Introduction

In 1992, Gagner et al. introduced laparoscopic transperitoneal adrenalectomy with the patient positioned in lateral decubitus [1]. Since then, the minimally invasive approach has been widely adopted for the surgical treatment of adrenal gland disease and is now considered the gold standard [2, 3]. Laparoscopic adrenalectomy (LA) is associated with lower morbidity, less blood loss, less postoperative pain and shorter hospital stay, as compared to open surgery [3,4,5].

The adrenal gland may be approached by the retroperitoneal route with the patient in the prone or lateral decubitus position, and by a transperitoneal route with the patient supine or in lateral decubitus position [6,7,8,9,10]. Currently, the most popular approaches are the lateral transperitoneal and retroperitoneal routes. Purported advantages are a wider working space and more easily identified anatomical landmarks for the former, and less postoperative pain with earlier recovery of bowel function due to the absence of intestinal manipulation, for the latter [6,7,8,9,10,11,12]. However, clear advantages of one approach over the other are still missing [10, 13].

The indication for a laparoscopic approach in case of large adrenal lesions is still debated in the literature [2, 12, 14, 15]. While laparoscopy in case of a bulky mass is associated with prolonged operative time, LA offers better postoperative outcomes as compared with an open approach [3,4,5]. For these reasons, some authors do not consider size to be an absolute contraindication for a minimally invasive approach [12, 14].

The aim of this case–control study is to compare the surgical outcomes in patients undergoing LA with an anterior approach for lesions measuring 6 cm or more versus lesions in which the diameter is smaller.

Materials and methods

This is a case–control study of prospectively collected data. Informed consent was provided by all participants and institutional review board approval was obtained. From January 1994 to August 2018, 552 LAs were performed in two centers which follow the same diagnostic and treatment protocol and identical surgical approach, as previously reported [8,9,10, 16]. Patients who underwent bilateral adrenalectomy were excluded from the present study (21 patients).

Out of 531 remaining patients, 81 patients with an adrenal lesion diameter ≥6 cm with no venous tumor thrombus who underwent LA were identified (intervention group) and were paired with 81 patients with adrenal lesion diameter ≤5.9 cm (control group), based on diagnosis (Conn–Cushing syndrome, pheochromocytoma, primary adrenal cancer or metastases, other types of lesions), lesion side (right, left), surgical technique (anterior transperitoneal for both right and left LA or anterior transperitoneal submesocolic for left LA, as published previously [8,9,10]) and body mass index (BMI) class divided into five subgroups (18–24.9, 25–29.9, 30–34.9, 35–39.9, ≥40 kg/m2) (Fig. 1). Subgroup analysis was performed according to diagnosis [Conn–Cushing syndrome (Group A), pheochromocytoma (Group B), primary adrenal cancer or metastases (Group C), other diseases (Group D)], lesion side, surgical technique and BMI.

Fig. 1
figure 1

Patient selection. BMI body mass index

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Study design

Data on gender, age, BMI, previous abdominal surgery, surgical approach, lesion size, associated procedures, conversions, operative time, postoperative complications (graded according to the Clavien–Dindo Classification [17]), blood transfusions, postoperative hospital stay and definitive histology were stored in a Microsoft Excel program (Microsoft Corporation, Redmond, Washington, USA).

Statistical analysis

Surgical outcomes were compared between patients with adrenal gland lesions ≥6 cm in diameter and patients with lesions ≤5.9 cm. For continuous variables, results are expressed as mean ± standard deviation (SD) and for categorical variables as frequencies and percentages. The student t test and Fisher’s exact test were employed for statistical analysis as appropriate. A p value lower than 0.05 was considered statistically significant. Statistical analyses were carried out with SPSS software 22.0 (SPSS Inc., Chicago, Illinois, USA).

Results

Patient characteristics and surgical outcomes for the entire series are shown in Table 1. Aside from the obvious statistically significant difference in mean lesion size (6.9 ± 1.4 and 3.3 ± 1.1 cm, p = <0.0001), mean operative time was statistically significantly longer (101.4 ± 52.4 min and 85 ± 31.6 min, p = 0.0174) in the intervention (vs. control) group (Table 1).

Table 1 Patient characteristics and surgical outcomes
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Overall, we observed eight conversions to open surgery in the intervention group. Two occurred during left submesocolic adrenalectomy due to: bleeding (n = 1) and adhesions from previous surgery (n = 1). Six conversions were performed during right adrenalectomy due to: bleeding (n = 3), vena cava adhesions (n = 1), retrocaval and medial adrenal mass growth (n = 1), difficult dissection of the adrenal mass (n = 1). Four conversions were necessary in the control group: three during left anterior adrenalectomy (bleeding, adhesions from previous surgery and adhesions to diaphragmatic crura) and one during right adrenalectomy (hepatomegaly). Five postoperative complications were observed in the intervention group, two during left submesocolic adrenalectomy [trocar hematoma (Clavien–Dindo I), fever (Clavien–Dindo II)] and three during right adrenalectomy [wound infection, anemia (Clavien–Dindo II), hemoperitoneum (Clavien–Dindo III-b)]. In the control group, three postoperative complications were observed: two during left anterior adrenalectomy [wound infection (Clavien–Dindo II), chylous ascites (Clavien–Dindo III-a)] and one during right adrenalectomy [wound infection (Clavien–Dindo II)]. Statistically significant differences regarding conversions and complications were not found (Table 1). Mortality was nil.

In subgroup analysis based on diagnosis, 48 patients (24 intervention and 24 control) were included in group A, 46 (23 intervention and 23 control) in group B, 22 (11 intervention and 11 control) in group C and 46 (23 intervention and 23 control) in group D (Tables 1, 2). A statistically significant difference was observed in mean hospital stay for group A only (p = 0.0392) (Table 2). With regard to intraoperative and postoperative outcomes among the four control subgroups, statistically significant differences were found in the mean operative time between groups A and D (p = 0.0327) and groups C and D (p = 0.0180), and in the mean hospital stay between groups A and B (p = 0.0298), B and D (p = 0.0124), and C and D (p = 0.0466). No statistically significant differences were found between the four subgroups in the interventional arm.

Table 2 Surgical outcomes based on diagnosis
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In subgroup analysis based on laterality, the operative time was statistically significantly longer for the intervention group in patients with right-sided lesions (p = 0.0237) (Table 3). For left-sided lesions, there was no statistically significant difference in outcomes (Table 3), as well as between patients with left-sided versus right-sided lesions. For left LA, mean hospital stay was statistically significantly longer for the submesocolic approach (vs. the control group, p = 0.0057) (Table 4). As well, in the control group, the conversion rate (p = 0.0369) and mean hospital stay (p < 0.0001) were statistically significantly higher and longer, respectively, when the anterior approach was compared with the submesocolic approach (Table 4).

Table 3 Surgical outcomes based on side of adrenal lesions
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Table 4 Surgical outcomes based on type of left approach
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With regard to BMI, the only statistically significant difference between the two groups was in operative time when BMI was between 25 and 29.9 kg/m2 (p = 0.0102) (Table 5). Comparing outcomes among the five BMI subgroups, statistically significant differences were observed in the mean lesion size between BMI 18–24.9 and 30–34.9 kg/m2 (p = 0.0127), and in the mean operative time between BMI 25–29.9 and 30–34.9 kg/m2 (p = 0.0195) and between BMI 25–29.9 and ≥40 kg/m2 (p = 0.0289) in the intervention group. Statistically significant differences were observed in the conversion rate between BMI 18–24.9 and 30–34.9 kg/m2 (p = 0.0166) and between BMI 25–29.9 and 30–34.9 kg/m2 (p = 0.0166), and in the mean operative time between BMI 25–29.9 and 30–34.9 kg/m2 (p = 0.0173) and between BMI 25–29.9 and ≥40 kg/m2 (p = 0.0080), in the control group.

Table 5 Surgical outcomes based on body mass index
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Discussion

Our study showed that the only statistically significant difference that was observed between patients with adrenal lesions ≥6 cm in diameter and patients with lesions ≤5.9 cm was the mean operative time, longer in case of larger lesions (p = 0.0174). Conversions and complication rates occurred more frequently in the intervention group, but this difference was not statistically significant (p = 0.3690 and p = 0.7196, respectively).

In the present study, we chose to adopt the 6 cm diameter cut-off value because this limit has been used most often in previously published articles [14, 15, 18,19,20,21,22]. In our opinion, the choice of this cut-off value in the literature could be related to the increased risk of intra- or postoperative complications due to the need for more extensive surgical dissection, the increased risk of adrenal cancer and the need of extended incision to extract the specimen. In order to obtain a homogeneous series of patients and to reduce the risk of bias that could have influenced the perioperative outcomes, we decided to pair the patients based on diagnosis, lesion side, surgical technique employed and BMI class. In previously published articles, all patients who underwent LA were included without any paired comparison, thus increasing the risk of selection bias and leading to erroneous interpretation of results [14, 15, 18, 19, 21, 23,24,25,26].

The observed difference in mean operative time between the intervention and the control group (101.4 ± 52.4 min and 85 ± 31.6 min, respectively) is similar to previously reported data [14, 15, 19, 21,22,23,24]. Natkaniec et al., using the transperitoneal lateral approach, found mean operative time was statistically significantly longer in patients with adrenal lesion diameter ≥6 cm (n = 89) compared to patients with adrenal lesion diameter <6 cm (n = 441) (111.9 ± 43.7 min vs. 86.6 ± 35 min, respectively, p = <0.0001) [15]. Highlighting pheochromocytoma, Chung et al. reported that the lateral retroperitoneal approach required significantly longer operative time for pheochromocytoma >6 cm, compared to pheochromocytomas ≤6 cm [19]. Rao et al., in a retrospective analysis of LA with a transperitoneal lateral approach for pheochromocytoma and using a cut-off value of 4 cm, reported a longer operative time but this difference was not statistically significant [23]. In our study, subgroup analysis based on diagnosis did not show any statistically significant difference between the groups, not even in case of pheochromocytoma. Similarly, no important differences were observed in the comparisons between left and right LA.

Natkaniec et al. reported a statistically significant difference in conversion rates between patients with lesions ≥6 cm vs. < 6 cm in diameter, 6.7% and 0.5%, respectively (p < 0.0001) [15]. This contrasts with Hwang et al., who retrospectively analyzed 133 patients using a 5 cm cut-off value adrenal lesion size [24], and Carter et al. in their series of 26 pheochromocytoma patients using a cut-off value size of 6 cm [18] where no conversion to open surgery was reported. However, in our study, conversion rates of 9.8% and 4.9% were observed in the intervention and control groups, respectively; this difference, however, was not statistically significant (p = 0.3690). The reasons for these discrepancies are that large adrenal masses bleed more easily than smaller lesions; in fact four out of eight conversions in the intervention group were caused by bleeding. Moreover, at right-sided lesions, retrocaval adrenal gland growth can complicate dissection especially with the anterior approach. To the contrary, dissection with patient in lateral decubitus allows to directly visualize the retrocaval space. This might explain why six out of eight conversions were necessary during right adrenalectomy.

In terms of postoperative morbidity, Natkaniec et al. reported a higher complication rate in patients with lesions ≥6 cm (15.7%) compared to patients with lesions <6 cm (9.3%), with a trend toward statistical significance (p = 0.0692) [15]. Hobart et al. reported complication rates of 21.4% and 8.9%, respectively (p = 0.21) in a series of 14 patients [12] similar to our findings (p = 0.7196).

In accordance to others [18, 24], we found no statistically significant difference in mean hospital stay between the two groups (p = 0.1957). However, in contrast, Chen et al. found a statistically significant difference (7.43 days vs. 2.07 days, p = 0.001) in their observational study for patients with adrenal gland lesions measuring more or less than 5 cm, respectively [25].

Worldwide, most surgeons use the transperitoneal approach with patients positioned in lateral decubitus and the retroperitoneal approach with patients in the prone position [10, 13]. We prefer the anterior transperitoneal approach for right adrenalectomy and the anterior transperitoneal submesocolic approach for left adrenalectomy with patients positioned in the supine position [8,9,10]. To the best of our knowledge, the anterior approach is performed in very few centers around the world [9, 27,28,29,30,31]. This is in agreement with the lack of a clear superiority of one approach over the other in the literature [8,9,10, 13, 32], and the recommendations of the Society of American Gastrointestinal and Endoscopic Surgeons (SAGES) that suggest the surgeon should employ the surgical approach for LA with which he or she is most familiar [13].

Our study has several limitations including its retrospective nature, the lack of control groups with another approach (lateral or retroperitoneal) and the limited number of patients in each group that might have affected the statistical significance.

In conclusion, based on the present study, an adrenal gland lesion of 6 centimeters or more with no venous tumor thrombus is not a contraindication for a laparoscopic management, even in case of pheochromocytoma, provided the necessary experience in LA is present. Further prospective studies with a larger sample size and control groups based also on other minimally invasive approaches are necessary to confirm these data.