Comparative outcomes of partial versus total adrenalectomy in patients with unilateral adrenal tumors: a systematic review and meta-analysis

Introduction

The adrenal gland is a triangle-shaped gland on the top of each kidney and consists of the cortex and medulla, which produce hormones, including glucocorticoids, mineralocorticoids, sex hormones, catecholamines, epinephrine, and norepinephrine.^1,2 Enlargement of the adrenal gland, either benign or malignant, can alter hormone production. Approximately 55% of primary adrenal tumors are functional. Hyperfunctional tumors can be classified as tumors with Cushing’s syndrome, tumors with primary hyperaldosteronism, and tumors with adrenogenital syndrome.³

Based on the European Society of Endocrinology clinical practice guidelines for adrenal adenoma, the lesion is considered malignant if more than four centimeters inhomogeneous or has >20 Hounsfield units (HU) on unenhanced computed tomography (CT) imaging. Surgery is always indicated in patients with functionally benign or malignant adrenal tumors. In benign cases, surgery is indicated only if the mass causes clinically significant hormone excess. Minimally invasive adrenalectomy was recommended.⁴ Moreover, the laparoscopic approach has been the standard treatment for benign adrenal tumors since 1992.³

Adrenal tumors can occur bilaterally or unilaterally. In the management of unilateral adrenal tumors with clinically significant hormone excess, whether benign or malignant, total adrenalectomy (TA) is considered the standard approach. However, TA leads to adrenal insufficiency requiring corticosteroid replacement therapy, which may cause complications such as adrenal crisis, Cushing syndrome, obesity, immunodeficiency, and cardiovascular disease.⁵ Partial adrenalectomy (PA) was then performed to preserve residual adrenal function and minimize the need for lifelong corticosteroid therapy. Partial adrenalectomy for adenoma management was first reported by Walz et al. in 1996.⁶ Since then, there has been an increasing tendency toward PA in adrenal tumor surgery.

Currently, the accepted indication for partial adrenalectomy in adenomas is bilateral adenoma and adenoma in a solitary adrenal gland.⁶ The efficacy and safety of partial adrenalectomy for unilateral adrenal tumors have been investigated in a few studies and have shown similar therapeutic surgical and biochemical results to total adrenalectomy. However, higher recurrence rates with PA need to be considered compared with those with TA.^6–8 Given the variability of outcomes from recent studies, there is no clear justification for performing partial adrenalectomy in unilateral adrenal tumors with suspected benign lesions. A higher level of evidence is needed to compare the outcomes of PA and TA, specifically in patients with unilateral adrenal tumors. Therefore, we performed this study to compare the outcomes of TA and PA in patients with unilateral adrenal tumors.

Methods

Results

Study selection

A total of 55 studies were identified from the three databases and manually searched using Litmaps (https://www.litmaps.com/). Three duplicate articles were excluded from analysis. After title and abstract screening, 43 articles were excluded, leaving 9 articles for full-text screening. After full-text screening, one article was excluded because it did not compare partial and total adrenalectomies. The study selection process, following the PRISMA flowchart, is shown in Figure 1.

Figure 1. PRISMA flowchart.

Results of meta-analysis

Meta-analyses were performed to compare the operative time, intraoperative blood loss, hospital stay, overall complications, persistent hypertension, and persistent hypokalemia. The follow-up period was discharge from hospital. The forest plot is shown in Figures 2–7. A meta-analysis of surgical outcomes only showed a significant reduction in hospital stay in patients who underwent partial adrenalectomy (MD -0.49 days; 95% CI −0.78 to −0.21; I² = 0%; p = 0,0006).^10–13 We found no significant differences between partial adrenalectomy and total adrenalectomy in operative time (MD -4.96 minute; 95% CI -11.96 to -2.03; I² = 93%; p = 0.16)^10–12,14 and intraoperative blood loss (MD -0.68 ml; 95% CI −22.98 to 20.62; I² = 94%; p = 0.95),^10–12,14 and overall complication (OR 0.76; 95% CI 0.47 to 1.23; I² = 30%; p = 0.27).^10,12,13,15 For biochemical outcomes, meta-analysis showed no significant difference between partial adrenalectomy and total adrenalectomy in postoperative hypertension (OR, 0.75; 95% CI 0.50 to 1.14; I² = 0%; p = 0.18)^12–14 and persistent hypokalemia (OR, 1.24; 95% CI 0.56 to 2.74; I² = 0%; p = 0.6).^12–14

Figure 2. Meta analysis of operative time showed insignificant difference of operative time between partial adrenalectomy and total adrenalectomy.

Figure 3. Meta analysis of intraoperative blood loss showed insignificant difference of intraoperative blood loss between partial adrenalectomy and total adrenalectomy.

Figure 4. Meta analysis of hospital stay showed significant shorter hospital stay in partial adrenalectomy group.

Figure 5. Meta analysis of overall complications showed insignificant difference of overall complications between partial adrenalectomy and total adrenalectomy.

Figure 6. Meta analysis of persistent hypertension showed insignificant difference of persistent hypertension between partial adrenalectomy and total adrenalectomy.

Figure 7. Meta analysis of persistent hypokalaemia showed insignificant difference of persistent hypokalaemia between partial adrenalectomy and total adrenalectomy.

Risk of bias assessment

Based on ROBINS-1, four studies yielded low bias and three studies yielded moderate bias. Sources of bias were identified as selection bias, missing data, and measurement of outcomes, as shown in Figure 8. Based on the RoB 2.0, the study yielded a low risk of bias, as shown in Figure 9.

Figure 8. Risk of bias analysis of included studies using ROBINS-I.

Figure 9. Risk of bias analysis using RoB 2.0.

Discussion

In this study, we identified three main pathologies of unilateral adrenal tumors: adrenal adenoma, adrenal pheochromocytoma, and adrenal hyperplasia. We included only tumors with benign characteristics. These tumors lead to secondary hypertension, which has a higher rate of cardiovascular complications, metabolic dysfunction, and target organ damage than primary hypertension does. Therefore, surgical removal of adrenal tumors is more beneficial than conservative treatment. However, total removal of adrenal tumors can lead to adrenal insufficiency that requires lifetime hormone replacement therapy.^1,16,17

In our study, 620 tumors underwent TA and 362 tumors underwent PA. This shows that there are more cases of adrenal tumors that were surgically removed with TA than that surgically removed with PA. This means that many urologists are unwilling to perform partial adrenalectomy because of technical difficulties. Adrenal glands are a pair of organs, and unilateral TA does not affect the physiology, which is preferred due to its risk-to-benefit ratio, especially when the tumor size is small.^7,18 This was also confirmed by our meta-analysis, which showed comparable outcomes between TA and PA. Our meta-analysis showed only a significant reduction in hospital stay (MD -0.49 days; 95% CI −0.78 to −0.21; I² = 0%; p = 0,0006). This is also in line with previous studies that reported comparable outcomes between PA and TA.^7,8,10–15

Hypertension is a common complication of adrenal tumors. Controlling blood pressure after tumor removal is considered an important parameter for effective therapy. Although not statistically significant, partial adrenalectomy resulted in a lower risk of persistent hypertension (OR, 0.75; 95% CI 0.50 to 1.14; I² = 0%; p = 0.18). This may be influenced by the coexistence of primary hypertension, patient age, and vascular remodelling, which has been investigated in most studies. In most studies, patients required spironolactone preoperatively. Although not statistically significant, PA was associated with a higher risk of persistent hypokalemia than TA (pooled OR, 1.24; 95% CI 0.56 to 2.74; I² = 0%; p = 0.6). However, these results show that the biochemical outcomes of PA and TA were comparable.

Brauckhoff et al. and Kaye et al. investigated the critical size of the residual adrenal tissue after partial adrenalectomy, which had the least impact on adrenal function. They found at least 15-30% residual adrenal tissue is necessary to preserve adequate adrenal function. With residual function from the remaining adrenal tissue, most patients do not need steroid replacement therapy during the follow-up period.^18,19 In addition to the residual adrenal tissue, the adrenal vein should be preserved. The adrenal vein is important for maintaining hemostasis and ensuring a functioning stump to avoid congestion of the gland by adequate drainage into the minor venous plexuses of the retroperitoneal space.²⁰ Therefore, the size of the tumor also needs to be considered when deciding whether PA or TA should be used to surgically remove patients with unilateral adrenal tumors so that the residual adrenal tissue is about 15-30% of the functional adrenal tissue. In addition, tumor characteristics need to be considered, whether benign or malignant. Based on the European Society of Endocrinology clinical practice guidelines for adrenal adenoma, the lesion is considered malignant if more than four centimetres inhomogeneous or has >20 Hounsfield units (HU) on unenhanced computed tomography (CT) imaging. For malignant cases, total adrenalectomy is the standard management of choice.⁴

Recurrence was found in only two cases in Liu et al.¹⁴ This is consistent with the results of previous studies. Nagaraja et al. performed a meta-analysis to compare partial adrenalectomy and total adrenalectomy in adrenal tumors and reported a low recurrence rate (8%). Brauckhoff et al. also found that residual adrenal tissue has a negligible malignancy rate and low recurrence rate after partial adrenalectomy.¹⁹ In addition, a meta-analysis by Nagaraja et al.²¹ showed that the local recurrence rate of partial adrenalectomy is infrequent in benign cases (8% (95% CI 0.05-0.12)). Partial adrenalectomy is a method used to preserve the adrenal gland in cases of future contralateral adrenal surgery.²¹

Some studies have also included adrenal hyperplasia, Cushing’s syndrome, and Conn’s disease. There is little concern about this pathology because it affects the entire adrenal gland. Logically, these lesions should have evidence of recurrence or biochemical and clinical partial or absent responses due to an unresected hyperplasia gland. However, it did not occur in most cases because there was no recurrence observed in the study that included adrenal hyperplasia, Cushing syndrome, and Conn’s disease.

In this pathology, hyperplasia was not homogenously distributed throughout the gland. Previous studies have shown evidence of hormonally active micronodules or aldosterone-producing cell clusters (APCC). Some studies have shown that this cluster may exist concurrently with unilateral aldosterone-producing adenomas. Therefore, resection should involve hormonally active micronodules or APCC.^22–24 However, there is no recent method to clinically identify the area, and the presence of these structures tends to limit the effect of partial adrenalectomy in adrenal hyperplasia, Cushing syndrome, and Conn’s disease.

In conclusion, partial adrenalectomy is associated with a shorter hospital stay than total adrenalectomy in patients with unilateral adrenal tumors. Some outcomes showed high heterogeneity and wide confidence intervals; therefore, these findings should be interpreted with caution.