Procedure-Related Uptake on CXCR4 PET/CT: A Frequent Pitfall Independent of Time and Anatomical Site

Technical Summary: Procedure-Related Uptake on CXCR4 PET/CT

Problem Statement
Chemokine receptor 4 (CXCR4)-directed molecular imaging using the radiotracer [68Ga]Ga-PentixaFor has emerged as a valuable tool for staging and evaluating hematological malignancies and solid tumors. However, CXCR4 is not exclusively overexpressed in malignant cells; it is also upregulated in activated immune cells, fibroblasts, and endothelial cells during physiological processes such as wound healing and tissue repair. Consequently, non-malignant tracer accumulation can occur in inflammatory conditions, potentially leading to false-positive interpretations in oncological settings. While procedure-related uptake is a known phenomenon for other tracers like [18F]FDG and fibroblast activation protein inhibitors (FAP), systematic data regarding the frequency, intensity, and temporal characteristics of such uptake on [68Ga]Ga-PentixaFor PET/CT following surgical or interventional procedures remains limited. The study addresses the critical need to determine if recent invasive procedures constitute a significant diagnostic pitfall and whether the timing of the procedure or the anatomical site influences the likelihood of tracer accumulation.

Methodology
This was a single-center, retrospective study analyzing 425 consecutive [68Ga]Ga-PentixaFor PET/CT examinations performed for various clinical indications, primarily in patients with hematological malignancies (e.g., multiple myeloma, marginal zone lymphoma) and solid tumors.

• Cohort Selection: The authors screened medical records to identify patients who had undergone a surgical or interventional procedure (including biopsies, vascular interventions, endoscopy, or drainage) prior to imaging. The final cohort consisted of 87 invasive procedures where the anatomical site was clearly identifiable on PET/CT.
• Stratification: Patients were stratified into an "early" group (0–30 days post-procedure) and a "late" group (≥31 days post-procedure). Procedures were further categorized by type (surgical vs. interventional) and anatomical compartment (bone, organ, (sub-)cutaneous tissue, muscle).
• Image Analysis: Two experienced nuclear medicine physicians performed visual and quantitative analysis. Quantitative metrics included the maximum standardized uptake value (SUVmax) and the target-to-background ratio (TBR), calculated against the superior vena cava.
• Correlative Analysis: In a subset of patients (21/51) who underwent paired [18F]FDG PET/CT within a median of 2 days, quantitative correlations between the two radiotracers were assessed using Spearman rank correlation.
• Statistical Approach: Non-parametric tests were used to compare uptake across time intervals and anatomical regions. A p-value < 0.05 was considered statistically significant.

Key Results

• Frequency of Uptake: Among the 87 identified procedures, 51 (58.6%) demonstrated visual CXCR4 tracer accumulation at the procedural site. This included 45.1% of surgical sites and 54.9% of interventional sites.
• Temporal Independence: The study found no significant association between the time elapsed since the procedure and the presence or intensity of uptake.
  • In the early group (0–30 days), 53.7% of patients showed uptake.
  • In the late group (≥31 days), 66.7% of patients showed uptake.
  • Quantitative analysis confirmed no significant correlation between SUVmax or TBR and the time since intervention (SUVmax: ρ = -0.05, p = 0.717; TBR: ρ = 0.02, p = 0.876).
  • Uptake was observed as late as 169 days post-surgery and 138 days post-intervention.
• Anatomical Independence: There were no significant differences in SUVmax (p = 0.482) or TBR (p = 0.696) across different anatomical compartments (bone, organ, (sub-)cutaneous, muscle).
• Correlation with FDG: In the subset with paired [18F]FDG PET, there was a significant positive correlation between [68Ga]Ga-PentixaFor and [18F]FDG uptake at procedural sites (SUVmax: ρ = 0.55, p = 0.016; TBR: ρ = 0.68, p = 0.001), suggesting that both tracers capture similar inflammatory signatures at these sites.

Significance and Claims
The paper concludes that post-procedural CXCR4 uptake is a frequent phenomenon, occurring in nearly 60% of cases, and represents a significant diagnostic pitfall for interpreting physicians. Crucially, the authors claim that this uptake is independent of both the time elapsed since the intervention and the specific anatomical compartment involved.

The study emphasizes that, unlike some other theranostic tracers where uptake may diminish predictably over time, CXCR4 uptake in procedural sites appears to persist homogeneously over both short and long intervals (up to several months). Therefore, the authors assert that nuclear medicine physicians must exercise caution when interpreting [68Ga]Ga-PentixaFor PET/CT scans, even in patients who underwent interventions long prior to imaging. The authors suggest that while this phenomenon can lead to false positives, correlation with procedural history and anatomical imaging (CT) allows for correct classification in most cases. They also propose that these findings support the potential development of a CXCR4-specific Reporting and Data System (RADS) to standardize the interpretation of such equivocal lesions.

The authors maintain a modest tone regarding the biological mechanisms, acknowledging that while the correlation with FDG suggests a link to macrophage and lymphocyte infiltration, the exact cellular source cannot be definitively determined without histopathological correlation. They also note limitations, including the retrospective nature of the study, the lack of delayed imaging, and the inability to directly assess the impact on clinical decision-making rates.