Most adrenal incidentalomas are nonfunctioning adrenal adenomas (NFA) without classical clinical signs and symptoms that are commonly observed with glucocorticoid hyper-secretion.¹ Subclinical Cushing syndrome (SCS) is also a common endocrine disease with an estimated incidence of approximately 20% in patients presenting with adrenal incidentalomas.² The 3 criteria commonly used to diagnose SCS are: (1) incidental detection of an adrenal adenoma using an imaging modality, (2) no clear phenotypic findings associated with Cushing syndrome, (3) subtle biochemical abnormalities such as adrenocorticotropic hormone (ACTH)-independent secretion of cortisol.³ Patients with SCS do not demonstrate the typical clinical signs and symptoms of Cushing syndrome (CS), and a majority may demonstrate nonspecific findings including hypertension, dyslipidemia, osteoporosis, and glucose intolerance.⁴

Although undeniably, adrenalectomy is the treatment of choice for the management of CS, optimal management of NFA and SCS remains a controversial issue with a lack of consensus in terms of conservative and/or surgical treatment.^2,5 Although a few patients presenting with NFA demonstrate mild elevation of cortisol secretion without any symptoms of overt CS, indicating a state of SCS, only a small percentage of patients with SCS progress toward the development of overt CS.⁶ Thus, the benefit of adrenalectomy for patients with NFA or SCS remains a controversial issue. A few authors have claimed that surgical therapy to treat these patients is associated with a higher risk of perioperative morbi-mortality than is observed with conservative therapy. However, a few others have reported that laparoscopic adrenalectomy (LA) is followed by normal-ization/improvement in the adverse metabolic profile noted in patients with NFA and SCS.^4,7,8

A number of small-scale studies have been performed in patients with either NFA or SCS; however, few studies have compared the effects of a LA directly in patients with NFA and SCS. We examined the perioperative outcomes of LA to determine its efficacy in patients with NFA and SCS, focusing on a comparison of the postoperative metabolic improvement observed between these groups.

Table 1 shows the baseline demographic data and perioperative outcomes. Additionally, the pathologic results of NFA are summarized in Supplementary Table 1. Patients with SCS showed a smaller median tumor size than those with NFA (2.5 cm [IQR, 2.1-3.5] vs. 5 cm [IQR, 3.5-7.0], respectively, p <0.001). The median operative time was shorter in patients with SCS than in those with NFA (90 minutes [IQR, 75-102] vs. 110 minutes [IQR, 97.5-132.5], respectively, p=0.002). Conversely, median duration of postoperative hospitalization was longer in patients with SCS compared to those with NFA (6 days [IQR, 5-7] vs. 4 days [IQR, 3-4.5]). However, there were no statistically significant differences observed with respect to other variables including age at the time of surgery, sex, tumor laterality and EBL between patients with SCS and NFA. Notably, patients with SCS compared to those with NFA demonstrated a higher occurrence of diabetes (29.5% vs. 11.4%, respectively), hypertension (59.1% vs. 34.3%, respectively), and dyslipidemia (43.2% vs. 14.3%, respectively) (Table 2). No statistically significant difference was observed in the occurrence of overweight (BMI ≥ 25 kg/m²) between the groups (Table 2).

Notably, there were no significant perioperative complications categorized as Clavien-Dindo classification grade III or higher in both groups of patients (those with SCS or NFA). Among 9 patients who demonstrated intraoperative complications, 4 demonstrated bleeding and 5 demonstrated an injury to the adjacent organs. Among those who demonstrated an injury to the adjacent organs such as the liver and/or spleen, 2 patients belonged to the SCS and 3 to the NFA group. Bleeding was successfully controlled with the use of electrocoagulation and absorbable hemostatic materials. Additionally, 2 post-operative complications were observed: 1 paralytic ileus and 1 acute kidney injury. These complications were successfully controlled by conservative management without an invasive intervention.

We assessed the postoperative metabolic profile (Table 3) in all patients to determine whether various metabolic abnormalities had been normalized/improved after performing the adrenalectomy. Patients with SCS showed significant post-operative improvement in hypertension (50.0% [13 of 26]), diabetes (53.9% [7 of 13]), dyslipidemia (31.6% [6 of 19]), and obesity (29.2% [7 of 24]). In contrast, patients with NFA showed a significant postoperative improvement only in dyslipidemia (40.0% [2 of 5]), and while only 1 patient with obesity (4.8%) showed improvement, no patient showed normal-ization/improvement in hypertension and diabetes in this group.

Given the variability in diagnostic criteria and optimal management of SCS, the most appropriate treatment for SCS patients remains a highly controversial issue,¹⁰ although a few studies provide evidence that surgical treatment may be associated with a positive effect on the long-term clinical and metabolic outcomes in patients with SCS.^11-15 However, the limitations of most studies cannot be ignored including multi-ple/diverse definitions of SCS, a high degree of variability in the definition of study endpoints and surgical outcomes, and uncontrolled study designs.² In this study, we reported that LA was an effective and safe treatment modality for the management of patients with SCS, particularly because it was not associated with any significant perioperative complications and patients demonstrated significant postoperative improvement in hypertension, diabetes, dyslipidemia, and overweight. However, LA was not associated with beneficial effects in patients with NFA. To our knowledge, ours is the first study assessing the outcomes of LA in Korean patients diagnosed with NFA and SCS, particularly with respect to a comparison of the outcomes of postoperative improvement in metabolic profile in these patients.

Similar to our findings, the first randomized controlled trial performed to study this subject reported that diabetes improved in 62.5% (5 of 8), hypertension in 67% (12 of 18), dyslipidemia in 37.5% (3 of 8), and obesity in 50% (3 of 6) in the surgical group, whereas some patients demonstrated worsening of diabetes and hypertension in the conservative treatment group.¹¹ Miyazato et al.¹² have shown that LA used for the management of patients with SCS demonstrated significant clinical efficacy in improving hypertension (66.7%), diabetes (47.1%), and dyslipidemia (20.0%). Iacobone et al.⁸ have demonstrated efficacy of LA in inducing remission of hormonal abnormalities and improvement of blood pressure, glycemic control, body weight, and health-related quality of life in patients with SCS. Chiodini et al.¹⁶ have reported that adrenalectomy was more beneficial for patients with SCS compared to conservative management, particularly in those with nonsecreting adenomas measuring >4 cm in diameter or those with a >1-cm increase in size of the mass noted during surveillance.

In contrast to these findings, the Semmelweis University group analyzed 125 patients with NFA, and clearly noted that surgical treatment failed to normalize or improve the abnormal metabolic profile observed in these patients.⁵ They also indicated that adrenalectomy did not reduce the rates of athero-sclerosis-related morbi-mortality in patients with NFA.⁵ Furthermore, an adrenalectomy was observed to be associated with a risk of postoperative adrenal insufficiency of the adrenal remnant, requiring cortisol replacement therapy.¹⁷ A recent systematic review of 28 selected papers described that post-operative adrenal insufficiency was observed in 65.3% among 248 patients with SCS.¹⁸

Interestingly, no mortality was observed and only minor perioperative complications were observed in patients with either SCS or NFA in our study. These results are in agreement with those of previous studies. Alesina et al.¹⁴ have reported a study showing a 0 mortality rate and no major intraoperative complications associated with an adrenalectomy. They reported only minor postoperative complications including segmental relaxation of the abdominal wall (n=4) and hematoma formation (n=1), which were successfully managed conservatively.¹⁴ Raffaelli et al.¹⁵ have also demonstrated that only 2 of 29 patients with SCS showed Clavien-Dindo classification grade II complications (1 patient with superficial phlebitis and 1 with postoperative pneumonia) following an adrenalectomy. To summarize, we reckon that LA is a feasible, safe and clinically effective method to treat patients with SCS and is associated with a low perioperative complication and 0 mortality rate.

Our study has some limitations: (1) Our study was a retrospective study; therefore, an unavoidable bias such as selection bias, missing clinical data, and potential misclassification of enrolled patients could have affected our results. (2) Our study included a small number of patients, and we used only a single tertiary center database. Further studies need to be planned using a multicenter database for conclusive validation of our findings. (3) The median follow-up duration was only 12 months (IQR, 6-27) and 5 months (IQR, 1-10) in patients with SCS and NFA, respectively. Therefore, long-term outcomes of LA could not be evaluated in these patients.

In summary, our results demonstrated that LA was an effective and safe option to treat patients with SCS, particularly because it was associated with no significant perioperative complications and significant postoperative improvement in metabolic abnormalities such as hypertension, diabetes, dyslipidemia and obesity. However, LA was not observed to show beneficial effects in correcting/improving the metabolic profile in patients presenting with NFA. Our study offers valuable information to determine an optimal therapeutic strategy for the management of patients with SCS or NFA who present with metabolic manifestations.