Positron emission tomography/computed tomography (PET/CT) with 18 Ffluorodesoxyglucose (FDG) is an integral component in the primary staging of most lymphomas. However, its utility is limited in marginal zone lymphoma (MZL) due to inconsistent FDG avidity. One diagnostic alternative could be the targeting of CXC-motif chemokine receptor 4 (CXCR4), shown to be expressed by MZL cells. This study investigated the value of adding CXCR4-directed 68 Ga-Pentixafor PET/CT (CXCR4 PET/CT) to conventional staging. Methods22 newly diagnosed MZL patients were staged conventionally and with CXCR4 PET/CT.Lesions exclusively identified by CXCR4 PET/CT were biopsied as standard of reference and compared to imaging results. The impact of CXCR4-directed imaging on staging results and treatment protocol was assessed. ResultsCXCR4 PET/CT correctly identified all patients with viable MZL and was superior to conventional staging (P < 0.001). CXCR4-directed imaging results were validated by confirmation of MZL in 16/18 PET-guided biopsy samples. Inclusion of CXCR4 PET/CT in primary staging significantly impacted staging results in almost half, and treatment protocols in one third of patients (upstaging, n = 7; downstaging, n = 3; treatment change, n = 8; P < 0.03). ConclusionsCXCR4 PET/CT is a suitable tool in primary staging of MZL and holds the potential to improve existing diagnostic algorithms.

Beyond being a key factor for tumor growth and metastasis in human cancer, C-X-C motif chemokine receptor 4 (CXCR4) is also highly expressed by a number of immune cells, allowing for non-invasive read-out of inflammatory activity. With two recent studies reporting on prognostic implications of the spleen signal in diffusion-weighted magnetic resonance imaging in patients with plasma cell dyscrasias, the aim of this study was to correlate splenic 68 Ga-Pentixafor uptake in multiple myeloma (MM) with clinical parameters and to evaluate its prognostic impact. Methods: Eighty-seven MM patients underwent molecular imaging with 68 Ga-Pentixafor-PET/CT. Splenic CXCR4 expression was semi-quantitatively assessed by peak standardized uptake values (SUVpeak) and corresponding spleen-to-bloodpool ratios (TBR) and correlated with clinical and prognostic features as well as survival parameters. Results: 68 Ga-Pentixafor-PET/CT was visually positive in all MM patients with markedly heterogeneous tracer uptake in the spleen. CXCR4 expression determined by 68 Ga-Pentixafor-PET/CT corresponded with advanced disease and was inversely associated with the number of previous treatment lines as compared to controls or untreated smouldering multiple myeloma patients (SUVpeakSpleen 4.06 ± 1.43 vs. 6.02 ± 1.16 vs. 7.33 ± 1.40; P < 0.001). Moreover, reduced splenic 68 Ga-Pentixafor uptake was linked to unfavorable clinical outcome. Patients with a low SUVpeakSpleen (<3.35) experienced a significantly shorter overall survival of 5 months as compared to 62 months in patients with a high SUVpeakSpleen >5.79 (P < 0.001). Multivariate Cox analysis confirmed SUVpeakSpleen as an independent predictor of survival (HR 0.75; P = 0.009). Conclusion: These data suggest that splenic 68 Ga-Pentixafor uptake might provide prognostic information in pre-treated MM patients similar to what was reported for diffusion-weighted magnetic resonance imaging. Further research to elucidate the underlying biologic implications is warranted.