PSA and Grade Reveal Who Benefits Most from PSMA SPECT/CT Staging

Prostate cancer is the most commonly diagnosed cancer in men in many countries, and the moment of diagnosis triggers a cascade of decisions that will shape a patient’s entire treatment trajectory. Central to those decisions is one deceptively simple question: has the disease already spread beyond the prostate? A new retrospective study published in the European Journal of Nuclear Medicine and Molecular Imaging offers clinicians a practical, data-driven answer framework, showing that two routine clinical measurements—the initial prostate-specific antigen level and the ISUP grade assigned to biopsy tissue—can predict, with remarkable reliability, which men will turn out to have metastatic disease on molecular imaging. The findings carry particular weight for health systems where positron emission tomography remains scarce or unaffordable.

The research team, led by Knut Liepe of the Department of Nuclear Medicine at GH Hospital Klinikum Frankfurt (Oder) in Germany, together with colleagues from Ruhr University Bochum’s Johannes Wesling Hospital Minden and independent collaborators, examined 91 patients who underwent primary staging with [99mTc]Tc-PSMA SPECT/CT. Each patient received a median administered activity of 670 megabecquerels of the radiotracer [99mTc]Tc-MIP-1404, with a range of 470 to 792 megabecquerels. The imaging technique fuses single-photon emission computed tomography, which maps the distribution of the radiolabelled prostate-specific membrane antigen ligand, with computed tomography, which provides anatomical context. Together, the two modalities allow physicians to visualise both the primary tumour within the prostate and any metastatic deposits in pelvic lymph nodes or distant organs.

PSMA—prostate-specific membrane antigen—is a transmembrane protein expressed abundantly and relatively homogeneously on the surface of prostate cancer cells, a biological property that has made it one of the most successful molecular imaging targets in oncology. Radiolabelled ligands such as MIP-1404 bind to PSMA, concentrating radiation signal at tumour sites and enabling detection of lesions that conventional bone scans and CT frequently miss. While PSMA PET/CT has become the reference standard for staging in high-income centres, guided by landmark randomised trials such as proPSMA, PET infrastructure is expensive, dependent on short-lived isotopes, and unevenly distributed globally. SPECT cameras, by contrast, are far more widespread, which is precisely why the German team’s analysis of when technetium-based PSMA SPECT/CT delivers meaningful diagnostic yield matters so much.

The core of the study is a statistical interrogation of how two pre-imaging variables interact to determine what the scan will find. Using univariate and multivariate nominal logistic regression, the investigators tested whether the initial PSA level (iPSA) and the International Society of Urological Pathology grade group—assigned from 1, the least aggressive, to 5, the most aggressive—predicted the presence of metastatic disease. Both emerged as independent predictors. The effect of PSA was the stronger of the two, with a p-value of 0.0004, while ISUP grade remained significant at p equal to 0.0015. In practical terms, a man’s blood test and his biopsy pathology, taken together, already encode much of the information the scanner will later confirm.

The detection-rate thresholds that emerged from the analysis are strikingly concrete. Detection rates of metastatic disease on [99mTc]Tc-PSMA SPECT/CT exceeded 50 percent in two patient subgroups: those with ISUP grades 1 to 3 whose initial PSA exceeded 50 nanograms per millilitre, and those with ISUP grades 4 to 5 whose initial PSA exceeded 20 nanograms per millilitre. Even more dramatically, metastases were detected in every single patient whose initial PSA was above 50 nanograms per millilitre, regardless of how indolent or aggressive the tumour appeared under the microscope. For clinicians weighing whether to order the scan, these cutoffs offer an evidence-based filter: below them, the probability of finding spread disease drops enough that the examination may not justify its cost and radiation exposure.

Beyond the headline thresholds, the study revealed that the two risk variables shape not just whether metastases appear but where they appear. Among patients with ISUP grades 1 to 3 across all PSA levels, and among those with ISUP grades 4 to 5 whose PSA was 20 nanograms per millilitre or below, pelvic lymph node metastases predominated—spread confined to the regional drainage basins around the prostate. In contrast, patients with ISUP grades 4 to 5 and initial PSA above 50 nanograms per millilitre were far more likely to harbour distant metastases, the true game-changers in treatment planning, since they shift management from curatively intended surgery or radiotherapy toward systemic therapy. The pattern echoes the biological logic of tumour progression: increasingly disorganised, high-grade tumours paired with heavy tumour burden, reflected in soaring PSA, are more capable of seeding far-flung sites.

The team also examined whether the scanner’s own quantitative output could substitute for pathology. The maximum standardised uptake value, SUVmax, which reflects the peak concentration of the radiotracer in the primary tumour, correlated strongly with ISUP grade, with a correlation coefficient of 0.61. Yet the authors caution that SUVmax was not a reliable surrogate marker for aggressiveness. The correlation, while robust statistically, is too loose to replace histopathological grading, whose tissue-based assessment captures architectural and nuclear features that tracer uptake only approximates. The finding is a reminder of a broader lesson in molecular imaging: quantitative biomarkers complement but do not supplant the pathologist’s verdict on biopsy material.

The implications reach well beyond the German centres where the data were collected. In the United States, Europe, and Australia, PSMA PET/CT is increasingly embedded in guidelines for high-risk disease, but in much of Asia, Africa, Latin America, and Eastern Europe, PET capacity remains a bottleneck. Technetium-99m, the isotope used in this study, is produced in widely distributed generator systems, requires no on-site cyclotron, and its SPECT cameras are already installed in thousands of nuclear medicine departments worldwide. When PSMA PET/CT is simply unavailable, the authors conclude, [99mTc]Tc-PSMA SPECT/CT may represent a valuable alternative for the primary staging of carefully selected prostate cancer patients—and the combined PSA-plus-ISUP criteria from this study supply exactly the selection logic that such an alternative needs to be used economically and effectively.

Of course, the study’s retrospective design and modest cohort of 91 patients mean the findings require prospective validation before they can be written into guidelines. Selection bias is possible, since the patients who received SPECT/CT may not represent the full spectrum of newly diagnosed disease, and detection thresholds derived from one tracer, one administered activity range, and one scanner generation may not transfer unchanged to other settings. The authors received no external funding for the work and declared relevant consultancy and lecture-fee relationships in the nuclear medicine industry. Still, the core message is likely to endure: the two numbers sitting at the top of every prostate cancer chart—the PSA value and the biopsy grade—together form a powerful pre-test probability engine. Used deliberately, they can direct PSMA imaging, whether by SPECT or PET, to the men most likely to benefit, sparing others an unnecessary scan while ensuring that metastatic disease, wherever it hides, is found before treatment plans are locked in.

Subject of Research: Patient selection criteria for primary staging of prostate cancer using [99mTc]Tc-PSMA SPECT/CT based on PSA level and ISUP grade

Article Title: Patient selection for primary staging with [99mTc]Tc-PSMA SPECT/CT: influence of combined PSA and ISUP grade on detection of metastatic disease

Article References: Liepe, K., Hoang, T. M., Dietrich, I., Piechota, H.-J., & Baehr, M. (2026). Patient selection for primary staging with [99mTc]Tc-PSMA SPECT/CT: influence of combined PSA and ISUP grade on detection of metastatic disease. European Journal of Nuclear Medicine and Molecular Imaging. https://doi.org/10.1007/s00259-026-08168-8

Image Credits: AI Generated

DOI: 10.1007/s00259-026-08168-8

Keywords: prostate cancer, PSMA SPECT/CT, PSA, ISUP grade, primary staging, metastatic disease, [99mTc]Tc-MIP-1404, SUVmax, pelvic lymph node metastases, nuclear medicine, patient selection, molecular imaging