Society for Endocrinology
Improved and individualized approach to adrenal surgery
Tobias Carling® and Meredith LaRue
Carling Adrenal Center and Department of Surgery, Hospital for Endocrine Surgery, Tampa, Florida, USA
Correspondence should be addressed to T Carling: tcarling@adrenal.com
Abstract
Adrenal surgery has undergone significant advancements, driven by technological innovations, enhanced surgical techniques, and a deeper understanding of adrenal gland pathophysiology. This review highlights the transition toward modern, individualized adrenal surgery, emphasizing minimally invasive techniques, precision medicine, and the development of specialized centers performing more than 500 adrenalectomies a year. Minimally invasive adrenalectomy, specifically the mini back scope adrenalectomy (MBSA, also known as posterior retroperitoneoscopic adrenalectomy), has become the standard of care for most adrenal pathologies, enabling precise function-preserving (partial) adrenalectomy, and offering reduced morbidity, shorter hospital stays, and faster recovery compared to open and transabdominal surgery, whether robotic or laparoscopic. Molecular pathology and enhanced imaging modalities have improved preoperative planning and intraoperative decision-making, allowing for precise tumor localization and preservation of adrenal function. Molecular profiling of adrenal tumors has provided insights into tumor behavior, enabling tailored surgical approaches. In addition, multidisciplinary collaboration has been crucial in developing comprehensive treatment strategies, particularly for complex cases such as familial pheochromocytomas, equivocal unilateral and bilateral primary hyperaldosteronism, and ACTH-independent adrenal hypercortisolism due to bilateral adrenal lesions, adrenocortical carcinoma, and metastatic adrenal disease. Patient-specific factors, including genetic predispositions and comorbidities, are increasingly considered to optimize surgical outcomes and personalize postoperative care. As we enter this improved and individualized era of adrenal surgery, ongoing research and technological advancements are expected to continue to enhance patient outcomes and expand the indications for adrenal surgery.
Keywords: adrenal surgery; adrenalectomy; function-preserving; partial adrenalectomy; hyperaldosteronism; Conn’s syndrome; hypercortisolism; Cushing’s syndrome; mild autonomous cortisol secretion; pheochromocytoma
Introduction
Adrenal surgery has undergone significant advancements in recent years, driven by technological innovations, enhanced surgical techniques, and a deeper understanding of adrenal gland pathophysiology. Despite these advances, adrenal tumor disease remains highly underdiagnosed and undertreated, especially when it comes to aldosterone- and cortisol-producing adrenal lesions (Starker et al. 2014, Hundemer & Vaidya 2020). The use of adrenalectomy has increased in the United States (Saunders et al. 2004) and is likely to
continue to do so given that currently only a fraction of patients with potentially curative adrenal endocrinopathies (again, mainly aldosterone- and cortisol-producing adrenal lesions) are diagnosed and referred for adrenal surgery (Huang et al. 2022). The relationship between operative volume and perioperative outcomes after several operations (including endocrine surgery) is well documented (Kazaure & Sosa 2019). Recent studies on adrenalectomy reveal a robust association between higher surgeon volume and improved patient outcomes
(Park et al. 2009). Studies have demonstrated that outcomes are improved when surgeons perform at least six adrenalectomies annually. Based on this threshold definition of a high-volume surgeon, more than 80% of adrenalectomies in the United States are performed by low-volume surgeons. Naturally, performing only six adrenalectomies per year is not regarded as truly high-volume, but there is a dearth of true high-volume adrenal surgeons, those performing at least 100 adrenal operations annually, both in the United States and worldwide (Carling 2010, Vrielink et al. 2018, Mihai et al. 2019).
Minimally invasive adrenalectomy, specifically the mini back scope adrenalectomy (MBSA, also known as posterior retroperitoneoscopic adrenalectomy (PRA)), has become the standard of care for most adrenal pathologies, enabling precise function-preserving (partial) resections and offering reduced morbidity, shorter hospital stays, and faster recovery compared to open and transabdominal surgery, whether robotic or laparoscopic (Walz 2004, Alesina et al. 2010, 2022, 2024, Carling 2010). Furthermore, centers and hospitals entirely dedicated to adrenal and endocrine tumor disease have been developed, enabling efficient and superiorly high-volume surgical care. One such center is the Carling Adrenal Center, established in January 2020. Since January 2022, it has provided all its surgical care at the subspecialty Hospital for Endocrine Surgery (HFES) in Tampa, FL, where over 60% of patients come from outside Florida. The value and need for centers and hospitals focusing on adrenal tumor disease is exemplified by the rapid growth in patients being referred for evaluation. Figure 1A depicts the number of new adrenal intake patients per week referred to the Carling Adrenal Center over a 30-month period (January 1, 2022 to June 30, 2024), whereas Figure 1B and 1C demonstrate the preoperative indications and final pathological diagnosis of consecutive patients undergoing adrenalectomy (n = 1,032 adrenalectomies over the same 30-month period), respectively.
Molecular pathology and enhanced imaging modalities have also improved preoperative planning and intraoperative decision-making, allowing for precise tumor localization and preservation of adrenal function. Molecular profiling of adrenal tumors has provided insights into tumor behavior, enabling tailored surgical approaches (Ono et al. 2020, Mete et al. 2022). This review highlights some of the important advancements leading to improved and individualized approaches to adrenal surgery.
Surgical approaches to adrenalectomy
There are four major surgical approaches to adrenalectomy: the mini back scope adrenalectomy (MBSA, also known as PRA), laparoscopic
transabdominal adrenalectomy (LTA), robotic laparoscopic transabdominal adrenalectomy (RLTA), and open standard transabdominal adrenalectomy (Table 1). Of note, open adrenalectomy can be performed through thoracoabdominal, posterior, and retroperitoneal approaches, all of which are currently uncommon. In addition, a variant of LTA includes the use of a hand-port, often employed for larger tumors (>7-12 cm), tumors that are suspected or known to be malignant, or large pheochromocytomas when an open standard transabdominal adrenalectomy is not required. In addition, the lateral retroperitoneoscopic approach (LPRA) is an alternative to MBSA (PRA) and is commonly used by urologists familiar with performing partial nephrectomies. All approaches have their advantages and disadvantages (Table 1), but the most minimally invasive approach is the MBSA, whereas the open, standard transabdominal adrenalectomy is maximally invasive.
At the Carling Adrenal Center, the MBSA is the preferred technique in more than 95% of adrenal surgery cases. The operation is performed with an endoscope through three small incisions in the patient’s flank. Because the operation is performed exclusively in the retroperitoneum, avoiding the intra-abdominal space required by all other techniques, it allows direct access to the adrenal gland (Walz 2004, Alesina et al. 2010, 2022, 2024, Carling 2010). The direct access minimizes the need for mobilization and dissection of surrounding structures, unlike transabdominal approaches, which require manipulation of surrounding structures such as the liver, spleen, pancreas, bowel, and major vessels such as the inferior vena cava (IVC). While the MBSA avoids mobilization of intraperitoneal organs, it requires retroperitoneal kidney mobilization, particularly of the upper pole, to access the adrenal gland. A robot-assisted approach may reduce the extent of kidney mobilization, whereas the LTA involves minimal kidney mobilization, typically limited to the medial/cranial side of the kidney capsule. The overall reduced mobilization and dissection of tissues associated with the MBSA leads to shorter operative times (typically <15-20 min of operative time from incision to closure in experienced hands) and anesthesia duration, quicker recovery, less pain, and excellent cosmetic outcomes (Walz 2004, Alesina et al. 2010, 2022, 2024, Carling 2010). Furthermore, the MBSA is ideal for function-preserving (partial) adrenal surgery since it gives superior visualization and accessibility to the adrenal gland and its fine vessels compared to all other adrenalectomy approaches (Knyazeva et al. 2025). Transabdominal approaches require dissection of the intra-abdominal fat, which, especially in obese individuals, may obscure the fine vasculature to the adrenal gland. The MBSA is also ideal for bilateral surgery, as it eliminates the need to reposition the patient between sides and is the most cost-effective surgical approach. Another advantage is that the surgeon does not need to enter the intra-abdominal
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Forecast
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B
1%
Subclinical Cushing’s syndrome
1%
2%
Primary Hyperaldosteronism
2%
5%
Atypical Imaging Phenotype
10%
41%
Pheochromocytoma
16%
Other
Adrenal Metastasis
22%
Hyperaldosteronism/Hypercortisolism
Overt Cushing’s syndrome
Adrenocortical carcinoma
C
Cort-CPA
Cort-BMaNAD
Cort-BMiNAD
1%
4%
Aldo-APA
1%
9%
3%
29%
Aldo-MAPM
2%
Aldo-APN
1%
3%
Aldo-APDH
9%
Pheochromocytoma
Adrenocortical Carcinoma
4%
11%
1%
7%
12%
3%
Myelolipoma
Adrenal Metastasis
NF-Adenoma
NF-SNAD
Adrenal cystic lesions
Ganglioneuroma
Other
cavity. This means that even for patients with previous abdominal operations, the surgeon does not need to deal with adhesions. Intra-abdominal scars (adhesions) may result from previous operations such as bariatric surgery (gastric band, sleeve gastrectomy, gastric bypass),
gallbladder surgery (cholecystectomy), liver surgery, stomach surgery, bowel surgery of any kind (e.g., colectomy, appendectomy), or any previous kind of gynecological operation (e.g., Cesarean section, hysterectomy).
| Surgical feature | MBSA | LTA | RLTA | Open |
|---|---|---|---|---|
| Direct access to the adrenal | +++ | + | + | + |
| Operative time | +++ | ++ | + | + |
| Anesthesia time | +++ | ++ | + | + |
| Amount of dissection | +++ | + | + | + |
| Suitability in those with prior intra-abdominal surgery | +++ | + | + | + |
| Function-preserving (partial) adrenal surgery | +++ | ++ | ++ | ++ |
| Recovery time | +++ | ++ | ++ | + |
| Postoperative pain | +++ | ++ | ++ | + |
| Cosmetic outcome | +++ | ++ | ++ | + |
| Cost efficiency | +++ | ++ | + | ++ |
| Tumors >9-12 cm | +/- | + | + | +++ |
| Tumors invading other organs or major vessels | - | - | - | +++ |
| Patient BMI >40-45 kg/m2 | + | + | + | + |
| Familiarity for low-volume adrenal surgeons | + | ++ | ++ | ++ |
The various surgical approaches are graded based on their unique features from superior (+++), reasonable (++), inferior (+), and should be avoided (-). MBSA, mini back scope adrenalectomy (also known as posterior retroperitoneoscopic adrenalectomy; PRA); LTA, laparoscopic transabdominal adrenalectomy; RLTA, robotic laparoscopic transabdominal adrenalectomy and open adrenalectomy.
The major disadvantages with the MBSA are that the working space is smaller, providing less operative room for large tumors (>7-12 cm), and that the learning curve for surgeons seems to be more significant (Carling 2010, Vrielink et al. 2018, Mihai et al. 2019). In patients with body mass index (BMI) ≥35 kg/m2, the smaller working space in MBSA can pose challenges, as noted by Barczynski et al. who suggest BMI <35 kg/m2 as suitable for the approach (Barczyński et al. 2014). At the Carling Adrenal Center, a substantial proportion of patients undergoing successful MBSA have a BMI ≥35 kg/m2. As discussed below, patients with severe obesity (BMI >40-45 kg/m2) usually benefit from preoperative weight loss management, since transabdominal adrenalectomy approaches are typically equally challenging in this cohort of patients.
In general, low-volume adrenal surgeons are less familiar with retroperitoneal anatomy and the smaller working space compared to transabdominal surgery. The primary reason the MBSA is not more widely available to patients in the United States is that most adrenal surgeries are performed by low-volume surgeons (Kazaure & Sosa 2019, Chiu et al. 2021).
The LTA approach is performed with the patient in the lateral position, with three to four surgical ports, and is the most commonly used minimally invasive adrenalectomy approach performed by surgeons in the United States, especially among general surgeons. Compared to the MBSA, the dissection and mobilization are much more extensive to obtain exposure of the retroperitoneal space, which harbors the adrenal glands. Naturally, this leads to longer operative times, slower recoveries, and increased discomfort. Hand-port-assisted LTA is beneficial for larger tumors (>7-12 cm) and tumors that are suspected or known to be malignant or very large pheochromocytomas, in cases
where an open standard transabdominal adrenalectomy is not required. The robotic LTA is a similar approach but uses a surgical robot system and larger ports with bigger incisions. The operative (typically two to four hours) and anesthesia times for RLTA are the greatest, and the approach is the least cost-effective, but may provide some benefits for surgeons not familiar with endoscopic surgery (Greilsamer et al. 2019, Isiktas et al. 2024). Open standard transabdominal adrenalectomy currently is primarily used for large tumors (>9-12 cm) and tumors suspected or known to be malignant, particularly when they invade surrounding structures such as the kidney, liver, spleen, pancreas, bowel, or major vessels such as the IVC. In such cases, where an en bloc resection for suspected or known adrenocortical carcinoma is required, an open approach is often needed (Glenn et al. 2019).
In addition to tumor size and locoregional invasion, morbid obesity is the most common factor that makes adrenal surgery challenging, regardless of the surgical approach. The adrenal gland is located in the retroperitoneal fat pad, and morbid obesity is associated with both enhanced retroperitoneal and subcutaneous fat. One study demonstrated that a BMI ≥30 kg/m2 was associated with the need for intraoperative conversion from laparoscopic to open adrenalectomy (Vidal et al. 2020), whereas another demonstrated that obesity BMI ≥28 kg/m2 exerts a significant influence on surgical outcomes, particularly with regard to operative time and intraoperative blood loss (Zhao et al. 2024). In the context of practicing in the United States, patients with BMI of less than 30 kg/m2 would typically be regarded as being on the slender side and would not provide a surgical challenge. However, once the BMI is >40-45 kg/m2, adrenalectomy can become significantly more challenging due to the lack of working space and significant torque on the instruments. To quantify the
retroperitoneal and subcutaneous fat, we developed the Carling Adiposity Index (CAI), measured as the distance from the skin surface to the center of the adrenal gland (tumor; Fig. 2). In patients with a BMI >40-45 kg/m2 and/or a CAI >150 mm, adrenalectomy may need to be postponed in favor of medically supervised weight loss approaches, which can include pharmaceutical or surgical options. Gender differences also exist in the retroperitoneal anatomy; men more frequently exhibit adherent perinephric fat, so-called ‘sticky fať, which can hinder kidney mobilization and isolation of the tumor. In addition, men tend to have a greater volume of
retroperitoneal fatty tissue (Alesina & Walz 2020). Beyond the CAI, other preoperative tools such as nomograms and radiological measurement systems have been developed to estimate the complexity of MBSA, aiding in surgical planning (van Uitert et al. 2022).
Function-preserving (partial) adrenalectomy
Total, unilateral adrenalectomy is often the only surgical option offered to patients, even at major university-based
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hospital systems. However, the interest in function- preserving (partial) adrenalectomy has steadily increased over the past two decades. Since most adrenal pathologies are benign, and there is always a possibility of development of a contralateral adrenal tumor, function-preserving surgery is very attractive for patients and physicians alike to minimize the risk of adrenal insufficiency. It has been well established in both animal models and humans that preserving about 30% of one adrenal gland is function-preserving and does not lead to adrenal insufficiency (Walz et al. 2004, Alesina et al. 2022). The key to successful partial adrenalectomy is to preserve sufficient normal adrenal cortex tissue (again, at least 30% of one adrenal gland, or 15% of both glands) and simultaneously not compromise the surgical resection margin. The MBSA approach is particularly well suited for function-preserving (partial) adrenalectomy compared to other techniques (open, laparoscopic, and robotic transabdominal), since it provides direct access and better visualization of the adrenal gland and its fine but numerous supplying vessels (Knyazeva et al. 2025). Furthermore, a precondition for successful partial adrenal surgery is special knowledge of the retroperitoneal anatomy and surgical technique (Fig. 3). Adrenal glands are perfused from medial, inferior, and cranial directions, but not from the lateral. Therefore, any remaining tissue in situ must retain intact perfusion, necessitating precise and gentle
dissection of the numerous small adrenal arteries and veins. Thus, the adrenal tissue can be dissected from any direction, so long as it preserves at least one line of perfusion. The preservation of the main vein is not mandatory. Planning of cortical-sparing procedures is based on a detailed analysis of preoperative imaging in order to understand the position and size of the tumor within the gland (Alesina et al. 2022). Some authors suggest that intraoperative imaging with endoscopic ultrasound is a valuable tool for defining the surgical plane during partial adrenalectomy, ensuring function preservation while minimizing the risk of leaving functional benign tumor tissue behind. In our practice, we have not found it useful since patients undergo a high- resolution modified adrenal CT scan the day of surgery, which provides excellent anatomical detail.
In general, there are six major considerations when offering a patient function-preserving (partial) adrenalectomy. The indications and feasibility of the operation are dependent on: i) the tumor type (functional status and which hormones are overproduced), ii) risk of malignancy, iii) the size of the tumor and its relationship to the adrenal vein, surrounding organs, and major vessels such as the IVC, iv) whether there is sufficient adjacent normal tissue present to preserve, v) amount of retroperitoneal fat and its nature, since massive amounts or ‘sticky’, inflamed fat may obscure anatomical landmarks and
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may make the visualization of vessel perfusion more challenging, and vi) expertise of the surgeon, since performing function-preserving (partial) adrenalectomy is an operation more technically advanced than routine total adrenalectomy.
Improved, individualized surgical approach to primary hyperaldosteronism (PA)
Most aldosterone-producing lesions causing PA (Conn’s syndrome) are monoclonal tumors with recently defined tumor-specific somatic mutations in genes encoding mainly potassium and voltage-gated calcium channels, leading to cell proliferation and aldosterone hypersecretion (Choi et al. 2011, Scholl et al. 2013, 2015, Mete et al. 2022). Pathologically, these aldosterone-producing lesions include aldosterone- producing adrenocortical carcinoma (APACC), aldosterone-producing adenoma (APA, >1 cm), aldosterone-producing nodule (APN, <1 cm), aldosterone-producing micronodule (APM, <1 cm and visible on CYP11B2; aldosterone synthase staining; formerly known as aldosterone-producing cell cluster), multiple aldosterone-producing nodule and micronodule (MAPN/MAPM), and aldosterone-producing diffuse hyperplasia (APDH; Fig. 4) (Mete et al. 2022).
The only curative therapy for PA is surgical resection of the aldosterone-producing cells/tumor via adrenalectomy. Once the diagnosis of PA has been established, preoperative cross-sectional imaging (CSI), typically with CT or MRI, is performed for PA subtype classification, surgical planning, and determination of whether adrenal vein sampling (AVS) is needed. The role of AVS in PA subtype classification remains controversial and is still evolving, with some centers using it routinely and others selectively (Funder et al. 2016, Turcu & Auchus 2021). The major disadvantage with AVS is that it is an invasive and technically challenging procedure. In the United States, the study is mainly performed by low-volume interventional radiologists, which frequently leads to failure to obtain adequate samples (especially from the right adrenal vein), lost samples, or inability to accurately interpret the findings. One study from Germany demonstrated success rates as low as 8-10% at low-volume centers (Vonend et al. 2011). Numerous patients lack access to AVS or have failed AVS, which leads to denial of putative curative adrenalectomy (Buffolo et al. 2017, Turcu & Auchus 2021). In addition, the only randomized controlled trial comparing CT-based versus AVS-based management of PA failed to show superiority in patients undergoing AVS when it came to postoperative outcomes, where the primary endpoint was intensity of medical management needed to achieve a target blood pressure at 1 year after adrenalectomy
| Preoperative PA Subtype | Surgical options | ||
|---|---|---|---|
| CSI, +/- AVS | Conservative | Aggressive | |
| APACC | |||
| APA | or | ||
| Bi-APA | or | ||
| APN | or | ||
| APM | or | ||
| MAPN /MAPM | or | ||
| APDH | RIGHT LEFT | or | |
Figure 4
Suggested rational approach to the surgical management of various subtypes of PA. Once the diagnosis of PA has been established, preoperative subtype classification is performed after CSI (typically CT- or MRI-based), which may include the use of AVS, especially in the setting of negative CSI or bilateral lesions. The surgical options may range from conservative to aggressive depending on whether a partial (function- preserving) approach is used, and the surgical extent and percentage of total adrenal cell mass left in situ. The X represents the resected tissue. For patients with bilateral lesions, unilateral surgery may be performed initially, followed by a postoperative subtype classification, determined based on CYP11B2 staining, tumor genetic studies, postoperative biochemical indices, and clinical response. Additional contralateral, partial (function-preserving) adrenalectomy would be performed based on the postoperative PA subtype classification. Primary hyperaldosteronism (PA), Cross sectional imaging (CSI), adrenal vein sampling (AVS), aldosterone-producing adrenocortical carcinoma (APACC), aldosterone-producing adenoma (APA), bilateral aldosterone- producing adenoma (Bi-APA), aldosterone-producing nodule (APN), aldosterone-producing micronodule (APM), multiple aldosterone- producing nodule (MAPN), multiple aldosterone-producing micronodule (MAPM), aldosterone-producing diffuse hyperplasia (APDH).
(Dekkers et al. 2016). Several aspects of this SPARTACUS trial remain controversial, however (Beuschlein et al. 2017). The role of functional PET imaging (primarily using 11C-metomidate or 68Ga-Pentixafor) in PA subtype classification is of great interest (Chaman Baz et al. 2022, Wu et al. 2023). Although not yet widely available, it represents a promising non- invasive alternative to AVS.
When total unilateral adrenalectomy is the only available surgical approach, effective management of PA relies heavily on preoperative adjuncts such as AVS to ensure operating on the ‘correct’ side (Funder et al. 2016, Turcu & Auchus 2021). However, with the increased availability of function-preserving adrenalectomy (such as tumor enucleation, uni- and bilateral, partial, and subtotal adrenal resections) and postoperative subtype classification using CYP11B2 (aldosterone synthase) staining of resected specimens with or without genetic evaluation, the role of AVS is less critical. This approach helps avoid adrenal
insufficiency even in patients with bilateral aldosterone- producing lesions. At the Carling Adrenal Center, we use an improved, individualized approach to AVS, which factors in the patient’s geographic location and demographics; the biochemical, clinical, and radiological findings; as well as the patient’s desire for uni- and bilateral function-preserving (partial) adrenalectomy. In general, we recommend AVS for patients where CSI is negative, bilateral tumors, an equivocal biochemical diagnosis of PA, or when specifically requested by the patient. Conversely, patients with an unequivocal unilateral adrenal tumor on CSI, especially women (higher likelihood of KCNJ5 mutant tumors), those of young age, and overt biochemical indices of PA, may undergo adrenalectomy without AVS (Ip et al. 2015, Scholl et al. 2015, Meyer et al. 2021, Azizan et al. 2023).
Based on the preoperative PA subtype classification using CSI with or without AVS, the surgical options range from conservative (more adrenal cell mass remains in situ) to aggressive (less adrenal cell mass remains in situ; Fig. 4). Theoretically, an aggressive approach would lead to a higher cure rate and less risk of recurrence, but presents a greater risk of adrenal insufficiency, and vice versa. The surgical option for an APACC would obviously be a total unilateral (en bloc) adrenalectomy, but the options for unilateral APA could be unilateral function-preserving (partial, or enucleation; conservative) adrenalectomy or total unilateral adrenalectomy (aggressive). Similar options exist for the other PA subtypes as outlined in Fig. 4. Again, the key to successful function-preserving adrenalectomy is to preserve sufficient normal adrenal cortex tissue and its perfusion (at least 30% of one adrenal gland, or 15% of both glands). The decision to perform a function-preserving (partial) adrenalectomy in PA should be thoughtful and individualized, realizing that lesions staining positive for CYP11B2, and thus indicating aldosterone hypersecretion, may be numerous even in the presence of a dominant APA. Thus, some authors caution that such an approach may be associated with a higher rate of incomplete cure after adrenalectomy (van de Wiel et al. 2021). At the Carling Adrenal Center, we tend to use a more aggressive surgical approach when operating on the index adrenal gland, which allows for complete postoperative pathological subtype classification using CYP11B2 staining and biochemical evaluation, whereas a function-preserving (partial) adrenalectomy is used on the contralateral gland, if needed.
The role of adrenalectomy in APDH (formerly known as bilateral hyperplasia) is of great interest, evolving, and somewhat controversial. It is not controversial that unilateral adrenalectomy for unilateral PA (typically defined based on CSI and AVS) has better outcomes, both clinically and biochemically, than unilateral adrenalectomy for bilateral PA (Williams et al. 2017, Meyer et al. 2021). However, there is increasing evidence that unilateral or bilateral (function-preserving) adrenalectomy, even in bilateral
PA, may be superior to medical management, at least in selected patients (Williams et al. 2022). Patients in a recent international retrospective cohort study had undergone AVS demonstrating bilateral disease, followed by either unilateral total adrenalectomy or bilateral (function-preserving) adrenalectomy. In patients undergoing unilateral or bilateral (function-preserving) adrenalectomy (n = 56 patients), a complete biochemical cure was obtained in 65 and 85% of the cases, respectively, and only one patient had evidence of long-term adrenal insufficiency requiring glucocorticoid supplementation after bilateral surgery (total adrenalectomy on one side and partial adrenalectomy on the other) (Williams et al. 2022). These findings are consistent with those of the Carling Adrenal Center, which include 224 adrenalectomies for PA over 30 months (January 2022 to June 2024; Fig. 1B), except we have yet to have a single patient requiring long- term glucocorticoid supplementation. Thus, these novel data challenge the current dogma of routine medical management of patients with bilateral aldosterone hypersecretion.
It has not been well studied whether performing bilateral (function-preserving) adrenalectomy simultaneously or in a staged fashion is superior. However, at the Carling Adrenal Center, we typically prefer to perform these operations for PA in a staged fashion, since initial unilateral adrenalectomy allows for postoperative subtype classification based on CYP11B2 staining, tumor genetic studies, postoperative biochemical indices, and clinical response. Additional contralateral function-preserving (partial) adrenalectomy would then be performed based on the postoperative PA subtype classification, typically at least 6 weeks after the index operation. We believe this approach minimizes the risk for adrenal insufficiency and avoids unnecessary surgery in patients with an excellent response to initial unilateral adrenalectomy.
Improved, individualized surgical approach to cortisol-producing lesions
ACTH-independent hypercortisolism and adrenal Cushing’s syndrome may be subclinical (also known as mild autonomous cortisol secretion; MACS) or overt, and is due to uni- or bilateral cortisol-producing lesions. Similar to PA, adrenalectomy is the only curative treatment, whether the clinical presentation is subclinical or overt. Pathologically, the benign lesions causing cortisol hypersecretion are classified as cortisol-producing adenoma (CPA), bilateral macronodular adrenocortical disease (BMaNAD: multiple nodules size >1 cm), and bilateral micronodular adrenocortical disease (BMiNAD; multiple nodules size <1 cm; Fig. 1) (Mete et al. 2022).
Cortisol-producing adrenocortical carcinoma (CPACC) represents approximately 50% of all ACC and typically presents with overt Cushing’s syndrome, although a subclinical manifestation is occasionally seen (Lebastchi et al. 2012).
The distinction between benign subclinical (MACS) and overt disease (typically more rapid onset, more severe biochemical abnormalities, and the classical signs and symptoms of Cushing’s syndrome) may seem arbitrary and unnecessary since the ultimate treatment (adrenalectomy) is the same (Starker et al. 2014). Nonetheless, the entities are distinct both clinically and genetically, since tumor-specific mutations in the PRKACA gene, causing cell proliferation and cortisol hypersecretion, occur exclusively in adrenal adenomas causing overt, severe Cushing’s syndrome (Beuschlein et al. 2014, Goh et al. 2014). Certainly, subclinical Cushing’s syndrome (MACS) is by far the most common manifestation of adrenal cortisol hypersecretion, accounting for 41% of the 1,032 adrenalectomies performed at the Carling Adrenal Center over a 30-month period. By contrast, overt, severe Cushing’s syndrome due to CPA and ACC represented 1% of all cases, respectively (Fig. 1).
It is uncontroversial that adrenalectomy should be offered to all patients with overt, severe adrenal Cushing’s syndrome, whether benign or malignant, whenever feasible. Given that subclinical Cushing’s syndrome (MACS) is associated with cardiovascular morbidity, neurocognitive symptoms, frailty, fragility fractures, decreased quality of life, and increased mortality, the use of adrenalectomy to reverse these effects of hypercortisolism is becoming increasingly attractive for patients and physicians alike (Prete & Bancos 2024).
With the increased availability of function-preserving adrenalectomy (such as tumor enucleation, uni- and bilateral, partial, and subtotal adrenal resections), there are enhanced options for resecting the cortisol-producing cells/tumor (whether uni- or bilateral), while preserving normal (or mostly normal) adjacent adrenal tissue, avoiding adrenal insufficiency. Similar to resecting PA adrenal lesions, the surgical options range from conservative (more adrenal cell mass remains in situ) to aggressive (less adrenal cell mass remains in situ; Fig. 4). Theoretically, an aggressive approach would lead to a higher cure rate and less risk of recurrence, but a greater risk of adrenal insufficiency, and vice versa (Alesina et al. 2022). One study recently compared patients with unilateral Cushing’s syndrome (overt, n = 124 and subclinical, n = 17) treated with either partial or total unilateral adrenalectomy. The authors demonstrated a shorter duration of corticosteroid therapy and fewer patients requiring such therapy >2 years (4 vs 25%) for those with a function- preserving adrenal operation (Alesina et al. 2024). This suggests that even in patients undergoing solely
unilateral adrenal surgery, preserving adrenal cell mass is beneficial in the setting of adrenal hypercortisolism. Recurrent ipsilateral disease occurred in one case after partial adrenalectomy and was treated by completion adrenalectomy.
For patients with bilateral lesions (BMaNAD and BMiNAD), there are three different operative strategies: bilateral total adrenalectomy, unilateral adrenalectomy guided by the size of the glands or result of AVS, and function-preserving (partial) bilateral adrenalectomy. Various function-preserving (partial) adrenalectomy approaches were used in two studies of patients with bilateral ACTH-independent Cushing’s syndrome, demonstrating overall cure rates of 92-98%, with low rates of both recurrence and long-term need for steroid hormone replacement (He et al. 2012, Lowery et al. 2017). During a 30-month period (January 2022 to June 2024), the Carling Adrenal Center performed 444 adrenalectomies on patients for subclinical and overt Cushing’s syndrome, and 66.4% displayed unilateral, whereas 33.6% had bilateral lesions (Fig. 1).
It should be mentioned that we do not advocate for AVS in the setting of adrenal hypercortisolism. Some authors use AVS as a guide to remove the most hormonally active side in patients with bilateral adrenal lesions overproducing cortisol, since total unilateral adrenalectomy may be the only surgical option available (Ueland et al. 2018, Johnson et al. 2023). Since excess cortisol is still produced by the contralateral adrenal lesion(s), bilateral function- preserving adrenalectomy is favored at the Carling Adrenal Center. Similar to PA patients, performing the operation in a staged fashion is often preferable, allowing for the unilateral remnant to recover - typically for at least 6 weeks - before contralateral function-preserving (partial) adrenalectomy. We believe this approach reduces the risk of long-term adrenal insufficiency and the need for even transient glucocorticoid replacement therapy.
In general, we prefer function-preserving adrenalectomy approaches for most patients with benign, cortisol- producing lesions, whether uni- or bilateral. Although not well studied, bilateral total adrenalectomy rendering the patient adrenally insufficient may be preferable in patients with a genetic cause of bilateral ACTH-independent Cushing’s syndrome, especially in those with severe hypercortisolism (Powell et al. 2008, Cavalcante et al. 2022).
Similar to the operative approach, our approach to glucocorticoid replacement is more tailored and individual than currently published practice guidelines (Yip et al. 2022, Fassnacht et al. 2023). For instance, perioperative glucocorticoid treatment at surgical stress doses is not used in all patients, but rather only for those with severe, overt Cushing’s syndrome or those undergoing bilateral total adrenalectomy (for instance, ACTH-dependent Cushing’s syndrome patients who have failed pituitary therapies), which comprise less than 2%
of patients (Fig. 1). All other patients (regardless of preoperative indications) are subject to a cosyntropin stimulation test at 04:00 h following adrenalectomy (DeLozier et al. 2022). Evaluation of cortisol at baseline and at 30 and 60 min following administration, respectively, leads to improved identification of patients at risk for adrenal insufficiency and avoids unnecessary glucocorticoid overtreatment in numerous patients.
Improved, individualized surgical approach to pheochromocytoma
The surgical management of pheochromocytoma is typically straightforward, uncontroversial, and frequently includes function-preserving adrenalectomy approaches (such as tumor enucleation, uni- and bilateral, partial, and subtotal adrenal resections) (Lenders et al. 2014). Once the diagnosis of pheochromocytoma has been established by biochemical evaluation and CSI, many providers prepare the patient preoperatively for 1 to 2 weeks, typically with an alpha-blocker and hydration. In the modern era of adrenal surgery, where a typical pheochromocytoma often can be resected in less than 20-30 min, especially with the MBSA approach and using an expert anesthesia team, preoperative blockade is less critical. In fact, many authors advocate for a selective use of preoperative blockade (Isaacs & Lee 2017, Holscher et al. 2024). In the 104 patients undergoing adrenalectomy for pheochromocytoma during a 30-month period (January 2022 to June 2024), preoperative blockade was used selectively and typically included those already started on therapy by their referring physician or those with catecholamine levels five times the upper normal range (Fig. 1). This strategy resulted in no cardiovascular events (e.g., stroke, myocardial infarction, and arrhythmia), no intensive care unit (ICU) admissions, or mortality.
Function-preserving (cortical-sparing) adrenalectomy is particularly well-suited for the treatment of pheochromocytoma, given that there is i) significant risk of bilateral disease due to the high prevalence of genetic mutations associated with any of the known tumor-susceptibility syndromes causing pheochromocytoma, and ii) the distinct colorization of a pheochromocytoma vis-a-vis the surrounding adrenal cortex, making function-preserving adrenalectomy less challenging compared to operating on tumors of adrenocortical origin. The main consideration when performing function-preserving adrenalectomy, especially in hereditary pheochromocytoma, is the possible development of recurrent disease that needs to be weighed against avoidance of lifelong steroid therapy (Rossitti et al. 2018). Data from an international registry including a total of 625 patients with bilateral tumors show that partial adrenalectomy was performed for
smaller tumors compared to total adrenalectomy (3 vs 3.5 cm) and more often since 2010 (Neumann et al. 2019). This seems to be correlated with the enhanced use of minimally invasive techniques, which allow a more precise dissection. Recurrent ipsilateral pheochromocytoma developed in 35 of 625 patients (5.6%); 33 out of 248 patients (13%) after partial adrenalectomy, and two out of 301 (0.6%) after total adrenalectomy. Moreover, metastatic pheochromocytoma was diagnosed in eight of 625 patients (1.3%). A recent study by Xu et al. found that partial adrenalectomy in hereditary pheochromocytoma results in a higher recurrence rate but similar mortality and metastasis rates compared to radical adrenalectomy, with the benefit of preserved adrenal function, particularly in metachronous contralateral disease (Xu et al. 2024).
The MBSA approach was used in 98% of patients with pheochromocytomas at the Carling Adrenal Center, but for giant pheochromocytomas (range 8-19 cm), either laparoscopic, hand-port-assisted, or open standard transabdominal adrenalectomy approaches were useful. Metastatic pheochromocytoma and pheochromocytomatosis (due to tumor implantation following tumor rupture at the index operation) remain challenging and require an individualized surgical and possibly systemic treatment (Javid et al. 2017, Fishbein et al. 2021).
Improved, individualized surgical approaches to adrenocortical carcinoma and adrenal metastases
Adrenocortical carcinomas (ACC) are rare and represented 1.3% of all cases operated on at the Carling Adrenal Center between January 2022 and June 2024 (Fig. 1). The treatment of choice for ACC, and the only possibility for a cure, is complete surgical extirpation of the tumor and adrenal gland, en bloc resection of invaded organs, and, if necessary, peri-aortic/retroperitoneal lymphadenectomy. Unfortunately, most of these patients are diagnosed with stage IV disease, where surgery is not feasible (Lebastchi et al. 2012, Fassnacht et al. 2023). The key to the adrenalectomy approach is to ensure clean resection margins and avoid capsule rupture and tumor spillage from manipulation of the tumor. Given the nature of ACC, often presenting at a late stage with large tumors >8-12 cm, either laparoscopic, hand-port-assisted, or open standard transabdominal adrenalectomy approaches are most frequently used. In the current consecutive series at the Carling Adrenal Center, the MBSA approach was primarily used in patients with a preoperative diagnosis of an adrenal tumor with an atypical imaging phenotype, and the diagnosis of ACC was made postoperatively. In all those cases, there was no
evidence of tumor rupture or positive margins, suggesting that complete resections can be achieved via this minimally invasive approach in expert hands. However, we wish to emphasize that for ACC, complete removal (R0 resection) and avoiding tumor spillage is crucial to avoid loco-regional recurrence. Thus, in the vast majority of cases (especially in large tumors, evidence of vascular or regional invasion, and those with venous thrombi), a transabdominal approach is needed. The role of concomitant regional lymphadenectomy in ACC is controversial, and the quality of the data is limited. The adrenal bed and retroperitoneal space are not particularly lymph node- rich areas, but we advocate for careful visualization and inspection of peri-adrenal lymph nodes in all adrenal operations, whereas a loco-regional dissection is performed in an individualized manner in patients with ACC and adrenal metastases. A recently published meta-analysis suggests an oncologic benefit of lymphadenectomy in patients undergoing curative- intended surgery for localized (stage I-III) ACC (Hendricks et al. 2022).
Similarly, the MBSA approach was used between January 2022 and June 2024 (Fig. 1) in 17 patients to remove a solitary metastasis from another malignancy, such as renal, gastric, colorectal, lung, and breast cancer, as well as malignant melanoma. The most common diagnosis was adrenal metastasis from renal cell carcinoma, and a previous ipsilateral partial or total nephrectomy may have altered the anatomical landscape and created adhesions in the retroperitoneum. Nonetheless, in our hands, the MBSA approach has proven successful also in these cases. Minimally invasive adrenalectomy approaches are feasible for most adrenal metastases, and most studies demonstrate improved disease-free and overall survival for selected patients (Strong et al. 2007, Kwak et al. 2024).
Conclusion
Adrenal surgery is increasingly used in the treatment of adrenal pathology, especially in uni- and bilateral hyperaldosteronism and hypercortisolism. It has undergone significant advancements driven by technological innovations, enhanced surgical technique, and a deeper understanding of adrenal gland pathophysiology. Minimally invasive adrenalectomy, specifically the mini back scope adrenalectomy (MBSA), has become the standard of care for most adrenal tumors, enabling precise function-preserving (partial) adrenalectomy with reduced morbidity, shorter hospital stays, and faster recovery compared to open and transabdominal surgery, whether robotic or laparoscopic. Molecular pathology and enhanced imaging modalities have improved preoperative planning and intraoperative decision-making, allowing for precise tumor localization and preservation of adrenal function. Molecular profiling
and advancement in the pathological diagnosis of adrenal tumors have provided insights into tumor behavior, enabling tailored surgical approaches.
As we enter this improved and individualized era of adrenal surgery, ongoing research and technological advancements are expected to continue to enhance patient outcomes and expand the indications for adrenal surgery.
Declaration of interest
The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of this work.
Funding
This work did not receive any specific grant from any funding agency in the public, commercial, or not-for-profit sector.
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