The indication for surgical treatment of an adrenal mass (AM) is based individually on the underlying disease, weighing non-surgical treatment options and potential complications. The goal of surgical treatment is the safe and as permanent as possible elimination of the disease-causing adrenal disorder.
Adrenalectomy (AE) is a domain of minimally invasive surgery [Walz, 2012; Carr et Wang, 2016]. The advantages of the minimally invasive execution of adrenal interventions are overwhelming compared to an open approach. There is no evidence for the often assumed 6-cm limit of AM [Palazzo et al., 2006; Walz et al., 2005]. For hormonally inactive AM > 6 cm, current guidelines continue to recommend the open procedure due to the statistically increasing malignancy rate [Lorenz et al., 2019), although numerous studies have shown that even with large adrenal tumors > 6 cm and corresponding expertise, a minimally invasive approach can be safely pursued (Palazzo et al., 2006; Walz et al., 2005; Asari et al., 2012).
The transabdominal laparoscopy and retroperitoneoscopy have established themselves as access routes [Walz et al., 2006]. While a randomized controlled study with 83 patients showed no difference between the two surgical methods [Chai et al., 2019], other studies demonstrate advantages. Retroperitoneoscopic surgical methods are also unrestrictedly possible after abdominal pre-operations. The posterior approach also allows bilateral adrenalectomy without repositioning the patient. The retroperitoneal procedures utilize a direct approach to the adrenal gland, eliminating the need for preparation and mobilization of intraperitoneal organs. They are considered faster, with less blood loss, reduced pain burden, and shorter hospital stay [Barczynski et al., 2014; Conzo et al., 2016; Gavrilidis et al., 2021]. It is therefore up to the surgeon to apply the method according to personal training and expertise (Conzo et al., 2016).
The single-port adrenalectomy is an alternative [Wang et al. 2013], but significant advantages do not arise with limited data.
The robotically performed adrenalectomy is also safe. It even seems to be associated with less blood loss and a shorter hospital stay than laparoscopic adrenalectomy [Agrusa et al., 2017]. However, the operation time is longer, and the costs are higher [Samreen et al., 2019], so it does not yet appear suitable for widespread use.
The assessment of malignancy risk is based on tumor size and imaging procedures. Determining the Hounsfield units (HU) can provide additional clues. However, only the recognizable infiltration of neighboring structures or evidence of distant metastases is proof of malignancy. In addition to computed tomography, MRI with chemical shift imaging is established in the diagnosis of adrenal masses (Israel et al., 2004).
The standard therapy for unilateral tumors is adrenalectomy. The adrenal-sparing resection can be performed if the hormonally active primary tumor can be completely removed. In some diseases, such as hereditary bilateral pheochromocytomas (e.g., in MEN 2 a/b) or Cushing's syndrome due to bilateral macronodular hyperplasia [Lowery et al., 2017], parenchyma-sparing adrenal resections are preferred over total adrenalectomy to minimize the risk of postoperative life-threatening Addisonian crises (acute adrenal insufficiency). Retaining adrenocortical function can be achieved by leaving one-third of an adrenal gland (Brauckhoff et al., 2003). The adrenal vein does not necessarily have to be preserved. The advantage of function preservation must be weighed against the risk of local tumor recurrence in the remaining adrenal gland. The recurrence risk after parenchyma-sparing adrenal partial resections is estimated at 30% after 10 years in MEN-2a/b patients [Asari et al., 2006]. Further data show good symptom control in Conn- [Walz et al., 2009] and Cushing adenomas [Alesina et al., 2010].
Hormonally active tumors
Hormonally active, symptomatic adrenal masses/diseases (uni- and bilateral) represent an indication for surgery regardless of the tumor size. An exception can be primary hyperaldosteronism with bilateral hyperplasia without lateralization, which can be treated medically [Lorenz et al., 2019].
Conn syndrome (primary hyperaldosteronism, PHA)
Immediate screening for this disease is only recommended in an incidentaloma if arterial hypertension or unexplained hypokalemia is present [Fassnacht et al., 2016].
Preoperatively, primary hyperaldosteronism (PHA) is biochemically confirmed by determining the aldosterone-renin ratio (ARR). In primary hyperaldosteronism (PHA), there is autonomous, i.e., renin-independent aldosterone secretion. Determining this ratio is an excellent screening test in the diagnosis of primary hyperaldosteronism, as it also detects patients with mild primary hyperaldosteronism [Hiramatsu et al., 1981; Gordon et al., 2001].
In patients with an abnormal ARR, confirmatory diagnostics should be performed [Funder et al., 2016]. Various tests are available for this purpose [Namba et al., 2012]. The most commonly performed confirmation test is the intravenous saline loading test.
Preoperatively, localization diagnostics with lateralization of the disease cause is recommended, as this determines the indication and strategy for surgery. If localization is unclear in imaging, preoperative adrenal vein catheterization with selective blood sampling [Strajina et al., 2018] should be performed for functional lateralization of PHA.
If there is clear lateralization in cross-sectional imaging, adrenal vein catheterization can be omitted if the patient has been thoroughly informed about the risk of inadequate surgery (about 5%) [Lim et al., 2014] by removing hormonally inactive AM tumors while leaving unrecognized contralateral AM pathologies [Lombardi et al., 2007; Kline et al., 2014; Tan et al., 2006).
In the case of a solitary aldosterone-producing adenoma, partial removal of the affected adrenal gland can also be performed [Fu et al., 2011].
Cushing syndrome
In suspected or to exclude Cushing syndrome, three laboratory parameters are commonly used: dexamethasone suppression test with 1mg dexamethasone, determination of 11:00 PM cortisol in serum or saliva, and measurement of free cortisol in 24-hour urine (Niemann et al., 2008). If hypercortisolism is proven, determining ACTH is mandatory. In adrenal Cushing syndrome, ACTH must be suppressed or low-normal. If this is not the case, the genesis of Cushing syndrome is usually pituitary, i.e., due to an ACTH-producing pituitary adenoma (Cushing's disease) or ectopic ACTH production and not due to an AM. The therapy of choice for manifest adrenal Cushing syndrome is unilateral adrenalectomy (Niemann et al., 2015). Intra- and postoperatively, glucocorticoid substitution with hydrocortisone is required, as at least temporary adrenal insufficiency due to suppression of the contralateral AM by cortisol excess is to be expected [Bornstein et al., 2016].
In addition to clinically manifest Cushing syndrome, the subclinical Cushing syndrome, whose terminology in the AM incidentaloma guideline of the European Society of Endocrinology has been replaced by "autonomous cortisol secretion," has been more clearly characterized in recent years [Fassnacht et al., 2016: Chiodini, 2011; Chiodini et al., 2010; De Leo et al., 2012; Niemann 2015]. Biochemically, there is a mild cortisol excess, usually evidenced by non-suppressible cortisol after administration of 1mg dexamethasone (dexamethasone suppression test), but without the specific clinical signs of hypercortisolism. This mild cortisol excess is associated with an increased frequency of cardiovascular and metabolic comorbidities. However, high-quality studies with hard endpoint data such as mortality or cardiovascular events are lacking. Therefore, in this case, the indication for adrenalectomy versus medical therapy of comorbidities must be critically assessed and individually decided in a multidisciplinary team considering age and patient preference (Fassnacht et al., 2016).
Adrenal tumors with androgen/estrogen overproduction
For any estrogen- or androgen-producing adrenal tumor, an adrenocortical carcinoma (ACC) should be considered, as adenomas are rare [Lack, 2007].
Up to a tumor size of 6 cm, minimally invasive adrenalectomy is standard, provided it is ensured that this can be performed technically without capsular lesion or incomplete tumor resection. In case of suspected carcinoma or larger tumors, the indication for open surgery should be generously made (Else et al., 2014; Gaujoux and Mihai, 2017; Stigliano, 2016; Gaujoux et al., 2012).
Pheochromocytoma
The proportion of pheochromocytomas as tumors of adrenal origin is about 5% of incidentally discovered adrenal tumors. They originate from the adrenal medulla and produce catecholamines. They are often discovered incidentally rather than presenting with the classic symptomatology (hypertension, headaches, sweating, palpitations) [Gruber et al., 2019].
The diagnosis involves first the biochemical detection of free plasma metanephrines or alternatively fractionated metanephrines in 24-hour urine [Lenders et al. 2014; Gruber et al., 2019].
Only in the second step is an imaging procedure (computed tomography or magnetic resonance imaging) performed for localization diagnostics. Optionally, functional nuclear medicine imaging can be useful to detect metastasis preoperatively. Here, fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT) or DOTA-TATE-PET/CT, which is somewhat more sensitive but significantly more specific, can be considered [Castinetti et al., 2015; Janssen et al., 2015]. In any case, preoperative screening for the presence of metastases using PET/CT is recommended if the tumor is >5 cm, elevated levels of 3-methoxytyramine (3MT) in plasma are present, or a germline mutation of the SDHB gene is known [Fassnacht et al., 2020].
Most pheochromocytomas behave "benignly." The World Health Organization (WHO) now lists pheochromocytomas as a subgroup of paragangliomas, all of which are considered potentially malignant. In 10% of cases, pheochromocytomas occur as bilateral adrenal tumors and are associated with genetic changes in 30–40% [Bausch et al., 2017]. Familial, syndromic forms include multiple endocrine neoplasia type 2 (MEN2), von Hippel-Lindau syndrome (vHL), and neurofibromatosis type 1. In recent years, germline mutations of the succinate dehydrogenase subunit B and D (SHDB, SDHD) have come to the forefront of genetic diagnostics of pheochromocytoma. It has been found that patients with multiple endocrine neoplasia type 2 very rarely develop malignant pheochromocytomas, while patients with germline mutation in the SDHB gene have about 30% of pheochromocytomas being malignant.
Even with negative family history, unilateral disease, or older patients where the detection of a germline mutation is less likely, all patients with pheochromocytoma are now offered human genetic diagnostics to determine the individual resection concept (radical oncological in SDHB mutation versus adrenal cortex-sparing in RET mutation) [Nolting et al., 2022].
Assessing the dignity of pheochromocytomas is challenging because pheochromocytomas cannot be clearly classified as benign or malignant based on histopathological or molecular markers. Rather, malignancy is characterized by invasive growth or the presence of locoregional or distant metastases. This highlights the importance of regular follow-up and genetic testing of patients, as patients with certain germline mutations (e.g., SDH-B) have a significantly increased risk of malignant growth behavior [Mete et al., 2022].
Follow-up after pheochromocytoma surgery should last at least 10 years. For patients at high risk of recurrence or metastasis (proven mutation, young age, or large tumor), lifelong follow-up is recommended (Plouin et al., 2016).
The surgical removal of pheochromocytoma is the only possibility for curative therapy. Improvements in perioperative management and surgical technique have reduced historically high mortality rates to 0–2.9% [Fragundes 2022].
The minimally invasive removal of the adrenal tumor is standard, with transabdominal and retroperitoneoscopic laparoscopic procedures considered equivalent [Zang et al., 2023]. The choice of minimally invasive procedure depends on the expertise and experience of the surgeon and should primarily be adapted to this [Conzo et al., 2016].
Overall, the minimally invasive operation of pheochromocytomas requires high surgical expertise. A capsular injury must also be avoided here. Otherwise, disseminated multifocal seeding of pheochromocytoma cells, the so-called pheochromocytomatosis, threatens. A few years ago, it was postulated that minimally invasive surgery could be a reason for pheochromocytomatosis. However, even primary open adrenalectomy for pheochromocytoma cannot always avoid pheochromocytomatosis [Weber et al., 2020].
Current guidelines and a meta-analysis therefore recommend minimally invasive adrenalectomy for pheochromocytomas < 6 cm [Li et al., 2020; Lorenz et al., 2019].
In bilateral hereditary pheochromocytomas and exclusion of an SDHB mutation, a parenchyma-sparing resection preserving at least one-third of an adrenal gland should be performed to avoid postoperative adrenal insufficiency. Although retaining the adrenal cortex in the context of bilateral removal of pheochromocytomas theoretically increases the risk of recurrence, the risk of metastasis and overall mortality is comparable to complete bilateral adrenalectomy. In contrast, the advantage of function preservation by leaving the adrenal cortex clearly outweighs [Zawadzka et al., 2023]. However, a current international guideline for patients with SDH-B mutation strongly advises against organ-preserving surgery in this patient group, as the malignancy risk is considerable, sometimes over 50%.
The dogma of preoperative α-blockade is increasingly questioned by current data and has been controversially discussed in recent years. Current international [Fassnacht et al., 2016, Lenders et al. 2014] and national [Lorenz et al., 2019] guidelines recommend α-blockade before resection of a pheochromocytoma to prevent cardiovascular complications. However, a meta-analysis of all published studies and a large multicenter registry study from 2020 show that there is no evidence for this approach. In the meta-analysis, there was no difference in mortality and morbidity or intraoperative average blood pressure or heart rate between blocked and non-blocked patients [Schimmack et al., 2020].
Hormonally inactive tumors
The term incidentaloma does not represent a diagnosis per se but is purely descriptive. Since hormonally inactive adrenal tumors are usually asymptomatic, they are incidentally discovered through imaging procedures not initiated to clarify potential adrenal diseases. They are therefore called incidentalomas. The prevalence of these incidentally discovered adrenal masses increases with age and ranges from 1 to 9% depending on the study [Petersenn et al., 2015;] (up to 15% of which are bilateral [Barzon et al., 1998]).
All incidentalomas >1cm always require an assessment of dignity and functionality (hormone production) to make an etiological classification. The guidelines of the European Society of Endocrinology recommend clarifying the dignity immediately upon first discovery to avoid costly and time-consuming follow-up examinations in patients with benign lesions [Fassnacht et al., 2016].
As a functional baseline diagnosis, a dexamethasone suppression test to exclude adrenal Cushing syndrome, the determination of free metanephrines in plasma (and possibly in 24-hour urine) to exclude pheochromocytoma, and in hypertensive patients, the determination of the aldosterone/renin ratio to exclude Conn syndrome is recommended. If imaging is suspicious for adrenocortical carcinoma, DHEA-S, 17-OH-progesterone, and estradiol (only in men and postmenopausal women) should also be determined in serum [Fassnacht et al., 2016].
To assess the dignity of incidentalomas, a CT and MRI with dedicated adrenal examination protocols are suitable, while 18F-FDG-PET/CT is mainly used for detecting adrenal metastases in the context of extra-adrenal tumor history [Dinnes et al., 2016; Vaidya et al., 2019; Fassnacht et al., 2016].
As a basic procedure for depicting adrenal tumors, CT with and without contrast medium is recommended. It allows the determination of the size of the AM tumor and its fat content (Hounsfield units, HU), as well as an assessment of possible surrounding infiltrations. Adrenal adenomas are characterized in CT by a relatively high fat content with low Hounsfield units. This means that adrenal masses with < 13 HU are very likely benign [Petersenn et al., 2015].
Fat-poor adenomas can be differentiated by quantifying contrast medium washout. For adenomas, rapid inflow and washout of the contrast medium are characteristic, while most malignant lesions show rapid inflow but slower washout of the contrast medium [Fassnacht et al., 2016]. It is important to include the overall diagnostic context in the assessment of the determined washout value, as otherwise misclassifications can occur [Schloetelburg et al. 2021]).
Indications of malignancy include tumor size and documented growth tendency ˃ 13 Hounsfield units in native CT, unclear tumor margin, inhomogeneous tumor presentation, and signs of surrounding infiltration [Kapoor et al., 2011; Petersenn et al., 2015; Fassnacht et al., 2016]. For tumors > 6 cm, the malignancy rate is 25%, for tumors between 4.1 and 6 cm 6%, and for tumors < 4 cm 2% [National Institute of Health (NIH), 2002; Grumbach et al., 2003].
As an alternative procedure for clarifying adrenal tumors, MRI is accepted. Here, the so-called "chemical shift" imaging is particularly used to detect microscopic fat, as benign lesions in MRI typically show a significant signal drop between the "in-phase" and "opposed-phase" representation [Fassnacht et al., 2016; Haider et al., 2004; Shadev, 2017; Faruggia et al., 2017].
For tumors between 4 and 6 cm without radiological malignancy criteria, no clear recommendation can be made based on the current data. An individual approach should be discussed with the patient (waiting, observing versus minimally invasive surgery).
From a diameter of > 6 cm (exception myelolipoma), there is an indication for surgery due to the risk of malignancy.
Note: Adrenal myelolipomas are rare hormonally inactive benign tumors containing mature fat tissue and hematopoietic tissue. They most commonly occur in the 5th-7th decade of life. They usually cause no symptoms. However, in cases of large tumors, necrosis, or spontaneous bleeding, pain may occur. In these cases, resection may be required [Patel et al., 2006].
Adrenocortical carcinoma
Adrenocortical carcinoma ("adrenocortical carcinoma" [ACC]) is a rare and very aggressive tumor. At initial diagnosis, this tumor is almost always >4 cm (only 1–2% are < 4 cm) and exhibits endocrine activity in 50–80% of cases. Cortisol production or a combination of androgen and cortisol excess is typical and can be indicative in diagnosis [Bancos and Prete, 2021].
Preoperative staging should include molecular imaging using 18F-FDG (fluorodeoxyglucose)-PET (positron emission tomography)-CT) in addition to a CT or MRI of the abdomen to assess possible metastasis [Gaujoux et al., 2017]. This also allows differentiation from benign adrenal adenoma, which is FDG negative, and simultaneously a whole-body staging regarding metastases except for the brain.
Surgery is always indicated when there is no distant metastasis. It is the only chance for cure and should be performed early as a surgical R0 resection of the primary tumor while adhering to surgical-oncological principles (no violation of the tumor capsule) [Schimmack et al.,2020].
ACCs should only be performed in centers with more than 10 adrenalectomies per year and corresponding oncological visceral surgical experience (Lombardi et al., 2012; Gratian et al., 2014; Gaujoux et al. 2017).
The gold standard of surgical treatment of ACC, according to current European, German, and international guidelines, is open adrenalectomy regardless of tumor stage [Fassnacht et al., 2018¸Gaujoux et Mihai 2017; Lorenz et al., 2019; Shah et al., 2021].
Even patients with early stages (ENSAT I and II) of adrenocortical carcinoma have better recurrence-free survival after open adrenalectomy [Taffurelli et al, 2017].
Adrenal carcinomas can be operated on minimally invasively as long as no oncological compromises are made and no rupture of the tumor capsule threatens. The integrity of the capsule during resection is of such elemental importance for the prognosis of patients that even in ENSAT stage I, a comparably poor prognosis threatens if the capsule is violated as in patients in stage III (Fassnacht et al., 2016).
Data published in 2021 by Delozier et al. showed that conversion after minimally invasive adrenalectomy for patients with ACC is associated with poorer overall survival.
The concern that peritoneal carcinomatosis is increased in laparoscopically operated patients with ACC was confirmed in a meta-analysis [Autorino et al., 2016].
Although the incidence of lymph node metastases in adrenocortical carcinoma is about 20%, the value of lymphadenectomy is controversial and is rarely performed (Gaujoux et al., 2017) (Reibetanz et al., 2012). With poor data, the CAEK [Chirurgische Arbeitsgemeinschaft Endokrinologie] recommends this only if positive lymph nodes are suspected [Lorenz et al., 2019]. Other authors describe a positive effect on the overall prognosis. For example, a recent meta-analysis by Hendricks et al., 2022, shows that patients with ENSAT stage I–III benefit from lymphadenectomy and have improved disease-specific survival. At least for cases with proven lymph node enlargement in preoperative imaging and locally advanced tumors (T3 and T4), most authors advocate lymphadenectomy as a fixed component of surgical therapy. However, there is no definition of the extent of the required lymphadenectomy.
A molecular genetic analysis for TP53 (tumor protein 53) or MMR [mismatch repair protein] mutations should be performed in cases of conspicuous family history, especially at a young age.
The assessment of recurrence risk is conducted, among other things, using the Ki-67 index (high risk with Ki-67 > 10%).
Despite not fully conclusive data, adjuvant mitotane therapy is recommended for patients with a high individual local recurrence risk (RX, R1, Ki-67 index >10%). Patients with a low individual local recurrence risk (ENSAT I and II, R0 resection, Ki67 index < 10%) should not receive adjuvant mitotane therapy (Berutti et al., 2012; Gaujoux et al., 2017; Terzolo et al., 2007; Berruti et al., 2010).
Adrenal metastases
Among adrenal masses, metastases are the second most common after benign non-functional adenomas (Uberoi et al., 2009).
Primary tumors with adrenal metastases from non-small cell lung carcinomas (NSCLC) and breast carcinomas are the most common, but melanomas, hepatocellular, and renal cell carcinomas are also frequently associated with adrenal metastases (Sancho et al., 2012).
The indication for resection of adrenal metastases should always be made in an interdisciplinary tumor board and only in selected cases when a positive effect on overall survival can be expected.
Patients benefit from metastasis removal if the extra-adrenal tumor disease is successfully treated or controlled, it is an isolated adrenal metastasis, imaging and/or percutaneous biopsy prove adrenal metastasis or leave little doubt about it [Lo et al., 1996; Muth et al., 2010], the disease-free interval is longer than 6 months [Muth et al., 2010; Pfannenschmidt et al., 2005], the general condition of the patient justifies resection, and the histology of the primary tumor corresponds to an adenocarcinoma (Sancho et al. 2012). In inoperable patients, radiofrequency ablation can be considered an alternative [Carafiello et al., 2008; Wood et al., 2003].
In case of suspected metastasis, standard diagnostics (CT/MRI of the abdomen) should be supplemented by an FDG-PET/CT to examine the entire body for further metastases. In case of uncertainty, an exception can be made for puncturing the adrenal mass if a pheochromocytoma and an adrenocortical carcinoma have already been excluded. In the case of a negative result, the presence of AM tissue in the sample largely excludes an AM metastasis.
The operation must ensure that the tumor is removed in toto and without violating its capsule (Glenn et al., 2016). This can be done minimally invasively laparoscopically, retroperitoneoscopically, or conventionally via an open approach. Several studies have shown that the minimally invasive approach is not inferior to the open approach (Bradley et Strong, 2014). Furthermore, it has been shown that the advantages of the minimally invasive approach (less blood loss, shorter hospital stay) also apply to this indication and that so-called port-site metastases do not occur (Saraiva et al. 2003; Strong et al., 2007; Weyhe et al., 2007; Arenas et al., 2014). An open approach should therefore be reserved for the few cases where there is evidence of local infiltration or when the tumor exceeds a certain size (>10 cm).