When PSMA-targeted therapy is not enough: high-risk localized prostate cancer after repeated [177Lu]Lu-PSMA radioligand therapy
Published in Biomedical Research
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Newly diagnosed high-risk localized prostate cancer after multiple [177Lu]Lu-PSMA radioligand therapy in the context of metastatic parotid carcinoma: a case report
Why this case matters
[177Lu]Lu-PSMA radioligand therapy is best established in metastatic castration-resistant prostate cancer, but PSMA expression is not exclusive to prostate cancer. In this case, a 67-year-old man received multiple cycles of [177Lu]Lu-PSMA therapy for metastatic parotid carcinoma. During follow-up, rising PSA and PSMA uptake in the prostate led to prostate MRI and biopsy, which revealed high-risk localized prostate cancer: Gleason 9 = 4 + 5, WHO grade group 5.
The striking feature is that the prostate biopsy showed no meaningful histopathologic regression despite prior exposure to PSMA-targeted radioligand therapy. The authors therefore raise an important caution: PSMA uptake alone may not guarantee therapeutic vulnerability, and resistant high-grade prostate cancer may persist or emerge under treatment pressure.
Key takeaways
This case emphasizes that PSMA-directed therapy is not biologically equivalent to definitive prostate cancer treatment. Persistent PSA rise, new focal prostatic PSMA uptake, or suspicious MRI findings should still prompt standard diagnostic evaluation, including targeted biopsy when clinically appropriate.
The case also has implications for neoadjuvant [177Lu]Lu-PSMA approaches in high-risk localized prostate cancer. Early studies suggest feasibility and activity, but this report highlights the need for long-term follow-up, tissue-based correlation, and predictive biomarkers of resistance.
The visual material is central to the report: page 2 shows PSA progression over time; page 3 shows PSMA-tracer uptake in the prostate and the radioligand dosing history; page 4 shows PI-RADS 4 lesions and sacral bone biopsy imaging; page 5 shows prostate biopsy cores with Gleason grade 4 and 5 patterns without significant regression.
Clinical Take-Home Message
PSMA expression is useful diagnostically and therapeutically, but it should not be interpreted as proof of treatment sensitivity. In high-risk prostate cancer, especially as PSMA-radioligand therapy moves into earlier disease settings, careful PSA surveillance, prostate MRI, tissue confirmation, and histopathologic assessment remain essential.
Question:
A 67-year-old man received multiple cycles of [177Lu]Lu-PSMA radioligand therapy for metastatic parotid carcinoma. During follow-up, he developed rising PSA, focal PSMA uptake in the prostate, PI-RADS 4 lesions on prostate MRI, and biopsy-proven Gleason 9 prostate cancer without histopathologic regression. What is the most important clinical implication of this case?
A. PSMA uptake confirms that prostate cancer will respond reliably to [177Lu]Lu-PSMA therapy.
B. Prior [177Lu]Lu-PSMA therapy excludes the possibility of subsequent high-risk localized prostate cancer.
C. Rising PSA and suspicious prostate imaging still require standard diagnostic evaluation, including biopsy, even after prior PSMA-targeted therapy.
D. Parotid carcinoma commonly transforms into prostate adenocarcinoma after radioligand therapy.
Correct answer: C.
Explanation:
This case shows that PSMA expression and prior exposure to [177Lu]Lu-PSMA radioligand therapy do not guarantee eradication or regression of prostate cancer. Despite multiple cycles of therapy given for PSMA-expressing metastatic parotid carcinoma, the patient developed high-risk localized prostate cancer with Gleason 9 disease and no significant regressive histopathologic changes in biopsy tissue. Therefore, persistent PSA elevation, focal prostatic PSMA uptake, and suspicious MRI findings should still prompt conventional prostate cancer workup, including targeted biopsy.
Why the other answers are incorrect:
A is incorrect because PSMA uptake indicates target expression, not assured therapeutic sensitivity.
B is incorrect because prior PSMA-targeted therapy did not prevent diagnosis of high-risk prostate cancer in this case.
D is incorrect because the report describes two distinct malignancies: metastatic parotid carcinoma and newly diagnosed prostate adenocarcinoma, not malignant transformation from one into the other.
Journal of Medical Case Reports is the world’s first international, PubMed-listed, medical journal devoted to publishing case reports from all medical disciplines and will consider any original case report that expands the field of general medical knowledge, and original research relating to case reports. The journal is open access, and strongly endorses the CARE guidelines for case reports, requiring authors to submit populated CARE checklists with submissions to improve transparency in reporting.
Richard Alan Rison is the interim Editor-in-Chief of Journal of Medical Case reports. He is also an associate neurology editor (editorial board) for BMC Neurology, and the former lead editor for case reports of BMC Research Notes (currently on the editorial board). His scholarly work focuses on medical case reporting, reporting standards, and editorial methodology. Dr. Rison participated in the development and dissemination of the CARE guidelines for clinical case reporting and has authored numerous publications addressing both neurological disorders and the role of case reports in advancing medical knowledge. Dr. Rison practices general neurology and served as the founding medical director of the PIH Health Hospital-Whittier Stroke Program and the PIH Health Hospital-Whittier Non-Invasive Vascular Laboratory, is a clinical assistant professor of neurology at the University of Southern California Keck School of Medicine and Los Angeles County Medical Center, and is a Fellow of the American Academy of Neurology, the American Neurological Association, and the American Association of Neuromuscular and Electrodiagnostic Medicine. Dr Rison is board-certified by the American Board of Psychiatry and Neurology in neurology and vascular neurology, and neurocritical care and neuroimaging by the United Council of Neurologic Subspecialties. He is also board-certified by the American Board of Electrodiagnostic Medicine in electrodiagnostic medicine. Dr. Rison is a former president of the Los Angeles Neurological Society.
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