⁶⁸Ga-pentixafor PET pulmonary uptake in patients with suspected primary aldosteronism: incidence and etiology

Introduction

Although pentixafor positron emission tomography (PET) plays a crucial role in the diagnosis of aldosteronoma (1-3), it is not entirely specific to this condition. The established applications also include the evaluation of various hematologic malignancies (4-6), especially extranodal marginal zone lymphoma of mucosa-associated type (MALToma), which often involves the lung. Pentixafor positron emission tomography/computed tomography (PET/CT) also holds potential for assessing solid tumors (7-9) and inflammatory bowel disease (10). We have incidentally noted focal pentixafor uptake in the lung in a subset of patients with suspected primary aldosteronism (PA) on ⁶⁸Ga-pentixafor PET/CT or positron emission tomography/magnetic resonance (PET/MR) images, because part of the lung field is inevitably included within the scanning field. It might be misdiagnosed as tumor involvement in a patient with lymphoma or other malignancies. But this finding has not been preliminarily explored to date. Our study aimed to characterize the focal pulmonary uptake in patients with suspected PA undergoing ⁶⁸Ga-pentixafor PET scans and to investigate potential factors influencing this uptake. We present this article in accordance with the STROBE reporting checklist (available at https://qims.amegroups.com/article/view/10.21037/qims-2026-1-0100/rc).

Methods

Patient population and clinical data

This retrospective study was conducted between January 2023 and August 2024 at West China Hospital and included 217 consecutive patients with suspected PA who underwent ⁶⁸Ga-pentixafor imaging (206 PET/MR and 11 PET/CT scans) (Figure 1). Those who had prior malignancy and pulmonary disease were excluded. All remaining patients enrolled were referred by endocrinologists or cardiologists for evaluation of suspected PA based on clinical presentation such as hypertension and/or hypokalemia. Although some patients showed normal biochemical values, such as plasma aldosterone concentration (PAC), direct renin concentration (DRC), or the aldosterone-renin ratio (ARR), this was likely due to prior symptom-directed treatment, such as antihypertensive therapy or correction of hypokalemia. These patients were nonetheless considered clinically suspected of having PA. At the time of PET imaging, none had clinical or imaging evidence of adrenal malignancy or pulmonary metastases. All patients were followed for at least 1 year to exclude the presence of occult malignant lesions. For each of the 217 patients with ⁶⁸Ga-pentixafor scans, we collected data on age, sex, weight, height, body mass index (BMI), duration of hypertension, highest blood pressure, serum potassium, PAC, DRC, ARR, 8 AM cortisol (F), 8 AM adrenocorticotropic hormone (ACTH), urine cortisol, injected pentixafor activity, and uptake time. Blood routine tests and chest computed tomography (CT) were also collected if available. Elevated leukocyte or neutrophil counts were defined according to the institutional laboratory reference ranges. This study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by the Research Ethics Committee of West China Hospital of Sichuan University (Ethics No. 2020[1670]; Clinical New Technology Approval No. 2023005). Individual consent was waived due to its retrospective design and use of deidentified data.

Figure 1 Flow diagram shows patient selection details. PET/CT, positron emission tomography/computed tomography; PET/MR, positron emission tomography/magnetic resonance.

68Ga-pentixafor synthesis

⁶⁸Ga-pentixafor was synthesized in the Department of Nuclear Medicine, West China Hospital. Radiolabeling was performed using standard ⁶⁸Ga labeling methods, as previously described (11). Quality control of the radiosynthesis was performed by ultraviolet and radio high-performance liquid chromatography (HPLC). The radiochemical purity was over 95% for ⁶⁸Ga-pentixafor, and the final product was sterile and pyrogen-free.

⁶⁸Ga-pentixafor PET/CT and PET/MR image acquisition and protocol

Cross-calibration between the PET/MR and PET/CT scanners used in this study was performed according to institutional quality control procedures to ensure the consistency of quantitative PET measurements. ⁶⁸Ga-pentixafor was administered at a median dose of 137 MBq (range, 71–245 MBq). PET images were acquired in 3D mode, with acquisition times of 3 minutes per bed position for PET/CT and 6 minutes per bed position for PET/MR. All images were acquired using a PET/CT scanner (uMI780, United Imaging Healthcare, Shanghai, China) or a PET/MR scanner (SIGNA, GE Healthcare, Boston, MA). All imaging data were transferred and reviewed on the Advantaged Workstation (version AW 4.7; GE Healthcare).

Image analysis

Maximum intensity projection images were visually evaluated for the presence or absence of pentixafor uptake above the blood pool (BP) level in the lungs. Semiquantitative SUVmax measurements of all uptake foci were obtained by using three-dimensional volumes of interest (VOI) with an isocontour threshold of 40%. BP SUVmax and SUVmean were measured using a spherical VOI with a diameter of 1.2 cm, placed in the descending thoracic aorta at the level of the carina. To make SUVmax more comparable, the original SUVmax was normalized by dividing the uptake foci SUVmax by the BP SUVmean, yielding a normalized SUVmax (12). All uptake foci were manually measured using their longest diameters within the VOI on PET/CT and PET/MR images.

Statistical analysis

Continuous variables are mean ± standard deviation (SD) or median (range), qualitative variables are number and percentage. Pearson’s χ² or Fisher’s Exact tests were used for categorical variables, and unpaired T-test or Mann-Whitney U for continuous variables. Spearman rank correlation was used to assess the association between pulmonary uptake and clinical and PET-related variables. All statistical analyses were performed using SPSS 29.0 (IBM Corp.).

Results

Of the 217 included patients, 101 were male and 116 were female, with a mean age of 50±12 years. No patient was found to have malignancy in the follow up. There were no significant differences in clinical data (all P>0.05) (Table 1).

Of all subjects, 37 of 217 (17%) had focal uptake in their lungs. Thirteen were male and 24 were female, with a mean age of 52±11 years. To evaluate the potential influence of imaging modality, we compared pulmonary uptake incidence and quantitative PET parameters between PET/CT and PET/MR. The incidence of pulmonary uptake did not significantly differ between PET/CT and PET/MR groups (1/11, 9.1% vs. 36/206, 17.5%; P=0.695). Blood-pool SUVmax and SUVmean also showed no significant differences between PET/CT and PET/MR groups (SUVmax: median, 2.99 vs. 2.68, P=0.075; SUVmean: median, 2.03 vs. 2.02, P=0.799). Lesion-level standardized uptake value (SUV) comparison between modalities was descriptive because only one patient with pulmonary uptake underwent PET/CT. The highest pulmonary SUVmax was 8.15 in this patient and a median of 4.25 (range, 2.28–12.03) in the 36 patients with pulmonary uptake who underwent PET/MR. The blood-pool-normalized highest pulmonary SUVmax was 4.20 in the patient who underwent PET/CT and a median of 2.07 (range, 1.07–5.99) in the 36 patients who underwent PET/MR.

Table 2 describes characteristics of 53 uptake foci from 37 patients. Uni-focal uptake was observed in 27 patients (73%) (Figure 2), whereas multi-focal uptake was seen in the remaining patients: 6 (16%) had two foci, 2 (5%) had three foci, and 2 (5%) had four foci (P<0.05) (Figure 3). In patients with uptake, the original SUVmax of uptake foci showed no significant difference between the left and right lungs (median, 3.71 vs. 3.76; P=0.473). Similarly, blood-pool-normalized SUVmax did not significantly differ between left- and right-lung uptake foci (median, 1.75 vs. 2.15; P=0.478). No significant difference was observed between uptake in the lower lung fields (25 foci, 47%) and the upper lung fields (26 foci, 49%) (P>0.99).

Figure 2 Maximum-intensity projection (A), axial PET (B), and fused PET/MR (C) images depict a uni-focal pentixafor uptake (arrows) in a 38-year-old man, corresponding to negative CT-graphic (D) and MR-graphic (E) finding in left lung lower lobe. CT, computed tomography; MR, magnetic resonance; PET, positron emission tomography.

Figure 3 Summarizes multifocal pulmonary 68Ga-pentixafor uptake and corresponding CT/MR findings. Maximum-intensity projection image (A) shows multifocal pentixafor uptake (arrows) in a 58-year-old man. Axial PET, fused PET/MR and recent chest CT images (B-D) show corresponding negative MR-graphic and CT-graphic findings in bilateral lungs (arrows). CT, computed tomography; MR, magnetic resonance; PET, positron emission tomography.

To investigate further pulmonary uptake, we reviewed patients’ recent chest CT scans and laboratory tests. Of the 37 patients with focal pulmonary uptake, 20 patients had recent chest CT scans, with a median interval of 6 days (range, 2–42 days) between ⁶⁸Ga-pentixafor and CT. Abnormality was noted in one patient, who had subpleural linear opacity in the corresponding area (Figure 4). The remaining 19 scans showed no abnormalities at the corresponding site and the surrounding field. Twenty-seven patients with uptake had recent leukocyte and neutrophil counts, with a median time interval of 5 days (range, 0–11 days) between the scan and laboratory test; 106 patients without uptake had laboratory tests with similar time interval (median 5 days, range, 0–12 days). Elevated counts were seen in 7 of 27 patients with uptake (25.9%), significantly more often than in those without uptake (2/106, 1.8%; P<0.001). Among these 7 patients, the median increase in neutrophils was 23.5% (range, 6–90%), and that of leukocytes was 4% (range, 2–37%). The patient with abnormal CT finding showed a 90% increase in neutrophils and a 37% increase in leukocytes. To explore this relationship further, we assessed whether uptake intensity was related to inflammatory marker levels in the 27 patients with available laboratory data. No significant correlation was observed between the highest pulmonary SUVmax and either absolute neutrophil count (r=−0.250, P=0.208) or leukocyte count (r=−0.283, P=0.153) (Figure 5).

Figure 4 Maximum-intensity projection (A), axial PET (B), and fused PET/MR (C) images depict a uni-focal pentixafor uptake (arrows) in a 68-year-old woman, corresponding to fibrosis on CT (D) and high signal intensity on T2WI MR (E) in left lung upper lobe (arrow). CT, computed tomography; MR, magnetic resonance; PET, positron emission tomography.

Figure 5 Scatter plots showing the relationships between the highest pulmonary SUVmax and inflammatory markers in the 27 patients with pulmonary uptake and available laboratory data. (A) Relationship between the highest pulmonary SUVmax and absolute neutrophil count. (B) Relationship between the highest pulmonary SUVmax and leukocyte count. Fitted linear regression lines are shown for visualization. Spearman correlation analysis showed no significant correlation between the highest pulmonary SUVmax and absolute neutrophil count (r=−0.250, P=0.208) or leukocyte count (r=−0.283, P=0.153). SUVmax, maximum standardized uptake value.

Discussion

In our study, pulmonary uptake was observed in 17% of patients undergoing ⁶⁸Ga-pentixafor PET/CT or PET/MR. This uptake was potentially associated with elevated leukocyte and neutrophil counts in patients with suspected PA. Our findings raise the possibility of underlying inflammation in patients with pulmonary ⁶⁸Ga-pentixafor uptake.

C-X-C motif chemokine receptor 4 (CXCR4) PET imaging has been applied to various malignancies, including hematologic malignancies (multiple myeloma, mantle cell lymphoma, marginal zone lymphoma, acute lymphoblastoid leukemia), lung cancer (non-small cell lung cancer, small cell lung cancer, and lung neuroendocrine neoplasm), and adrenocortical carcinoma (5,7,9,13,14). These tumors may also involve or metastasize to the lungs. We noted an unusual pattern in which focal uptake on pentixafor PET was frequently seen in the lungs. It might mimic tumor especially in a patient with malignancy. Published examples of this pattern of CXCR4-targted pulmonary uptake are limited to some articles and case reports, primarily focus on pulmonary tumor, pulmonary fibrosis and radiation-induced lung injury, but do not explore incidental focal pulmonary uptake and its characteristics (7,13-16). One patient in our study, who exhibited subpleural fibrosis in the left upper lobe on chest CT, showed mild uptake (SUVmax =2.75). Derlin et al. (15) previously reported marked CXCR4 upregulation in fibrotic regions of the lungs using ⁶⁸Ga-pentixafor PET imaging and identified a significant positive correlation between uptake intensity and the overall extent of pulmonary fibrosis. Nevertheless, in most of our cases, pentixafor uptake varied from mild to intense, with focal uptake pattern that differed markedly from the diffuse uptake pattern typically observed in pulmonary fibrosis. Of note, no corresponding pulmonary abnormalities were detected on CT in these regions. This phenomenon may be partially explained by the findings of Derlin et al. (15), who suggested that macrophages in normal lung tissue might inherently exhibit low-level CXCR4 expression. Previous studies have demonstrated that ⁶⁸Ga-pentixafor PET can be applied to quantify non-infectious inflammatory processes (17,18). This tracer binds to CXCR4, which is known to be expressed on various immune cell types, including CD68⁺ macrophages and Ly6G⁺ granulocytes (17), as well as other macrophages and neutrophils (19,20). These findings support the interpretation that focal pulmonary ⁶⁸Ga-pentixafor uptake in our study may reflect CXCR4 expression on immune or inflammatory cells, rather than structural lung abnormalities. In addition, unlike their observations of predominant pentixafor uptake in the lower lobes of pulmonary fibrosis, the CT abnormality observed in one of our cases was in the upper lobe.

Upregulated CXCR4 expression has also been observed in activated inflammatory cells (20-24). CXCR4 signaling maintains neutrophil homeostasis in the blood by regulating neutrophil release from the bone marrow (19). In our study, no significant relationship was found between pulmonary uptake and clinical, or PET related parameters, except for elevated leukocyte and neutrophil counts. The finding suggests focal pulmonary uptake on ⁶⁸Ga-pentixafor scans may be associated with underlying inflammation, as patients with uptake had significantly higher incidence of increased leukocyte or neutrophil counts compared to those without uptake (25.9% vs. 1.8%, P<0.001). However, this association should be interpreted with caution because laboratory tests were not always performed on the same day as PET imaging. Leukocyte and neutrophil counts may fluctuate over a short period of time in response to transient inflammatory or infectious conditions. Although we used the closest available laboratory results, the time interval may still have influenced the observed association between pulmonary ⁶⁸Ga-pentixafor uptake and inflammatory markers. A previous study reported that splenic ⁶⁸Ga-pentixafor uptake was unrelated to disease stage or clinical outcomes in certain solid tumors, but positively correlated with leukocyte and platelet counts, indicating a potential relationship with systemic immune activity rather than tumor burden (25). These findings collectively suggest that ⁶⁸Ga-pentixafor uptake may not be specific to malignancy and could reflect underlying immune or inflammatory activity. To facilitate clinical interpretation, we summarized the major differential diagnostic considerations for pulmonary ⁶⁸Ga-pentixafor uptake in Table 3, including incidental inflammatory uptake, occult malignancy or pulmonary involvement of malignancy, and pulmonary fibrosis.

Recent technological advances have introduced the Internet of Things (IoT) and 3D printing into medical practice, with emerging implications for PA. Previous work on the Internet of Surgical Things has suggested that IoT-based technologies may support connected healthcare and remote monitoring, which could be applied to real-time blood pressure telemonitoring and follow-up in PA (26). Similarly, previous work on 3D printing in medicine has shown that medical imaging data can be translated into patient-specific anatomical models, which may support adrenal vein sampling (AVS) planning, especially for the challenging right adrenal vein (27). Both technologies remain underexplored in PA but hold promise to enhance diagnostic accuracy, procedural safety, and personalized care. Prospective studies are needed to validate their clinical utility.

This study has several limitations. First, its retrospective nature may limit the generalizability of the findings. In addition, imaging was limited to the lungs, without evaluating other regions potentially affected by inflammation, such as the nasal cavity, paranasal sinuses, pharynx, or gastrointestinal tract. Future studies could consider expanded imaging coverage or additional MRI sequences to better explore the relationship between pulmonary ⁶⁸Ga-pentixafor uptake and systemic inflammatory processes. Second, although cross-calibration was performed and additional modality-based analyses showed no significant differences in pulmonary uptake incidence or blood-pool SUV measurements between PET/CT and PET/MR, combining data from two imaging modalities may still introduce potential variability due to differences in attenuation correction and acquisition protocols. Third, the time interval between PET imaging and laboratory testing may have affected the evaluation of inflammatory markers, as leukocyte and neutrophil counts can fluctuate rapidly. Future prospective studies with same-day laboratory testing would help further clarify this relationship. Fourth, smoking status was not consistently available and therefore could not be included in the analysis. Smoking-related pulmonary inflammation may modulate C-X-C motif chemokine ligand 12 (CXCL12)/CXCR4 signaling in the lung, which could act as a potential confounding factor in the interpretation of pulmonary ⁶⁸Ga-pentixafor uptake (28). Finally, we did not confirm CXCR4 expression in pulmonary tissue with uptake through histopathology. Further prospective studies with additional imaging and histopathological correlation are needed to better understand the mechanism of pulmonary ⁶⁸Ga-pentixafor uptake.

Conclusions

Pulmonary uptake occurs in approximately one sixth of suspected PA patients undergoing ⁶⁸Ga-pentixafor PET/CT or PET/MR. Our findings raise the possibility of underlying inflammation in patients with pulmonary ⁶⁸Ga-pentixafor uptake. Further confirmation by histopathology would offer additional diagnostic certainty and strengthen the clinical relevance of these observations.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://qims.amegroups.com/article/view/10.21037/qims-2026-1-0100/rc

Data Sharing Statement: Available at https://qims.amegroups.com/article/view/10.21037/qims-2026-1-0100/dss

Funding: This work was supported by the National Key R&D Program of China (No. 2023YFC2414201-1), and the 1.3.5 Project for Disciplines of Excellence, West China Hospital, Sichuan University (No. ZYGD23016).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://qims.amegroups.com/article/view/10.21037/qims-2026-1-0100/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. This study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by the Research Ethics Committee of West China Hospital of Sichuan University (Ethics No. 2020[1670]; Clinical New Technology Approval No. 2023005). Individual consent was waived due to its retrospective design and use of deidentified data.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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