Percutaneous microwave ablation of adrenal tumours under ultrasound guidance in 33 patients with 35 tumours: A single-centre experience

Abstract

Purpose: The aim of this study was to investigate the efficacy and safety of percutaneous microwave ablation (MWA) of adrenal tumours under ultrasound (US) guidance.

Materials and methods: A total of 33 consecutive patients with 35 tumours were enrolled. The term ‘technical success’ is used to indicate whether the tumour was treated according to protocol and was covered completely by the ablation zone. Technical success, local tumour progression (LTP) and complications were recorded. For seven patients with eight biochemically active tumours, biochemical markers were recorded prior to and after the ablation procedure.

Results: In this study, technical success was achieved in all cases. Follow-up imaging was performed on 31 patients with 33 tumours (excluding two patients who were lost to follow-up). LTP occurred for five tumours (15.2%) at a mean of 24 months of follow-up (range 3–82 months). In the subgroup analysis of tumour size and LTP, a significant difference was noted between tumours with a diameter ≤5 cm compared with those >5 cm (p < 0.01). For seven cases of metabolically active adrenal tumours, technical success was confirmed in all patients, and LTP occurred in one case of recurrent pheochromocytoma. All patients demonstrated the normalisation of abnormal biochemical markers after ablation. No major complications were observed.

Conclusion: Percutaneous MWA under US guidance is effective in terms of good local control of adrenal tumours with a diameter of less than or equal to 5 cm and is capable of treating biochemically active tumours harbouring clinical syndromes.

Keywords:

• Adrenal neoplasm
• microwave
• thermal ablation

Introduction

Adrenal tumours are common and are incidentally detected in up to 3% of the middle-aged population and up to 10% of the elderly [1]. Although most of these masses are benign non-functional adenomas that do not require treatment, other less common primary tumours including pheochromocytoma, cortisol adenoma, aldosteronoma and adrenocortical carcinoma may affect the adrenal gland. Additionally, the adrenal gland is a common site of metastasis, which occurs in the late stage of tumour progression [2]. Surgical resection has been advocated by some scholars due to the potential for curative therapy and thus survival benefits [3]. However, this approach remains controversial because of unsatisfactory exposure of the operation field due to the deep tumour location and increased risks of complications (range 3–20%) [4]. Adrenal artery embolisation may be effective; however, this technique is limited by the reflux of embolic agents into normal arteries, which may cause ischaemia in non-target organs, including spinal infarction [5]. Chemical ablation is less commonly used due to the unsatisfactory efficacy and the increased prevalence of side effects related to chemical agent leakage outside the tumour capsule [6]. Thermal ablation has recently been accepted as showing potential for treating small adrenal tumours in patients who are not candidates for surgery and for providing palliative therapy for painful adrenal metastases that are contraindicated for surgical resection [7–9]. Microwave ablation (MWA), one of these ablation techniques, has become increasingly popular [10]. However, reports on the use of MWA to treat adrenal tumours remain limited. The purpose of this study was to determine the efficacy and safety of percutaneous MWA for the treatment of benign and metastatic adrenal neoplasms.

Materials and methods

Patients

From April 2006 to December 2014, percutaneous MWA was performed on 33 patients with 35 primary or metastatic adrenal tumours under ultrasound (US) guidance at the authors’ centre. This group of patients included 25 men and eight women aged 34–76 years (mean 54.8 ± 10.0 years). Seven patients with eight biochemically active tumours were enrolled, including three patients with functional cortical adenomas and four patients with a total of five pheochromocytomas (Table 1).

Table 1. Patient population and tumour characteristics.

Variables
Age, years	54.8 ± 10.0 (range 34–76)
Sex, male/female	25/8
Maximum tumour diameter, cm	3.4 ± 1.4 (range 1.4–6.8)
≤5 cm	30
> 5 cm	5
Tumour location, right/left	27/8
Histological findings
Cortical adenomas	9
Pheochromocytoma	5
Metastasis (lung/renal/hepatocellular carcinoma/other)	21

Inclusion and exclusion criteria

Patients with functional adrenal tumours who met the following criteria were enrolled: 1) aged no less than 18 years, 2) Eastern Cooperative Oncology Group performance status of 0 or 1, 3) unable or unwilling to undergo surgical resection, and 4) preoperative blood pressure decrease to normal (less than 140 mmHg) after taking antihypertensive drugs [11]. According to the latest standard [12], tumour diameter at 5-cm cut-off was chosen to distinguish between small and large tumours. The inclusion criteria for patients with adrenal metastasis were as follows: 1) unilateral adrenal neoplasm of 5 cm or smaller with no more than three indexed tumours, 2) unilateral adrenal tumours larger than 5 cm with the aim to reduce tumour load, 3) no extra-adrenal metastases or tumour thrombus, 4) a secure antenna needle path for US by the side of the peritoneum or by the retroperitoneum, 5) unwillingness to undergo surgical treatment or deemed a non-surgical candidate due to advanced staging and/or medical co-morbidities, and 6) prothrombin time less than 25 s and platelet count greater than 40 × 10⁹ cells/L [13]. Patients with bilateral adrenal lesions, general tumour progression, or a limited life expectancy were excluded. This study was approved by the Ethics Committee of the Chinese PLA General Hospital. Written informed consent was obtained from each patient prior to performing any procedures, and patient records and information were anonymised prior to analysis.

Procedures

Preoperative preparation

All patients underwent at least two types of enhanced imaging, including computed tomography (CT), magnetic resonance imaging (MRI) or contrast-enhanced ultrasound (CEUS), to acquire the pretreatment diagnosis. The diagnosis was confirmed via US-guided biopsy for all tumours prior to the ablation procedure. Grey-scale US and CEUS imaging were performed on each individual to determine the target tumour location, size, and blood supply as well as relationship with the surrounding structures. Routine laboratory tests, including complete blood biochemistry, blood count, viral titres, and coagulation profile, were obtained for all patients. Specific laboratory examinations were also required for all patients. Specific laboratory examinations were also required for patients with functional adrenal neoplasms. Phenoxybenzamine was taken orally (20 mg, 3/day) for 2 weeks preoperatively when ablating a pheochromocytoma with endocrine function. If patients exhibited marked fluctuations in blood pressure the ablation was performed in a surgical operating room. All patients fasted from food and water for 12 h. Intravenous propofol and fentanyl anaesthesia were used during each procedure. Electrocardiogram, respiration and arterial blood pressure data were carefully monitored throughout the procedure.

Microwave equipment and ablation procedures

A microwave system (KY-2000, Kangyou Medical, Nanjing, China) comprising a 15-gauge cooled shaft antenna and a 21-gauge thermocouple (Kangyou Medical, Nanjing, China) was used for all patients. For adrenal tumours located on the left side the patient was placed in the right decubitus position, and a posterior antenna path was recommended to avoid injury of the pancreatic cauda, spleen, or gastric fundus; for right-sided adrenal tumours the patient was placed in the left decubitus position, and a trans-hepatic approach was used. For patients with tumours adjacent to critical structures (e.g. diaphragm, inferior vena cava), prior to MWA needle insertion artificial ascites with normal saline was delivered into the peritoneal cavity to achieve a separation of ≥0.5 cm between the target lesion and the adjacent critical structures.

In general, for adrenal tumours less than 1.7 cm in diameter a single antenna was sufficient; for tumours equal to or greater than 1.7 cm in diameter multiple antennas were used with an inter-antenna distance of no more than 1.8 cm. One or two 21-gauge thermocouples were placed at the tumour border proximal to the diaphragm, inferior vena cava or intestine to avoid thermal injury. The temperature cut-off was set at 54 °C or 50 °C in patients without or with a history of laparotomy, respectively, to account for adhesion and reduced peristalsis. Microwave emission was not activated until the temperature decreased to 45 °C or colder. Additional small doses of ethanol were injected into the marginal tumour tissue when the target tumour abutted important structures such as the inferior vena cava and intestinal tract. The emitted frequency was 2450 MHz. An output power of 20 W was initially used, and the power was then gradually increased to 50 W when the patients adapted to the thermal stimulation and their blood pressure stabilised.

Several measures possibly contributed to minimising the occurrence of hypertensive crises, including 1) ensuring preoperative blood pressure reduction to the normal range, 2) maintaining close monitoring of the blood pressure and heart rate throughout the procedure, preparing adequate rescue medicine and equipment prior to the operation, and terminating the procedure immediately if apparent anomalies or a difficulty in correcting the situation occurred, 3) using an output power of 20 W initially and then gradually increasing the power to 50 W when patients adapted to the thermal stimulation and their blood pressure stabilised, 4) administering phenoxybenzamine orally (20 mg, 3/day) for 2 weeks preoperatively in patients with pheochromocytomas with endocrine function, and 5) performing the ablation procedure in the surgical operating room for patients with large fluctuations of blood pressure so that emergency measures could be more conveniently performed.

The ablation region was carefully monitored under real-time US guidance, and complete treatment was considered if the hyperechoic region on US covered the entire lesion. After tumour ablation, the cooled shaft water dump was stopped to maintain sufficient energy to heat the needle tract; the microwave emission continued for more than 5 s when the antenna was withdrawn to the hepatic capsule with the trans-hepatic approach or to the surface of the tumour without trans-hepatic approach.

Post-ablation management

Patients were carefully observed for 30 min and then returned to the ward if they were experiencing no discomfort. Vital signs were closely monitored for the first 6 h after the ablation procedure. No treatment was needed for mild pain after the procedure. If the pain was intolerable, drugs such as acetaminophen or meperidine hydrochloride were intramuscularly injected.

Outcome evaluation and follow-up

A CEUS or MRI examination was performed within 3 days after MWA to assess the treatment response. If a residual tumour was detected an additional ablation session was performed. Technical success was defined as the tumour being treated according to protocol and complete tumour coverage by the ablation zone. The follow-up period was calculated from the beginning of the ablation procedure. Two types of contrast images were obtained at 3-month intervals during the first year after ablation and then at 6-month intervals during the second year. For functional adrenal tumours, specific hormonal production was monitored following ablation. The interval of biochemical follow-up varied per discretion of the referring endocrinologist. Accordingly, biochemical markers obtained prior to ablation and at the last follow-up after ablation were compared. Local tumour progression (LTP) was considered to be the appearance of tumour foci at the edge of the ablation zone during the course of imaging follow-up [12]. Complications were reported using the standardised Society of Interventional Radiology (SIR) grading system [12].

Statistical analysis

The quantitative variables are presented as the means ± the standard deviation. Qualitative data is presented as a percentage. In this situation death was a competing risk factor for LTP, i.e. the occurrence of death will exclude the occurrence of LTP. Therefore, Gray’s competing risks regression analysis was performed to estimate the cumulative incidence of LTP and death, and Gray’s test was used to compare their differences. The data were analysed using SPSS (Version 17.0, IBM, Armonk, NY) and R statistical package (Version 3.2.2). P values <0.05 were considered statistically significant.

Results

All patient statuses were confirmed via CEUS or contrast-enhanced MRI within 1 week after the ablation procedure. Technical success was achieved in all cases (Figure 1). The total number of sessions was 44 (one session each for 26 tumours and two to four sessions each for nine tumours). Among the 33 patients, 11 tumours were adjacent to the inferior vena cava, and five cases were in the vicinity of the gastrointestinal tract. Artificial ascites was used in 16 cases for tumours located adjacent to the inferior vena cava or intestinal canal. The mean volume of injected normal saline was 525 ± 357 mL (range 130–1600 mL). The separation success rate was 100%. Adjuvant therapy with a small dose of ethanol was administered in 16 cases.

Figure 1. Microwave ablation (MWA) in a 56-year-old man with metastatic hepatocellular carcinoma in the right adrenal gland. (A) Contrast-enhanced ultrasound (CEUS) before MWA shows obvious enhancement in the arterial phase (arrow). (B) Antenna placement during the ablation of the right adrenal metastasis. (C) Computed tomography (CT) imaging obtained 6 days after MWA showed no enhancement (arrow). (D) Follow-up contrast magnetic resonance imaging (MRI) 1 year after MWA showed no enhancement of the target tumour.

Follow-up imaging was performed on 33 of 35 tumours (excluding those in two patients who were lost to follow-up). LTP was observed in five tumours (15.2%) at a mean of 24 months (range 3–82 months), including two cases with an initial tumour diameter ≤5 cm (7.1%) and three cases with an initial tumour diameter >5 cm (60%). A significant difference was found between the two subgroups (Q_Gray = 7.19, p < 0.01; Figure 2). Technical success was confirmed in all eight biochemically active tumours (Figure 3). LTP was observed in one case of a recurrent pheochromocytoma after surgical resection on the right side, and secondary efficacy was achieved after one additional session. All patients demonstrated relief of abnormal biochemical markers after ablation (Tables 2 and 3).

Figure 2. Cumulative incidence for local tumour progression (LTP) and death of ≤5 cm versus >5 cm tumour patients using Gray’s competing-risks regression analysis. There was a significant difference for LTP between the two groups (Q_Gray = 7.19, p < 0.01), but not for death (Q_Gray = 0.27, p = 0.61). Y-axis represents the cumulative incidence of LTP varied from 0 to 1, which is calculated using the formula (Number of LTP cases)/(Total population at risk). The larger the value of the y-axis, the higher the incidence of LTP. Q_Gray represents the statistics of the Gray test. 1, LTP; 2, death.

Figure 3. MWA in a 68-year-old female with an aldosterone-secreting adenoma on the right side of the adrenal gland. (A) Enhanced CT before the ablation treatment demonstrated obvious enhancement of a nodule (arrow) adjacent to both the right posterior lobe of the liver and the diaphragmatic crus. (B) Ultrasonograph during the ablation procedure showed the antenna placement (arrow) and the hyperechoic region covering the entire target lesion (arrow head). (C) CEUS 2 days after the procedure displayed no enhancement in the ablation zone (arrow) and no injury to the diaphragm. (D) Enhanced CT imaging 6 months after MWA showed a completely necrotising area (arrow).

Table 2. Biochemical markers of aldosterone-secreting adenomas.

	Aldosterone^a level (pmol/L)		Renin^b level (μg/L/h)		Potassium^c level (mmol/L)
Patient No.	Before ablation	After ablation	Before ablation	After ablation	Before ablation	After ablation
1	960.8	353.2	0.1	5.1	2.97	4.01
2	1006.7	306.7	0.2	4.0	3.31	4.22
3	835.9	315.2	0.1	6.1	2.51	4.34

^a Normal range 163–481 pmol/L.

^b Normal range <7.14 μg/L/h.

^c Normal range 3.5–5.5 mmol/L.

Table 3. Biochemical markers of pheochromocytomas.

	Metanephrine^a (nmol/L)		Systolic/diastolic blood pressure (mmHg)
Patient no.	Before ablation	After ablation	Before ablation	After ablation
1	65.36	0.37	160/90	131/89
2	72.53	1.41	148/89	127/83
3	83.61	0.55	155/92	114/80
4	47.22	2.05	149/95	130/79

^a Normal range 0.0–0.49 nmol/L.

No major (SIR C-E) or minor (SIR A-B) complications, such as hypertensive crisis, intraperitoneal bleeding, tumour seeding, or thermal injury to nearby structures were observed. During the ablation procedure three patients had a systolic blood pressure exceeding 170 mmHg and the blood pressure decreased to baseline after suspending the ablation procedure for several minutes and providing intravenous labetalol hydrochloride (one patient with a 4.5-cm right adrenal metastasis of hepatocellular carcinoma, one with a 3.7-cm right adrenal pheochromocytoma and one with a 4.0-cm right adrenal pheochromocytoma). Local pain was reported by seven patients. A slight fever was observed in two patients, and markedly elevated transaminase levels were detected in one patient with metastasis adjacent to the diaphragm. All of these side effects were relieved with supportive treatment.

Discussion

MWA is a relatively new ablative modality for treating adrenal tumours. There are limited clinical data regarding its therapeutic efficacy. Wang et al. [13] first demonstrated favourable local tumour control in five cases of adrenal metastasis treated with MWA, including no evidence of recurrence during at a median follow-up of 19 months. Li et al. [14] performed MWA on nine patients with 10 malignant adrenal tumours and obtained local control of all tumours at a mean follow-up of 11.3 months. Our results showed that MWA is an effective and safe method that provides good local control of adrenal tumours and is capable of treating biochemically active tumours with clinical symptoms. The rate of complications is lower than that reported in previous studies with a surgical resection approach (0% versus 3–20%) [4], and the capability of local tumour control is almost equal to that of adrenalectomy (84.8% versus 77–83%) [15–17]. In this study, LTP was observed in only 7.1% (2/28) of tumours in the small tumour group (≤ 5 cm); this rate is lower than that reported in a previous study [18]. We conclude that, with appropriate patient selection and more technical experience, MWA may achieve radical curative effects and become an alternative for those who are unable or unwilling to undergo surgical resection, especially for tumours less than 5 cm in diameter. Technical success was achieved for all five tumours larger than 5 cm. However, LTP was observed in 60% (3/5) of cases, perhaps due to the following tumour characteristics: larger target volumes, relatively rich blood supply, damaged capsule and greater possibility for invading neighbouring vascular structures. The results showed that the possibility of residual tumour and relapse after MWA increases markedly for larger tumours despite repeated ablation procedures at multiple sites.

This study demonstrated good local control of functional adrenal tumours (85.7%, 6/7). Biochemical abnormalities were resolved in all patients, and no major complications were observed. These data are in accordance with the results of Mendiratta et al. [9] in which 13 small functional adrenal tumours were treated via radiofrequency ablation and monitored for a median of 21.2 months, and of Abbas et al. [19] in which five aldosteronomas were treated via thermal ablation with a 12-month follow-up period. Despite the small sample size treated with MWA, we believe that this technique can be used to treat functional adrenal tumours with clinical symptoms.

One major concern regarding adrenal ablation is a hypertensive crisis due to the excessive release of catecholamine during the ablation procedure; the reported rate of this complication ranges from 9% to 41.6% [20–22]. Welch et al. [21] performed cryoablation on 12 patients with single adrenal tumours, and five cases of hypertensive crisis were recorded. This may be due to the absence of an alpha-blocker prior to the ablation procedure. Yamakado et al. [22] presented data from nine cases of adrenal tumours with an incidence of procedural hypertension (66.7%, 6/9); they found that careful blood pressure monitoring was important and suggested that adrenergic blocking medications help to improve hypertension in life-threatening situations. This was in accordance with the results reported by Sudheendra et al. [23] and Venkatesan et al. [24]. In the present study, only three patients had a blood pressure exceeding 170 mmHg; however, this decreased to baseline after suspending the ablation procedure for several minutes and providing intravenous labetalol hydrochloride. No patients experienced hypertensive crisis. This result may be due to the careful pre- and intra-operative management of blood pressure, a gradual increase in microwave output power, the timely suspension of the ablation procedure, and the adequate preparation of rescue medicine.

Another concern regarding adrenal ablation is thermal or mechanical injury to the adjacent organs, such as the pancreatic tail, the extreme underside of the spleen, the gastric fundus on the left side, as well as the liver and inferior vena cava on the right side. Welch et al. [18] reported a complication rate of 8.6%, which included haemothorax, pleural effusion and splenic haemorrhage. In this study, no patients experienced thermal or mechanical damage, potentially due to the careful review of prior imaging to determine the optimal needle path, the strict grasp of the indication, broad application of artificial ascites, close intraoperative real-time sonography monitoring of the needle tip and hyperechoic region, and strict temperature control within the tumour marginal tissue. In the present study, 11 tumours were adjacent to the inferior vena cava and five were in the vicinity of the gastrointestinal tract. Based on our previous experience [25], the temperature was held below 54 °C (the threshold of coagulation) but higher than 45 °C for patients without a previous history of laparotomy, to ensure adequate coverage of the microwave thermal field and to avoid thermal damage to the abutting bowel loop. For patients with a history of abdominal operation, the upper temperature limit was lowered to 50 °C due to possible intestinal adhesion and reduced peristalsis. Additional small doses of ethanol were injected into tumours abutting the important structures mentioned above to achieve a synergistic necrotising effect and to reduce the incidence of the residual tumour.

Despite these encouraging results, this study may have limitations. Firstly, because these data were obtained at a single centre with extensive MWA experience with solid tumours, better outcomes and lower complication rates were observed. And because of the retrospective nature of the study, the integrity and quality of the data obtained, such as biochemical markers of hormone active tumours, is not guaranteed. A multicentre study with a larger cohort or a randomised controlled clinical study is thus needed to minimise the risk of bias and to further confirm the local tumour control of MWA for adrenal tumours. Secondly, because of the mixed tumour pathologies with various types of primary and metastatic adrenal cancers, the inclusion of tumours over 5 cm and the inclusion of functional and non-functional tumours, this study only focused on the local efficacy. Long-term results relative to other modalities are required for individuals with a single pathological tumour type and unified tumour diameter. Thirdly, because numerous patients with metastatic adrenal tumours died of systemic disease progression prior to detecting LTP, the follow-up duration and ability to observe the natural history of the target tumours were limited by the extent of primary extra-adrenal malignancies. Tumours with homogeneous characteristics at uniform advanced stages are therefore required. Moreover, there are opportunities for improvement, especially in patients with large tumours. The combination of MWA with other techniques such as adrenal artery embolisation offers the potential for enhanced thermal efficiency.

Conclusions

Our results show that US-guided percutaneous MWA is safe and effective in providing good local control of benign and malignant adrenal tumours with diameter less than or equal to 5 cm and that MWA is capable of treating biochemically active tumours with clinical symptoms. However, studies with larger samples, continued patient follow-up, and technical improvements are required to determine the long-term efficacy of MWA as a treatment for adrenal tumours.

Disclosure statement

This study was supported by the National Natural Science Foundation of China (grant number 81127006) and by the National Key Technology R&D Programme of China (2013BAI01B01). The authors alone are responsible for the content and writing of this manuscript.