Kangbo Knife Cryoablation for the Treatment of Functional Adrenal Tumors

Abstract

Aldosterone-producing adenomas and cortisol-secreting adenomas are among the most common functional tumors of the adrenal gland. Primary aldosteronism often leads to refractory hypertension and significantly increases the long-term risk of stroke and cardiovascular events. Autonomous cortisol-secreting adenomas are associated with various complications, including hypertension, hyperglycemia, osteoporosis, infections, and thrombosis. This report presented 2 cases of adrenal tumors: one case involving an aldosterone-producing adenoma and the other involving a cortisol-secreting adenoma. The endocrine functionality of these tumors was assessed using standardized endocrine function tests, including supine and standing aldosterone tests and dexamethasone suppression tests. Bilateral adrenal vein blood sampling (AVS) was performed to localize the lesion responsible for the conditions. Both patients underwent treatment with Kangbo knife cryoablation. No immediate adverse events, such as puncture site pain, hematoma, or pneumothorax, were observed following the procedure. The patient with cortisol-secreting adenoma developed a postoperative pulmonary infection and minor pulmonary thrombosis, which were successfully managed. Postoperatively, both patients achieved biochemical remission, with normalization of aldosterone and cortisol levels. Clinical symptoms, including hypertension, hypokalemia, and moon facies, were significantly improved. Currently, there are no published reports on the use of cryoablation for the treatment of adrenal cortisol-secreting adenomas. To our knowledge, this study presents the first documented cases of AVS-guided Kangbo knife cryoablation for the treatment of aldosterone-producing adenoma and autonomous cortisol-secreting adenoma. The favorable clinical and biochemical outcomes achieved in this study highlight the potential of Kangbo knife cryoablation as a safe and effective novel therapeutic approach for these functional adrenal tumors.

Plain language summary

New minimally invasive treatments for functional adrenal tumors

Functional adrenal tumors are tumors that grow within the adrenal gland and can cause serious health problems such as hypertension, hypokalemia, and other complications. This report focuses on 2 patients: one had a tumor that produced too much aldosterone (a hormone secreted by the adrenal glands), and the other had a tumor that produced too much cortisol, (another hormone produced by the adrenal glands). Both patients underwent minimally invasive surgery using a Kangbo knife, which freeze and destroy tumor cells. After treatment, both patients showed significant improvement in hormone levels and symptoms, such as normalization of hypertension and hypokalemia. This study highlights that this new technique is safe and effective, providing a promising alternative to conventional surgery that may have more complications. However, this study was limited by its small sample size and short follow-up, so more studies are needed to confirm the long-term benefits of this treatment. In conclusion, this report suggests that Kangbo knife cryoablation may be a valuable option for the treatment of certain adrenal tumors.

Introduction

Aldosterone-producing adenomas account for approximately 35% of all cases of primary aldosteronism ¹ and are characterized by hypertension and hypokalemia. Laboratory assessments often reveal elevated aldosterone levels and decreased renin levels, resulting in a significantly increased aldosterone-to-renin ratio (ARR). Furthermore, captopril inhibition and saline instillation tests failed to suppress aldosterone secretion. Cortisol-secreting adenomas account for approximately 15% to 30% of all Cushing’s syndrome (CS) cases ² and are characterized by clinical features including central obesity, moon face, buffalo hump, and thin skin, along with associated complications such as hypertension, hypokalemia, osteoporosis, sexual dysfunction, decreased immunity, varying degrees of depression, irritability, insomnia, and memory loss. Laboratory test results often reveal disrupted plasma cortisol rhythm, elevated urinary free cortisol, and low plasma adrenocorticotropic hormone (ACTH) levels. Additionally, low-dose and high-dose dexamethasone suppression tests failed to suppress serum and urinary cortisol levels.

Adrenal computed tomography (CT) is the preferred imaging modality for evaluating functional adrenal tumors, offering a diagnostic accuracy of almost 100% for identifying adrenal lesions. However, differentiating unilateral adrenal functionality from bilateral adrenal functionality remains a significant diagnostic challenge. Adrenal vein sampling (AVS) ³ is considered the gold standard for determining lateralization of aldosterone secretion. Blind removal of unilateral lesions without prior AVS may fail to resolve aldosterone and cortisol hypersecretion, as the precise source of hormone hypersecretion may not be accurately identified and treated.

Conventional treatments for primary functional adrenal tumors include open and laparoscopic adrenalectomies. ⁴ Although surgical treatment is considered safe, effective, and the preferred treatment for functional adrenal tumors, it is not without limitations. Recent postoperative analyses have shown that up to 27% of patients with primary aldosteronism (PA) experience reduced adrenal cortical function after surgery. ⁵ Similarly, a meta-analysis of patients with subclinical hypercortisolemia and CS treated by surgical intervention reported a high incidence (99.7%) of postoperative secondary adrenal insufficiency. ⁶ Additionally, reported complication rates for laparoscopic adrenalectomy ranged from 25.2% to 28%, while open adrenalectomy carries a lower complication rate of approximately 10.9%. ⁷

Currently, various minimally invasive ablation techniques have been increasingly employed in the treatment of adrenal tumors, demonstrating favorable outcomes. ⁸ This report presented 2 cases of adrenal tumors treated with Kangbo knife cryoablation at Xi’an Daxing Hospital. The first case involved an aldosterone-producing adenoma, while the second case involved a cortisol-secreting adenoma. Both patients achieved clinical and biochemical remission without intraoperative or postoperative adverse events or complications.

Case Report

The first case involved a 56-year-old male patient who was diagnosed with primary hyperaldosteronism at an external hospital 8 years prior and was treated with spironolide (20 mg, 3 times daily). Following treatment initiation, his blood pressure was not regularly monitored, although his blood potassium level was assessed. Five months before admission to our clinic, the patient was hospitalized for a cerebral infarction, during which his systolic blood pressure ranged from 170 to 180 mmHg, and his diastolic blood pressure ranged from 90 to 100 mmHg. Hypokalemia was also observed, with the patient recalling a lowest potassium level of 2.7 mmol/l, although no laboratory report was available for confirmation. On November 1, 2023, the patient was admitted to Xi’an Daxing Hospital for further evaluation and treatment. Clinical investigation revealed a family history of hypertension (father, grandmother, and sister) but no reports of limb weakness or hypokalemia. Physical examination showed no signs of CS, such as acne, ecchymosis, purple abdomen or thigh striae, central obesity, or buffalo hump.

The patient presented with the following clinical characteristics: hypertension (170-180/90-100 mmHg), hypokalemia (2.62-2.75 mmol/l), and high urinary potassium concentration (72.8-123.9 mmol/l). Hormonal assessment revealed a renin concentration <0.5 ng/l (reference range: 1.8-24.5) in the supine position and an aldosterone level of 148.75 ng/dl (reference range: 2.9-24), resulting in an ARR exceeding calculable limits. In the standing position, renin concentration was 0.58 ng/l (reference range: 2.8-8.5), and aldosterone was 124.4 ng/dl (reference range: 3.1-35.1), with an ARR of 214.48. According to the 2016 clinical practice guidelines for the diagnosis and treatment of primary aldosteronism, when renin and aldosterone concentrations are measured in ng/l and ng/dl, respectively, the commonly used ARR threshold for diagnosis is 5.7. The patient’s results exceeded this threshold, thus confirming the diagnosis without the need for additional testing. ⁹ Contrast-enhanced CT of the adrenal glands revealed a space-occupying lesion in the lateral limb of the left adrenal gland measuring approximately 2.2 cm × 2.0 cm × 2.0 cm, with a CT value of 21.83 HU, highly suggestive of an adenoma (Figure 1(a)). Other adrenal hormones, including cortisol (assessed by a 1 mg dexamethasone suppression test) and catecholamines, showed no significant abnormalities.

Figure 1.

Imaging Studies of case 1. (a) CT images of the adrenal gland showed a left adrenal adenoma. (b) A needle was inserted into the tumor area of the left adrenal gland, and tissue biopsy was obtained. (c) The left adrenal tumor was puncturing with a Kang bo knife and frozen at −194°. CT scan showed that the ice ball covered the target area.

In the second case, a 45-year-old female patient presented with a history of consistently elevated blood pressure (>140/90 mmHg) 1 year prior. After treatment with metoprolol (12.5 mg, once daily), her blood pressure decreased to 120 to 130/70 to 80 mmHg. Six months before admission, the patient observed facial swelling but did not seek medical attention. Her antihypertensive medication was changed to amlodipine besylate (10 mg, once daily) 2 weeks before admission, due to inadequate blood pressure management. However, her blood pressure remained elevated at approximately 160/105 mmHg. On November 21, 2023, the patient was admitted to our hospital for further evaluation and treatment.

Physical examination revealed a round face and bilateral clavicular fat pads (Figure 2), with no obvious signs of CS such as buffalo hump, centripetal obesity, thin limbs, acne, thin skin, purpura, telangiectasia, or plethora. Laboratory tests showed hypokalemia (2.9-3.23 mmol/l), disrupted cortisol rhythm (cortisol levels at 8:00 a.m., 4:00 p.m., and 12:00 a.m. were 23.72, 9.2, and 20.6 µg/dl, respectively), significantly elevated 24-hour urinary cortisol (1263 µg; reference range: 75-520 µg/24 hours), and low ACTH levels (4.2 pg/ml at 8:00 a.m.). A low-dose dexamethasone suppression test showed a blood cortisol level of 24.7 µg/dl and a urinary cortisol level of 1174 µg/24 hours. A high-dose dexamethasone suppression test revealed a blood cortisol level of 26 µg/dl and a urinary cortisol level of 2025 µg/24 hours. Adrenal CT identified a 2.5 cm × 2.5 cm lesion in the medial limb of the right adrenal gland, with a CT value of 37.05 HU, consistent with an adenoma (Figure 3(a)). Aldosterone, renin, and ARR values in both supine and standing positions, as well as blood and urinary catecholamine levels, were within normal ranges.

Figure 2.

Cushing’s signs of the case 2. (a) Full moon face. (b, c) Fat pad formation in supraclavicular fossa.

Figure 3.

Imaging studies of case 2. (a) CT images of the adrenal gland showed a right adrenal adenoma. (b) A needle was inserted into the tumor area of the right adrenal gland, and tissue biopsy was obtained.

For both patients, surgical intervention was the preferred treatment. On November 13, 2023, bilateral AVS was performed under local anesthesia to lateralize adrenal hormone secretion (detailed procedure in Supplemental Material 1). AVS results for case 1 confirmed left-sided aldosterone hypersecretion, while case 2 exhibited right-sided cortisol hypersecretion, localizing the lesions to their respective adrenal glands ¹⁰ (Table 1).

Table 1.

Results of Blood Sampling From the Bilateral Adrenal Veins of Case 1 and Case 2.

Variables	Right adrenal vein	Left adrenal vein	Inferior vena cava
Case 1
Aldosterone (ng/dl)	818.1	28,256	170.7
Cortisol (ug/dl)	929.2	907.8	20.14
Index of selectivity 1	46.13	45.07	-
Dominant side index 2	0.028	35.35	-
Case 2
Aldosterone (ng/dl)	52.48	20.37	4.27
Cortisol (ug/dl)	470.30	40.71	27.23
Index of selectivity 3	12.29	4.77	-
Dominant side index 4	4.485	-	-

¹Index of selectivity: The ratio of cortisol in one adrenal vein to that in the inferior vena cava. If the value was greater than 3, the intubation was successful.

²Dominant side index: The ratio of the aldosterone-cortisol ratio of the ipsilateral side to the aldosterone-cortisol ratio of the contralateral side, if its value is >4, suggests that this side is the dominant side.

³Index of selectivity: On one side of the adrenal vein of aldosterone and the ratio of inferior vena cava aldosterone. If the value was greater than 2, the intubation was successful.

⁴Dominant side index: The ratio of the cortisol-aldosterone ratio of the ipsilateral side to the cortisol-aldosterone ratio of the contralateral side, if its value is >2, suggests that this side is the dominant side.

Functional adrenal adenoma was confirmed in both cases, with case 1 diagnosed as aldosteronoma and case 2 diagnosed as autonomous cortisol-secreting adenoma. After obtaining informed consent, cryoablation was performed on both patients using a Kangbo knife. For preoperative blood pressure management, case 1 received nifedipine controlled-release tablets (30 mg, qd), spironolactone (40 mg, bid), and phenbenzamine (10 mg, tid), while case 2 was treated with phenbenzamine alone. Both patients received vasodilators to maintain a blood pressure of 130 to 140/90 to 100 mmHg.

The first patient underwent adrenal tumor puncture biopsy and Kangbo knife cryoablation on November 18, 2023, while the second patient underwent the same procedure on December 2, 2023 (Figures 1(b), (c) and 3(b); see Supplemental Material 2 for details on the surgical procedure).

There were no postoperative complications in case 1, such as puncture site pain, hematoma, or pneumothorax. Pathological and immunohistochemical analyses conducted on December 8, 2023 confirmed an aldosterone-producing adrenocortical adenoma (Figure 4). Postoperative follow-ups on days 1, 12, and at 6 months revealed that renin, aldosterone, and ARR values were all within the normal range. Following surgery, blood pressure was managed with only nifedipine controlled-release tablets (30 mg, once daily) without potassium supplementation. Serum potassium levels remained within the normal range, and blood pressure was maintained at 120 to 130/76 to 86 mmHg (Table 2). Further laboratory evaluations were not conducted due to the patient’s inconvenience; however, blood pressure remained normal and no limb weakness was reported during a telephone follow-up.

Figure 4.

Pathological results of case 1 and case 2. CT-guided puncture pathology of the left adrenal adenoma of case 1: (a; HE×20): combined with morphology, clinical, imaging, and immunohistochemistry support adrenal cortical adenoma (aldosterone-producing adenoma). (b; Immunohistochemistry ×20): CYP11B2 (air +), CgA (−), Syn (+), Inhibin—a (+), Calretinin (CR), Melan part (+)—(−), a SE1 (+), according to (−), CD10 (−), PAX—8 (−), Ki—67 proliferation index (1%). CT-guided puncture pathology of right adrenal adenoma of case 2: (c; HE×20): right adrenal corticoid cell hyperplasia, combined with morphology, clinical and imaging, consistent with adrenal sebaceous adenoma; (d; immunohistochemical ×20): immunohistochemical CgA (−), Syn (+), Inhibin—a (+), CR (+), Melan—a (−). CYP11B2 (score 0, weakly positive in about 10% of cells), CYP11B1 (diffuse strong +).

Table 2.

Related Hormonal Changes Before and After Kang Bo Knife Ablation of Case 1 and Case 2.

Variables	Before surgery	Postoperative day 1	Postoperative day 12 (1 mo after surgery for case 2)	6 mo after surgery
Case 1
Renin (ng/l)	<0.5-0.58	3.21	2.94	-
Aldosterone (ng/dl)	124.4-148.75	17.62	10.91	-
ARR *	214.48	5.49	3.71	-
Cortisol (ug/dl)	15.76	10.18	14.75	-
ACTH (pg/ml) †	22.68	41.12	59.83	-
Potassium (mmol/l)	2.62–2.75	3.84	4.18	-
BP (mmHg)	140/90	140/90	120-130/76-86	120-130/70-80
Types of antihypertensive drugs	3	1	1	1
Case 2
Renin (ng/l)	5.09	1.7	-	-
Aldosterone (ng/dl)	6.56	2.7	-	-
ARR *	1.29	1.59	-	-
Cortisol (ug/dl)	23.72	13.01	1.27	6.59
ACTH (pg/ml) †	4.2	19.24	8.93	25.6
Potassium (mmol/l)	2.9	3.33	3.53	4.58
BP (mmHg)	160/105	120-140/70-80	120-140/70-80	120-130/70-80
Dose of hydrocortisone	0	0	20 mg	5 mg

^*ARR: aldosterone to renin concentration ratio.

^†ACTH: Adrenocorticotropic hormone.

Sixteen hours postoperatively, the patient in case 2 experienced a decrease in oxygen saturation to a low of 91% despite receiving supplemental oxygen. Pulmonary computed tomography angiography (CTA) revealed pulmonary embolism and pulmonary infection, requiring emergency pulmonary angiography and inferior vena cava filter placement. Hydrocortisone (100 mg, q8h) was administered to prevent adrenal crisis, along with anti-infection and other symptomatic treatments for pulmonary infection. Ten days postoperatively, the patient’s oxygen saturation stabilized, ranging between 95% and 98% without supplemental oxygen, and infection markers showed significant improvement. The hydrocortisone dose was gradually tapered to an oral regimen of 20 mg in the morning and 5 mg in the afternoon.

Postoperative pathological and immunohistochemical analyses confirmed the diagnosis of adrenal sebaceous adenoma in case 2 (Figure 4). After discharge, antihypertensive medications and potassium supplements were discontinued, as blood pressure and potassium levels normalized. Cortisol levels also returned to the normal range. Postoperative follow-up results are summarized in Table 2 and Supplemental Material 3.

Discussion

Aldosterone-producing adenomas and cortisol-secreting adenomas are among the most common functional tumors of the adrenal gland. AVS has emerged as a crucial diagnostic tool for determining the lateralization of hormone secretion in these conditions. Meta-analyses have shown that adrenal CT imaging has only a 50% consistency rate with AVS findings. Consequently, relying solely on CT imaging for treatment planning may lead to significant clinical errors, including misdiagnosis and mistreatment. For instance, 37.8% of PA patients are mismanaged: 14.6% undergo unnecessary surgical procedures, 19.1% requiring surgery are not operated on, and 3.9% receive the wrong surgical intervention. ¹¹ An international multicenter retrospective cohort study of 1625 PA patients revealed that patients with aldosterone-producing adenomas or unilateral adrenal hyperplasia, confirmed by AVS, exhibited a significantly higher rate of complete hypertension remission post-surgery than those who underwent surgery based on imaging results alone (40.0% vs 30.5%, P = .027). ¹² The pivotal role of AVS in PA diagnosis and management has been well-established in clinical guidelines ¹³ ; however, its application in diagnosing non-ACTH-dependent CS remains less common. ¹⁴ Previous studies have shown that AVS identified bilateral cortisol secretion in 9 of 20 patients with biochemically confirmed autonomous cortisol secretion and unilateral adrenal lesions identified by CT imaging. Recently, AVS has proven valuable in determining the dominant side of cortisol secretion in patients with autonomous cortisol-secreting adenoma, thus preventing diagnostic inaccuracies associated with CT examination alone. ¹⁵ In the 2 cases presented in this report, comprehensive endocrine assessments, functional tests, and AVS were performed to enable precise identification of the lesions responsible for the disease, allowing for targeted treatments in future studies.

Currently, various ablation techniques have been increasingly employed in the treatment of adrenal tumors. The 2020 American Association of Clinical Endocrinology guidelines recommend local ablation as an effective treatment option for adrenal tumors unsuitable for surgical intervention. ¹⁶ In 2021, the Adrenal Tumor Ablation Guideline Committee of the Asian Tumor Ablation Conference published the Adrenal Tumor Ablation Guidelines, recommending ablation for adrenal tumors based on B-level evidence, which supports the safety and effectiveness of the technique. ¹⁷ These guidelines and consensus underscore the growing clinical acceptance of ablation therapies for functional adrenal tumors.

Studies have reported complete tumor response rates of approximately 57.7% for chemical ablation in aldosteronomas and 80% in autonomous cortisol-secreting adenomas. Common complications include pain, pleural effusion, and pancreatitis.^18,19 The limitations of this treatment include incomplete embolization, recurrence risk, the inability to assess the extent of embolization postoperatively, and lack of histopathological specimens.

Radiofrequency ablation has been successfully employed in the treatment of functional adrenal tumors. Szejnfeld et al treated 9 patients with AVS-confirmed aldosterone-producing adenomas and 2 patients with CS using this technique. Aldosterone and ARR were normalized in 8 of the patients with aldosterone-producing adenoma, and clinical remission was observed in 2 of the patients with CS. ²⁰ Similarly, Qu et al used CT-guided radiofrequency ablation in treating 24 patients with adrenal cortisol-secreting adenomas. Despite intraoperative blood pressure fluctuations, no hypertensive crisis occurred. Postoperatively, 6 of the patients exhibited mild lumbar pain. During an 18-month follow-up, serum cortisol and ACTH returned to normal levels, CS-related symptoms gradually improved, and no tumor recurrence was observed in the 24 patients. ²¹

Cryoablation primarily uses an argon-helium knife and a Kango knife for targeted tissue necrosis. The Kangbo knife uses a dual-mode (high- and low-temperature) minimally invasive technique to induce tumor cell necrosis through cycles of cooling and rewarming. This technique involves percutaneous puncture of the target lesion with an ablation needle. Tumor necrosis is achieved through a freeze-thaw cycle using liquid nitrogen and anhydrous ethanol. ²² Huang reported 100% complete ablation and clinical success with CT-guided argon-helium cryoablation in 11 aldosteronoma patients. Fu et al reported successful outcomes in 3 patients with adrenocortical adenoma. In both studies, AVS was performed to confirm diagnoses, and no surgery-related complications were reported. ²³ Cryoablation offers several advantages, including enhanced visualization of treatment progress and tumor coverage, reduced postoperative pain, faster recovery, and minimal risk of damage to adjacent structures such as blood vessels and nerves. Compared with the argon-helium knife, the cryo-knife provides superior overall performance, with advantages such as lower costs for probes and liquid nitrogen. Additionally, it has a larger temperature range and ice ball coverage, requiring fewer probes, with enhanced efficacy and safety. ²⁴ However, cryoablation has limitations, including professional expertise requirements and non-standardized screening processes. In some studies, crucial preoperative endocrine function tests, AVS results, and postoperative hormone evaluations were omitted, which potentially affected treatment precision. ²⁵

Studies have shown that patients with hypercortisolism face a significant risk of postoperative thromboembolism (0.5%-5.6%) and life-threatening infections due to elevated cortisol levels. To mitigate these risks, perioperative management strategies, including antibiotic prophylaxis and anticoagulant therapy are recommended. ²⁶ In this study, these measures were effectively implemented to ensure patient safety and to optimize therapeutic outcomes.

Conclusion

To our knowledge, this report presents the first documented cases of AVS-guided cryoablation for adrenal cortisol-secreting adenomas using the Kangbo knife. Both patients, one with an aldosterone-producing adenoma and the other with an autonomous cortisol-secreting adenoma, achieved favorable clinical, and biochemical outcomes, highlighting the potential of this novel technique as a safe and effective treatment for functional adrenal tumors. However, this study has several limitations, including a small sample size, a short follow-up period, and a lack of direct comparison with laparoscopic surgery. Future research involving larger cohorts, longer follow-up periods, and controlled studies is essential to validate the long-term efficacy and safety of this novel treatment modality for adrenal tumors.