Abstract
Primary aldosteronism (PA) is one of the prevalent causes of secondary hypertension, characterized by the autonomous hypersecretion of aldosterone and concurrent renin inhibition. Clinical and biochemical remission rates for patients with PA achieved through surgery are far higher compared to those achieved through drug treatment; hence, subtyping PA is crucial for identifying patients who will benefit most from surgery. Computed tomography (CT) scan with adrenal protocol and adrenal venous sampling (AVS) is used conventionally for PA subtype classification. CT scans, being structural imaging, cannot provide functional information, while AVS is an invasive, technically challenging method with a limited success rate and a high risk of complications. The C-X-C chemokine receptor type 4 (CXCR4) is overexpressed in aldosterone-producing tissue but is almost negligibly expressed in nonfunctional adenoma. The positron emission tomography tracer 68Ga-pentixafor, a specific ligand for CXCR4, can detect aldosterone-producing adenoma noninvasively, which can guide surgical treatment. The image series below demonstrates the utility and patterns of findings on Ga-68-pentixafor for subtyping PA.
Keywords: 68Ga-pentixafor, adrenal adenoma, adrenal hyperplasia, adrenal venous sampling, aldosterone-producing adenoma, nonfunctional adenoma, primary aldosteronism
Introduction
Primary aldosteronism (PA) is one of the prevalent causes of secondary hypertension. PA is characterized by the autonomous hypersecretion of aldosterone and concurrent renin inhibition.[1] Unlike patients with essential hypertension, patients with PA have prolonged high aldosterone levels, resulting in a higher risk of cardiovascular and renal damage.[1,2] Clinical and biochemical remission rates for patients with PA achieved through surgery are far higher compared to those achieved through drug treatment.[3] Hence, subtyping PA is crucial for identifying patients who will benefit most from surgery.[4] Surgically eligible forms of PA include unilateral aldosterone-producing adenoma (APA) and unilateral adrenocortical hyperplasia (AH), and ineligible forms include bilateral AH with bilateral APA requiring more insights.
Endocrine Society practice guidelines recommend computed tomography (CT) scans with adrenal protocol and adrenal venous sampling (AVS) for PA subtype classification.[4] CT scans, being structural imaging, cannot provide functional information. Subcentimeter-sized lesion evaluation is very difficult on CT scans.[5] While AVS stands as the current “gold standard” for subtyping PA, it is an invasive, technically challenging method with a limited success rate and a high risk of complications.[6] Apart from that, there is a significant discordance between CT scans and AVS findings.[7]
The chemokine receptor type 4 (CXCR4) is a transmembrane G protein-coupled receptor that is overexpressed in aldosterone-producing tissue but is almost negligibly expressed in nonfunctional adenoma (NFA).[8] The positron emission tomography (PET) tracer 68Ga-pentixafor is a specific ligand for CXCR4.[9,10] Recent research demonstrated that 68Ga-pentixafor PET-CT can detect APA, mainly based on histopathology.[11,12,13,14,15,16] Ding et al. evaluated CXCR4 expression in patients with suspected primary hyperaldosteronism using 68Ga-pentixafor.[15] Thirty-nine adrenal lesions in 36 patients were found: 25 APA, 4 AH, and 10 NFA, according to histopathology and clinical assessment. Sensitivity, specificity, and accuracy of 68Ga-pentixafor PET-CT in distinguishing APA by visualization were 100%, 78.6%, and 92.3%, respectively. The SUVmax of APA (21.34 ± 9.41, n = 25) was significantly higher than that of non-APA lesions (6.29 ± 2.10, n = 14, P < 0.0001). All patients with removed positive lesions benefited from surgery. Hu et al. evaluated the accuracy of Ga-68-pentixafor PET–CT for subtyping diagnosis of PA.[13] Among 100 patients with PA, 43 individuals had unilateral APA, and 57 individuals had bilateral APA. Using a lateralization index based on Standardized Uptake Value Max (SUVmax) at 10 min to identify unilateral PA, the area under the receiver operating characteristic curve was 0.90 (95% confidence interval =0.83–0.97). The diagnostic concordance rate of PET-CT and AVS was 90% compared with 54% between traditional CT and AVS. Yin et al. did a comparison of the performance of 68Ga-pentixafor PET/CT versus adrenal vein sampling for subtype diagnosis in PA and showed that 68Ga-pentixafor PET-CT could enable noninvasive diagnosis in most patients with PA and identify additional cases of unilateral and surgically curable PA that could not be classified by AVS.[17] They concluded that 68Ga-pentixafor PET-CT should be considered a first-line test for the future classification of PA.
Methods
Labeling is done using ready-to-use kits by manual method. The peptide kit is taken out of the freezer and allowed to attain room temperature. Ready-to-use buffer is added to the peptide kit to adjust pH (840 µL buffer is added for 1 mL of 0.6 M HCl) and mixed properly. 68GaCl2 is eluted from the generator using 6 ml of 0.6 M HCl using the fraction method (best 1–2 ml can be used for preparation) directly to the clean vial (reaction vial containing buffer and peptide). The vial is sealed with an aluminum cap or micropore tape and gently mixed. The vial is incubated at 100°C in a water bath or dry heater for 20 min. It is allowed to cool for a few minutes, and Radiochemical Purity Quality Control (RCP QC) is carried out. After QC, the entire product is passed through a 0.22-µ filter to make it sterile and injected into the patient. 3–5 mCi of 68Ga-pentixafor was injected Intravenously (IV), followed by whole-body PET-CT images at 30 min. Whole-body PET-CT images were obtained from vertex to mid-thigh using a dedicated PET-CT scanner (Siemens Biograph Horizon with True V). Axial, sagittal, and coronal PET reconstructions were interpreted with and without attenuation correction. Corresponding postintravenous contrast medium multiphase adrenal protocol CT images were performed utilizing 3.75 mm axial slices, reconstructed in axial, sagittal, and coronal planes. No delayed PET-CT images were acquired. SUVmax was calculated. The patients had a normal diet with no special preparation.
The image series below demonstrates the utility and patterns of findings on Ga-68-pentixafor for subtyping PA.
Cases
Patients of PA diagnosed clinically and biochemically with unilateral or bilateral adrenal lesions on CT were referred to us for a 68Ga-pentixafor PET-CT scan. All patients were diagnosed with PA by clinical endocrinologists following the guidelines of the Endocrine Society. 68Ga-pentixafor PET-CT was conducted. Lesions were defined as adrenal nodules or thickenings [Table 1].
Table 1.
Clinical profile of patients and findings on 68Ga-pentixafor positron emission tomography–computed tomography
| Age (years) | Clinical presentation | Biochemical investigations | CT scan findings | PET findings SUVmax | Subtype |
|---|---|---|---|---|---|
| 60 | Persistent hypertension | Aldosterone - 20 ng/dL Renin - 1.0 µIU/mL |
Left adrenal nodule Hypodense (HU <10) Size - 1.4 cm×1.5 cm×1.3 cm Minimal late arterial enhancement |
NA | Unilateral NFA |
| 41 | Hypertension, burning sensation of feet, leg pain | Serum potassium - 2.5 mmol/L Aldosterone - 47.6 ng/dL Renin - <0.5 µIU/mL |
Left adrenal nodule Hypodense (HU <10) Size - 0.7 cm×0.8 cm×1.1 cm significant enhancement on late arterial phase |
6.5 | Unilateral APA |
| 50 | Persistent hypertension | Aldosterone: renin ratio - 100.81 pmol/mU | Bilateral adrenal nodules right: 1.0 cm×0.7 cm×0.8 cm Left: 1.3 cm×1.4 cm×1.4 cm Mild enhancement on late arterial phase |
NA | Bilateral NFA |
| 42 | Persistent hypertension | Aldosterone - 25 ng/dL Renin - 0.5 µIU/mL |
Bulky bilateral adrenal glands | Right - 7.0 Left - 6.8 |
Bilateral AH |
PET: Positron emission tomography, CT: Computed tomography, HU: Hounsfield units, SUV: Standardized uptake value, NFA: Non functional adenoma, AH: Adrenocortical hyperplasia, APA: Aldosterone-producing adenoma
Case 1
Unilateral Non functional adenoma (NFA): A 60-year-old male hypertensive patient diagnosed with PA with left adrenal incidentaloma on CT scan was referred for 68Ga-pentixafor PET-CT. His aldosterone level was 20 ng/dl, and his direct renin level was 1.0 uIU/ml. Scan findings showed a tracer nonavid hypodense nodule (Hounsfield units (HU) <10) involving the left adrenal gland measuring about 1.4 cm × 1.5 cm × 1.3 cm showing minimal enhancement on the late arterial phase with washout on delayed phase [Figure 1]. This patient is not a suitable candidate for surgical benefit and will require medical management.
Figure 1.
68Ga-pentixafor positron emission tomography–computed tomography (PET-CT) axial sections of CT and PET-CT fusion images show a hypodense (HU < 10) left adrenal nodule (arrow) measuring about 1.4 cm × 1.5 cm × 1.3 cm showing minimal late arterial enhancement without significant tracer uptake involving the left adrenal gland suggestive of unilateral NFA
Case 2
Unilateral APA: A 41-year-old male patient, known case of hypertension, presented with complaints of burning sensation at feet and leg pain. On clinical examination, his blood pressure was 150/90 mmHg. His serum potassium was 2.5 mmol/L. On further evaluation for hypokalemia, found to have hyperaldosteronism. His aldosterone level was 47.6 ng/dl, and his direct renin level was < 0.5 uIU/ml. He underwent a CT scan of the abdomen with an adrenal protocol and was found to have a left adrenal nodule. He was referred for 68Ga-pentixafor PET-CT, which showed a tracer-avid (SUVmax 6.5) hypodense nodule (HU < 10) measuring about 0.7 cm × 0.8 cm × 1.1 cm involving the left adrenal gland showing significant enhancement on late arterial phase with washout on delayed phase [Figure 2]. The patient underwent laparoscopic left partial adrenalectomy. Postsurgery, his blood pressure is well controlled, and hypokalemia is resolved.
Figure 2.
68Ga-pentixafor positron emission tomography–computed tomography (PET-CT) (a) axial, (b) coronal, and (c) sagittal sections of CT and PET-CT fusion images show a hypodense (HU <10) left adrenal nodule (arrow) measuring 0.7 cm × 0.8 cm × 1.1 cm with significant enhancement on late arterial phase and showing significant C-X-C chemokine receptor type 4 expression (SUVmax 6.5) suggestive of left aldosterone-producing adenoma
Case 3
Bilateral NFA: A 50-year-old male patient with persistent hypertension diagnosed with a case of PA was referred for 68Ga-pentixafor PET-CT. His aldosterone: renin ratio was 100.81 pmol/mU. Scan findings showed tracer nonavid hypodense nodules (HU < 10) involving bilateral adrenal glands measuring about 1.0 cm × 0.7 cm × 0.8 cm on the right side and 1.3 cm × 1.4 cm × 1.4 cm on the left side with mild enhancement on late arterial phase with washout on delayed phase [Figure 3]. This patient is not a suitable candidate for surgical benefit and will require medical management.
Figure 3.
68Ga-pentixafor positron emission tomography–computed tomography (PET-CT) (a) axial, (b) coronal, (c) axial, (d) axial, (e) coronal sections of CT and PET-CT fusion images show bilateral adrenal nodules (arrow) (measuring about 1.0 cm × 0.7 cm × 0.8 cm on the right side and 1.3 cm × 1.4 cm × 1.4 cm on the left side with mild enhancement on late arterial phase) without significant tracer uptake suggestive of bilateral Non functional adenoma (NFA) (f) abdominal MIP (g) whole-body MIP
Case 4
Bilateral AH: A 42-year-old hypertensive male patient diagnosed with a case of PA was referred for 68Ga-pentixafor PET-CT. His aldosterone level was 25 ng/dl, and his direct renin level was 0.5 uIU/ml. Scan findings showed bilateral adrenal hyperplasia showing increased tracer uptake (SUVmax 7.0 on the right side and SUVmax 6.8 on the left side) [Figure 4]. Surgery may not be a suitable option for this patient in view of bilateral involvement and will require medical management.
Figure 4.
68Ga-pentixafor positron emission tomography–computed tomography (PET-CT) (a) axial, (b) coronal, (c) axial, (d) coronal, (e) axial sections of CT and PET-CT fusion images show bulky bilateral adrenal glands showing significant C-X-C chemokine receptor type 4 expression (SUVmax 7.0 on the right side and SUVmax 6.8 on the left side) suggestive of bilateral adrenal hyperplasia (f) abdominal MIP (g) whole-body MIP
Patients with APA showed significant enhancement on postcontrast CT images compared to mild enhancement in patients with NPA. There was concordance between significant contrast enhancement and tracer avidity, although the cutoff value for enhancement is not known to differentiate between NPA and APA. There was no significant difference in SUVmax value between adenoma and hyperplasia. We could not evaluate delayed time point PET in our patients.
Conclusion
CT scan with adrenal protocol, being a structural, nonfunctional imaging modality, has its limitations in differentiating APA from NFA. Ga-68-pentixafor PET-CT, being a functional imaging modality, may facilitate PA subtyping diagnosis. Considering the universal need for safe, accurate, and noninvasive alternatives to AVS, 68Ga-pentixafor PET-CT may represent a novel and promising tool for PA subtyping, although it warrants evaluation in a large population. Further studies are required for standardizing the imaging protocols and assessing false positives and false negatives.
Declaration of patient consent
The authors certify that they have obtained all appropriate patient consent forms. In the form, the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.
Conflicts of interest
There are no conflicts of interest.
Acknowledgment
We would like to thank Dr. Om Lakhani, Department of Endocrinology, Zydus Hospital, Ahmedabad, and Dr. Maulik Shah, Department of Nephrology, Zydus Hospital, Anand.
Funding Statement
Nil.
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