Mixed Tracer PET Scans and Biopsy Reveal Pitfalls in Monitoring Rare Aggressive Prostate Cancer

A single-patient case report from Xinqiao Hospital of Army Medical University in Chongqing, China, has illustrated both the value and the hazards of relying on molecular imaging to track neuroendocrine prostate cancer, a rare and aggressive subtype of the disease. The report, published in Frontiers in Oncology, followed a 64-year-old man whose tumor contained both neuroendocrine carcinoma and adenocarcinoma components and had invaded the bladder. Over the course of his treatment and follow-up, the authors compared two different positron emission tomography tracers, fluorine-18 fluorodeoxyglucose (18F-FDG) and gallium-68 prostate-specific membrane antigen (68Ga-PSMA), against conventional blood markers. Their central message was a cautionary one: multi-tracer PET scans can reveal disease activity that blood tests miss, but imaging signals can also mislead, and in this patient a suspicious rise in bladder uptake ultimately turned out to be chronic inflammation confirmed only by repeat biopsy.

Neuroendocrine prostate cancer (NEPC) represents a small but clinically formidable fraction of prostate malignancies. It can arise de novo, accounting for less than 2% of prostate cancer cases, or emerge after androgen deprivation therapy or treatment with androgen receptor pathway inhibitors. Unlike typical prostate adenocarcinoma, NEPC is characterized by resistance to hormonal therapy, rapid clinical progression and poor overall survival, and no curative treatment has been established. The subtype is marked by a biological shift known as transdifferentiation or lineage reprogramming, in which tumor cells lose expression of the androgen receptor and prostate-specific antigen (PSA) while gaining expression of neuroendocrine markers such as neuron-specific enolase (NSE), chromogranin A, synaptophysin and NCAM1/CD56. Because PSA, the workhorse biomarker of prostate cancer follow-up, is often extremely low or normal in NEPC, clinicians are advised to monitor NSE, lactate dehydrogenase and chromogranin A instead, with NSE the most commonly used serum marker in practice.

The patient at the center of the report arrived with a six-month history of persistent urinary difficulty that had worsened over the preceding month. His serum PSA measured 5.54 ng/ml, and magnetic resonance imaging revealed a prostatic nodule assigned a PI-RADS score of 4, together with thickening of the bladder trigone wall suggestive of a neoplastic lesion. Transurethral resection of the bladder lesions and a transperineal prostate biopsy followed. Pathological examination of the prostate specimen showed neuroendocrine carcinoma of mixed type, tending towards intermediate-cell small cell carcinoma, while the adenocarcinoma component carried a Gleason score of 9 (5 + 4). The bladder specimen also revealed neuroendocrine carcinoma. Immunohistochemistry on the prostate tissue showed positive staining for CK, CgA, Syn and NKX3.1, a Ki-67 proliferation index of 70%, and negative staining for PSA, P63, GAT3 and CK7, a profile consistent with the neuroendocrine phenotype.

Imaging began with 18F-FDG PET/CT, performed 60 minutes after intravenous injection of 6.44 mCi of the tracer, with whole-body acquisition from the skull base to mid-thigh and an additional pelvic scan two hours after injection. The scan showed thickening of the posterior bladder wall with a soft tissue mass measuring approximately 5.31 by 2.01 centimeters and a maximum standardized uptake value (SUVmax) of 3.37, along with abnormally increased uptake in the prostate (SUVmax 4.49). Notably, increased bone density at the sixth thoracic vertebra showed no abnormal FDG uptake, leaving that skeletal finding uncharacterized by the glucose tracer. In light of the clinical picture and pathology, the team diagnosed neuroendocrine prostate cancer involving the bladder.

Treatment comprised five cycles of chemotherapy with 120 mg of docetaxel plus 100 mg of cisplatin, followed by two months of intensity-modulated radiotherapy directed at the pelvic and spinal lesions, with total prescribed doses of 70 Gy in 35 fractions, 63.6 Gy in 30 fractions, 60 Gy in 30 fractions and 50.4 Gy in 30 fractions delivered to the respective planning target volumes. Concurrently, the patient began long-term androgen deprivation therapy combined with bicalutamide. After one year of treatment, his PSA was undetectable at less than 0.01 ng/ml, and NSE stood at 8.24 ng/mL against a baseline of 8.13 ng/mL, both within the normal range. By every biochemical measure, the disease appeared controlled.

The follow-up 68Ga-PSMA PET/MR told a more complicated story. Scans were acquired 60 and 120 minutes after intravenous injection of 3.4 mCi of 68Ga-PSMA-11, again with whole-body coverage and a delayed regional pelvic examination using specialized MRI sequences. The images revealed a T2-hypointense, irregularly shaped mass within the bladder wall at the trigone, with indistinct margins from the prostatic lesion and restricted diffusion, showing intense uptake with an SUVmax of 43.64. A T2-hypointense mass in the right peripheral zone of the prostate also showed restricted diffusion, with an SUVmax of 22.39. Most strikingly, the sixth thoracic vertebra, which had shown no abnormal uptake on the pre-treatment FDG scan, now demonstrated increased PSMA uptake, as did both scapulae, with an SUVmax of 19.72 reported for the scapular lesions. The authors noted that bone lesions with high PSMA uptake may indicate bone metastases, and that the prostatic and bladder findings suggested potential continuing biological activity within the tumor despite normal blood markers.

A multidisciplinary case conference weighed the findings and elected to continue long-term androgen deprivation therapy with bicalutamide alongside regular surveillance. At the most recent follow-up, a further 68Ga-PSMA PET/MR showed decreased uptake in the prostate, the sixth thoracic vertebra and both scapulae compared with the previous scan, but elevated uptake at the bladder lesion. PSA remained below 0.01 ng/ml and NSE measured 8.52 ng/ml, essentially unchanged from baseline. Because rising PSMA uptake at a single site could reflect disease progression, a new tumor or an inflammatory process, the team performed a second biopsy of the bladder lesion. Pathology revealed chronic inflammation with no definitive evidence of residual cancer, a result that fundamentally changed the interpretation of the imaging signal and spared the patient an unwarranted change in disease assessment.

The report situates this experience within a broader, still-unsettled debate over which PET tracers best serve prostate cancer patients at different stages. PSMA, a type II membrane glycoprotein overexpressed in most primary and metastatic prostate cancer lesions, underpins imaging that is more accurate than CT, MRI and bone scans for detecting prostatic disease, and PSMA PET is recommended for assessing intermediate-to-high-risk cancer, detecting biochemical recurrence, evaluating progression and monitoring radioligand therapy. Yet 18F-FDG, the most widely used PET tracer of the past two decades despite its limited role in initial prostate cancer staging, holds recognized value in high-grade and metastatic castration-resistant disease according to the International Society of Urological Pathology. Studies cited by the authors indicate that FDG PET is more effective than PSMA PET at detecting lesions exhibiting neuroendocrine differentiation, whereas PSMA PET offers advantages for follow-up in newly diagnosed high-risk patients and those with biochemical recurrence or castration resistance. A study of eight NEPC patients using dual-tracer PET/CT with 18F-PSMA-1007 and 18F-FDG reported a patient-based detection rate of 98.9%, and tracers such as 68Ga-DOTATATE and FAPI have also shown value in detecting NEPC metastases, with one reported approach combining three imaging agents to characterize adenocarcinoma, neuroendocrine and invasive components from multiple perspectives.

The authors were explicit about the limitations of their single-case experience. The suspicious bone lesions were suspected to be metastases based on clinical and imaging findings but were never confirmed histologically, and because those lesions showed no FDG uptake, it remains unclear whether they were new or pre-existing; the absence of simultaneous baseline assessment with both tracers hinders a full understanding of the disease. No biopsy has confirmed the nature of the prostate lesion that continued to show high PSMA uptake after treatment, so it cannot be determined whether it represents residual neuroendocrine tumor, another tumor component or treatment-related change, and the team planned repeat biopsy if clinically indicated. The authors also stressed that this case does not establish PET as more accurate than biochemical monitoring, and that the comparative diagnostic performance of the tracers cannot be determined from one patient.

Within the scientific literature, the molecular drivers of NEPC continue to be mapped, with reported abnormalities in ASCL1, the AR-independent lineage activator ONECUT2, and factors including FOXA2, MYCN and TSP1 specifically expressed in the subtype, though these findings have not yet translated widely into clinical practice. For now, the practical lesson from this case is procedural rather than molecular. Biochemical tests such as PSA and NSE often fail to capture dynamic changes in a tumor type defined by high heterogeneity and aggressive behavior, making imaging the primary follow-up method, yet imaging findings themselves demanded cautious interpretation. Decreasing PSMA uptake across most lesions while bladder uptake rose, all against stable blood markers, resolved only when histopathology identified inflammation rather than tumor. The authors concluded that multi-tracer PET plays a crucial role in the initial treatment and follow-up of NEPC, but that image interpretation must integrate biochemical testing, the clinical course and, where necessary, pathological biopsy to guard against false-positive lesions. The patient continues his current regimen and regular follow-up.

Subject of Research: Multi-tracer PET imaging and biochemical monitoring in a case of neuroendocrine prostate cancer

Article Title: A comparison of 68Ga-PSMA PET/MR, 18F-FDG PET/CT and biochemical monitoring in neuroendocrine prostate cancer: a case report

Article References: Deng, Y., Li, X., Hu, J., Xue, R., & Zhang, S. (2026). A comparison of 68Ga-PSMA PET/MR, 18F-FDG PET/CT and biochemical monitoring in neuroendocrine prostate cancer: a case report. Frontiers in Oncology, 16, Article 1935144. https://doi.org/10.3389/fonc.2026.1935144

Image Credits: AI Generated

DOI: 10.3389/fonc.2026.1935144

Keywords: neuroendocrine prostate cancer, 68Ga-PSMA PET/MR, 18F-FDG PET/CT, PSA, neuron-specific enolase, androgen deprivation therapy, case report, bone metastases, biopsy, nuclear medicine, Gleason score, lineage reprogramming