Case Report: Five positive lesions on bilateral adrenal glands detected by a single 68 Ga-pentixafor PET/CT

Introduction

Aldosterone-producing adenomas (APAs) represent a predominant subtype of primary aldosteronism (PA), characterized by hypokalemia, elevated aldosterone levels, and Aldosterone to Renin Ratio (ARR) ≥ 30 (1). Precise subtype diagnosis is paramount for clinical management. Currently, APA diagnosis relies heavily on adrenal CT and adrenal vein sampling (AVS) for lesion localization and functional assessment. However, CT frequently misses adenomas <1 cm in diameter and lacks functional characterization, while AVS is an invasive and technically challenging procedure, limiting its widespread application (2). C-X-C chemokine receptor type 4 (CXCR4), a G-protein-coupled receptor (GPCR), is expressed on the cell membrane of APA cells (3). ⁶⁸Ga-Pentixafor, a high-affinity ligand for CXCR4, enables specific in vivo targeting. This allows CXCR4-directed PET/CT functional imaging, providing significant value for PA subtyping and guiding clinical treatment decisions. We report a case where a single ⁶⁸Ga-Pentixafor PET/CT scan identified five positive lesions on bilateral adrenal glands, highlighting its diagnostic impact for precise localization and functional characterization in the context of bilateral multiple adrenal adenomas.

Case presentation

A 62-year-old male was admitted with nausea, vomiting, and generalized fatigue. He had a 10-year history of hypertension with a maximum recorded blood pressure of 200/110 mmHg. Laboratory findings revealed hypokalemia (serum potassium: 2.5 mmol/L), elevated plasma aldosterone concentration (PAC) [upright Renin-Angiotensin-Aldosterone System (RAAS) test: 771.100 pg/mL], ARR > 37, and a positive captopril suppression test (aldosterone pre-captopril: 1036.200 pg/mL; post-captopril: 1013.300 pg/mL). On contrast-enhanced CT, all lesions exhibited mild-to-moderate heterogeneous enhancement with a rapid wash-in and wash-out pattern (Figures 1A–H). The clinical team suspicion for primary aldosteronism arose, but AVS failed to lateralize the side of dominant aldosterone secretion. Consequently, ⁶⁸Ga-Pentixafor PET/CT (Figure 1) was performed for further subtyping.

PET/CT imaging was performed 30 min after intravenous injection of 3.5 mCi (129.5 MBq) of ⁶⁸Ga-Pentixafor by a nuclear medicine physician. PET/CT images demonstrate five distinct nodular lesions in the bilateral adrenal glands, with varying degrees of tracer uptake in all five nodules (Figures 1I–L). Among the five adrenal nodules, the nodule in the medial branch of the left adrenal gland exhibited the highest metabolic activity, with a maximum standardized uptake value (SUVmax) of 31.3. The mean SUV (SUVmean) of normal liver parenchyma was 2.26. The lesion-to-liver ratios (LLR; calculated as SUVmax lesion/SUVmean liver) for the adrenal lesions ranged from 2.38 to 13.85. The SUVmean of normal adrenal cortex was 3.41. The lesion-to-normal-adrenal ratios (LAR; SUVmax lesion/SUVmean normal adrenal) ranged from 1.58 to 9.18. In ⁶⁸Ga-Pentixafor PET/CT imaging, the thresholds for diagnosing APA are defined as LLR≥2.5 and LAR≥2.4 (4). In this case, ⁶⁸Ga-Pentixafor PET/CT detected five adrenal adenomas, all of which exhibited heterogeneous tracer uptake with LLR and LAR values both exceeding the aforementioned diagnostic thresholds.⁶⁸Ga-Pentixafor PET/CT identified five adrenal adenomas demonstrating heterogeneous tracer uptake. The clinical team integrating these findings with the laboratory results and contrast-enhanced CT, all five adenomas were considered functional APAs. Therefore, conservative medical management was initiated. After switching the antihypertensive regimen to a mineralocorticoid receptor antagonist for 30 days, the patient's serum potassium normalized to 4.3 mmol/L and blood pressure remained within normal limits.

Discussion

PA is an endocrine disorder characterized by autonomous, excessive aldosterone secretion from the zona glomerulosa of the adrenal cortex. This leads to sodium retention and plasma volume expansion, consequently suppressing renin activity. Clinical manifestations typically include hypertension with or without hypokalemia, while a minority of patients may experience paresthesias or carpopedal spasm (5). The two principal subtypes are APA and idiopathic hyperaldosteronism (IHA), making subtype differentiation a critical aspect of clinical management (5). APAs typically present as unilateral, solitary adrenal lesions, with simultaneous bilateral APA involvement being uncommon.

Laboratory findings in APA often include hypokalemia (serum K⁺ < 3.5 mmol/L).PAC is typically elevated. During upright RAAS testing, normal upright PAC levels range from 70 to 300 pg/mL. The ARR is widely used as a screening tool; an ARR ≥ 30 strongly suggests PA. Furthermore, a positive captopril challenge test (defined as <30% decrease or an increase in PAC post-captopril) supports an APA diagnosis.

Current APA diagnosis primarily relies on adrenal imaging and AVS for lesion localization and functional assessment (6, 7). Computed tomography (CT), as the first-line imaging modality, typically reveals unilateral or bilateral adrenal adenomas (<2 cm in diameter), appearing oval/round, well-circumscribed, with ring-like enhancement on contrast study and a hypodense center, without ipsilateral or contralateral adrenal atrophy. However, CT has limitations: it may miss smaller adenomas (short axis <1 cm) and cannot differentiate functional status (5, 8). AVS is considered the current diagnostic ‘gold standard' for identifying the source (unilateral vs. bilateral) of aldosterone excess, establishing lateralization which is crucial for treatment selection. Nevertheless, AVS is an invasive, technically challenging procedure associated with complication risks, hindering its widespread implementation (9, 10). Furthermore, APAs result in excessive aldosterone secretion on both sides, thereby imposing certain limitations on AVS application and potentially obscuring the identification of the dominant side (11).

C-X-C chemokine receptor type 4 (CXCR4), a G-protein-coupled receptor, is highly expressed on APA cell membranes and strongly correlates with aldosterone synthase (CYP11B2) expression (12–14). However, the expression of this receptor is not specific to APAs and is also detectable in other adrenal lesions such as cortisol-producing adenomas (15). ⁶⁸Ga-Pentixafor specifically targets membrane CXCR4. This functional PET/CT imaging modality aids PA subtyping and clinical decision-making (4, 15). Studies indicate that functional APAs show significantly higher ⁶⁸Ga-Pentixafor uptake compared to nonfunctional adrenal nodules on the contralateral side, with over 90% of functional nodules demonstrating tracer uptake (12).

In this case, ⁶⁸Ga-Pentixafor PET/CT identified five adrenal adenomas exhibiting heterogeneous tracer uptake. Correlated with laboratory findings and contrast-enhanced CT, these were diagnosed as APAs. For patients with bilateral tracer-avid lesions on ⁶⁸Ga-Pentixafor PET/CT, treatment strategy should be individualized based on lesion size, number, and SUVmax values to assess the relative dominance on each side.

Current APA treatments include adrenalectomy(surgical removal of the dominant aldosterone-secreting gland) and medical therapy. However, non-dominant lesions on the contralateral side may still possess autonomous aldosterone secretion. If hypertension or hypokalemia persists post-operatively or recurs, further medical therapy or repeat surgery may be required. For patients unsuitable for or declining surgery, mineralocorticoid receptor antagonists (MRAs) are the mainstay medical treatment (16, 17). Our patient opted for medical management, achieving significant improvement in both hypokalemia and hypertension during follow-up. Furthermore, the SUVmax of the lesion in the medial limb of the left adrenal gland was markedly higher than those of the remaining lesions in this case, suggesting a potential positive correlation between SUVmax and aldosterone secretion levels. Ding (3) confirmed that CXCR4 was significantly positively correlated with CYP11B2, and SUVmax was also significantly positively correlated with CXCR4 expression. These findings further indicate that SUVmax can indirectly reflect the aldosterone-secreting capacity of lesions, though this conclusion still requires validation in larger sample sizes.

⁶⁸Ga-Pentixafor could enables molecular characterizations of CXCR4 in PA lesions; thus,⁶⁸Ga-Pentixafor PET/CT holds significant clinical value in APA subtyping diagnosis, determining the functional lateralization of aldosterone-producing lesions, and guiding treatment decisions. As a non-invasive technique providing simultaneous morphological and functional assessment, ⁶⁸Ga-Pentixafor PET/CT compensates for the limitations of CT—its inability to characterize the functional status of lesions—and the technical challenges associated with performing AVS in this case. Thus, it holds considerable clinical value for the localization and functional characterization of bilateral adrenal adenomas. However, as this study is a single case report with a limited sample size, the clinical value of its conclusions still requires further validation.

Conclusions

⁶⁸Ga-Pentixafor PET/CT identified five positive lesions on bilateral adrenal glands, the clinical team confirming bilateral multifocal APA. Given the pattern of bilateral autonomous secretion without unilateral dominance, medical therapy with aldosterone antagonists is the primary treatment. Surgery is unsuitable for such diffuse bilateral involvement. ⁶⁸Ga-Pentixafor PET/CT enables optimal subtype differentiation and treatment guidance.

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Footnotes

Edited by: Anna Katrin Szardenings, Janssen R&D, United States

Reviewed by: Liza Lindenberg, National Cancer Institute (NIH), United States

Mani Salarian, Johnson & Johnson, United States