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Adrenal Tumors: Anatomy, Physiology, Diagnosis, and Treatment
Abstract: Adrenal tumors are relatively common as seen on autopsy studies and computed tomography scans. Currently surgery is the treatment of choice for functioning adrenal adenomas and malignancies. Laparoscopy is the preferred surgical approach in the treatment of adrenal tumors as it is effective and less invasive. Minimally invasive procedures such as percutaneous ablations and transarterial embolizations have had an enormous impact on the treatment of tumors in other organs like the liver. More studies are needed to determine the appropriate place for these minimally invasive procedures in the management of adrenal tumors. The intent of this paper is to review the normal anatomy and physiology of the adrenal glands, as well as the workup and treatment of adult patients with adrenal tumors.
Key words: adrenal ablation, adrenal cancer, adrenal tumor, adrenal surgery, interventional oncology
Adrenal tumors are relatively common; autopsy studies show that approximately 5% to 15% of the general adult population has adrenal masses.1,2 Further, incidental adrenal lesions larger than 1 cm are seen in about 4.4% of all computed tomography (CT) scans.3 Approximately 90% of these lesions are benign nonfunctioning adenomas.4 Once an adrenal lesion is discovered, two basic questions need to be answered. First, is the lesion benign or malignant? Next, if benign, is the lesion a functioning or nonfunctioning mass? In the case of a primary malignancy and/or functioning adrenal mass, surgery is currently the first-line treatment of choice.
Functional adrenal masses represent a small percentage of adrenal tumors and are particularly complex to manage given the hormonal and neuroendocrine imbalances produced by these lesions. In these cases, pathophysiologic effects such as hypertension and abnormal electrolytes must be managed until definitive treatment can be provided. The management of functional malignancies can be particularly arduous given the dual task of treating the effects of excess hormone production as well as typical manifestations of malignancies such as mass effect, local invasion, and regional and distant metastasis.
Other than surgery, current treatment options include pharmacological therapies. These are used as an adjunct to surgery or as palliative treatment in those who are not surgical candidates. While there has been a move toward less invasive surgery with laparoscopy, the exact role of minimally invasive treatments as a part of the treatment algorithm for adrenal masses has yet to be determined. Interventional oncology is a growing field in which procedures like percutaneous ablations and transarterial embolizations are routinely used in the treatment of many cancers. These treatments have demonstrated a profound impact in the management of malignancies in various organs; liver malignancy is probably the best example. The advantages over surgery often include less trauma to the soft tissues, reduced recovery time, and decreased periprocedural morbidity and mortality. The literature about their use in this context is growing but still largely lacking. Further investigations are certainly warranted given the potential benefits of these procedures.
The intent of this review is to highlight key points about the normal anatomy and physiology of the adrenal glands, as well as the workup of adult patients with adrenal tumors. Further, current treatment strategies for adrenal masses will be assessed particularly when compared to the potential role of minimally invasive procedures offered by interventional oncologists.
Anatomy and Physiology
The adrenal glands are small paired organs located near the superior aspect of each kidney within Gerota’s fascia. They each weigh about 5 grams and represent far less than 1% percent of the total body weight. Each gland is made up of 2 very distinct regions, the cortex and medulla.
The adrenal cortex originates from mesoderm while the adrenal medulla arises from neuroectoderm. The cortex will eventually develop into 3 distinct layers, the zona glomerulosa, fasciculata and reticularis. Cholesterol is converted to aldersterone, cortisol, and androgen hormones in these zones, respectively. The adrenal medulla, on the other hand, is considered a part of the sympathetic nervous system. Stimulation of this portion of the gland results in the conversion of tyrosine to catecholamines.
During the majority of gestation, the fetal adrenal gland lacks the 3-beta-hydroxysteroid dehydrogenase enzyme, which is required to synthesize cortisol and aldostoerone; this directs steroid production toward dehydroepiandrosterone-sulfate (DHEA-S) production.5,6 It is postulated that placental corticotropin-releasing hormone (CRH) may regulate the increase in fetal adrenal steroidogenesis during the last weeks of gestation.7
Ultrasound is the preferred modality in the evaluation of the adrenal gland in neonates and infants given the lack of ionizing radiation. In adults, the adrenals are often not adequately visualized with ultrasound so CT or magnetic resonance (MR) imaging are the imaging modalities most often used. On cross-sectional imaging like CT, the right gland has an inverted ”V” shape and the left an inverted “Y” shape. The right gland is located posterior to the inferior vena cava (IVC), medial to the liver and lateral to the right diaphragmatic crus. On the left, the gland is positioned posterior to the splenic vein and pancreas, somewhat anteromedial to the upper pole of the left kidney and lateral to the left diaphragmatic crus.
The adrenal gland is supplied classically by the superior, middle, and inferior adrenal arteries. The superior branch supplies the superomedial aspect of the gland and originates from the inferior phrenic artery. The middle supplies the anteromedial aspect of the gland and arises from the lateral aspect of the aorta. The Inferior branch supplies the thickest portions of the gland, posterior and inferolateral and is a branch of the superior aspect of the renal artery.
The right adrenal gland is drained by 3 tributaries that join to form a trunk that drains into the IVC above the right renal vein. On the left, a draining vein from the adrenal gland forms a confluence with the inferior phrenic vein and becomes a common trunk that drains into the superior aspect of the left renal vein. Variations of this anatomy may be present in any given individual.
The cortex of these glands is a part of a complex axis involving the relay of homeostatic messages, the hypothalamo-pituitary-adrenal (HPA) axis. The hypothalamus produces corticotropin-releasing hormone (CRH), which stimulates the production of adrenocorticotropin hormone (ACTH) in the pituitary gland. This in turn generates a signal for the production of aldosterone, cortisol, and androgens in the adrenal glands.
As a part of a negative feedback mechanism, overproduction of any of these cortical hormones sends a message back to the hypothalamus and pituitary gland signaling a decrease in production of CRH and ACTH. In the case of a unilateral hyperfunctioning nodule, this likewise results in decreased hormone production from the contralateral gland as it no longer receives the neurohormonal stimulation from the pituitary gland.
In the adrenal medulla, the release of catecholamines is usually secondary to a response to stress. This results in a release of epinephrine and norepinephrine which leads to an increased cardiac output and a redistribution of the blood flow to muscular and hepatic circulations. When the circulating concentrations are low to moderate this usually causes only a small change in mean arterial pressure. When these concentrations are high, the arterial pressure is increased.
Pathophysiology
Abnormal conditions result when there is an overproduction of hormones from the cortex or catecholamines in the case of the medulla. These may be the result of an increased release of hormone from the hypothalamus or pituitary gland with increased stimulation of the adrenal cortex. Further, hyperplasia or neoplasia of the adrenal glands can cause elevated levels of hormones independent of pituitary stimulation. Conditions that may result include excessive cortisol (Cushing syndrome), overproduction of aldosterone (Conn disease), and increased levels of androgens.
In the medulla, elevated levels of catecholamines can occur in neoplastic processes such as pheochromocytoma or paragangliomas. This excess adrenaline may lead to significant adverse effects on the cardiovascular system as discussed previously.
On the other hand, surgical removal of a functioning adrenal cortical tumor can lead to an Addisonian crisis. This occurs because there is suppressed production of hormones from the hypothalamus, pituitary gland and the contralateral gland in the case of a unilateral nodule. When the hyperfunctioning gland is removed, this leaves a void in steroid production and the recovery is not immediate. This failure of adrenal function will result in disordered electrolytes and carbohydrate metabolism, which may lead to circulatory collapse, hypoglycemic coma, and death. Exogeneous steroid therapy is used to treat this condition particularly in the postoperative period.
Adrenal Tumors
Adenomas are the most common benign adrenal lesions.8,9 Most adenomas are nonfunctioning, 6% are functioning.8 Five percent of these functioning lesions are cortisol-secreting while 1% are aldosterone or sex-hormone secreting.8
Adrenal cortical cancer (ACC) is rare, comprising less than 5% of all incidentalomas. Sixty percent of these masses are functional.10 In the medulla, pheochromocytomas or paragangliomas can occur. The incidence of pheochromocytoma is 4% to 5% in patients with adrenal incidentalomas.11-14 Classically only about 10% of pheochromocytomas are malignant lesions.
Metastatic lesions to the adrenal gland are the most common malignancy of this organ. Lung cancer is the most common primary to metastasize to the adrenal gland.15
Myelolipomas are benign neoplasms composed of mature adipose tissue and a variable amount of hematopoietic elements. They represent 5% to 10% of incidentalomas and have a postmortem prevalence of 0.08% to 0.2%.16,17
Metastatic lymphoma to the adrenal gland is found in about 25% of autopsies and 4% of CT exams in patients with disseminated non-Hodgkin lymphoma.18,19 On the other hand, primary adrenal lymphoma accounts for 3% of extranodal lymphoma with <100 cases reported.20
Bilateral adrenal masses are seen in about 10% to 15% of the cases of adrenal incidentalomas. Etiologies of this finding include metastatic disease, congential adrenal hyperplasia, cortical adenomas, lymphoma, infection, hemorrhage, corticotropin (ACTH)-dependent Cushing disease, pheochromocytoma, amyloidosis, infiltrative disease of the adrenal glands, and bilateral macronodular adrenal hyperplasia.21,22
The focus of this review is primarily on the adult patient, but it is worth mentioning neuroblastoma given its tremendous significance in the pediatric population. They are the most common solid extracranial neoplasms of childhood and are developmentally derived from the sympathetic nervous system. They represent 8% to 10% of all pediatric neoplasms and 15% of pediatric cancer mortality.23 Approximately 10.5 per million children younger than 15 years of age are affected.23 The adrenal medulla is the site of origin in 35% of children younger than 15 years.
Diagnosis
Clinical Presentation
In the case of excessive cortisol production, Cushing syndrome can develop. This is characterized by obesity, rounding and reddening of the face, high blood pressure, diabetes mellitus, osteoporosis, thinning and easy bruising of the skin, muscle weakness, depression, and amenorrhea. One must keep in mind that there is an intricate relay of messages between the hypothalamus, pituitary gland, and adrenal gland. As a result, the major causes of this syndrome include corticotrophin-producing tumor of the pituitary gland, production of corticotrophin by a nonendocrine tumor, or a benign or malignant adrenal tumor.
Elevated aldosterone results in hypertension, muscle weakness, cramps, increased thirst, and increased urination. Laboratory abnormalities seen in these patients include metabolic alkalosis and hypokalemia. This is usually caused by a benign adrenal tumor (adenoma) and in some instances hyperplasia of both adrenal glands. Surgical removal results in a reduction of blood pressure and cessation of potassium loss.
In the case of elevated androgens, women develop excess hair growth most notable in the face along with amenorrhea. In adult men, the excess adrenal androgens may suppress gonadal function and cause infertility.24 A major cause is late-onset congenital adrenal hyperplasia and adrenal tumors.
In patients with pheochromocytoma, there may be vague symptoms at presentation. These include dizziness, dyspnea, and chest pain. The most common clinical sign in most patients with this lesion is hypertension. In up to 90% of cases, headaches may be a presenting symptom. Other symptoms include visual disturbances, polyuria, polydipsia, anorexia, weight loss, and psychiatric disorders including severe anxiety.
Labs
All incidentalomas should have evaluation with laboratory tests. Dexamethasone is a drug that acts like cortisol. If given to someone who does not have an adrenal tumor, it will decrease production of cortisol and similar hormones. In someone with a functioning adrenal cortex tumor, these hormone levels will remain high after they receive dexamethasone. The levels of cortisol are measured in the blood and in the urine. If an adrenal tumor produces cortisol, these levels will be abnormally high. These tests may be done after giving the patient a dose of dexamethasone.
Dexamethasone suppression test (DST) is used to confirm subclinical adrenal adenoma. If there is an abnormal 1 mg overnight dexamethasone suppression, this should be confirmed with 24-hour urinary free cortisone, serum ACTH concentration, dehydroepiandrosterone sulfate (DHEA-S) and high-dose (8 mg) overnight DST. If the elevated secretion of glucocorticoids is clinically evident, this is confirmed when the DST 8 AM serum cortisol concentration is greater than 5 mcg/dL (greater than 138 nmol/L).
Blood levels of ACTH will also be measured to help distinguish adrenal tumors from other diseases that can cause high cortisol levels. Other lab evidence of overproduction of adrenal cortisol is a low level of DHEA-S secondary to suppression of ACTH. Both may have undetectable serum levels as a result of the feedback inhibition caused by elevated cortisol.
Aldosteronomas are an infrequent cause of incidentalomas, with an occurrence rate of about 1%. As such, serum evaluation is recommended in patients with hypertension in the setting of an adrenal lesion. When these criteria are met, plasma renin activity and aldosterone should be measured.
Recommendations for the clinical evaluation of pheochromocytomas include cases in which there is a high pretest probability of pheochromocytoma based on imaging. A fractionated plasma free metanephrine level may be measured in addition to a 24-hour urine collection for creatinine, total catecholamines, vanillylmandelic acid, and metanephrines.
Most masses that are not typical for adenoma based on CT and MRI and not characteristic for pheochromocytoma based on imaging and laboratory tests may require biopsy, especially in the setting of known or suspected malignancy. Other indications include an adrenal lesion in patients with multiple malignancies, the need for staging a known malignancy, defining an unknown primary source or differentiating benign from malignant adrenal masses with equivocal imaging findings. While primary adrenal lymphoma is rare with fewer than 100 cases reported in the literature, secondary adrenal involvement is common and may occur in up to 25% of patients with lymphoma. In these patients, an adrenal biopsy is often necessary to establish the tissue diagnosis.25
Imaging
Imaging may be used to evaluate an adrenal lesion, including imaging of lesion size, density measurement on non-contrast-enhanced CT, in-phase and opposed-phase imaging characteristics on chemical shift (CS) MR, and enhancement pattern on multiphase CT. The primary goal is to distinguish benign from malignant lesions. Because the characterization of lesions as functional or not is also very important, laboratory assessment should also be performed in each of these cases as mentioned above.
Size is an important factor in the evaluation of an adrenal lesion. When lesions are smaller than 4 cm they are unlikely to represent an adrenal cortical carcinoma. This alone is not a reliable criterion, however. The size should be used in the context of other imaging features in order to characterize an adrenal lesion as an adenoma. About 70% of adenomas are lipid rich.26 On unenhanced CT, Hounsfield unit (HU) measurement of less than 10 has a sensitivity of 71% and specificity of 98% in the diagnosis of adenoma.9 When the density measurement of the lesion is 10 HU to 30 HU, intracytoplasmic fat is found in about 89% of the patients using CS MR.27 However, if the HU measurement is greater than 30, the sensitivity of CS MR for adenomas is only 13%. CT with washout assessment has been found to have a sensitivity of 100% and specificity of 80% when the density is greater than 10 HU as compared to CS MR with 76% sensitivity and 60% specificity.28
With the multiphase CT protocol, unenhanced series, arterial phase, and 15-minute delayed phase images are acquired. An absolute washout of greater than 40% or a relative washout of greater than 60% is consistent with a lipid-rich adenoma.
Absolute washout = [(enhanced HU) – (15 min delayed HU) / (enhanced HU) – (unenhanced HU)] x 100
Relative washout = [(enhanced HU) – (15 min delayed HU) / (enhanced HU)] x 100
Metser et al evaluated the performance of 18F-2-fluoro-2-deoxy-D-glucose-PET (18FDG-PET) in differentiating adenomas from malignant lesions. Using a standard uptake value cut-off of 3.1, for combined PET/CT data there was 100% sensitivity, 98% specificity, 97% positive predictive value, and 100% negative predictive value.29 Another PET radiotracer, 11C-metomidate, has been able to differentiate subcentimeter functioning adenomas from other adrenal incidentalomas.30
Adrenal Vein Sampling
Unilateral vs bilateral disease is also an important distinction to make in patients with primary hyperaldosteronism. Adrenal vein sampling is performed to make this determination. Localizing a unilateral, autonomous aldosterone-secreting adenoma or confirming bilateral adrenal hyperplasia has implications for patient treatment. In the case of the unilateral adenoma, surgery is the standard treatment while patients with adrenal hyperplasia are managed medically.31 Adrenal vein sampling is most commonly performed in primary aldosteronism.32-34 When no lesion is seen on imaging, it is also performed in cases of biochemically proven pheochromocytoma. In very few instances, it may be performed in adrenal Cushing disease or for syndromes of androgen excess.35
Treatment
Surgery
Surgery is considered the reference standard for the treatment of functioning adrenal tumors and appropriately selected malignancies. There has been a trend toward less-invasive surgical approaches with laparoscopy being the favored surgical option when possible over open surgery. Medical therapy is considered as an adjunct to surgery to ensure residual tumor is treated or as an alternative when surgery is contraindicated. Though the number is growing growing, there are relatively few studies that evaluate the use of other minimally invasive options such as percutaneous ablation or transarterial embolization. These procedures potentially represent the evolution of how adrenal tumors are treated, much the way liver and renal tumors are treated, for example.
There are many surgical approaches with associated advantages and disadvantages. The trend toward less-invasive surgical approaches in part is secondary to the recognition that less trauma generally leads to a faster recovery and decreased morbidity and mortality. The challenges faced by a surgical approach include the ability to easily reach the glands without manipulation of the bowel and other organs. Further, the presence of adhesions in patients with prior surgery makes an anterior open approach more difficult. Another problem arises when the adrenal gland or lesion is located about the renal hilum, a difficult location to access. The need to directly assess the region about the gland for evidence of direct spread or regional lymph nodes can make laparoscopy less effective. The following is a brief discussion of various approaches and the associated key advantages and limitations.
In the open approach, a major advantage is the ability to remove large tumors and adrenal cortical cancers. The posterior approach is limited in the assessment of intraperitoneal organs, an evaluation that is important in the determination of the presence of metastasis. Injury to the neurovascular bundle of the lower ribs can also lead to ongoing pain after the surgery. In the thoracoabdominal open approach, an incision is made 2 cm inferior to the ipsilateral scapula and the diaphragm is incised to enable access to the chest and abdomen with excellent visualization of the retroperitoneal structures. This technique may lead to pulmonary issues or prolonged time for gastroinstestional function, both of which may increase overall recovery time.36
In the less invasive laparoscopic approach, using posterior retroperitoneoscopy allows easier access when bilateral adrenalectomy is needed. Further, when the posterior approach is used, there is not an issue of tackling adhesions if the patient has had intra-abdominal surgery in the past. However, this approach can be a challenge for anesthesia and limit access to lesions located anteriorly or about the renal hila. Of note, with the use of robotic surgery, there is improved dexterity. This may allow for better access to the anteriorly located lesions and those about the hila.
In an attempt to avoid the potential complication of Addisonian crisis (occurs in 15% of surgical patients), partial adrenalectomies are performed. The goal is to preserve at least 30% of the gland function and avoid the need for supplement steroid therapy.37 This is particularly helpful in patients with functional adenomas but can also be helpful in patients with pheochromocytomas, multiple endocrine neoplasia type 2, or von Hipple-Lindau syndromes.38,39
Medical Management
Mitotane is an oral chemotherapeutic agent that inhibits cells of the adrenal cortex and their production of hormones. It is the most commonly used medication to treat patients with adrenal tumors. The drug destroys both cancer cells and normal adrenal tissue. About 80% of patients who use this medication have improvement. Side effects include nausea, vomiting, diarrhea, rashes, confusion, and sleepiness. This can be used as adjuvant therapy in patients who have had adrenal cancer resected or it can be used to mitigate the effects of hormonal excess. It has been used alone or in combination with other medications like the cocktail of cisplatin, doxorubicin, etoposide, and mitotane. In patients who do not respond to mitotane, ketoconazole and metyrapone may be useful in reducing the effects of hormone overproduction.
Percutaneous Ablation
The literature regarding the use of percutaneous ablation in the treatment of adrenal tumors is growing but still largely lacking. There is an expanding body of work to support the use of percutaneous ablations as an effective alternative in the treatment of adrenal tumors. The treatment of malignant tumors demands that every measure is taken to ensure the lesion is eradicated. When treating functional, nonmalignant adrenal tumors the key focus is on the adverse effects of the excess hormones produced. Certainly there is some risk of recurrent symptoms if the lesion is incompletely treated and residual tumor grows. However, in these cases, close imaging monitoring and the option to perform additional treatments make percutaneous ablations a very good therapeutic choice. Of note, in patients who otherwise may not be candidates for surgery, effective treatment can be achieved even in the case of malignant lesions.
There are a number of percutaneous ablative techniques that are potential options for therapy. These include radiofrequency ablation (RFA), microwave ablation (MWA), cryoablation, chemical ablation and nonthermal ablation with irreversible electroporation (IRE).
Radiofrequency ablation is the modality that is the most established of those listed above and has the largest body of research. This technology uses electrical current in the RF range in order to generate heat. This results in tissue necrosis in the lesion treated. In order to cause this effect, the temperature range should be 50-60 degrees celsius (C). Wood et al found that radiofrequency ablation was a safe and well tolerated procedure for the treatment of unresectable primary and metastatic adrenocortical carcinoma.40 There was minimal morbidity with effective control of adrenal cortical carcinomas, especially those lesions smaller than 5 cm. Fifteen lesions were treated and 53% showed nonenhancement on follow-up of about 10 months. Twelve lesions measured less than or equal to 5 cm; 8 showed complete loss of enhancement and decrease in size. In addition, this treatment has been used in patients with functioning cortical and medullary tumors. Mayo-Smith and Dupuy demonstrated that aldosteronomas and pheochormocytomas could be effectively treated with RF ablation.41 With a follow-up period of about 1 year, symptoms disappeared in both groups.
Microwave is still considered a relatively new ablative treatment modality. This technology uses microwave-range electromagnetic energy in tissue to cause water molecule agitation. This results in frictional heat and eventual cell death from coagulative necrosis. Major advantages over RF include shorter treatment times and potential larger ablative areas. Its efficacy has been demonstrated in the treatment of adrenal metastases. Li et al treated 9 adrenal metastases and demonstrated local control at 11.3 month follow-up.42 Wang et al treated 5 metastatic lesions to the adrenal gland and no recurrence was seen at 19 months.43 Further, 4 patients treated by Wolf et al demonstrated local control at 14.5 months.44
Cryoablation is on the other end of the thermoablation spectrum. As the name implies, subfreezing intratumoral temperatures lead to cell death. Argon gas under high pressure is passed through an internal aperture. This leads to expansion of gas within the aperture. As a result there is cooling by the Joule-Thomson effect. Two treatments are applied consisting of alternating 10-minute freeze with 8-minute thaw. This results in mechanical injury; intracellular ice crystals form and then melt. The cell ruptures due to intracellular hypotonicity, protein denaturation, and tissue ischemia develops from intravascular thrombosis. Temperatures as low as -150 degrees C can be achieved. One distinct advantage of this modality is that the ablation zone can be monitored by the size of the ice ball formed. Further, less pain has been reported. However, there is an increased risk of bleeding secondary to the inability to coagulate tissue during probe withdrawal when compared to RFA and MWA.
Welch et al achieved local control following cryoablation of 11 of 12 (92%) adrenal metastases with a mean follow-up of 18 months.45 In 4 patients treated with cryoablation, Abbas et al demonstrated a decrease in the number of antihypertensive medications required, blood pressure, aldosterone-renin ratio, and requirement of treatment for hypokalemia.46
In percutaneous chemical ablation ethanol or acetic acid induces denaturation, which leads to coagulative necrosis, small vessel thrombosis, and formation of fibrotic and granulomatous tissue, which deters tumor cell growth. An advantage in this treatment is the reduced risk of nontarget tissue injury, typically performed using several small (19-22 gauge) needles. However, this small ablation zone generally requires more frequent treatment sessions when compared to RFA.47,48
Xiao et al in 2008 performed 48 adrenal ablations using ethanol and acetic acid for primary functional and nonfunctional neoplasms.49 These treatments resulted in a complete response rate of 92.3% (24 of 26) and a partial response rate of 7.7% (2 of 26). In the case of metastases, there was only a complete response rate of 30% (6 of 20) and a partial response rate of 70% (14 of 20) 24 months after therapy.
Irreversible electroporation (IRE) is another percutaneous ablative technique that may have a potential role in the treatment of adrenal tumors. It uses short high-voltage pulses, which make cell membranes irreversibly permeable and cause cell death. Because there is no thermal energy used, it can be used close to critical structures unlike the above thermal-based techniques. In addition, heat sink is not a concern with IRE. Though there is growing data on the use of this nonthermal ablative technique in liver, pancreas, kidney, and lung, the use in the treatment of adrenal tumors is not well documented.50-54
Complications that can be seen in the above ablations include hypertensive crisis, Addisonian crisis, thermal injury to adjacent structures (IRE is the exception), bleeding, infection, tract seeding, and cryoshock (associated with cryoablation).
In patients who are not surgical candidates and those who are stage IV with metastases to the adrenal gland, these ablative treatments appear to hold promise. The same is the case for patients with functional tumors. This is in contradistinction to adrenal cell carcinoma, which may be potentially curable with surgical resection. The reduced risks of residual or recurrent disease in patients who undergo surgical resection explains why surgery is the treatment of choice in this context.
In keeping with the philosophy that the least invasive techniques potentially represent the best chance to further reduce morbidity, mortality, and cost, ablative techniques appear to represent the next step in the evolution of how adrenal tumors are routinely treated.
Transarterial Embolization
The current indications for the use of adrenal artery embolization are centered around palliation and adjunctive therapy to surgery. These include the use for pain relief and size reduction in order to minimize the effect of large adrenal masses. Transarterial embolization is also used in the preoperative treatment to reduce bleeding when there is increased tumor vascularity. Further, this technique can be effective in the suppression of excess adrenal hormone production, treatment of traumatic adrenal artery injury, and occlusion of adrenal artery aneurysms.
There is the potential for significant challenges given the small caliber of the vessels, which can make catheterization of adrenal arteries difficult. These arteries are visualized at catheter aortography in 57% to 92% of patients without adrenal disease and typically are not seen well at CT angiography.55 As a result, additional radiation exposure and more contrast medium may be required. These are both undesirable as they pose risks to the patient. Further, as the bleeding source could arise from any one or more of the 3 branches of the adrenal artery, embolization may involve more than 1 vessel. This could make treatment even more tedious.
If transarterial embolization is deemed the best course of treatment, there is no consensus about the best embolic agent to use. In large part, the agent chosen is dependent on the clinical scenario and operator preference. In the case of hemorrhage, proximal embolization with microcoils may be preferred so to allow for continued distal circulation. The deployment may be difficult if the vessel is particularly small and/or tortuous. Polyvinyl alcohol (PVA) and triacryl gelatin microspheres such as embospheres may serve as good choices for the treatment of adrenal tumors without hemorrhage as distal embolization is desirable. Ethanol, a liquid embolic agent, may be advantageous in this context as it can permeate to the level of the capillary bed. It causes coagulative necrosis by sclerosis of the endothelium and resultant fibrotic reaction in the lumen. Other liquid embolic agents include N-butyl cyanoacrylate glue and onyx. Particularly in the case of glue, which is an adhesive agent, care must be taken to avoid the entrapment of the catheter in the embolized vessel. Gelatin sponge is a temporary agent that may be effective in the treatment of hemorrhagic tumor masses and suppression of hormonal function. There are only a few reports about chemotherapeutic agents but not enough to draw conclusions about their effectiveness at this point.
The potential complications as with any other transarterial embolization include nontarget embolization, contrast induced nephropathy, and the skin/soft tissue effects of excess radiation exposure. It is worth noting that spinal arteries can originate from the middle adrenal artery.56 A case of transverse palsy of the lower extremities has been reported after inadvertent embolization of the anterior spinal artery in a patient treated for a hepatocellular carcinoma met to the adrenal gland.57 As such, particular care must be taken prior to the administration of an embolic agent as is usual practice.
External Beam Radiation Therapy
External beam radiation treatment uses photon beams generated by linear accelerators. A specific type of this treatment is called stereotactic body radiation therapy (SBRT) also known as stereotactic ablative body radiotherapy (SABR). As opposed to the daily small fractions of radiation provided over several weeks by traditional external beam radiation therapy, SABR delivers larger fractions of radiation over a few treatments, typically 3 to 5. Further, most of these systems use image guidance to ensure the planned target is irradiated while minimizing damage to adjacent tissue. There are limited data on the use of these therapies in the treatment of adrenal tumors; most of the studies focus on the use in the treatment of adrenal oligometastases.58,59 In a systematic review comparing surgery to ablative techniques in the treatment of adrenal metastases, 45 papers were evaluated (30 adrenalectomy, 6 perctaneous ablation, and 9 SABR).60 Given the variable reporting, there was insufficient evidence to determine the best local treatment modality. Nonetheless, weighted 2-year local control for adrenalectomy was 84% and SABR 63%. In the case of percutaneous RFA/MW ablation, the extrapolated figure for 2-year local control was 64%.60 There were no overall survival data provided for the percutaneous ablative techniques, but for surgery the 2-year weighted figure was 46% and for SABR 19%. The authors concluded that more studies were warranted before percutaneous ablative techniques could be recommended in the treatment of adrenal oligometastatic disease.
Summary
Adrenal tumors can be particularly complex to manage when the lesions are functional and/or malignant. Surgery is currently the treatment of choice for these masses. There has not yet been a comprehensive evaluation of minimally invasive procedures like percutaneous ablations and transarterial embolizations in the treatment of these lesions. Given the potential benefits of reduced postprocedural complications, morbidity, and mortality, further studies are warranted to evaluate their role as a part of the treatment algorithm of adrenal tumors.
Editor’s Note: Disclosure: The author reports no financial relationships or conflicts of interest regarding the content herein. Address for correspondence: Please email all inquiries to r.baker1@med.miami.edu.
Suggested citation: Baker RL. Adrenal tumors: anatomy, physiology, diagnosis, and treatment. Intervent Oncol 360. 2015;3(1):E1-E14.
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