normal physiologic uptake can be asymmetric, and SUV cutoffs—the numbers often used to measure how hot a spot is—are simply not dependable for distinguishing a normal ganglion from a malignant lymph node. What matters far more is morphology and location. A normal ganglion has a characteristic teardrop shape and sits in a predictable anatomic location, often near the sympathetic chain, the celiac plexus, or along the para-aortic region. Recognizing those features is what separates an experienced reader from a cautious but inexperienced one. Returning to Dr. Mendel’s point about ureteral activity, Dr. Ghesani recalled publishing an early FDG biodistribution atlas years ago, a project born out of the very same problem: normal structures being misread as disease because they looked odd on one plane of view. His recommendation is refreshingly simple. He urged clinicians and radiologists to routinely reformat PSMA PET studies into sagittal and coronal planes before making a final interpretation. On axial images alone, a ureter can appear as a single hot dot, and that dot can masquerade as a lymph node. But once the image is reformatted, the ureter’s full course becomes obvious. It is a tube, not a node. It follows a defined path from the kidney down to the bladder, with no branching, no irregularity, and no mass effect. The reformat does not require sophisticated technology; it is simply a matter of looking at the study the way the body actually exists in three dimensions. It is a reminder that sometimes the most important interpretive skill is not pattern recognition of disease, but pattern recognition of normal anatomy in all its variability.
The broader conversation will continue in a panel titled “Variation in PSMA PET Adoption for Prostate Cancer Care,” where these themes will be explored in the context of real-world practice. Across academic medical centers, large community hospitals, and small private practices, the adoption of PSMA PET is far from uniform. Some settings have easy access to scanners, experienced readers, and integrated tumor boards where images are routinely reviewed by urologists, medical oncologists, radiation oncologists, and nuclear medicine physicians together. Others face logistical barriers, reimbursement concerns, limited tracer availability, or a scanner that is used only intermittently and read by radiologists who may not have developed deep familiarity with PSMA-specific patterns. That variation matters because a test is only as good as the clinician’s ability to understand it and act on it. Imaging changes conversations with patients in profound ways. A man who was told he has localized prostate cancer may suddenly be facing a scan that shows disease in a distant bone. A man who was deciding between surgery and radiation may now be directed toward systemic therapy instead. A man on active surveillance may hear, for the first time, that what was once considered low-risk is now being treated as an urgent problem. These are not just technical changes; they are deeply human moments, filled with anxiety, relief, fear, and sometimes hope. What the panel will emphasize is that the adoption of PSMA PET is not merely about acquiring a new technology. It is about creating the conditions for it to be used wisely—training readers to recognize physiologic patterns, arming urologists and oncologists with enough knowledge to review images themselves, and building a culture where multidisciplinary review is the norm rather than the exception. With that foundation, PSMA PET can do what it was meant to do: illuminate the unseen, spare patients from futile treatments, and guide the right therapy to the right patient at the right time.