Abstract
Background:
Limitations still exist in the surgical strategies for primary aldosteronism (PA), the most common cause of secondary hypertension. This study aimed to compare the effectiveness of 68Ga-pentixafor PET/CT versus adrenal venous sampling (AVS) in guiding surgical management for PA.
Materials and methods:
A prospective cohort of 197 PA patients were assigned to Group PET (n = 137) and Group AVS (n = 60), in which the surgical interventions were guided by 68Ga-pentixafor PET/CT and AVS, respectively. Postoperative clinical and biochemical outcomes were analyzed referring to Primary Aldosteronism Surgical Outcomes classification system, with subgroup analysis on clinical characteristics and outcomes conducted in Group PET.
Results:
During a median follow-up of 27 (16, 39) months, the postoperative clinical and biochemical outcomes were comparable between 134 patients in Group PET and 57 patients in Group AVS, with unilateral or bilateral adrenal lesions. The rates of complete, partial, and absent clinical success were 51.5%, 38.1%, 10.4% in Group PET, and 35.1%, 50.9%, 14.0% in Group AVS (P = 0.115). For biochemical success, the corresponding rates were 82.1%, 12.7%, 5.2% in Group PET, and 75.4%, 17.5%, 7.0% in Group AVS (P = 0.533). The proportion of complete biochemical success was significantly higher than that of complete clinical success (80.10% vs 46.6%, P < 0.001). Female gender was associated with increased likelihood of complete clinical and biochemical success, and lower preoperative systolic blood pressure and shorter duration of hypertension indicated increased likelihood of complete clinical success. The SUVmax was significantly correlated with lesion diameters, age, duration of hypertension, blood potassium level, pathological type and clinical outcomes. A cutoff value of 5.5 for SUVmax demonstrated a sensitivity of 82.8% and a specificity of 92.6% in identifying functional adrenal lesions with autonomous aldosterone secretion.
Conclusions:
68Ga-pentixafor PET/CT demonstrated potential non-inferiority to AVS in guiding the surgical management for PA patients, with comparable postoperative clinical and biochemical outcomes.
Keywords: 68Ga-pentixafor PET/CT, adrenalectomy, adrenal venous sampling, CXCR4 receptor, primary aldosteronism
HIGHLIGHTS
68Ga-pentixafor PET/CT could effectively guide the surgical management for PA, achieving favorable clinical and biochemical outcomes not inferior to AVS, and the overall benefit rate was 95.5% versus 93%.
Especially for PA patients demonstrating unilateral positive adrenal lesions and contralateral negative lesions on 68Ga-pentixafor PET/CT imaging, the postoperative benefit rate was 100%.
The postoperative biochemical outcomes of PA patients are better than clinical outcomes.
Gender, preoperative systolic blood pressure and duration of hypertension were independently associated with postoperative outcomes of PA.
Introduction
Primary aldosteronism (PA), the most common cause of secondary hypertension, occurs in approximately 5–20% of patients with hypertension and results from autonomous excessive aldosterone secretion[1]. The main clinical features include hypertension, hypokalemia, decreased plasma renin activity (PRA) or increased plasma aldosterone concentration (PAC), and the main clinical subtypes are the aldosterone-producing adenoma (APA) and idiopathic hyperaldosteronism (IHA)[2]. Surgery is the first-line therapy for APAs, and also an important option for IHA patients with poor response or intolerance to medication[2]. The key-point of surgical management for PA lies in the identification of functional adrenal lesions and lateralization of aldosterone secretion, which is sometimes challenging for PA patients with bilateral adrenal lesions[3,4].
Adrenal venous sampling (AVS) is the current gold standard for identifying the lateralization of aldosterone secretion, which could reveal the dominant side of autonomous excessive secretion of aldosterone[5]. However, the numerous limitations of AVS, including its high cost, scarce availability, technical challenges, and lack of standardized protocols, have driven efforts to develop alternative non-invasive tools to identify functional lesions and the lateralization of aldosterone secretion.
CXC chemokine receptor type 4 (CXCR4) has been proven positively correlated with the expression of aldosterone synthase (CYP11B2) and highly expressed in APAs, while exhibiting low or no expression in nonfunctional adenomas and normal adrenal tissues[6]. The 68Ga-pentixafor positron emission computed tomography (68Ga-pentixafor PET/CT) was a novel nuclear imaging modality particularly suitable for PA patients, which was designed based on CXCR4 ligand, and has been confirmed effective in the identification of APAs and subtyping diagnosis of PA[7–10]. Our team has been performing 68Ga-pentixafor PET/CT in PA patients since 2018, and previously published results have demonstrated its effectiveness in identifying functional lesions secreting aldosterone autonomously[7–9]. Based on previous findings, this prospective cohort study is the first to compare the role of 68Ga-pentixafor PET/CT with adrenal venous sampling (AVS) in guiding surgical management of PA, focusing on the postoperative outcomes. This work has been reported in line with the STROCSS 2025 criteria[11].
Methods and materials
Participants
This prospective cohort study enrolled 197 patients (inclusion/exclusion criteria detailed in Supplemental Digital Content, Methods, available at: http://links.lww.com/JS9/F59) diagnosed with PA in single medical center, from July 2018 to December 2023, based on the aldosterone/renin ratio (ARR), captopril challenge test (CCT) and CT imaging, in accordance with the guideline established by multiple endocrinology societies[2]. Patients were non-randomly assigned to Group PET and Group AVS, with surgical interventions guided by the results of 68Ga-pentixafor PET/CT and AVS, respectively. This study has been approved by the ethics committee of our hospital and registered in ClinicalTrials.gov, with written informed consent obtained from patients.
Group PET initially included 152 PA patients receiving 68Ga-pentixafor PET/CT before surgery, and 15 cases were excluded due to the negative results on PET/CT. Group AVS initially enrolled 70 PA patients, with 10 cases excluded due to the absence of significant lateralization of aldosterone secretion. Ultimately, 137 patients in Group PET and 60 patients in Group AVS underwent surgery guided by 68Ga-pentixafor PET/CT and AVS, respectively, for the final analysis on the clinical characteristics and postoperative outcomes.
Preoperative interventions
68Ga-pentixafor preparation followed the procedure mentioned in the previous article[8], with the radiochemical purity of 68Ga-pentixafor exceeding 95%. Each patient underwent scanning using a dedicated PET/CT scanner (PoleStar m660; SinoUnion Healthcare Inc., Beijing, China), 20–40 minutes after an intravenous injection of the 68Ga-pentixafor reagent. The images were interpreted through visual analysis combined with the maximum standardized uptake value (SUVmax), to identify the lesions as positive or negative, by two experienced nuclear medicine physicians blinded to the clinical data. The SUVmax represented the peak lesional tracer uptake on PET/CT, which was measured and calculated for the adrenal lesions, as well as normal adrenal tissues and a 2 cm liver region adjacent to the right adrenal gland. Positive lesions were defined by radiotracer uptake higher than that of adjacent or contralateral normal adrenal tissues, while negative lesions demonstrated uptake not exceeding normal tissue.
AVS without adrenocorticotropic hormone stimulation was performed in PA patients between 8:00 am to 12:00 am, to determine the lateralization of aldosterone hypersecretion. The successful cannulation of the adrenal veins was defined as a selectivity index (SI) ≥2. A diagnosis of unilateral dominant side of aldosterone secretion was made with the lateralization index (LI) ≥2, referring to the guideline composed by multiple societies of endocrinology[2].
Surgical management
In Group PET, surgical strategies were formulated based on the results of 68Ga-pentixafor PET/CT as follows: (1) For patients with unilateral positive adrenal lesions, surgery was performed on the positive side; (2) For patients with unilateral positive adrenal lesions and negative lesions on the contralateral side, surgery was performed on the positive side; (3) For patients with bilateral positive adrenal lesions, surgery was performed on the side with the higher SUVmax. In Group AVS, surgery was performed on the dominant side of aldosterone secretion determined by AVS.
Total adrenalectomy was recommended as the primary surgical intervention for PA patients. For patients who were anatomically feasible and actively requested preservation of partial normal adrenal tissues, partial adrenalectomy was performed to remove only the lesions.
Evaluation criteria of postoperative outcomes
The follow-up interval and evaluation criteria of postoperative outcomes (Supplemental Digital Content, Table 1, available at: http://links.lww.com/JS9/F58) referred to Primary Aldosteronism Surgical Outcomes (PASO) classification system published in 2017[12,13]. The first follow-up should be conducted within 3 months after surgery, and the final outcomes should be assessed at 6–12 months after surgery, then followed by yearly reassessment indefinitely to monitor for persistence or reoccurrence of PA. Evaluation criteria consisted of clinical outcomes (complete, partial or absent success) and biochemical outcomes (complete, partial or absent success)[12], and clinical or biochemical outcomes categorized as either complete or partial success were both interpreted as postoperative benefit.
Statistical analysis
The statistical analyses were conducted by using SPSS software (Statistical Product and Service Solutions version 24.0, USA). The normally distributed and non-normally distributed continuous variables were described by mean ± standard deviation (SD) and median with interquartile range (Q1, Q3), respectively. The categorical variables were reported by absolute numbers and percentages, and the chi-square test was used for comparison analysis. The nonparametric statistical method with Spearman rank correlation coefficient was used for correlation analysis of continuous variables. The influencing factors of clinical and biochemical outcomes were analyzed using the logistic regression analysis with Odds ratios (ORs). The two-tailed test was adopted, and P <0.05 was taken as the test standard with significant statistical difference.
The anticipated surgical benefit rate is 90% for the Group PET and 80% for the Group AVS. To demonstrate the non-inferiority of the Group PET compared to the Group AVS in terms of surgical benefit rate, with a non-inferiority margin of 10%, a one-sided significance level of 0.025, and 80% statistical power, a minimum of 53 subjects per group (total sample size of 106) is required, accounting for a 10% dropout rate.
Theory
The CXCR4 has been proven to be highly expressed in adrenal lesions with autonomous aldosterone secretion, which is positively correlated with the expression of aldosterone synthase (CYP11B2). Previous studies have confirmed the effectiveness of 68Ga-pentixafor PET/CT targeting CXCR4 in the identification of APAs and subtyping diagnosis of PA. Therefore, the 68Ga-pentixafor PET/CT has the potential to guide the surgical strategies for PA, by identifying the functional adrenal lesions and lateralization of aldosterone secretion. Our team has been conducting 68Ga-pentixafor PET/CT in PA patients since 2018, and aimed to explore its role in guiding surgical management for PA compared with AVS, focusing on postoperative outcomes.
Results
Table 1 summarized the baseline characteristics of 197 PA patients in two groups. Group AVS demonstrated higher proportion of male (70.0% vs 48.2%, P = 0.005) and advanced mean age (51.6 ± 10.0 vs 44.5 ± 10.8, years, P = 0.013) compared with Group PET. Additionally, Group AVS exhibited a prolonged median duration of hypertension compared with Group PET [10.0 (6.0, 19.3) vs 8.0 (3.0, 13.0), years, P = 0.005]. The median PAC in Group PET was 21.9(17.2, 29.0) ng/dL, higher than 18.7(15.5, 24.9) ng/dL in Group AVS (P = 0.029). The rate of patients with unilateral adrenal lesion (59.9% vs 36.7%, P = 0.003) and rate of patients undergoing partial adrenalectomy (69.3% vs 53.3%, P = 0.031) were both higher in Group PET. There was no significant difference in other clinical characteristics between the two groups.
Table 1.
Preoperative baseline clinical characteristics
| Index | Group PET (n = 137) | Group AVS (n = 60) | P value |
|---|---|---|---|
| N (%) with follow-up data | 134 (97.8%) | 57 (95.0%) | - |
| Gender, male/female, n | 66/71 | 42/18 | 0.005 |
| Age, mean ± SD, years | 44.5 ± 10.8 | 51.6 ± 10.0 | 0.013 |
| Clinical symptoms, n (%) | |||
| hypertension and hypokalemia | 123 (89.8%) | 56 (93.3%) | 0.257 |
| hypertension with normal blood potassium | 12 (8.8%) | 2 (3.3%) | |
| hypokalemia with normal blood pressure | 2 (1.5%) | 2 (3.3%) | |
| Blood pressure, median (Q1, Q3), mmHg | |||
| systolic pressure | 180(160, 190) | 180(160, 190) | 0.989 |
| diastolic pressure | 110(100, 120) | 110(100, 120) | 0.451 |
| Duration of hypertension, median (Q1, Q3), years | 8.0(3.0, 13.0) | 10.0(6.0, 19.3) | 0.005 |
| Blood potassium, mean ± SD, mmol/L | 2.8 ± 0.6 | 2.7 ± 0.5 | 0.438 |
| PAC, median (Q1, Q3), ng/dL | 21.9(17.2, 29.0) | 18.7(15.5, 24.9) | 0.029 |
| PRA, median (Q1, Q3), ng/ml/h | 0.03(0.01, 0.17) | 0.09(0.01, 0.25) | 0.068 |
| Lesion Types, n (%) | 0.003 | ||
| unilateral adrenal lesions | 82(59.9%) | 22(36.7%) | |
| bilateral adrenal lesions | 55(40.1%) | 38(63.3%) | |
| Lesion Diameter, median (Q1, Q3), cm | 1.5(1.2, 1.8) | 1.4(1.1, 1.9) | 0.433 |
| Surgical approaches, n (%) | 0.031 | ||
| total adrenalectomy | 42(30.7%) | 28(46.7%) | |
| partial adrenalectomy | 95(69.3%) | 32(53.3%) | |
| Pathological Type, n (%) | 0.114 | ||
| adrenocortical adenoma | 106(77.4%) | 40(66.7%) | |
| adrenocortical nodular hyperplasia | 31(22.6%) | 20(33.3%) |
PAC, plasma aldosterone concentration; PRA, plasma renin activity.
Data of lesion diameter and types were obtained from conventional CT imaging.
Bolded P-values represent statistically significant differences.
The median follow-up duration was 27 (16, 39) months, spanning from 9 to 75 months, with 6 cases lost to follow-up, and the two groups demonstrated comparable clinical and biochemical outcomes during postoperative surveillance (Table 2). Group PET achieved complete, partial and absent clinical success in 69 (51.5%), 51 (38.1%) and 14 (10.4%) cases, respectively, and Group AVS showed corresponding outcomes in 20 (35.1%), 29 (50.9%) and 8 (14.0%) cases (P = 0.115). Biochemical outcomes followed similar patterns: 110 (82.1%), 17 (12.7%) and 7 (5.2%) patients in Group PET achieved complete, partial and absent biochemical success, with 43 (75.4%), 10 (17.5%) and 4 (7.0%) patients in Group AVS showing corresponding biochemical outcomes (P = 0.533). Notably, the postoperative benefit rate of Group PET was not inferior to that of Group AVS (95.5% vs in 93.0%, P = 0.714), and the calculated statistical power was 90.5% with a non-inferiority margin of 10%. The total patients exhibited a significantly higher proportion of complete biochemical success compared to complete clinical success (Fig. 1A).
Table 2.
Postoperative outcomes of patients with follow-up data in Group PET versus Group AVS
| Total | Group PET (n = 134) | Group AVS (n = 57) | P value |
|---|---|---|---|
| Clinical outcomes, n (%) | 0.115 | ||
| Complete success | 69 (51.5%) | 20 (35.1%) | |
| Partial success | 51 (38.1%) | 29 (50.9%) | |
| Absent success | 14 (10.4%) | 8 (14.0%) | |
| Biochemical outcomes, n (%) | 0.533 | ||
| Complete success | 110 (82.1%) | 43 (75.4%) | |
| Partial success | 17 (12.7%) | 10 (17.5%) | |
| Absent success | 7 (5.2%) | 4 (7.0%) | |
| Overall benefit, n (%) | 128 (95.5%) | 53 (93.0%) | 0.714 |
| Unilateral adrenal lesions | Group PET (n = 81) | Group AVS (n = 22) | P value |
| Clinical outcomes, n (%) | 0.256 | ||
| Complete success | 48 (59.3%) | 9 (40.9%) | |
| Partial success | 29 (35.8%) | 12 (54.5%) | |
| Absent success | 4 (4.9%) | 1 (4.5%) | |
| Biochemical outcomes, n (%) | 0.561 | ||
| Complete success | 69 (85.2%) | 19 (86.4%) | |
| Partial success | 11 (13.6%) | 2 (9.1%) | |
| Absent success | 1 (1.2%) | 1 (4.5%) | |
| Overall benefit, n (%) | 81 (100.0%) | 21 (95.5%) | 0.214 |
| Bilateral adrenal lesions | Group PET (n = 53) | Group AVS (n = 35) | P value |
| Clinical outcomes, n (%) | 0.747 | ||
| Complete success | 21 (39.6%) | 11 (31.4%) | |
| Partial success | 22 (41.5%) | 17 (48.6%) | |
| Absent success | 10 (18.9%) | 7 (20.0%) | |
| Biochemical outcomes, n (%) | 0.389 | ||
| Complete success | 41 (77.4%) | 24 (68.6%) | |
| Partial success | 6 (11.3%) | 8 (22.9%) | |
| Absent success | 6 (11.3%) | 3 (8.6%) | |
| Overall benefit, n (%) | 47 (88.7%) | 32 (91.4%) | 0.954 |
Figure 1.
(A) For 191 PA patients in follow-up, the rate of complete biochemical success was significantly higher than the rate of complete clinical success (80.1% vs 46.6%, P<0.001). (B) ROC analysis determined the optimal cutoff value of 5.5 for SUVmax to identify the functional lesions with autonomous aldosterone secretion, with a sensitivity of 82.8% and a specificity of 92.6% (area under receiver-operating-characteristic curve, 0.93; P<0.001).
The optimal SUVmax cutoff value for identifying adrenal lesions with autonomous aldosterone secretion was analyzed, utilizing the postoperative outcomes as reference standard to confirm the functional status of aldosterone secretion in excised or unresected lesions (Fig. 1B). The optimal cutoff value of 5.5 for SUVmax showed a sensitivity of 82.8% and a specificity of 92.6% to identify the functional adrenal lesions for PA patients (area under receiver-operating-characteristic curve, 0.93; P < 0.001).
Subgroup analyses stratified by adrenal laterality also revealed no significant differences in postoperative outcomes between the two groups (Table 2). For patients with unilateral adrenal lesions, 100% (81/81) of cases in Group PET achieved clinical or biochemical benefit, compared with 95.5% (21/22) in Group AVS (P = 0.256). Similarly, for patients with bilateral adrenal lesions, postoperative benefit rates were 88.7% (47/53) in Group PET and 91.4% (32/35) in Group AVS (P = 0.747). Detailed analysis of 53 patients with bilateral adrenal lesions in Group PET (Table 3) revealed 34 cases exhibiting unilateral positive lesions with contralateral negativity (Figure 2A and B). And all the 34 patients achieved postoperative benefit, comprising 16 (47.1%) cases with complete clinical success, 15 (44.1%) cases with partial clinical success, 30 (88.2%) cases with complete biochemical success, and 4 (11.8%) cases with partial biochemical success. The remaining 19 patients exhibited bilateral positive adrenal lesions (Figure 2C and D), with 13 (68.4%) attaining postoperative benefit: complete clinical success in 5 (38.5%) cases, partial clinical success in 7 (53.8%) cases, complete biochemical success in 11 (84.6%) cases, and partial biochemical success in 2 (15.4%) cases.
Table 3.
Outcomes of 53 patients with bilateral adrenal lesions in Group PET
| Index | Unilateral positive and contralateral negative | Bilateral positive |
|---|---|---|
| N | 34 | 19 |
| Clinical outcomes, n (%) | ||
| Complete success | 16 (47.1%) | 5 (26.3%) |
| Partial success | 15 (44.1%) | 7 (36.8%) |
| Absent success | 3 (8.8%) | 7 (36.8%) |
| Biochemical outcomes, n (%) | ||
| Complete success | 30 (88.2%) | 11 (57.9%) |
| Partial success | 4 (11.8%) | 2 (10.5%) |
| Absent success | 0 | 6 (31.6%) |
| Overall benefit, n (%) | 34 (100.0%) | 13 (68.4%) |
Figure 2.
68Ga-pentixafor PET/CT images of bilateral adrenal lesions Case 1: A 47-year-old male PA patient presented with bilateral adrenal lesions. 68Ga-pentixafor PET/CT imaging revealed no significant uptake in the right adrenal lesion (A, indicated by red arrow, SUVmax 2.7, diameter 1.0 cm), whereas the left lesion showed markedly increased uptake (B, indicated by red arrow, SUVmax 7.0, diameter 1.4 cm). The left lesion was identified as positive, indicating autonomous aldosterone secretion. The patient subsequently underwent laparoscopic partial adrenalectomy on the left side, and achieved both complete clinical and biochemical success, with a pathological diagnosis of APA. Case 2: A 43-year-old male PA patient presented with bilateral adrenal lesions. 68Ga-pentixafor PET/CT revealed positive tracer uptake in both sides, and the right lesion (C, indicated by red arrow, SUVmax 12.5, diameter 1.5 cm) showed lower SUVmax than the left lesion (D, indicated by red arrow, SUVmax 14.3, diameter 1.8 cm), might indicating dominant aldosterone secretion from the left side. The patient underwent laparoscopic total adrenalectomy on the left side, achieving both partial clinical and biochemical success, with a pathological diagnosis of nodular adrenocortical hyperplasia.
The influencing factors associated with complete clinical and biochemical success were identified by assessing ORs in logistic regression analysis, compared with partial plus absent success (Table 4). Gender, preoperative systolic blood pressure and duration of hypertension were identified as the factors independently associated with complete clinical success: female, lower systolic blood pressure, and shorter duration of hypertension indicated increased likelihood of complete clinical success. Gender was the only factor independently associated with complete biochemical success, and female patients were more likely to achieve complete biochemical success. Whether the surgical management was guided by 68Ga-pentixafor PET/CT or by AVS had no impact on the postoperative clinical and biochemical outcomes.
Table 4.
Factors associated with postoperative clinical and biochemical outcomes
| Factors* (complete success vs partial plus absent success) | Clinical outcomes | Biochemical outcomes | ||
|---|---|---|---|---|
| Odds ratio (95%CI) | P value | Odds ratio (95%CI) | P value | |
| Group (reference: Group AVS) | 0.969 (0.430–2.183) | 0.940 | 0.956 (0.406–2.251) | 0.918 |
| Gender (reference: female) | 2.153 (1.033–4.487) | 0.041 | 2.985 (1.220–7.302) | 0.017 |
| Age (per 1 year) | 0.999 (0.960–1.039) | 0.947 | 1.023 (0.973–1.076) | 0.375 |
| Systolic pressure (per 1 mmHg) | 1.039 (1.021–1.058) | 0.001 | 1.015 (0.996–1.034) | 0.133 |
| Duration of hypertension (per 1 year) | 1.146 (1.066–1.233) | 0.001 | 1.021 (0.945–1.104) | 0.598 |
| Blood potassium (per 1 mmol/L) | 1.308 (0.631–2.712) | 0.470 | 0.604 (0.261–1.396) | 0.238 |
| Lesion diameter (per 1 cm) | 1.026 (0.598–1.760) | 0.927 | 0.481 (0.220–1.053) | 0.067 |
| Lesion type (reference: bilateral lesions) | 0.466 (0.213–1.017) | 0.055 | 0.497 (0.202–1.222) | 0.128 |
| Surgical approach (reference: partial adrenalectomy) | 1.297 (0.586–2.871) | 0.521 | 0.456 (0.178–1.168) | 0.102 |
| Pathological type (reference: adrenocortical nodular hyperplasia) | 1.626 (0.651–4.065) | 0.298 | 2.920 (0.944–9.029) | 0.063 |
Logistic regression analyses were conducted to identify independent factors associated with clinical and biochemical outcomes, and the corresponding odds ratios were adjusted for the confounding effects of the other covariates. An OR less than 1 indicates an increased likelihood of complete success and an OR greater than 1 indicates an increased likelihood of partial or absent success.
Bolded P-values represent statistically significant differences.
86 female patients demonstrated higher rates of complete clinical success (58.1% vs 37.1%, P = 0.004) and complete biochemical success (88.4% vs 73.3%, P = 0.01) compared with 105 male patients (Table 5). Patients achieving complete clinical success (n = 89) exhibited significantly shorter duration of hypertension [6.0 (2.0, 10.0) vs 10.0 (6.8, 17.3), years, P < 0.001] and lower preoperative systolic blood pressure [170 (160, 180) vs 180 (170, 200), mmHg, P < 0.001] than those achieving partial or absent clinical success (Table 5). Both clinical and biochemical outcomes showed no significant differences in rates of complete success between 69 patients undergoing total adrenalectomy with 122 patients undergoing partial adrenalectomy (Table 5). Postoperative pathological results confirmed adrenocortical adenomas in 142 patients and adrenocortical nodular hyperplasia in 49 patients, and no significant difference was observed in the clinical and biochemical outcomes between the two pathological types (Table 5).
Table 5.
Correlation analysis between clinical characteristics with postoperative outcomes
| Characteristics | Clinical success | Biochemical success | ||||
|---|---|---|---|---|---|---|
| Complete | Partial plus absent | P value | Complete | Partial plus absent | P value | |
| Age, mean ± SD, years | 46.2 ± 9.7 | 50.8 ± 11.1 | 0.020 | 48.1 ± 10.2 | 50.8 ± 12.5 | 0.128 |
| Gender, N (%) | 0.004 | 0.010 | ||||
| Male (n = 105) | 39 (37.1%) | 66 (62.9%) | 77 (73.3%) | 28 (26.7%) | ||
| 76 (88.4%) | 10 (11.6%) | |||||
| Female (n = 86) | 50 (58.1%) | 36 (41.9%) | ||||
| Hypertension duration, median (Q1, Q3), yeas | 6.0 (2.0, 10.0) | 10.0 (6.8, 17.3) | 0.001 | 9.0 (3.3, 13.0) | 10.0 (3.0-17.0) | 0.247 |
| Systolic pressure, median (Q1, Q3), mmHg | 170 (160, 180) | 180 (170, 200) | 0.001 | 180 (160, 190) | 180 (170, 200) | 0.047 |
| Blood potassium, mean ± SD, mmol/L | 2.8 ± 0.6 | 2.7 ± 0.5 | 0.073 | 2.8 ± 0.5 | 2.6 ± 0.5 | 0.006 |
| Lesion diameter, median (Q1, Q3), cm | 1.5 (1.1, 1.8) | 1.5 (1.2, 1.8) | 0.843 | 1.5 (1.2, 1.8) | 1.4 (1.1, 1.8) | 0.351 |
| Lesion type, N (%) | 0.009 | 0.046 | ||||
| Unilateral (n = 103) | 57 (55.3%) | 46 (44.7%) | 88 (85.4%) | 15 (14.6%) | ||
| Bilateral (n = 88) | 32 (36.4%) | 56 (63.6%) | 65 (73.9%) | 23 (26.1%) | ||
| Surgical approach, N (%) | 0.210 | 0.514 | ||||
| 57 (82.6%) | 12 (17.4%) | |||||
| Total adrenalectomy (n = 69) | 28 (40.6%) | 41(59.4%) | ||||
| Partial adrenalectomy (n = 122) | 61 (50.0%) | 61 (50.0%) | 96 (78.7%) | 26 (21.3%) | ||
| Pathological type, N (%) | 0.782 | 0.254 | ||||
| 111 (78.2%) | 31 (21.8%) | |||||
| adrenocortical adenoma (n = 142) | 67 (47.2%) | 75 (52.8%) | ||||
| adrenocortical nodular hyperplasia (n = 49) | 22 (44.9%) | 27 (55.1%) | 42 (85.7%) | 7 (14.3%) | ||
Bolded P-values represent statistically significant differences.
Correlation analysis between SUVmax with clinical characteristics and postoperative outcomes showed that the SUVmax was positively correlated with lesion diameter (r = 0.262, P = 0.002), while negatively correlated with the age (r = −0.315, P < 0.001), duration of hypertension (r = −0.191, P = 0.029) and blood potassium level (r = −0.296, P = 0.001). The median SUVmax of 106 patients diagnosed with APA was 12.1 (8.5, 16.4), significantly higher than the 7.8 (5.5, 12.8) of 31 patients with nodular adrenocortical hyperplasia (P = 0.005). Patients achieving complete clinical success showed higher median SUVmax than those with partial clinical success [13.1 (9.3, 20) vs 9.1 (6.8, 13.9), P = 0.003]. No significant difference was observed between SUVmax with other characteristics and biochemical outcomes.
Discussions
PA remains the most prevalent etiology of secondary hypertension due to autonomous hypersecretion of aldosterone, initially described by Conn in 1955[14,15]. Current therapeutic guidelines recommend adrenalectomy as the definitive management for unilateral APA and a viable intervention option for select cases of IHA, with these subtypes constituting approximately 30% and 60% of PA cases, respectively[1]. Accurate identification of functional lesions and lateralization of aldosterone secretion is crucial for surgical strategies in PA, as it could directly influence postoperative outcomes, particularly in patients with small or bilateral adrenal lesions.
AVS is still recommended as the gold standard for identifying the lateralization of aldosterone secretion for PA. However, its clinical application is limited due to the invasiveness, high cost, technical complexity, controversial interpretation of results, and potential failure rate[16]. In a meta-analysis published in 2021, the rates of unsuccessful cannulations and incorrect lateralization of AVS without ACTH stimulation in PA patients were 51.3% and 25.9%, respectively[17]. A systematic review involving 950 PA patients reported that the lateralization of aldosterone secretion indicated by AVS was opposite to the lesion location shown on CT imaging in 17% cases[18]. Besides, patients with renal insufficiency and older ages have difficulty tolerating AVS. Therefore, a non-invasive and accurate evaluation method for identifying the lateralization of aldosterone secretion was needed urgently.
Our previous studies have demonstrated that the 68Ga-pentixafor PET/CT targeting CXCR4 could effectively identify functional adrenal lesions secreting aldosterone autonomously in PA[7-9], and its reliability in identifying the lateralization of aldosterone secretion has also been discussed in other studies. The 68Ga-pentixafor PET/CT achieved a sensitivity of 93.0%, a specificity of 84.6%, and an accuracy of 91.1% in detecting APAs in 56 cases[9]. Furthermore, in a cohort study including 120 patients, 68Ga-pentixafor PET/CT achieved a sensitivity of 92.4%, specificity of 94.4% and accuracy of 93.3% in the classification and diagnosis of PA[19]. In a small sample (n = 26) study, the agreement on the lateralization diagnosis between 68Ga-pentixafor PET/CT and AVS was 77%, and the accuracy was 92% and 85%, respectively[20]. In a retrospective study including 25 PA patients undergoing both 68Ga-pentixafor PET/CT and AVS, the concordance rate in identifying the lateralization of aldosterone secretion between 68Ga-Pentixafor PET/CT and AVS was 65.2% (15/23)[21].
Although our previous study has preliminarily reported the favorable postoperative outcomes of 91 PA patients undergoing surgery guided by 68Ga-pentixafor PET/CT[22], there is still a lack of large-sample cohort compared with AVS. In this prospective cohort study the postoperative clinical and biochemical outcomes of 134 PA patients undergoing surgery guided by 68Ga-pentixafor PET/CT were comparable with the outcomes of 57 cases guided by AVS. Although it was not sufficient to completely replace AVS, 68Ga-pentixafor PET/CT showed the potential to effectively guide the surgical management for PA as a preliminary examination conducted in front of AVS.
The images of 68Ga-pentixafor PET/CT could clearly differentiate the positive functional lesions from the normal adrenal tissues or negative non-functional lesions, providing a potential theoretical basis for the feasibility of partial adrenalectomy in PA treatment. Although current guidelines typically recommend total adrenalectomy as the preferred surgical approach for PA[23], partial adrenalectomy has shown therapeutic results comparable to total adrenalectomy in APAs[24]. In this study, our analysis results also supported the view that partial adrenalectomy was safe and effective for the surgical treatment of PA. By accurately identifying positive adrenal lesions, 68Ga-pentixafor PET/CT contributed to targeted removal of functional lesions while preserving normal adrenal tissue, thereby supporting partial adrenalectomy as a viable approach for PA patients.
Additionally, for PA patients with bilateral adrenal lesions, 68Ga-pentixafor PET/CT could develop precise and personalized surgical strategies, by providing detailed information for each lesion, such as amount, size, location and SUVmax. The SUVmax was positively correlated with the expression level of CXCR4 and aldosterone synthase (CYP11B2)[25], suggesting that lesions exhibiting higher SUVmax might have stronger functional status of aldosterone secretion. In this study, all the 34 patients with unilateral positive lesions and contralateral negative lesions identified by 68Ga-pentixafor PET/CT benefited from surgery on the positive sides, and 68.4% (13/19) of patients with bilateral positive lesions benefited from surgery on the side with higher SUVmax. However, AVS had difficulty in providing detailed information for each lesion, and the significant lateralization of aldosterone secretion identified by AVS was not sufficient to rule out the possibility of functional lesions on the contralateral adrenal gland.
In this study, the proportion of complete biochemical success was significantly higher than that of complete clinical success. Similarly, a previous study involving approximately 700 PA patients with surgical intervention reported that 94% of patients achieved complete biochemical success, while only 37% of patients achieved normalization of blood pressure without the use of antihypertensive drugs[12]. This discrepancy might result from that the factors affecting blood pressure are more complex, such as gender, age, pre-existing primary hypertension, family history of hypertension, duration of hypertension, cardiac function, renal function, dyslipidemia and arteriosclerosis, which might lead to irreversible vascular resulting in persistent hypertension after surgery[15,26]. Hypertension could cause endothelial damage in blood vessels, which could lead to loss of vasomotor activity, disproportionate vascular contractility, and cause further elevation of blood pressure, creating a self-perpetuating vicious cycle that aggravates the development and progression of hypertension[27]. The difference in clinical outcomes between female and male presumably reflects the vascular protective effect of estrogen, which might lessen the likelihood of irreversible vascular damage, while the older age might increase this damage leading to hypertension[12]. Therefore, we need to pay attention to the fact that nearly half of PA patients still require medication to control blood pressure after surgery.
Although this study did not focus on discussing the diagnostic efficacy of 68Ga-pentixafor PET/CT for PA, we still explored the optimal cutoff for SUVmax to identify functional lesions with autonomous aldosterone secretion based on postoperative outcomes. In this study, the cutoff of 5.5 for SUVmax showed a sensitivity of 82.8% and a specificity of 92.6% to identify functional adrenal lesions. However, the SUVmax might vary depending on the PET/CT machine model, imaging time, sample size, and concentration of the radiopharmaceutical. Therefore, the optimal cutoff for SUVmax provided in current studies should not be recommended as a uniform standard for all units. Each medical unit should explore the appropriate cutoff for SUVmax based on the specific situation of its own nuclear medicine examination process, combined with visual assessment.
The correlation between SUVmax and pathological diagnosis represented a notable observation. In the new WHO classification of adrenal cortical tumors published in 2022[28], the pathological classification of PA has been redefined, anchoring diagnosis to CYP11B2 immunohistochemistry to identify the functional sites of aldosterone production. CXCR4 has been proven to be positively correlated with the expression of CYP11B2. We hypothesize that the expression level of CYP11B2 in APAs might be higher than that in adrenocortical nodular hyperplasia, which might lead to the correspondingly higher SUVmax in APAs. This molecular-imaging correlation requires further validation in future.
Limitations and prospects
This study should acknowledge some limitations. Firstly, despite the largest sample size currently available, the number of patients with bilateral adrenal lesions was still limited. It is still necessary to continue expanding the sample size to further verify the role of 68Ga-pentixafor PET/CT in guiding the surgical treatment of PA. Secondly, this study did not conduct 68Ga-pentixafor PET/CT and AVS simultaneously on the same patients, to compare the role of the two methods in guiding surgical treatment for PA. Thirdly, the role of 68Ga-pentixafor PET/CT in guiding surgical management for PA patients with bilateral lesions was not analyzed based on the ratio of SUVmax between bilateral lesions, and it might be possible to explore more detailed surgical strategies by grouping SUVmax ratios of bilateral positive lesions. Despite the aforementioned limitations, this prospective study preliminarily demonstrated the effectiveness of 68Ga-pentixafor PET/CT in guiding surgical management of PA, with comparable postoperative outcomes to AVS. It suggested the potential of 68Ga-pentixafor PET/CT to serve as a standard preoperative modality for PA patients in clinical practice. Furthermore, it might be possible to establish a novel surgical classification system based on CXCR receptor imaging to optimize surgical management of PA, by integrating parameters derived from 68Ga-pentixafor PET/CT results, such as lesion number, size, location, and SUVmax ratios.
Conclusions
68Ga-pentixafor PET/CT could effectively guide the surgical management for PA, achieving favorable clinical and biochemical outcomes comparable to AVS. The postoperative biochemical outcomes of PA patients were usually better than clinical outcomes. Gender, preoperative systolic blood pressure and duration of hypertension were the independent factors associated with complete clinical success, and the gender was the only factor independently associated with complete biochemical success.
Footnotes
Guoyang Zheng, Shengyan Liu, and Yinjie Gao contributed equally to this work.
Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article.
Supplemental Digital Content is available for this article. Direct URL citations are provided in the HTML and PDF versions of this article on the journal's website, www.lww.com/international-journal-of-surgery.
Contributor Information
Guoyang Zheng, Email: guoyang198966@163.com.
Shengyan Liu, Email: 18811029569@163.com.
Yinjie Gao, Email: 1097156268@qq.com.
Xinchun Yan, Email: daleyenxc@outlook.com.
Wenda Wang, Email: wangwenda1989@126.com.
Yang Zhao, Email: zhaoyangkypumch@163.com.
Zhan Wang, Email: yingshangwangzhan@126.com.
Wenjia Zhu, Email: zhuwenjia-pumch@163.com.
Yushi Zhang, Email: zhaoyangkypumch@163.com.
Anli Tong, Email: tonganli@hotmail.com.
Li Huo, Email: huoli@pumch.cn.
Ethical approval
This study complied with the principles of the World Medical Association Declaration of Helsinki, as revised in 2013, and received ethical approval from the ethics committee of our hospital.
Consent
The written informed consent has been obtained from patients.
Sources of funding
Supported by the Fundamental Research Funds for the Central Universities, Peking Union Medical College (3332024022).
Author contributions
Yushi.Zhang, L.H., A.T., G.Z.: study concept or design; G.Z., S.L., Yinjie.Gao, X.Y. project implementation; W.W., Yang.Zhao, Z.W.: data collection; G.Z., S.L., Yinjie.Gao, Yushi.Zhang, L.H., A.T.: data interpretation; W.W., Yang.Zhao, Z.W., W.Z.: statistical analysis; G.Z.: funding acquisition; Yushi.Zhang, L.H., A.T., W.Z.: project administration and supervision; G.Z., S.L., Yinjie.Gao: writing – original draft; Yushi.Zhang, L.H., A.T.: writing – review & editing; all the authors: approval of final manuscript.
Conflicts of interest disclosure
The authors have no relevant financial or non-financial interests to disclose.
Guarantor
Yushi Zhang.
Research registration unique identifying number (UIN)
This study was registered at https://www.clinicaltrials.gov/ (NCT04859959).
Provenance and peer review
Not commissioned, externally peer-reviewed.
Data availability statement
The datasets generated during and/or analyzed during the current study are available upon reasonable request by sending email to yszhangpumch@163.com
References
- [1].Monticone S, Burrello J, Tizzani D, et al. Prevalence and clinical manifestations of primary aldosteronism encountered in primary care practice. J Am Coll Cardiol 2017;69:1811–20. [DOI] [PubMed] [Google Scholar]
- [2].Funder JW, Carey RM, Mantero F, et al. The management of primary aldosteronism: case detection, diagnosis, and treatment: an endocrine society clinical practice guideline. J Clin Endocrinol Metab 2016;101:1889–916. [DOI] [PubMed] [Google Scholar]
- [3].Nanba AT, Nanba K, Byrd JB, et al. Discordance between imaging and immunohistochemistry in unilateral primary aldosteronism. Clin Endocrinol (Oxf) 2017;87:665–72. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [4].Williams TA, Burrello J, Sechi LA, et al. Computed tomography and adrenal venous sampling in the diagnosis of unilateral primary aldosteronism. Hypertension 2018;72:641–49. [DOI] [PubMed] [Google Scholar]
- [5].Rossitto G, Amar L, Azizi M, et al. Subtyping of primary aldosteronism in the AVIS-2 study: assessment of selectivity and lateralization. J Clin Endocrinol Metab 2020;105:dgz017. [DOI] [PubMed] [Google Scholar]
- [6].Heinze B, Fuss CT, Mulatero P, et al. Targeting CXCR4 (CXC Chemokine Receptor Type 4) for molecular imaging of aldosterone-producing adenoma. Hypertension 2018;71:317–25. [DOI] [PubMed] [Google Scholar]
- [7].Ding J, Zhang Y, Wen J, et al. Imaging CXCR4 expression in patients with suspected primary hyperaldosteronism. Eur J Nucl Med Mol Imaging 2020;47:2656–65. [DOI] [PubMed] [Google Scholar]
- [8].Ding J, Tong A, Zhang Y, et al. Functional characterization of adrenocortical masses in nononcologic patients using 68Ga-pentixafor. J Nucl Med 2022;63:368–75. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [9].Gao Y, Ding J, Cui Y, et al. Functional nodules in primary aldosteronism: identification of CXCR4 expression with 68Ga-pentixafor PET/CT. Eur Radiol 2023;33:996–1003. [DOI] [PubMed] [Google Scholar]
- [10].Hu J, Xu T, Shen H, et al. Accuracy of gallium-68 pentixafor positron emission tomography-computed tomography for subtyping diagnosis of primary aldosteronism. JAMA Network Open 2023;6:e2255609. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [11].Agha RA, Mathew G, Rashid R, et al. Revised strengthening the reporting of cohort, cross-sectional and case-control studies in surgery (STROCSS) guideline: an update for the age of artificial intelligence. Prem J Sci 2025;10:100081. [Google Scholar]
- [12].Williams TA, Lenders JWM, Mulatero P, et al. Primary aldosteronism surgery outcome (PASO) investigators. Outcomes after adrenalectomy for unilateral primary aldosteronism: an international consensus on outcome measures and analysis of remission rates in an international cohort. Lancet Diabetes Endocrinol 2017;5:689–99. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [13].Miller BS, Turcu AF, Nanba AT, et al. Refining the definitions of biochemical and clinical cure for primary aldosteronism using the primary aldosteronism surgical outcome (PASO) classification system. World J Surg 2018;42:453–63. [DOI] [PubMed] [Google Scholar]
- [14].Conn JW, Louis LH. Primary aldosteronism, a new clinical entity. Ann Intern Med 1956;44:1–15. [DOI] [PubMed] [Google Scholar]
- [15].Zennaro MC, Boulkroun S, Fernandes-Rosa FL. Pathogenesis and treatment of primary aldosteronism. Nat Rev Endocrinol 2020;16:578–89. [DOI] [PubMed] [Google Scholar]
- [16].Dekkers T, Prejbisz A, Kool LJS, et al. Adrenal vein sampling versus CT scan to determine treatment in primary aldosteronism: an outcome-based randomised diagnostic trial. Lancet Diabetes Endocrinol 2016;4:739–46. [DOI] [PubMed] [Google Scholar]
- [17].Yang J, Yu Y, Zhang Z, Wu Y, He Z. Adrenal venous sampling with adrenocorticotropic hormone stimulation: a meta-analysis. Int J Clin Pract 2021;75:e14438. [DOI] [PubMed] [Google Scholar]
- [18].Kempers MJ, Lenders JW, van Outheusden L, et al. Systematic review: diagnostic procedures to differentiate unilateral from bilateral adrenal abnormality in primary aldosteronism. Ann Intern Med 2009;151:329–37. [DOI] [PubMed] [Google Scholar]
- [19].Zheng Y, Long T, Peng N, et al. The value of targeting CXCR4 with 68Ga-Pentixafor PET/CT for subtyping primary aldosteronism. J Clin Endocrinol Metab 2023;109:171–82. [DOI] [PubMed] [Google Scholar]
- [20].Yin X, Ai K, Luo J, et al. A comparison of the performance of 68Ga-Pentixafor PET/CT versus adrenal vein sampling for subtype diagnosis in primary aldosteronism. Front Endocrinol (Lausanne) 2024;15:1291775. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [21].Zuo R, Liu S, Li W, Xia Z, Xu L, Pang H. Clinical value of 68Ga-pentixafor PET/CT in patients with primary aldosteronism and bilateral lesions: preliminary results of a single-centre study. EJNMMI Res 2024;14:61. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [22].Zheng G, Ding J, Gao Y, et al. 68Ga-pentixafor PET/CT in guiding surgical management of primary aldosteronism. J Clin Transl Endocrinol 2025;39:100384. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [23].Hundemer GL, Vaidya A. Primary aldosteronism diagnosis and management: a clinical approach. Endocrinol Metab Clin North Am 2019;48:681–700. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [24].Fu B, Zhang X, Wang GX, et al. Long-term results of a prospective, randomized trial comparing retroperitoneoscopic partial versus total adrenalectomy for aldosterone producing adenoma. J Urol 2011;185:1578–82. [DOI] [PubMed] [Google Scholar]
- [25].Itcho K, Oki K, Kobuke K, et al. Aberrant G protein-receptor expression is associated with DNA methylation in aldosterone-producing adenoma. Mol Cell Endocrinol 2018;461:100–04. [DOI] [PubMed] [Google Scholar]
- [26].Moiz A, Zolotarova T, Eisenberg MJ. Outpatient management of essential hypertension: a review based on the latest clinical guidelines. Ann Med 2024;56:2338242. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [27].Hurtubise J, McLellan K, Durr K, Onasanya O, Nwabuko D, Ndisang JF. The different facets of dyslipidemia and hypertension in atherosclerosis. Curr Atheroscler Rep 2016;18:82. [DOI] [PubMed] [Google Scholar]
- [28].Mete O, Erickson LA, Juhlin CC, et al. Overview of the 2022 WHO classification of adrenal cortical tumors. Endocr Pathol 2022;33:155–96. [DOI] [PMC free article] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
The datasets generated during and/or analyzed during the current study are available upon reasonable request by sending email to yszhangpumch@163.com