The indication for surgical treatment of an adrenal mass (AM) is based individually on the underlying disease, weighing non-surgical treatment methods and possible 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 minimally invasive performance of adrenal interventions are overwhelming compared to an open approach. There is no evidence for the often assumed 6-cm limit of the AM [Palazzo et al., 2006; Walz et al., 2005]. For hormone-inactive lesions of the adrenal gland > 6 cm, current guidelines still 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 appropriate expertise, a safe minimally invasive approach is possible (Palazzo et al., 2006; Walz et al., 2005; Asari et al., 2012).
As access routes, transabdominal laparoscopy and retroperitoneoscopy have established themselves [Walz et al., 2006]. While a randomized controlled study with 83 patients showed no difference between both surgical methods [Chai et al., 2019], other studies demonstrate advantages. Retroperitoneoscopic surgical methods are possible without restriction even after abdominal pre-operations. The posterior access also allows bilateral adrenalectomy without repositioning the patient. Retroperitoneal procedures use a direct access to the adrenal gland, eliminating the preparation and mobilization of intraperitoneal organs. They are considered faster, blood loss is said to be smaller, pain burden lower, and hospital stay shorter [Barczynski et al., 2014; Conzo et al., 2016; Gavrilidis et al., 2021]. It is therefore left to the surgeon which method to apply according to personal training and expertise (Conzo et al., 2016).
The single-port adrenalectomy is an alternative [Wang et al. 2013], but with limited data, no significant advantages result.
Also the robotic performed adrenalectomy is safe. It seems to be associated with less blood loss and shorter hospital stay than laparoscopic adrenalectomy [Agrusa et al., 2017]. However, the operating 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. The determination of Hounsfield units (HU) can provide additional clues. However, only detectable 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 hormone-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 preferable to total adrenalectomy to minimize the risk of postoperative life-threatening Addisonian crises(acute adrenal insufficiency). Preservation of 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 functional preservation must be weighed against the risk of local tumor recurrence in the remnant adrenal gland. The recurrence risk after parenchyma-sparing partial adrenal 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].
Hormone-Active Tumors
Hormone-active, symptomatic adrenal masses/diseases (uni- and bilateral) represent a surgical indication regardless of tumor size. An exception may be primary hyperaldosteronism with bilateral hyperplasia without side assignment, which can be treated medically [Lorenz et al., 2019].
Conn Syndrome (primary hyperaldosteronism, PHA)
Immediate screening for this disease is recommended for an incidentaloma only if arterial hypertension or unexplained hypokalemia is present at the same time [Fassnacht et al., 2016].
Preoperatively, primary hyperaldosteronism (PHA) is confirmed biochemically by determining the aldosterone-renin ratio (ARR). In primary hyperaldosteronism (PHA), there is autonomous, i.e., renin-independent aldosterone secretion. The determination of 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 [Namba et al., 2012]. The most commonly performed confirmation test is the intravenous saline load test.
Preoperatively, localization diagnostics with side determination of the cause of the disease is recommended, as this determines the surgical indication and strategy. In case of unclear localization in imaging, preoperative adrenal vein catheterization with selective blood sampling [Strajina et al., 2018] should be performed for functional lateralization of PHA.
In case of clear side assignment in cross-sectional imaging, adrenal vein catheterization can be dispensed with if the patient has been thoroughly informed about the risk of inadequate surgery (approx. 5%) [Lim et al., 2014] due to removal of hormone-inactive adrenal tumors while leaving unrecognized contralateral adrenal pathologies [Lombardi et al., 2007; Kline et al., 2014; Tan et al., 2006).
For solitary aldosterone-producing adenoma, partial removal of the affected adrenal gland can also be performed [Fu et al., 2011].
Cushing Syndrome
In suspicion or to exclude Cushing's 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 by this, determination of ACTH is mandatory. In adrenal Cushing's syndrome, ACTH must be suppressed or low-normal. If not, the genesis of Cushing's 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 adrenal mass. The therapy of choice for manifest adrenal Cushing's syndrome is unilateral adrenalectomy (Niemann et al., 2015). Intra- and postoperatively, glucocorticoid substitution with hydrocortisone is required, as at least temporarily adrenal insufficiency due to suppression of the contralateral adrenal gland by cortisol excess must be assumed [Bornstein et al., 2016].
In addition to clinically manifest Cushing's syndrome, subclinical Cushing's syndrome, whose terminology in the adrenal 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]. Here, there is biochemically 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 must be critically weighed against medical treatment of comorbidities and decided individually in a multidisciplinary team, taking into account age and patient preference (Fassnacht et al., 2016).
Adrenal Tumors with Androgen/Estrogen Overproduction
For every estrogen- or androgen-producing adrenal tumor, an adrenal 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 capsule lesion or incomplete tumor resection. In case of suspicion of carcinoma or larger tumors, the indication for open surgery should be generously made (Else et al., 2014; Gaujoux und 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. Often they are discovered incidentally rather than with the classic symptomatology (high blood pressure, headaches, sweating, palpitations) [Gruber et al., 2019].
Diagnostics first capture the biochemical detection of free plasma metanephrines or alternatively fractionated metanephrines in 24-hour collected urine [Lenders et al. 2014; Gruber et al., 2019].
Only in the second step does cross-sectional imaging (computed or magnetic resonance tomography) follow for localization diagnostics. Optionally, functional nuclear medicine imaging may 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, comes into question [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].
The majority of 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 alterations 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 addition, germline mutations of succinate dehydrogenase subunit B and D (SHDB, SDHD) have come into focus in the genetic diagnosis of pheochromocytoma in recent years. It has been found that malignant pheochromocytomas develop extremely rarely in patients with multiple endocrine neoplasia type 2, while in patients with germline mutation in the SDHB gene, approx. 30% of pheochromocytomas are malignant.
Even with negative family history, unilateral disease, or older patients where detection of a germline mutation is less likely, genetic diagnostics are now offered to all patients with pheochromocytoma to define the individual resection concept (radical oncological for SDHB mutation versus adrenal cortex-sparing for RET mutation) [Nolting et al., 2022].
Assessing the dignity of pheochromocytomas poses a challenge, as 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 as well as genetic testing of patients, as patients with certain germline mutations (e.g., SDH-B) show a significantly increased risk of malignant growth behavior [Mete et al., 2022].
Follow-up after surgery for pheochromocytoma should last at least 10 years. For patients with high risk of recurrence or metastasis (proven mutation, young age, or large tumor), it is recommended for life (Plouin et al., 2016).
Surgical removal of pheochromocytoma represents the only possibility of curative therapy. Improvements in perioperative management and surgical technique have reduced the historically high mortality rates to 0–2.9% [Fragundes 2022].
Minimally invasive removal of the adrenal tumor is standard, with transabdominal and retroperitoneoscopic laparoscopic procedures to be 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 that [Conzo et al., 2016].
Overall, minimally invasive surgery for pheochromocytomas requires high surgical expertise. Capsule injury must also be absolutely avoided here. Otherwise, disseminated multifocal seeding of pheochromocytoma cells, so-called pheochromocytomatosis, threatens. A few years ago, it was postulated that minimally invasive surgery could be a reason for pheochromocytomatosis. But even primary open adrenalectomy for pheochromocytoma cannot always avoid pheochromocytomatosis [Weber et al., 2020].
Current guidelines as well as 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 SDHB mutation, parenchyma-sparing resection with preservation of at least one third of an adrenal gland should be performed to avoid postoperative adrenal insufficiency. After preservation of the adrenal cortex in the context of bilateral removal of pheochromocytomas, there is in principle an increased recurrence risk, but the risk of metastasis and overall mortality are comparable to complete bilateral adrenalectomy. In contrast, the advantage of functional preservation with leaving the adrenal cortex clearly outweighs [Zawadzka et al., 2023]. A current international guideline for patients with SDH-B mutation strongly advises against organ-preserving surgery in this patient group, as the malignancy risk here 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. A meta-analysis of all published studies as well as a large multicenter registry study from 2020 show, however, that there is no evidence for this approach. In the meta-analysis, there was no difference in mortality and morbidity nor in intraoperative average blood pressure or heart rate between blocked and non-blocked patients [Schimmack et al., 2020].
Hormone-Inactive Tumors
The term incidentaloma per se does not represent a diagnosis but is purely descriptive. Since hormone-inactive adrenal tumors are usually asymptomatic, they are discovered incidentally through imaging procedures that were not initiated to clarify potential adrenal diseases. They are therefore called incidentalomas. The prevalence of these incidentally discovered adrenal masses increases with age and is between 1 and 9% depending on the study [Petersenn et al., 2015;] (of which up to 15% bilateral [Barzon et al., 1998]).
All incidentalomas >1cm always require assessment of dignity and functionality (hormone production) to enable etiological classification. The guidelines of the European Society of Endocrinology recommend clarifying dignity immediately upon initial discovery to avoid elaborate and costly follow-up examinations in patients with benign lesions [Fassnacht et al., 2016].
As functional basic diagnostics, a dexamethasone suppression test to exclude adrenal Cushing's syndrome, determination of free metanephrines in plasma (and possibly in 24-h urine) to exclude pheochromocytoma, and in hypertensive patients determination of the aldosterone/renin ratio to exclude Conn syndrome are recommended. If imaging is suspicious for adrenocortical carcinoma, DHEA-S, 17-OH-progesterone, and estradiol (only in men and postmenopausal women) should additionally be determined in serum [Fassnacht et al., 2016].
For assessing the dignity of incidentalomas, CT and MRI with dedicated adrenal examination protocols are suitable, while 18F-FDG-PET/CT is mainly used for detecting adrenal metastases in extra-adrenal tumor history [Dinnes et al., 2016; Vaidya et al., 2019; Fassnacht et al., 2016].
As the basic procedure for imaging adrenal tumors, CT with and without contrast medium is recommended. It enables determination of the size of the adrenal tumor and its fat content (Hounsfield units, HU), as well as 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].
Low-fat adenomas can be differentiated by quantifying contrast medium washout. For adenomas, rapid inflow and washout of contrast medium are characteristic, while most malignant lesions show rapid inflow but slower washout of contrast medium [Fassnacht et al., 2016]. It is important to include the diagnostic overall context in the assessment of the determined washout value, otherwise misclassifications can occur [Schloetelburg et al. 2021]).
Indications of malignancy include, in addition to tumor size and documented growth tendency ˃ 13 Hounsfield units in native CT, indistinct tumor margins, inhomogeneous tumor appearance, 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. In particular, so-called "chemical shift" imaging is used to detect microscopic fat, as benign lesions in MRI typically show a significant signal drop between "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 current data. An individual approach should be discussed with the patient (wait-and-see, observational versus minimally invasive surgery).
From a diameter of > 6 cm (exception myelolipoma), there is a surgical indication due to the malignancy risk.
Note: Adrenal myelolipomas are rare hormone-inactive benign tumors containing mature adipose tissue and hematopoietic tissue. They occur most frequently in the 5th-7th decade of life. They usually cause no symptoms. However, with large tumors, necrosis, or spontaneous hemorrhage, pain can occur. In these cases, resection may be necessary [Patel et al., 2006].
Adrenocortical Carcinoma
The 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 are typical here and can be indicative in diagnosis [Bancos und Prete, 2021].
Preoperative staging should include, in addition to CT or MRI of the abdomen, molecular imaging using 18F-FDG(fluorodeoxyglucose)-PET(positron emission tomography)-CT) to assess possible metastasis [Gaujoux et al., 2017]. This can also differentiate from benign adrenal adenoma, which is FDG negative, and simultaneously perform whole-body staging regarding metastases except for the brain.
Surgery is always indicated if there is no distant metastasis. It is the only chance for cure and should be performed early as surgical R0 resection of the primary tumor 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 for ACC is, according to currently valid European, German, and international guidelines, 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 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, capsule injury threatens a comparably poor prognosis as in patients in stage III (Fassnacht et al., 2016).
Data published in 2021 by Delozier et al. showed that conversion after minimally invasive started adrenalectomy for patients with ACC is associated with worse overall survival.
The concern that peritoneal carcinomatosis is increased in laparoscopically operated patients with ACC could be 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 rather rarely performed (Gaujoux et al., 2017) (Reibetanz et al., 2012). With poor data, the CAEK [Surgical Working Group Endocrinology] recommends it only in suspicion of positive lymph nodes [Lorenz et al., 2019]. Other authors describe a positive effect on overall prognosis. For example, a current 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 part of surgical therapy. However, there is no definition of the extent of required lymphadenectomy.
Molecular genetic analysis for TP53(tumor protein 53)- or MMR [mismatch-repair protein] mutations should be performed in case of conspicuous family history, especially in young age.
The assessment of recurrence risk is carried out, among other things, with the help of the Ki-67 index (high risk at Ki-67 > 10%).
Despite not fully conclusive data, adjuvant mitotane therapy is recommended for patients with high individual local recurrence risk (RX, R1, Ki-67 index >10%). Patients with 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 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 if 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 patient's general condition 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 as an alternative [Carafiello et al., 2008; Wood et al., 2003].
In suspicion of metastasis, standard diagnostics (CT/MRI of the abdomen) should be supplemented by FDG-PET/CT to examine the entire body for further metastases. In case of uncertainty, puncture of the adrenal mass can exceptionally be performed if pheochromocytoma and adrenocortical carcinoma have already been excluded. In case of a negative result, the presence of adrenal tissue in the sample largely excludes an adrenal metastasis.
The surgery must ensure that the tumor is removed in toto and without injury to its capsule (Glenn et al., 2016). This can be done either minimally invasive laparoscopically, retroperitoneoscopically, or via an open access conventionally. Several studies have shown that the minimally invasive approach is not inferior to the open approach (Bradley et Strong, 2014). Moreover, it has been shown that the advantages of the minimally invasive approach (less blood loss, shorter hospital stay) also exist for this indication and 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 are indications of local infiltration or if the tumor exceeds a certain size (>10 cm).