management of isolated adrenal lesions in cancer patients

April 2011, Vol 18, No. 2 Cancer Control 113

From the Endocrine Tumor Program (KM, HL, JBT, WBC) and the Radiation Oncology Program (SH) at the H. Lee Moffi tt Cancer Center & Research Institute, Tampa, Florida.

Submitted October 29, 2010; accepted January 29, 2011.

Address correspondence to W. Bradford Carter, MD, Endocrine Tumor Program, Moffi tt Cancer Center, 12902 Magnolia Drive, FOB-2, Tampa, FL 33612. E-mail: Bradford.Carter@moffi tt.org

The authors report no signifi cant relationship with the companies/organizations whose products or services may be referenced in this article.

IntroductionWithin the cancer population, the discovery of an adrenal mass inevitably leads to a discussion of appropriate man-agement. Since a high percentage of these masses are metastatic, tissue diagnosis may be essential to treatment planning. In many patients, the morbidity of an image-guided biopsy may be avoided and even contraindicated

if the mass is a primary adrenal neoplasm. In this review, we explore the incidence, diagnosis, and indication for resection of adrenal lesions in cancer patients, and we suggest a pathway for evaluation and treatment.

Adrenal masses are among the most common of all human tumors, with the prevalence of adrenal inci-dentaloma at 3% in middle age and increasing to up to 10% in the elderly.1 Between 1% to 4% of all abdominal imaging studies reveal an adrenal incidentaloma, so with the prolifi c use of imaging, the number of incidentalomas is increasing. Most are benign, but 2.5% are metastatic disease to the adrenal from another cancer.2 In a meta-analysis of 32 studies ranging from 1982 to 2002, 19% of adrenal incidentalomas were metastases and 10% were primary adrenal cortical cancers. These studies included 20 or more patients and did not exclude patients with known cancers. Studies that excluded patients with

The incidence, diagnosis, and indication

for resection of adrenal lesions in cancer

patients are reviewed, and a pathway for

evaluation and treatment is presented.

Rebecca Kinkead. Rope Swing (detail), 2010. Oil on canvas, 46� × 52�.

Management of Isolated Adrenal Lesions in Cancer PatientsKelly McLean, MD, Howard Lilienfeld, MD, Jamie T. Caracciolo, MD, Sarah Hoffe, MD,

John B. Tourtelot, MD, and W. Bradford Carter, MD

Background: Adrenal lesions are commonly identifi ed in patients with extra-adrenal cancer. When lesions are present, it is important to identify if the lesion is a metastasis of the primary cancer or a primary adrenal neoplasm. If primary, the adrenal lesion must be evaluated for hypersecretion and its malignant potential determined for appropriate treatment planning.Methods: Recent literature was reviewed that focused on the normal investigation of adrenal lesions including radiographic imaging and hormonal evaluations as well as specifi c focused therapeutic options available for isolated metastatic adrenal lesions. Results: This review presents a pathway approach in investigating these lesions and also discusses various potential treatment options.Conclusions: A proper investigative workup of an adrenal lesion in a cancer patient is critical for proper management. Isolated adrenal metastatic lesions in the cancer patient should be surgically removed when possible, but other options can be considered. In patients who do not have metastasis from extra-adrenal cancer, the decision for surgical resection is dependent on functionality of the tumor and it’s potential for malignancy. Observation plays a key role in those tumors that are nonfunctioning and have a low risk of malignancy.

114 Cancer Control April 2011, Vol 18, No. 2

known malignancies reported much lower incidences of incidental metastases.3 The median time from cancer diagnosis to identifi cation of adrenal metastases was 2.5 years, although adrenal metastases have been discovered up to 22 years after initial treatment.4

IncidenceMany metastases to the adrenal glands remain undetect-ed. In a retrospective study over 30 years, Lam and Lo5 identifi ed 464 patients with metastases to the adrenal gland. Of these, 435 (94%) had metastases that were detected postmortem. A total of 49% of the patients had bilateral adrenal metastases at the time of discovery. Adrenal metastases were the initial presentation in 6 pa-tients, and in two-thirds of the patients, their metastases were detected at the same time as the primary. Of the remaining patients, the adrenal tumors were identifi ed over a median duration of 7 months after the primary, with only 8 patients (< 2%) having adrenal metastases detected over 5 years from the initial tumor diagnosis.

The most common malignant lesions that metasta-size to the adrenal include malignant melanoma, renal, breast, colon, lung, and bronchial carcinomas. Lung and breast cancers account for 39% and 35% of adrenal me-tastases, respectively. Adrenal metastases can be seen in up to 40% to 50% of patients with late-stage melanomas and renal cell cancers.6-8

However, with more cancers detected at earlier stag-es, fewer metastases are found. For example, in renal cell carcinoma, > 60% of all new cases are now incidentally detected on imaging and present with early stage I or II disease. Adrenal metastasis should be suspected in any

patient with a history of cancer who presents with an adrenal tumor, especially if the tumor is > 2 cm.9

DiagnosisPatients with adrenal metastases are typically asymptom-atic. When they are symptomatic, they typically present with back pain representing local invasion, retroperito-neal hemorrhage from tumor necrosis, or adrenal insuf-fi ciency.6 Lam and Lo5 reported that 4% of patients with adrenal metastases presented with symptoms. Also, 1% of all patients were Addisonian due to lack of cortisol release. The low incidence of Addison’s disease in adre-nal metastases may be attributed to the fact that > 90% of the adrenal glands must be destroyed before there is functional adrenal cortical loss. Even in patients with a history of a known malignancy, 50% of adrenal masses are benign and thus a defi nitive diagnosis must be made.10

Imaging of the adrenal glands is largely performed by cross-sectional imaging modalities including computed tomography (CT) and magnetic resonance imaging (MRI). Ultrasonography (US) has a limited role in the evaluation of adrenal masses, though occasionally a suprarenal mass may be detected at abdominal or renal US performed for other clinical indications. Nuclear medicine studies such as I131 MIBG scans are often utilized once an adrenal lesion is detected and/or there is clinical suspicion for pheochromocytoma. Newer radiopharmaceuticals are also available in select cases for the evaluation of adre-nal adenoma. Additionally, [18F]FDG positron emission tomography (PET) may help to differentiate between benign and malignancy lesions based on threshold stan-dardized uptake value (SUV).

Table. — Diagnostic Imaging Characteristics of Adrenal Lesions

Adrenal Lesion Diagnostic Imaging Characteristics Comments

Adenoma Unenhanced CT < 10 HUSignal suppression on chemical shift MRI> 60% washout

Most common massOften detected incidentallyCan be hyperfunctional

Hyperplasia Bilateral adreniform thickeningMay suppress at chemical shift MRI

Usually stable over timeCan be hyperfunctional

Hemorrhage Hyperdense on CTHyperintense on T1-weighted MRIResolves over time

Often seen in trauma, anticoagulation, and sepsisExcludes underlying mass

Cyst/pseudocyst Fluid attenuation or signal intensityLack of enhancement

Often sequela of hemorrhage or infection

Myelolipoma Macroscopic fat on CT or fat-saturated MRI Larger lesions at risk for spontaneous hemorrhage

Pheochromocytoma Hyperintense signal on T2-weighted MRIPositive MIBG scan

Typical clinical presentation or elevated catecholaminesExtra-adrenal pheoparaganglioma

Primary adrenocortical carcinoma Large heterogeneous aggressive tumor with necrosis and hemorrhage

Often locally invasiveMay metastasizeMay be hyperfunctional

Metastatic disease Large heterogeneous massOften bilateral masses

Most commonly from lung, breast, gastrointestinal, renal, pancreas


Fig 1. — Lipid-rich adrenal adenomas in 2 patients. Unenhanced abdominal CT (A) demonstrates ovoid, homogeneous left adrenal mass with attenuation < 10 HU. In-phase (B) and opposed-phase (C) T1-weighted gradient echo (GRE), or chemical shift MRI, demonstrates lipid rich adenoma of the left adrenal with marked signal suppression on the out-of-phase acquisition.

When an adrenal mass is detected, characterization can be performed by several different imaging tech-niques (Table). The technique employed is usually de-termined by institutional preference and experience as well as other clinical factors such as patient history and presentation (ie, known malignancy or hypertension). However, adrenal masses are often detected incidentally at contrast-enhanced abdominal CT performed for other reasons such as abdominal pain or trauma. In this case, many masses are deemed indeterminate, and a dedicated examination is required for further characterization.

Unenhanced abdominal CT can reliably differentiate between lipid-rich adrenal adenomas and nonadenomas, with a specifi city of 98% and a sensitivity of 71%.11 Lipid-rich adrenal adenomas demonstrate unenhanced attenu-ation values < 10 Hounsfi eld units (HU) due to the pres-ence of intracellular lipids. The presence of intracellular lipids also allows for diagnosis of lipid-rich adenomas at chemical shift MRI, also known as in-phase and opposed-phase T1-weighted gradient echo (GRE) imaging (Figs 1A-C). Intracellular lipids and water protons process at different frequencies such that at a predetermined echo time based on magnetic fi eld strength, the protons will be pointed in exactly opposite directions (“opposed” or “out of phase”). Therefore, any voxel containing both lipid and water will demonstrate signal suppression on chemical shift MRI. The signal intensity (SI) index can be used to quantify signal suppression, defi ned as:

(SI in phase – SI out of phase) / (SI in phase) × 100

When the SI index is > 16.5%, chemical shift MRI can differentiate adenoma from metastatic disease with 100% accuracy12 and can identify lipid-rich adenomas with 100% sensitivity and 67% specifi city.13 Unenhanced and contrast-enhanced CT with percentage washout calcula-tion can also be used to evaluate adrenal masses. This technique requires the acquisition of unenhanced phase (U), early phase (E; 60 seconds), and delayed phase (D; 15 minutes) contrast-enhanced imaging for percentage washout calculation defi ned as:

(E – D) / (E – U) × 100

Greater than 60% washout yields 96% sensitivity and 88% specifi city for adrenal adenomas.14

Several other common adrenal masses have specifi c imaging characteristics that allow for a confi dent diag-nosis (Figs 2A-D). The presence of macroscopic or bulk fat with negative HU on CT or signal suppression on fat saturation MRI techniques indicates myelolipoma, an adrenal tumor containing myeloid and fatty elements. Pheochromocytomas classically demonstrate markedly increased signal intensity on T2-weighted MRI and accu-mulate MIBG on nuclear medicine scans. Adrenal hem-orrhage demonstrate increased attenuation on CT and

increased signal intensity on T1-weighted MRI and should resolve or decrease in size over time. Adrenal hemorrhage often occurs in the setting of trauma, anticoagulation, or sepsis, but an underlying lesion should be excluded. Adrenal cysts demonstrate similar imaging characteristics to simple cysts elsewhere in the body, such as fl uid attenu-

A

B

C


ation/signal intensity and lack of enhancement. Adrenal hyperplasia usually presents with bilateral adreniform thickening of the adrenal glands that is often stable over time and can be hyperfunctional. Primary adrenocorti-cal carcinoma and metastatic disease are typically large, heterogeneous masses that do not demonstrate signal suppression on chemical shift imaging and often show areas of hemorrhage and necrosis (Figs 3A-B and Fig 4). Metastatic disease is commonly bilateral.

Certain imaging characteristics of an adrenal mass may limit the differential diagnosis and require further evaluation, such as biopsy or PET. In general, adrenal adenomas measure > 3 to 4 cm, are rounded or ovoid in confi guration, and demonstrate internal homogene-ity. Conversely, malignant masses are often much larger, exceeding 5 cm with irregular margins and internal het-erogeneity. Aside from adrenal cysts, most benign and malignant lesions enhance following the administration of iodinated or gadolinium-based contrast agents; there-fore, enhancement alone is not a predictive feature of malignancy. Finally, lipid-poor adrenal adenomas, which

may represent up to 30% of adrenal adenomas, do not demonstrate signal suppression at chemical shift imaging due to minimal intracellular fat, but they usually show other imaging characteristics suggestive of benignity such as small size and homogeneity. In this case, surveil-lance to ensure stability may be a reasonable manage-ment strategy. As the most common adrenal mass, adrenal adenoma should lead the differential diagnosis of an in-cidental adrenal mass, and imaging should be performed to confi rm the diagnosis. In fact, one study noted that in 973 consecutive patients with an incidental adrenal mass and no history of primary neoplasm, no malignant lesions were identifi ed.15 However, medical history plays an important role in other patients with primary tumor or signs of hypersecretion. In patients with known primary malignancy, metastatic disease should be excluded fi rst since distant metastatic disease would upstage the patient and have a profound effect on management. Similarly, in patients with clinical signs of hypersecretion, imaging evaluation should be performed to diagnose hyperfunc-tional adrenal adenoma or pheochromocytoma.

A B

C D

Fig 2. — Common benign adrenal masses. (A) Contrast-enhanced abdominal CT demonstrates right adrenal myelolipoma with well-defi ned margins, measuring < 4 cm and containing a globular area of internal fat. (B) Fat-suppressed T2-weighted MRI demonstrates right adrenal pheochromocytoma with markedly increased signal intensity greater than that of the spleen. (C) T1-weighted MRI demonstrates adreniform thickening of the left adrenal and a right adrenal nodule in a patient with adrenal hyperplasia. (D) T2-weighted MRI demonstrates simple-appearing cyst of the left adrenal that did not enhance.


In the common clinical scenario of an adrenal mass detected in a patient with a known or recently diagnosed primary malignancy, unenhanced CT or chemical shift MRI could initially be performed in an effort to diagnosis a lipid-rich adenoma. If the mass remains indeterminate, [18F]FDG-PET has been shown to differentiate between benign and malignant disease with a sensitivity of 100% and specifi city of 98% at a threshold SUV of 3.1.16

Metabolic StudiesAll patients with adrenal masses should undergo bio-chemical evaluation for cortical or medullary hyperfunc-tion, particularly prior to biopsy or therapy.17 Patients should be questioned for signs and symptoms of a meta-bolically active primary adrenal tumor such as hyperten-

sion, tachycardia, headache, palpitations, hirsutism, gyne-comastia, sudden weight gain, change in body habitus (particularly truncal obesity), and progressive myopathy.6

A complete metabolic workup is necessary to iden-tify a pheochromocytoma and any functional adrenal mass. Functional adrenal tumors effectively rule out a metastatic lesion. Anywhere from 26% to 94% of adre-nocortical carcinomas are hyperfunctioning,3 and when multiple adrenal hormones are elevated, a primary adre-nocortical carcinoma should be suspected.18 A metabolic evaluation should be performed to determine excess cortisol, aldosterone, and androgens as well as metaneph-rines. Supraphysiologic hormone production suggests primary adrenal neoplasia and not metastatic disease.

Plasma levels of testosterone and estradiol may be measured; however, hypersecretion of sex hormones is usually clinically evident by signs of virilization or feminization. Benign masses secreting androgens or es-trogens are rare, and therefore all should be approached as if malignant.

Measuring the levels of fractionated plasma-free metanephrines is a more sensitive and convenient test for pheochromocytoma than measuring 24-hour urine levels of fractionated metanephrines, free catecholamines or vanillylmandelic acid (VMA). Levels of plasma cat-echolamines, however, are less specifi c than a urinary test.

Spontaneous hypokalemia (≤ 3.5 mmol/L) combined with hypertension is highly suspicious for mineral corti-coid excess. However, more than 50% of patients with pri-mary aldosteronism are normokalemic. Although plasma potassium should be checked, a normal level does not exclude an aldosterone-secreting mass.19 The most effec-tive test for screening for an aldosterone-secreting tumor is measurement of the plasma levels of aldosterone and renin activity checked with the patient sitting upright. An aldosterone-to-renin ratio ≥ 20 is suspicious for an aldosterone-secreting tumor if plasma aldosterone is also

Fig 3. — Contrast-enhanced CT through the right adrenal. (A) A large, heterogeneous, irregular mass and (B) an ill-defi ned mass proven to be primary adrenocortical carcinoma presenting with rib metastasis are shown.

Fig 4. — Contrast-enhanced CT demonstrating large, bilateral, heterogeneous adrenal masses with areas of internal hemorrhage and necrosis in a patient with lung cancer and right pleural effusion.

A

B


elevated (> 15 ng/dL).19 A ratio of plasma aldosterone to plasma renin of > 30 combined with a plasma aldosterone level > 20 ng/dL has a sensitivity of 90% and a specifi city of 91%.20 Kidney failure, beta blockers, antisympathetic agents, and calcium channel blockers all interfere with the aldosterone-renin pathway and may alter plasma al-dosterone and renin levels.3 Additional testing with the 25-mg captopril test, salt-loading or saline infusion tests, or fl udrocortisone suppression test should be used to con-fi rm primary aldosteronism.3 If biochemical evidence of hyperaldosterism is obtained, selective venous sampling for aldosterone should be obtained prior to resection. A ratio of at least 3:1 confi rms lateralization of production and subsequent correction after adrenalectomy. At least 60% of Conn’s syndrome is bilateral, even with imaging that identifi es a unilateral tumor.21

Adrenocortical carcinomas, adrenal adenomas, and bilateral hyperplasia may secrete cortisol. Screening for a cortisol-secreting tumor should include a 24-hour uri-nary free cortisol level or a fasting a.m.cortisol level, with an adrenocorticotropic hormone (ACTH) level and a dexamethasone suppression test to confi rm autonomy.17

A basal urinary free cortisol excretion > 3 times the upper limit of normal is diagnostic for hypercortisolism. Cortisol-secreting tumors may alter the circadian rhythm of cortisol secretion, leading to an elevated midnight cortisol level. Based on this premise, testing the midnight salivary cortisol level has gained popularity due to its higher sensitivity and ease of collection19 and should be performed on two consecutive days. The addition of the dexamethasone suppression test helps catch false-neg-ative results in patients who were not identifi ed by the urinary free cortisol test. Failure to suppress the cortisol level to < 1.8 mg/dL identifi es autonomous production of cortisol. ACTH levels may be suppressed or normal on baseline but should suppress with dexamethasone. A dexamethasone level may be drawn concurrently to confi rm compliance with taking the medication, particu-larly with equivocal results.

We recommend that all functioning adrenal lesions be removed, if practical (Fig 5).

BiopsyIn patients with known extra-adrenal malignancy, 32% to 72% of incidentally found adrenal masses were metastases and 28% to 68% were benign.1 In patients with operable non–small cell lung cancer (NSCLC) and an adrenal mass, 44% are benign neoplasms and not metastases.22 In the absence of other metastases, due to the high incidence of benign adrenal masses in patients with malignancies, an adrenal biopsy may be required in patients with a nonmetabolically active adrenal mass and inconclusive imaging.23 Several studies have shown that the sensitivity of fi ne needle aspiration (FNA) to diagnose malignancy ranged from 81% to 100% and specifi city ranged from 83% to 100%.3 However, in patients with an already known

extra-adrenal malignancy, percutaneous FNA has a positive predictive value of 100% and a negative predictive value of 92%.24 Cytological indicators of metastatic carcinoma include increased nuclear hyperchromasia, prominent nucleoli, necrotic debris, and increased nuclear/cytoplas-mic ratio in intact cells.6 A skilled cytopathologist who can confi rm the adequacy of a specimen is critical in the accuracy of fi ne needle biopsy.

Although FNA tends to be more accurate for larger masses when larger gauge needles are used,25 the use of smaller needles (22–25 gauge) has reduced the incidence of bleeding from the biopsy.10,26

Complication rates for percutaneous FNA of the ad-renal range from 0% to 3%, most of which are self-limit-ed.24,26,27 In a review of the literature, 36 complications were reported on 888 adrenal mass biopsies, including 1 tract site recurrence and 26 potentially serious complica-tions, 9 of which required hospitalization.3

In general, FNA is highly accurate in distinguish-ing between adrenal cortical lesions and metastases in patients with a known malignancy. FNA can also help defi ne a primary malignancy of unknown origin.6 His-tologic distinction between benign adrenal lesions and primary malignant ones, however, is much less accurate, with sensitivity ranging from 54% to 86%.17

Indications for ResectionIn general, increased median and overall survival has been demonstrated for resection of clinically isolated adrenal metastases when compared to nonsurgical therapy.28-32 Since resecting isolated metastases in other organs has achieved long-term, disease-free survival, it is reason-able to expect that resecting isolated metastases to the adrenal gland should provide similar results. Numerous reports exist about patients who are cancer-free many years after resection of isolated adrenal metastases. Crit-ics argue that these patients may have survived just as long without resection because their underlying disease is slow-growing.32

Two studies reported improved survival in patients who had NSCLC with isolated adrenal metastases treated with surgical resection over those treated nonsurgical-ly.32,33 Luketich and Burt33 reported a median survival of 31 months for patients who underwent adrenalectomy compared with a median survival of 8.5 months for those receiving chemotherapy alone. No patients in the che-motherapy group survived more than 22 months. In another study of patients with lung cancer whose solitary site of metastasis was to the adrenal gland,34 a review of 11 reports that included a total of 32 patients showed a median survival of 2 years, with one-third of the patients surviving > 5 years after adrenalectomy. In general, 1 in 4 patients achieve a 5-year disease-free survival; therefore, adrenalectomy should be offered to patients with isolated adrenal metastases, particularly when the primary cancer is well controlled.29


1 Autonomous production of cortisol, aldosterone, metanephrines, and estradiol/testosterone.2 In all cancer patients, consideration for surgery must include an overall assessment of prognosis and alternate treatments as infl uenced by the primary cancer. 3 Change in size (> 4 cm or 1 cm/year); progression of features not consistent with lipid-rich adenoma.

Adrenal neoplasm in the extra-adrenal cancer patient

Positive Hormonal evaluation for excess adrenal function1

Systemic therapy

for primary cancer

Negative

Isolated adrenal neoplasm

Metachronous presentation (> 6 months from diagnosis)

No

No

Size > 4 cm

Imaging typical for lipid-rich adenoma

Surgical resection2

FNA Positive for metastasis

Negative for metastasis

Interval surveillance

imaging every 3-6 months

No, synchronous presentation

No, multiple

metastasis

Yes

Yes

Yes

Yes

Change in malignant potential3

No

Yes

Fig 5. — Algorithm for evaluation and treatment of an adrenal neoplasm in the extra-adrenal cancer patient.


Adrenalectomy may also be palliative. Patients who have abdominal pain or other symptoms caused by their adrenal metastases usually report improvement in their symptoms after adrenalectomy.9 Adrenalectomy or de-bulking may relieve local compressive symptoms or allow the patient a disease-free holiday from chemotherapy. If the patient is not a candidate for surgery or when the tumor is unresectable, radiation or an alternative therapy is indicated to control local symptoms.35 Isolated stud-ies of radiofrequency ablation (RFA), embolization, and cryoablation have reported some success in achieving palliation in the patients. These studies are discussed in the following sections.

Laparoscopic Vs Open ResectionLaparoscopy is the accepted approach of choice for be-nign adrenal lesions. Laparoscopy allows for inspection of the entire abdomen and facilitates dissection in the upper quadrants of the abdomen.9 Compared with open adrenalectomy, laparoscopic adrenalectomy is associ-ated with less pain, lower blood loss, reduced morbid-ity, and shorter hospital stay. Laparoscopic resection of malignant tumors is more controversial. The question of whether laparoscopic adrenalectomy is oncologically comparable to open adrenalectomy with equivalent re-currence rates and disease-free survival is not completely answered, although oncologic principles of adequate margins should govern any surgical decision.32

Solitary adrenal metastases are usually confi ned with-in the capsule of the adrenal gland and thus are amenable to laparoscopic adrenalectomy. To reduce the risk of local recurrence, the periadrenal fat should be resected along with the adrenal gland. Laparoscopic resection has been shown to be safe if preoperative studies do not indicate local tumor invasion into adjacent organs, lymphadenopathy, extra-adrenal metastases, tumor size of > 9 cm, or inferior vena cava (IVC) thrombus.9,10

Strong et al28 compared 31 attempted laparoscopic adrenalectomies with 63 open adrenalectomies over an 11-year period. Four patients (13%) required conversion to open adrenalectomies. Local recurrence was 17%, and neither local recurrence nor disease-free survival differed between the open and the laparoscopic ap-proaches. For the entire group, the median survival was approximately 30 months and did not differ between the two operative approaches. Similarly, for patients with tumors < 4.5 cm, the median survival was 40 months and did not differ between operative approaches. For patients with tumors > 4.5 cm, however, the difference in survival was signifi cant, favoring the open adrenal-ectomy group. Microscopic margins were positive in 29% of the open adrenalectomy group and in 22% of the laparoscopic group without statistical signifi cance. Laparoscopy was associated with fewer complications, less blood loss, reduced operative times, and shorter hospital stay.

Castillo et al36 performed 34 laparoscopic adrenalec-tomies in 32 patients for suspected adrenal metastases. Patients with tumors > 10 cm with evidence of periadre-nal infi ltration, thrombus of the inferior vena cava, or locoregional lymphadenopathy were excluded. Of the 34 glands resected, 22 (64.7%) contained malignancy upon pathologic analysis, with a mean tumor size of 5.1 cm. The mean survival time of patients with malignancy was 26 months. Two positive margins and no open conver-sions or port site recurrences were reported. Similarly, in another series of 13 patients who underwent laparo-scopic resection, none had positive margins and none had local recurrence.37 Port-site recurrences have been estimated at 0% to 6.25%,37 while open adrenalectomy has a wound recurrence rate of approximately 0.4%.6 Recent studies reported that local recurrence rates and incidence of peritoneal metastases were similar for open and laparoscopic approaches.38 Preventing tumor spill-age, coupled with using standard laparoscopic specimen bags, reduces the higher rates of port site and peritoneal metastases.38 Currently, it is acceptable to begin all re-sections of isolated adrenal metastases laparoscopically except those that are > 9 cm or show local invasion or IVC thrombus. Conversion to an open approach is recommended if tumor adhesion, invasion into adjacent organs, or lymphadenopathy is evident or if the tumor is too large to be safely resected laparoscopically.9 We also recommend en bloc resection of peritumoral Gerota’s fat for margin.

OutcomesIn a retrospective review of 37 patients who underwent open adrenalectomies for isolated metastases, Kim et al30 found a median length of stay of 8 days and a 19% incidence of complications with 1 perioperative death. A total of 43% of the metastases were synchronous with the primary carcinoma. The median disease-free interval for metachronous lesions was 15 months. The median disease-free survival was 11 months, with a 5-year disease-free survival rate of 21%. The median overall survival was 21 months, with a 5-year survival rate of 24%. A disease-free interval between resection of the primary tumor and adrenalectomy of the metastasis of more than 6 months and a complete resection were predictors of improved survival.

In a retrospective review of 92 patients who un-derwent a combination of laparoscopic and open ad-renalectomies for metastatic disease,28 the only predic-tors of decreased survival were adrenal size of > 4.5 cm and local recurrence. No one in the locally recurrent group survived 5 years. Overall, the 5-year survival rate was estimated to be 31%. The median survival for those with negative margins was 36 months compared with 18 months for those with positive margins. The major-ity of these patients had NSCLC as their primary tumor. Similarly, Lo et al39 demonstrated a median survival of


13 months and a 2-year survival rate of 40%. The major-ity of these patients had renal cell carcinoma as their primary tumor. In general, mean survival for all patients after adrenalectomy for isolated metastatic disease ranges from 20 to 30 months compared with 6 to 8 months for patients who do not undergo resection.30 The 5-year sur-vival rate after adrenal metastatectomy is approximately 25%.29,30 Solitary metastases, longer disease-free interval between resection of the primary tumor and detection of the adrenal metastases, and smaller tumor size portend a better chance for cure.30,31,33

The literature is more controversial in describing survival for patients with metachronous primary and metastatic lesions compared with patients presenting with synchronous lesions, where synchronous is defi ned as a disease-free interval of less than 6 months.28,40 In a retrospective review by Strong et al,28 patients with synchronous metastases had a 73% 1-year survival rate and a 38% 3-year survival rate. Those with metachronous metastases had an 86% 1-year survival rate and a 46% 3-year survival rate. These were not signifi cantly differ-ent (P = .62). On the other hand, in a pooled analysis of the literature of patients with NSCLC and isolated adrenal metastases who underwent resection, Tanvetya-non et al41 found that the median overall survival was lower for patients with synchronous metastases com-pared with metachronous metastases (12 months vs 31 months). Similarly, the 1- and 2-year survival rates were better for metachronous lesions than for synchronous lesions (80% and 52% vs 45% and 30%, respectively). By 5 years, however, the survival rates were similar for both groups (25% vs 26%). Adler et al40 demonstrated similar results. Patients with synchronous disease had a higher early mortality with a median survival of 8 months and a 5-year actuarial survival rate of 27%, while patients with metachronous disease had a median survival of 19 months and a 5-year actuarial survival rate of 53%. This difference was not signifi cant (P = .06). With the low numbers in each group (5 and 12), the study may have been underpowered, and actuarial data were described.

Although patients with synchronous metastases may initially have worse survival than those who present with metachronous lesions, a 25% 5-year survival rate may still be a benefi t, and an attempt at resection may be considered. As imaging modalities improve the detection of additional metastases, the selection of appropriate candidates for adrenalectomy should improve.32

Alternatives to Surgical ResectionNot all patients are candidates for surgical resection due to medical comorbidities, local tumor invasion of sur-rounding viscera, the presence of multiple metastases, or personal preference. Although surgical resection extends survival, alternative therapies for patients who are not surgical candidates may also prolong survival and palli-ate symptoms.

Minimally invasive therapies can be divided into catheter-based therapies, ablative therapies, and thermal ablative therapies. Most of the experience with these therapies exists in treating primary liver malignancies or metastases to the liver.42 A few studies, which are discussed in the next section, have examined the use of these techniques in both benign and malignant adrenal disease. Tumor ablation is an attractive option for small adrenal tumors, for palliation of painful metastases not amenable to resection, and for treatment of patients who are not candidates for surgery. Most procedures can be performed on an outpatient basis under radiological guid-ance with sedation and minimal morbidity. In addition, the procedures may be repeated multiple times, can be used in conjunction with other treatment modalities, and may be less expensive than surgical resection.

Radiofrequency AblationRFA has been used to ablate tumors in multiple tissues. RFA produces coagulative necrosis via an alternating high-frequency electric current in the radiofrequency range (460 to 500 kHz). By converting radiofrequency waves to thermal energy, radiofrequency denatures the intracellular and extracellular proteins in a tumor. When compared to other ablative techniques, the use of RFA in the liver for hepatocellular carcinoma (HCC) has shown the best overall survival rate. Case reports in the litera-ture have shown that RFA is a safe and well-tolerated procedure for unresectable adrenocortical carcinoma43-47 as well as HCC metastases to the adrenal.48 RFA has been suggested to be superior to radiation for pain palliation because the onset of relief is faster and because there is less damage to surrounding tissues.49

Lo et al50 reported on successful palliative ablation of bilateral adrenal metastases in a patient with met-astatic lung cancer. The lesions were 4.7 cm and 4.3 cm. Six months after ablation, the patient was still pain free without signs of adrenal insuffi ciency. Mayo-Smith et al51 studied RFA in 13 adrenal masses in 12 patients. Eleven adrenal lesions were metastases, 1 lesion was a pheochromocytoma, and 1 was an aldosteronoma. The mean tumor size was 3.6 cm. At a mean follow-up of 11.2 months, 11 of the 13 tumors were successfully ablated after one session without any residual tumor or growth on imaging. Two of the 11 patients with metastases had enhancement of residual tissue on follow-up imaging, suggesting incompletely treated residual tumor. The mean size of these tumors was 6.0 cm vs a mean size of 3.4 cm in the successfully ablated masses, although the difference was not statistically signifi cant. None of the patients who were completely treated had recurrent tumor or tumor progression, indicating adequate local control. Also, none of the patients developed hyperten-sion. Complications included a self-resolving hematoma in a thrombocytopenic patient, shortness of breath that resolved with diuretics, and adrenal insuffi ciency in a


patient with bilateral metastases treated at separate ses-sions. As a result, the authors recommend ablation for masses < 5 cm. Although it is possible to treat bilateral adrenal metastases, caution is advised in this group of pa-tients as posttreatment adrenal insuffi ciency may result.51

Compared with other ablative therapies, RFA tends to have higher rates and severities of adverse events, including pain, fever, and cutaneous burns, with a re-ported mortality rate of 0.5% and complication rates of 8% to 35%.43,51,52 These outcomes are similar to surgical outcomes reported by Kim et al.30 The key limitation in RFA is creating adequate volumes of tissue destruction,

particularly in areas close to blood vessels, which act as heat sinks.42 Complications from RFA can be broken into those related to electrode placement and those related to thermal ablation. Complications from electrode place-ment include bleeding, infection, and tumor seeding. The reported rate of needle track seeding is approxi-mately 3%,42 which is similar to the laparoscopic port site seeding rate of 0% to 6%.38 Adrenal ablation offers little room for probe placement error due to the closely adjacent heat-sensitive structures. Right adrenal lesions are thought to be easier to ablate due to coverage by the liver. The left adrenal gland is surrounded by the

Fig 6. — Axial, sagittal, and coronal views of a patient treated with external beam radiation therapy in the prone position to the right adrenal bed following resection. Note that the patient has only one remaining right kidney and that the treatment fi eld was able to avoid signifi cant dose to preserve function.


spleen, pancreas, stomach, and colon. Complications from thermal ablation include damage to nontarget tis-sues, grounding pad burns, and metabolic complications such as acute malignant hypertension.53,54 Occurrence of malignant hypertension can be minimized by preopera-tive alpha blockade followed by beta blockade.55

RadiotherapyTechnological advances in radiation planning and deliv-ery have now expanded this noninvasive modality as an-other potential form of local therapy. Historically, exter-nal beam radiotherapy (EBRT) has been associated with the treatment of large target volumes with signifi cant concern for normal tissue morbidity. Modern techniques, however, now permit the safe delivery of higher doses of radiation to the target region while sparing the adjacent normal tissues (Figs 6-7). This evolution has paralleled the integration of CT-based software into radiation planning systems so that the dose received by volumes of tissue can be measured. Radiation oncologists now use data from the dose volume histogram (DVH) to prospectively evaluate treatment plans for the individual patient.

Treatment of adrenal metastases with EBRT is chal-lenging. First, with the location of the tumor in the up-per abdomen, tumor motion associated with respiration

is possible.56-58 In fact, these studies of upper abdominal structures have shown potential for signifi cant respira-tion-associated motion in the superoinfero, mediolateral, and anteropostero directions. Second, potential acute and late normal tissue toxicity is a concern, given the proximity of the adjacent kidney, liver, small intestine, stomach, and spinal cord. Third, the daily target treat-ment position is uncertain since organ motion (gastroin-testinal tract fi lling, peristalsis) can vary from day to day.59

Current techniques permit management of these issues so that treatment of adrenal metastases not only is technically possible but also may offer improved op-portunities for local control with minimal toxicity. Data on how best to exploit the benefi ts of EBRT in this set-ting continue to emerge. One potential role for radia-tion would be in the adjuvant setting following surgical resection. Studies exploring this are limited; however, Oshiro et al60 recently reported their experience with 19 patients who were treated adjuvantly following resection of adrenal metastasis from lung cancer. With a metachro-nous metastasis, overall 1- 2-, and 5-year survival rates were 83%, 56%, and 56%, respectively.

Another consideration for EBRT is its role as defi ni-tive ablative therapy. With the translation of intracranial stereotactic radiosurgery techniques to extracranial ap-

Fig 7. — Beam arrangement accompanying the images in Fig 1. This shows the patient in the prone position with multiple beams that were chosen to selectively target the right adrenal bed while sparing adjacent normal tissue as much as possible.


plications, stereotactic body radiation therapy (SBRT) is now available.61 This treatment differs from that of con-ventional 5- to 6-week therapy since it compresses the course to 5 days or less with a signifi cantly more biologi-cally potent dose strategy. Timmerman et al62 reported the confi rmation of effi cacy based on multiple prospec-tive trials using SBRT in a variety of patient populations. In the abdomen, the largest SBRT trials to date have been conducted in those patients with liver metastases or with pancreatic primary lesions. Rusthoven et al63 reported the multi-institutional experience of treating 47 patients with 63 liver metastases with an SBRT dose of 60 Gy in 3 fractions, reporting a median survival of 20.5 months and a 2-year actuarial local control rate of 92%. Rule et al64 reported a 5-fraction, phase I dose escalation trial that did not reach the maximum tolerated dose on a series of 27 patients with liver metastases, showing an actuarial 2-year local control rate of 100%. Finally, Chang et al65 updated the Stanford single-fraction SBRT experience for their series of 77 pancreatic cancer patients, noting a rate of freedom from local progression at 12 months of 84%.

Reports are now emerging for outcomes with SBRT in the setting of adrenal metastasis. Torok et al66 reported data on 7 patients with 9 adrenal lesions treated. The primary malignancies in this series were mainly lung (4 non–small cell and 1 small cell), with 2 patients having primary HCC. Patients received 1- to 3-fraction SBRT, with a 1-year actuarial local control rate of 63% and a median overall survival of 8 months from SBRT. Japanese investigators reported a series of 10 patients treated with SBRT to 48 Gy with no patient developing signifi cant toxicity and 5 patients achieving a complete response. The 1-year overall survival rate was 78% and the local control rate was 100%.67

As more studies evaluate the hypothesis that local control of oligometastatic disease might lead to improved systemic control, there may be an expanding role for high-dose, short-course stereotactic treatment.68,69 The ability to offer a noninvasive, well-tolerated form of therapy that can be given to patients who are medically inoperable or have surgically unresectable disease is readily advanta-geous. Now that advanced techniques have paved the way for the safe delivery of high-dose radiation to the adrenal gland while minimizing adjacent normal tissue toxicity, it is time for future trials to better characterize outcomes so that the role of radiotherapy as an alternative or adjunct to surgical resection can be better defi ned.

Arterial EmbolizationArterial embolization has been successful in ablating functional benign adrenal tumors in patients with one or two feeding vessels.70 A total of 88% were successfully treated as measured by loss of tumor stain on angiogra-phy and decreased CT enhancement and by normaliza-tion of adrenal hormone. The mean duration of success was 45 months, and most patients required multiple

procedures.70 Complications included back or fl ank pain, mild fever, labile blood pressure, and pleural effu-sion. Hypertensive crisis has been reported with ethanol injection into the adrenal artery.71,72 Arterial emboliza-tion may be less effective for malignant masses than for benign adrenal masses since malignant adrenal tumors are usually fed by multiple blood vessels.73,74

A combination of RFA and chemoembolization has been used to treat primary HCC liver lesions with good response. Momoi et al73 retrospectively analyzed 20 patients with adrenal metastases from HCC. Seven patients treated with transarterial chemoembolization or percutaneous ethanol ablation had a median survival of 11.1 months. Because of a heat-sink effect, the size of the ablative zone resulting from RFA is infl uenced by blood fl ow. As both adrenals and HCC tumors are usually hypervascular, combining chemoembolization and RFA should augment both modalities.

Yamakado et al75 reported on 6 patients with 8 adre-nal HCC metastases that were managed with combined-modality therapy. All patients either were not surgical candidates or refused surgery. In 7 of the 8 tumors, CT enhancement disappeared after a single RFA treatment. In the remaining tumor, CT enhancement disappeared after two treatments. During a mean follow-up of 37.7 ± 27.6 months, local progression occurred in 2 of the 8 tumors at 3.0 and 7.7 months. Both tumors were ini-tially larger than 5.0 cm (5.9 cm and 7.4 cm) and in both tumors, progression was seen at the renal hilum. In all other tumors, enhancement continued to be absent and tumors regressed. Median survival was 24.9 months, with 2 patients surviving > 4 years. In patients with poorly controlled liver disease, mean survival time was 13.8 months.

Even combined with chemoembolization, tumors larger than 5 cm are diffi cult to control with RFA, which may be due to a combination of the heat-sink effect and an inability to embolize the entire tumor blood supply. Without treatment, the median survival time of patients with HCC adrenal metastases is as low as 5.64 months.74 Combined-modality treatment with RFA and arterial che-moembolization offers a safe, feasible treatment option for patients with HCC adrenal metastasis who are not surgical candidates.

Chemical AblationXiao et al76 reported on the largest series of patients in the literature undergoing percutaneous chemical abla-tion for adrenal tumors. In their retrospective review of 37 patients with 46 tumors, 20 of which were metastatic lesions, acetic acid was injected into tumors > 3.0 cm and ethanol into those < 3.0 cm. Response was better in primary adrenal lesions than in metastatic lesions. Of the 20 metastatic lesions, 6 had a complete response and 14 had a partial response at 2-year follow-up. Transient pain was the only reported complication.


Percutaneous ethanol ablation was fi rst reported in 1986 on a small series of patients with nonresectable HCC.77 Ethanol lyses cell membranes, denatures cell proteins, and induces vascular thrombosis. However, in order for ethanol to be effective, it must reach the entire tumor. Tumor heterogeneity caused by necrosis and fi brosis can impede effective distribution of ethanol within the target tumor.

Shibata et al78 reported on 7 patients with 9 meta-static HCC adrenal lesions treated with percutaneous ethanol ablation. The patients required two to four ses-sions, with adequacy of treatment judged by lack of tu-mor enhancement on CT imaging. The main side effects were pain and fever during injection. At a follow-up of 6 to 36 months, 4 patients were alive, and 3 had died (1 of liver failure at 8 months, 1 of brain metastases at 15 months, and 1 of multiple metastases at 36 months).

Other TherapiesCryoablation has been used as a surgical alternative for the treatment of tumors in many tissues. Cryoablation of adrenal masses has been reported as safe and effi cacious in canines.79 In humans, however, the majority of cases reported in the literature have been complicated by acute malignant hypertension during the procedure. Therefore, preoperative treatment with alpha blockade and possibly beta blockade is recommended at a minimum of 10 to 14 days before the procedure.55

CT-guided or MR thermotherapy-controlled laser-induced interstitial thermotherapy has also been used to ablate metastatic adrenal tumors in 9 patients. At a mean follow-up of 10 months, 7 of 9 tumors were completely ablated, while the remaining 2 tumors had progressed at 5 and 6 months. Mean tumor size was 4.3 cm.80 Further studies are indicated since this is a single case study.

ConclusionsAlthough the adrenal gland is a common site of metas-tasis for many malignancies, primary adrenal lesions are also commonly found in cancer patients. The extensive use of cross-sectional imaging for staging and follow-up has substantially increased the identifi cation of isolated adrenal lesions. Stratifying these tumors based on risk of malignancy and hypersecretion allows for appropriate treatment planning. Complete biochemical and radio-logic workup should be completed prior to initiating treatment for metastatic disease to assess for hyperse-cretion of cortical hormones and metanephrines and to determine the risk of malignancy. Hypersecreting tumors should be surgically resected. Benign adenomas by im-aging criteria can be followed by serial, cross-sectional imaging. Tumors with higher malignant potential should be resected. Resection of solitary metastases, specifi cally metachronous lesions, can improve long-term survival and should be considered as primary treatment. Syn-chronous adrenal metastasis or metastasis associated

with additional metastatic disease should be treated with systemic therapy and may be considered for palliative ab-lative therapies. When surgical resection is not an option, several minimally invasive treatment options and newer radiotherapy techniques exist to palliate symptoms with some success.

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