SPECIAL SECTION: ADRENAL IMAGING
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Evaluation and management of adrenal neoplasms: endocrinologist and endocrine surgeon perspectives
Peter J. Mazzaglia1 · Jeena Varghese2 · Mouhammed A. Habra2
@ Springer Science+Business Media, LLC, part of Springer Nature 2020
Abstract
The evaluation and management of adrenal disease is a complex endeavor that relies on an expert knowledge of human physiology and anatomy. Careful and proper patient assessment mandates a balanced approach which marries the disciplines of endocrinology, surgery, and radiology. Any of these three specialties may be on the front line in performing the initial workup when an adrenal neoplasm is discovered. With an ever-increasing volume of cross-sectional imaging, be it CT, MRI, or PET, large numbers of adrenal incidentalomas are being discovered. A close collaboration amongst specialties should strive to streamline the initial evaluation and minimize unnecessary testing and treatment.
Keywords Adrenal neoplasm · Adrenocortical carcinoma . Cushing syndrome · Pheochromocytoma
Introduction
An adrenal incidentaloma, defined as any adrenal lesion> 1 cm discovered on imaging performed for other reasons, is often the first indication of potential adrenal pathology. The prevalence of adrenal nodules is about 4% on computed tomography (CT) scans and 6% in postmor- tem series, and the incidence increases with age [1-4]. The recognition of adrenal masses has risen significantly due to the increased use of various cross-sectional imag- ing modalities [3]. Most adrenal incidentalomas are benign, non-functioning adrenocortical adenomas. However, a com- prehensive evaluation is recommended to identify lesions that require treatment, such as hormone-producing tumors (e.g., pheochromocytoma, Cushing, and Conn syndrome)
[5] and malignant neoplasms (e.g., adrenocortical cancer, metastases).
Evaluation
Guidelines published by the American Association of Clini- cal Endocrinologists and the American Association of Endo- crine surgeons recommend evaluation of incidentally found adrenal lesions > 1 cm. Workup of smaller lesions can be undertaken if there is clinical suspicion for adrenal hormone excess [5].
Detailed history and physical examination can identify signs and symptoms of adrenal hormone excess related to Cushing syndrome, pheochromocytoma, primary aldoster- onism, and hyperandrogenism. About 15% of adrenal inci- dentalomas are hormonally active. However, patients may frequently be asymptomatic or have sub-clinical signs of adrenal hyperfunction [5]. Therefore, it is recommended that all patients with incidentaloma undergo biochemical testing to exclude hypercortisolism and pheochromocy- toma. Workup for primary aldosteronism is recommended in patients with hypertension or hypokalemia. Adrenal andro- gen and other steroid hormone levels should be checked in patients with clinical presentations suggestive of androgen excess or if imaging studies are suggestive of adrenocortical cancer [6] (Table 1).
☒ Peter J. Mazzaglia peterjmazzaglia@gmail.com
Jeena Varghese jvarghese@mdanderson.org
Mouhammed A. Habra MAHabra@mdanderson.org
1 Warren Alpert School of Medicine at Brown University, 2 Dudley St., Providence, RI 02905, USA
2 Endocrine Neoplasia and Hormonal Disorders, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| Hormonal abnormality | Whom to test | Recommended screening test | Expected results |
|---|---|---|---|
| Cushing's/subclinical Cushing's | All patients | Overninght 1 mg Dexamethasone sup- pression test | A.M. Cortisol Level Non-functional: < 1.8 mcg/dl Indeterminate: 1.8-5 mcg/dl Cortisol producing: > 5.0 mcg |
| Pheochromocytoma | All patients | Plasma metanephrines or 24 h urine catecholamines | Levels >2 to 4 times the upper limit of the reference range indicative of pheochromocytoma |
| Primary hyperaldosteronism | Patients with hypertension and/or unexplained hypoka- lemia | Measure Serum Aldosterone and Plasma Renin Activity. Calculate Serum Aldosterone to Plasma Renin Ratio (ARR) | ARR>20-30 is indicative of hyper- aldosteronism |
If imaging is suggestive of adrenocortical cancer consider measuring sex hormones and steroid precursors
Every year millions of cross-sectional imaging studies identify thousands of adrenal incidentalomas, of which only a tiny fraction will be malignant [7]. The odds of inciden- tally finding a primary adrenal malignancy, adrenocortical carcinoma (ACC), are extremely low. In fact, the incidence of such malignancies is 1 in 2 million people [8] Most adre- nal masses noted incidentally in patients without a known extra-adrenal malignancy are benign lesions, such as lipid- rich adrenocortical adenomas, myelolipomas, ganglioneu- romas, and cysts. Most malignant adrenal incidentalomas turn out to be metastatic carcinoma from either known or yet undiagnosed distant primary cancers. ACC can be hor- monally inactive or make one or more adrenal hormones. Patients with hormonally active ACC present with severe and rapid onset of symptoms of cortisol excess, hyperandro- genism, and rarely hyperaldosteronism.
Imaging
Imaging features of CT, magnetic resonance imaging (MRI), and positron emission tomography with 18F-2-deoxy-D-glu- cose (18FDG-PET) combined with CT help to distinguish benign from malignant lesions. Non-contrast CT allows cal- culation of a lesion’s tissue density measured in Hounsfield units (HU). Lesions measuring < 10 HU indicate a lipid-rich, benign adrenal adenoma. CT scans enhanced with contrast
allow for calculation of absolute or relative washout. Malig- nant lesions enhance rapidly but have delayed washout, so an absolute washout> 60% (10 to 15 min after contrast injec- tion) suggests a benign adenoma [9-11] as shown in Fig. 1. MRI has better contrast resolution than CT and does not expose patients to ionizing radiation. The loss of signal on opposed phase imaging is indicative of an adenoma [12-14].
The utility of FDG-PET/CT is based on the fact that many malignancies have increased glucose metabolism. However, functional, non-malignant lesions like pheochromocytoma may also demonstrate uptake of the FDG radiotracer, [15]. Although other modalities of functional imaging are not recommended for initial workup of adrenal lesions, meta- iodobenzylguanidine (MIBG) scans can be used in patients with suspected pheochromocytoma (Fig. 2).
The size of the nodule is also a predictor of malignancy. Most current guidelines recommend adrenalectomy for tumors >4 cm. The 4 cm cutoff has a sensitivity for malig- nancy of over 93%, but has very low specificity of 42%, due to the low prevalence of ACC [16, 17]. Because ACC is a highly aggressive cancer with very poor prognosis, surgery is often recommended for adrenal lesions > 4 cm, especially in younger patients without other comorbidities or extra- adrenal malignancy [13, 14]. Fine-needle aspiration biopsy is currently not recommended for adrenal lesions except in cases where the results will change the treatment, such as in
a Pre-contrast
b 2 min post- contrast
C 15 min post- contrast
a MRI
A
b MIBG
F
C MIBG
patients suspected to have metastatic disease to the adrenal gland. It has no role in the diagnosis of primary ACC [18]. Pheochromocytoma must be ruled out prior to biopsy to pre- vent catecholamine crisis [19].
Cortisol-producing tumors
It is reported that 5% to 20% of adrenal incidentalomas will secrete cortisol [1], causing classic Cushing syndrome or subclinical Cushing/autonomous cortisol production. Patients with Cushing syndrome have increased mortality and increased morbidity. High cortisol levels cause diabetes, hypertension, obesity, suppressed immunity, delayed wound healing, osteoporosis with fractures, and other symptoms that decrease quality of life. Clinical findings in patients with overt Cushing syndrome are proximal muscle weakness, thin skin with easy bruising and violaceous abdominal striae, and fullness of the dorsal and supraclavicular fat pads.
There are multiple ways to screen for hypercortisolism. A 24-h urine collection provides assessment of cortisol secre- tion. Late-night salivary cortisol measurement helps estab- lish the loss of normal diurnal variation, and dexamethasone suppression testing evaluates the negative feedback of cor- tisol on the hypothalamic-pituitary-adrenal axis-both of which are lost in patients with autonomously functioning nodules.
Although 24-h urine cortisol levels can detect increased glucocorticoid production, adequacy of collection needs to be ensured. Excretion of creatinine in the urine appropriate for age and sex (15 to 20 mg/kg in women and 20 to 25 mg/ kg in men) is often a good marker. In addition, multiple collections (2 to 3) can be done to improve accuracy. False- positive findings can result from physiological conditions such as those in patients who have exercised during the col- lection period. Depending on the assay used, certain drugs or medications can interfere with the measurement of uri- nary free cortisol (e.g., fenofibrate and carbamazepine if the HPLC assay is used). Twenty-four hour urine collection may be the test of choice for patients receiving estrogen therapy,
as estrogen increases cortisol-binding globulin and the value of total cortisol.
A low-dose (1 mg) dexamethasone suppression test is done by measuring serum cortisol level the morning after giving the dexamethasone dose between 11 pm and mid- night. A value < 1.8 mcg/dL is indicative of normal adrenal function, whereas a value > 5 mcg/dL is indicative of corti- sol-producing adenoma. Values in between are considered indeterminate and require additional testing with a high-dose dexamethasone suppression test. A value > 1.8 mcg/dL done after high-dose dexamethasone suppression test (8 mg over- night or 0.5 mg every 6 h for 2 days) has high sensitivity and can be used to establish the diagnosis of Cushing syndrome [20, 21]. Similar to the 24-h urine collection test, exercise and poor sleep after taking the medication can affect the results of dexamethasone suppression tests. Medications or conditions that affect metabolism of dexamethasone (i.e., drugs that affect CYP34A) or absorption (i.e., celiac dis- ease) can result in false-negative or false-positive results. Measuring dexamethasone level simultaneously with the cortisol is recommended. Dexamethasone suppression tests are not recommended in women receiving estrogen because the tests measure total cortisol, and estrogen increases the binding protein.
In a person with Cushing syndrome, there is loss of the cortisol nadir at midnight that happens in healthy individu- als. Therefore, a patient suspected to have Cushing syn- drome will have elevated cortisol, and it can be measured from a sample of saliva collected late at night. This test has high diagnostic accuracy. However, this test has limitations in certain people, such as shift workers or in people who have disrupted sleep patterns and are physically active or psychologically stressed at that time.
The most common hormonal abnormality noted in patients with adrenal incidentalomas is mild autonomous cortisol production, also called subclinical Cushing syn- drome. Patients lack overt symptoms and signs, but may present with comorbidities such as hypertension, diabetes, and osteoporosis. The diagnosis is based on biochemical evaluation; however, there is debate on diagnostic criteria.
An abnormal 1 mg dexamethasone suppression test result in combination with at least one other abnormal screening test is suggestive of subclinical/mild hypercortisolism.
Classic Cushing syndrome caused by a cortisol-secret- ing adrenal adenoma will be cured by adrenalectomy and is always an indication for surgery. Likewise, removing the source of excess cortisol in patients with subclinical Cushing syndrome is likely to diminish the severity or even eliminate the associated diseases. While adrenalectomy for patients with subclinical Cushing syndrome was often debated in the past, indications for surgery are broadening [5].
Numerous factors play into the operative and postop- erative management of Cushing syndrome. Normally, the tumors are rarely larger than several centimeters and are removed by laparoscopy. If a cortisol-producing tumor is larger than 4 to 6 cm, then the possibility of a hormonally active ACC has to be given serious consideration [6]. Adre- nalectomy tends to be technically difficult in patients with Cushing syndrome due to their body habitus. Not only are they usually obese, they also have a large amount of retrop- eritoneal fat deposition. Sometimes a golden yellow adrenal gland can be difficult to identify in a sea of golden yellow retroperitoneal fat. In such cases, laparoscopic ultrasonog- raphy can be helpful. On intraoperative ultrasonography, the adrenal gland and neoplasm appear hypoechoic compared with the surrounding fat. While not essential to the conduct of laparoscopic adrenalectomy, this tool can be a highly valuable adjunct to the surgeon skilled in its use [22, 23].
Immediately after adrenalectomy, patients with overt and subclinical Cushing’s develop adrenal insufficiency and require corticosteroid replacement. While surgeons do not administer stress dose steroids intraoperatively since levels are already elevated, all patients are started on intravenous hydrocortisone at a dose of 50 mg every 8 h postopera- tively. Since the vast majority of patients will go home on the first day after surgery, they are transitioned rapidly to oral hydrocortisone or prednisone. Because the duration of postoperative cortisol deficiency can be quite prolonged due to inadequate production by the contralateral adrenal gland, it is very important for patients to be monitored carefully. Return of function to the remaining gland may take 6 to 12 months or longer [5].
Aldosterone-secreting tumors
Only 1% to 3% of adrenal incidentalomas are aldoster- one-producing tumors [1], yet 5% to 10% of hypertensive patients have primary hyperaldosteronism [24]. Aldoster- onomas can present as unilateral or bilateral adrenal ade- nomas or adrenal hyperplasia. All adrenal incidentaloma patients with hypertension and/or unexplained hypokalemia should be screened for hyperaldosteronism. The aldosterone to renin ratio (ARR) of> 20-30 test is the most sensitive
for detecting hyperaldosteronism. Samples are best col- lected in the morning after the patient has been sitting for about 15 min. Potassium should be replete, and, if possible, patients should avoid medications that can have effect on ARR, particularly aldosterone antagonists.
False-positive results are seen in the presence of low renin levels even if plasma aldosterone is low. To overcome this, experts suggests using an aldosterone cutoff of>10 to 15 ng/dL while screening. Patients with increased ARR should consider undergoing testing with 1 or more of the confirmatory tests, except in the settings of unequivocal ele- vated aldosterone, suppressed renin, or low potassium. Oral sodium loading, saline suppression, fludrocortisone suppres- sion, and captopril challenge are the commonly available tests. There is no definitive evidence to recommend one test over the others. The choice of test is best determined by cost, patients’ capability, availability of lab testing, and physi- cian expertise. Identifying the source of excessive aldoster- one secretion is critical. Imaging cannot distinguish non- functioning from aldosterone-producing adenomas. Even in patients in whom CT or MR imaging demonstrates a uni- lateral neoplasm, the excess aldosterone may be the result of bilateral secretion or even a microadenoma within the contralateral gland [25]. As patients age, they are increas- ingly likely to develop non-functioning adrenal neoplasms, so the potential for harboring a non-functioning adenoma in a patient with bilateral adrenal hyperplasia increases in older subjects [7, 26].
Adrenal venous sampling (AVS), is the gold standard in distinguishing unilateral from bilateral disease [27]. AVS can be challenging and should be undertaken only after confirmatory testing. Such testing requires an interventional radiologist with special interest and expertise in cannulat- ing the adrenal veins. AVS is an invasive test not without risks, and because of technical challenges it is not success- ful 100% of the time. Interpretation of the results, which involves comparison of cortisol and aldosterone levels from each of the adrenal veins, as well as the inferior vena cava both before and after ACTH stimulation, can be intricate. Because blood in the left adrenal vein is diluted by its mix- ing with blood from the left inferior phrenic vein, the ratio of aldosterone to cortisol in each adrenal vein is compared rather than straight aldosterone levels. The other critical ele- ment in assuring an accurate assessment is the confirmation of at least a threefold increase in the cortisol levels between the adrenal veins and the infrarenal vena cava. Without that, it is not possible to guarantee adrenal vein blood was sam- pled [24].
Most endocrine surgeons recommend lateralization using AVS prior to adrenalectomy. However, if the patient in question is under 40, his or her likelihood of harboring an incidental adrenal adenoma is only 1% to 2%, and there- fore it is reasonable to schedule adrenalectomy based on
cross-sectional imaging alone [28]. As the vast majority of aldosteronomas are small, measuring anywhere from 5 to 15 mm, the finding of an adenoma> 2 cm in a patient with hyperaldosteronism should raise suspicion of a coincidental non-functioning neoplasm. In such a case, AVS is strongly advised.
Intraoperative management of hyperaldosteronism does not require any special consideration. Most patients are receiving multiple blood pressure medications, including potassium-sparing diuretics such as spironolactone or ami- loride as well as potassium chloride. If the operation has been successful, the need for potassium supplementation should cease within the first 24 h. Therefore, after any adre- nalectomy for aldosteronoma, potassium chloride should be discontinued and its value measured on the first postopera- tive day. In addition to potassium-sparing diuretics, many patients receive a combination of antihypertensive medica- tions such as beta blockers, calcium channel blockers, alpha blockers, ACE inhibitors, angiotensin II receptor blockers, and-in more severe cases-clonidine or minoxidil. Most providers will discontinue at least 2 of the antihypertensive agents, starting with diuretics and possibly agents used less frequently in the general population. Blood pressure read- ings will determine how many agents can be discontinued and over what period. This is a gradual process, and succes- sive decrements have been seen up to 1 year after adrenal- ectomy [29].
Catecholamine-secreting tumors
Pheochromocytomas are rare neuroendocrine tumors aris- ing from the chromaffin cells of the adrenal medulla with an incidence of 1 to 2 cases per million people [30]. They are also seen in various inherited endocrinopathies, including multiple endocrine neoplasia type 2, von Hippel-Lindau, neurofibromatosis type 1, and succinate dehydrogenase syn- dromes. The clinical presentation of pheochromocytomas varies. Patients may present with hypertension, palpitations, headache, and sweating. About 20% of patients present with normal blood pressure and none of the classic symptoms of pheochromocytoma. Such tumors are sometimes called “silent pheochromocytoma,” and hence it is recommended that all patients with adrenal incidentaloma be screened for pheochromocytoma.
Plasma and urine (24-h urine collection) metanephrine tests can be used to screen for pheochromocytoma. Most providers prefer the plasma metanephrine test because it is easier to perform. Moreover, it has 99% sensitivity and 89% specificity. Levels above 3-4 times the upper limit of normal are considered diagnostic of pheochromocytoma [30]. Because levels of plasma metanephrines are affected by many factors (e.g., position, activity, smoking, stress), it is recommended that the sample be collected from an
indwelling intravenous cannula after the patient has rested in a supine position for 30 min, as well as refrained from smoking for at least 4 h. In patients with elevated plasma metanephrine levels, additional testing, such as clonidine suppression, as well as additional imaging with nuclear medicine scans such and MIBG and FDG- PET can be help- ful to establish a diagnosis of pheochromocytoma. False- positive-plasma metanephrine results are seen in cases of sympathetic overactivity (e.g., acute illness/injury, pain, and anxiety), or can be secondary to many medications (tricy- clic antidepressants, selective serotonin reuptake inhibitors, serotonin norepinephrine reuptake inhibitors, MAO inhibi- tors, pseudoephedrine, and amphetamines), weight loss preparations (phentermine) and recreational drugs (cocaine). Patients should be screened for these causes and medica- tions will need to be discontinued whenever possible. Due to the high sensitivity false-negative results are extremely rare, and normal plasma metanephrines almost always rule out pheochromocytoma.
Once the diagnosis is made, surgery is virtually always indicated. Prior to proceeding to the operating room, several critical steps must be taken. It is important to consider the possibility of a genetically inherited disease. Recent reports suggest that > 30% of patients with pheochromocytoma har- bor a heritable gene mutation [31]. The well-known genetic conditions associated with pheochromocytoma are multiple endocrine neoplasia type 2, neurofibromatosis type 1, and von Hippel-Lindau syndrome. At the turn of the century, mutations in the succinate dehydrogenase (SDH) genes were found to be associated with familial pheochromocytoma and extra-adrenal pheochromocytoma, otherwise known as para- ganglioma. These include SDHB, SDHC, SDHD, SDHAF2, and SDHA gene mutations. More recently identified muta- tions in pheochromocytoma are those in the TMEM127, MYC-associated factor X (MAX), and Hypoxia-inducible factor (HIF2a) genes. Identification of a causative mutation plays an important role in the management of pheochro- mocytoma, not only for the patient but also for the family members. Certain mutations (e.g., SDHB) are associated with increased risk of metastatic spread and development of recurrent disease. Hence genetic testing is now recom- mended for all patients presenting with pheochromocy- toma, especially younger patients (younger than 50 years) and patients with paraganglioma. Patients with heritable pheochromocytoma, may present with unilateral or bilat- eral tumors. Those who present with unilateral tumor may develop contralateral disease in the future. For those reasons, some surgeons will leave behind some of the adrenal cortex when resecting the neoplastic portion of the gland [32, 33].
At the time of presentation, pheochromocytoma may be metastatic. Therefore, it is important during radiographic assessment to closely examine the tumor borders for evi- dence of irregularity or possible invasion of surrounding
structures as well as the presence of retroperitoneal ade- nopathy and possible liver metastases. The suspicion of malignant or metastatic pheochromocytoma does not preclude resection of the primary tumor, and it has been reported that removal of the primary tumor may be ben- eficial even in patients with metastatic disease. In cases of metastatic pheochromocytoma, the primary tumor is best removed via an open operation, which facilitates complete tumor removal without fracture of the capsule, as well as en bloc resection of the periadrenal lymph nodes and pos- sibly adjacent involved structures [30].
All patients with pheochromocytoma require preopera- tive medical management to control the effects of catecho- lamine excess intraoperatively [34]. Although the optimal preoperative preparation is often debated, most guide- lines recommend normalizing blood pressure along with restoring volume status with salt and fluids. Traditionally, a minimum of 2 weeks of phenoxybenzamine has been the gold standard [35]; however, many other agents, includ- ing alpha blockers such as doxazosin and calcium channel blockers, have been shown to be efficacious [30]. Phe- noxybenzamine is an irreversible, non-competitive alpha blocker and hence can have prolonged duration of action, which can cause hypotension in the postoperative period. Compared with other alpha blockers, phenoxybenzamine is quite expensive, and hence its use is decreasing.
The development of postural hypotension is a good indi- cation of adequate alpha blockade. A beta blocker should be added when patients develop tachycardia as a result of alpha blockade [30]. During surgery, the anesthesia team must be prepared to deal with sudden and rapid fluctua- tions in both heart rate and blood pressure. Adequate and appropriate preoperative management will help mitigate these fluctuations.
The choice of operative approach (open vs laparoscopic) should be based on the tumor’s size and malignant poten- tial and the surgeon’s expertise in order to cause minimal manipulation of the pheochromocytoma. Many surgical texts recommend dissection of the adrenal vein first so that it can be clamped, which will diminish potential spikes in circulating catecholamine levels. The potential problem of such an approach is that venous drainage is occluded, lead- ing to engorgement of the gland, increased bleeding, and therefore more difficulty carrying out a more lengthy opera- tion. For that reason, we believe that the best approach is to adequately chemically block the patient preoperatively and then perform the dissection by freeing the gland from the surrounding retroperitoneal fat and adjacent organs, clipping the vein once a good degree of mobilization has occurred and the vein is easily exposed. At the point when the vein is about to be transected, the surgeon must always alert the anesthesia provider, as there may be a sudden drop in blood pressure.
Pheochromocytomas may induce a surrounding inflam- matory response in the retroperitoneum, thus increasing the difficulty of dissection. This may lead to increased propen- sity to bleeding as well as to fracture of the tumor itself. Tumor fracture may increase the likelihood of recurrence and must be avoided [36-38].
After adrenalectomy for pheochromocytoma, patients should be monitored on telemetry in a special unit, as they are at risk of hemodynamic derangement in the immedi- ate 24 h after surgery. All antihypertensive agents should be discontinued, and some patients may need vasopressors briefly. Catecholamines inhibit pancreatic insulin secretion and hence there is rebound hyperinsulinemia with removal of pheochromocytoma [39]. Therefore, hypoglycemia is a potential complication after resection of pheochromocy- toma, and patients need routine glucose monitoring for 12 to 24 h.
Adrenocortical carcinoma
Suspicion for ACC is usually based on the tumor’s radio- graphic characteristics. Traditionally, large tumor size has been considered one of the most suspicious characteris- tics. The risk of malignancy is extremely low when tumors are <4 cm, whereas tumors> 6 cm are said to have a 25% risk of malignancy [16]. However, that risk is derived from retrospective surgical series. In a recent review published in the radiology literature, the risk is much lower [26]. Other features suggestive of malignancy include tumor heterogene- ity, irregular borders, infiltration of surrounding structures, and retroperitoneal adenopathy. Right sided tumors can pre- sent with invasion of the vena cava and pulmonary emboli [40] Fig. 3.
Up to two-thirds of ACCs are hormonally active. Patients may present with hypercortisolism alone (45%) or combined with hyperandrogenism (25%). Less than 10% of the patients present with only hyperandrogenism or hyperaldosteronism [41-43]. Other than symptoms associated with hormonal over activity, patients may present with local symptoms such as pain, early satiety, and fullness [42].
Surgery is recommended for all suspicious adrenal masses, especially above 4 cm. While some authors have advocated a laparoscopic approach to small adrenocortical cancers, most endocrine surgeons recommend open adre- nalectomy [44-47]. Manipulating an adrenal gland with laparoscopic instruments carries a higher risk for disrup- tion of the adrenal gland than does carrying out the same operation by a traditional open approach, and fracture of an ACC has been shown to increase recurrence rates [48]. The open approach also facilitates en bloc resection of retroperi- toneal lymph nodes and adjacent structures if invaded [44, 47]. Beginning with a laparoscopic approach is reasonable when an adrenal neoplasm is well circumscribed, < 10 cm,
a Pre-contrast
b 2 min Post-contrast
C 15 min Post-contrast
and of uncertain malignant potential. However, if evidence of malignant behavior is encountered during the course of surgery, the operation should be converted to open lapa- rotomy. At this time there, is no effective chemotherapy for ACC, and complete surgical removal offers the only real chance for cure. Multiple endocrine and surgical societies continue to recommend open adrenalectomy as the standard of care when adrenocortical cancer is suspected [6, 49, 50].
Metastatic cancer
In 27% to 73% of patients with a prior cancer diagnosis, the discovery of an adrenal neoplasm will prove to repre- sent metastatic disease [51]. Common primary tumors that metastasize to the adrenal glands include melanoma and can- cers of the lung, kidney, breast, and colon [52]. For many cancers, the finding of an isolated adrenal metastasis may not portend imminent death for the patient. There are reports of prolonged survival, and even cure, in such patients who have undergone metastasectomy [53]. Laparoscopic adrenal- ectomy for metastatic disease provides equivalent outcomes to an open operation with less morbidity and is the preferred approach. Metastases > 6 cm may require an open approach to ensure complete resection [54-56].
Surgery
As outlined above, adrenalectomy is recommended for patients with functional adenomas, indeterminate nod- ules>4 cm, and suspicion of malignancy. When a patient is referred for adrenalectomy, there are many considerations factored into the decision to operate, and this decision must be individualized based on a patient’s age and comorbidities. Increased patient age is not the only predictor of increased perioperative morbidity [57]. Rather, the presence of sig- nificant comorbidities, such as coronary artery disease, car- diomyopathy, chronic obstructive pulmonary disease, diabe- tes, and renal failure, may be contraindications to surgery, depending on their severity. However, in the era of laparo- scopic adrenalectomy, postoperative morbidity in the face
of these diseases is minimized because there is significantly less pain, and the inflammatory response is also much lower than that caused by conventional laparotomy [58].
Most adrenalectomies today are performed using lapa- roscopy. In 1992, the first report of such an approach was published [59]. The ability to safely remove an adrenal gland under general anesthesia using 3 to 4 incisions that meas- ured 5 to 15 mm each changed the approach to adrenal sur- gery almost overnight [60, 61]. Before this, adrenalectomy required a long subcostal incision that enabled exposure of this walnut-sized retroperitoneal gland tucked between the diaphragm and kidney, and surrounded by major vessels and multiple other organs. For larger tumors and those thought to be malignant, an even larger thoraco-abdominal incision was often employed.
The laparoscopic approach safely allows trained sur- geons to remove small benign functional or non-functioning neoplasms relatively quickly, and its use has significantly reduced perioperative morbidity. The benefits of the lapa- roscopic approach include decreased operative times, sig- nificantly less blood loss, decreased length of hospital stay, and less postoperative pain [62-65]. Initially, the maximum tumor size that was considered safe for laparoscopic removal was 6 to 10 cm, but over the past 2 decades, reports of safely removing tumors up to 15 cm have been published [66, 67]. As the ease and safety of adrenalectomy improved, the over- all number of adrenalectomies performed has significantly increased [68].
The first laparoscopic adrenalectomies were performed via a transabdominal approach, and this remains the most common technique. Subsequently, a posterior retroperitoneal approach was described and found to be equally safe and effective [32]. Its advantages include avoiding the perito- neal cavity, which is useful in patients who have had prior abdominal surgery and are likely to have many adhesions, as well as the ability to perform bilateral adrenalectomies with- out repositioning the patient. This is rarely necessary but can be useful in patients with inherited endocrinopathies who present with bilateral pheochromocytomas or in patients with a refractory pituitary or ectopic source of ACTH
leading to bilateral adrenal hyperplasia and severe Cush- ing syndrome. The disadvantage of the posterior approach is a small working space, and thus the inability to remove tumors that are> 6 cm in diameter [32, 69]. The posterior approach is also much more challenging in obese patients such as those with Cushing syndrome, in whom it is not possible to achieve the necessary angles for tumor removal with laparoscopic instruments.
Most American surgeons began by learning the laparo- scopic transabdominal approach. The initial transition from an open to a laparoscopic approach was facilitated because the anatomic landmarks and sequence of dissection were the same. The posterior retroperitoneal approach was cham- pioned by Dr. Martin Walz in Essen, Germany [32]. Now many surgeons are facile with both approaches. Mobility is limited in the confined space of the retroperitoneum. There- fore, if the adrenal is not readily visible when dissecting in its usual location, superior and medial to the upper pole of the kidney, the aid of laparoscopic ultrasonography can be highly valuable [22]. The operating surgeon should have thoroughly examined the adrenal gland’s location on CT or MRI. These glands may range in location from the renal hilum up to a completely supra-renal position. A gland that is located low and medial to the kidney will be especially difficult to remove from the retroperitoneal approach, and that should be factored into the operative plan. Both laparo- scopic approaches are superior to the open approach in terms of operative morbidity, and patients do equally well when operated on by experienced surgeons [69-71].
Robotic adrenalectomy has not been demonstrated to hold significant advantages for the patient over the more traditional laparoscopic approaches. [72] It remains a more expensive approach and is not used widely by endocrine surgeons.
Hormonally inactive benign incidentaloma
Prospective data with regard to natural history of benign- appearing non-functional adrenal masses is limited. Rec- ommendations are based on retrospective studies and are variable. AACE and AAES guidelines published in 2009 recommend that hormonally inactive lesions <4 cm with benign radiological characteristics undergo follow-up imag- ing in 3 to 6 months, and then annually for 1 to 2 years. The risk of enlargement is 14% at 2 years and 29% at five. They also recommend hormonal evaluation annually for 5 years, as the risk of developing hormonal activity is reported as 47%.[6] This typically manifests as sub-clinical Cush- ing syndrome. Beyond 5 years an individualized approach should be taken, monitoring for evidence of hormonal excess such as development of diabetes, hypertension etc. During follow-up, adrenalectomy is recommended if the neoplasm becomes hormonally active or increases in size by > 1 cm,
especially if accompanied by other radiological features sus- picious for malignancy.
In contrast the European Society of Endocrinology Clini- cal Practice Guideline does not recommend follow-up imag- ing in masses <4 cm with benign features. For indeterminate lesions that are not resected, follow-up imaging is recom- mended in 6 to 12 months, and resection is recommended if the lesion grows by 20%. They recommend against repeat hormonal evaluation unless signs of excess develop [5].
Conclusions
Adrenalectomy in the era of laparoscopic surgery is safe and effective for treating the majority of patients with adre- nal pathology. When an adrenal incidentaloma is identified, a biochemical workup and evaluation of the neoplasm’s malignant potential should be performed in all cases .. When considering surgery for a hormonally active neoplasm, the surgery and endocrinology consultants must not only make sure that proper patient workup and preparation have been performed prior to operating, but also that the appropriate medical management is instituted postoperatively. Deter- mining whether or not to remove a non-functioning adrenal lesion requires a comprehensive understanding of the radio- logical signs of malignancy, and is best done in concert with a skilled abdominal radiologist. Caring for these patients is very much a team effort, and patients will benefit from a close collaboration amongst the three specialties.
Acknowledgements Bryan Tutt in Scientific Publications provided editorial support.
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