Download Management of Isolated Adrenal Lesions in Cancer Patients

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 Patients
Kelly 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 identified 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 specific 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.
Introduction
Within the cancer population, the discovery of an adrenal
mass inevitably leads to a discussion of appropriate management. Since a high percentage of these masses are
metastatic, tissue diagnosis may be essential to treatment
planning. In many patients, the morbidity of an imageguided biopsy may be avoided and even contraindicated
From the Endocrine Tumor Program (KM, HL, JBT, WBC) and the
Radiation Oncology Program (SH) at the H. Lee Moffitt Cancer
Center & Research Institute, Tampa, Florida.
Submitted October 29, 2010; accepted January 29, 2011.
Address correspondence to W. Bradford Carter, MD, Endocrine Tumor
Program, Moffitt Cancer Center, 12902 Magnolia Drive, FOB-2,
Tampa, FL 33612. E-mail: [email protected]
The authors report no significant relationship with the companies/
organizations whose products or services may be referenced in
this article.
April 2011, Vol 18, No. 2
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 incidentaloma 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 prolific 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 metaanalysis 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
Cancer Control 113
known malignancies reported much lower incidences
of incidental metastases.3 The median time from cancer
diagnosis to identification of adrenal metastases was 2.5
years, although adrenal metastases have been discovered
up to 22 years after initial treatment.4
Incidence
Many metastases to the adrenal glands remain undetected. In a retrospective study over 30 years, Lam and Lo5
identified 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 patients, 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 identified
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 metastasize to the adrenal include malignant melanoma, renal,
breast, colon, lung, and bronchial carcinomas. Lung and
breast cancers account for 39% and 35% of adrenal metastases, 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 stages, 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
Diagnosis
Patients with adrenal metastases are typically asymptomatic. When they are symptomatic, they typically present
with back pain representing local invasion, retroperitoneal hemorrhage from tumor necrosis, or adrenal insufficiency.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 adrenal 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 definitive 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 adrenal adenoma. Additionally, [18F]FDG positron emission
tomography (PET) may help to differentiate between
benign and malignancy lesions based on threshold standardized uptake value (SUV).
Table. — Diagnostic Imaging Characteristics of Adrenal Lesions
Adrenal Lesion
Diagnostic Imaging Characteristics
Comments
Adenoma
Unenhanced CT < 10 HU
Signal suppression on chemical shift MRI
> 60% washout
Most common mass
Often detected incidentally
Can be hyperfunctional
Hyperplasia
Bilateral adreniform thickening
May suppress at chemical shift MRI
Usually stable over time
Can be hyperfunctional
Hemorrhage
Hyperdense on CT
Hyperintense on T1-weighted MRI
Resolves over time
Often seen in trauma, anticoagulation, and sepsis
Excludes underlying mass
Cyst/pseudocyst
Fluid attenuation or signal intensity
Lack 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 MRI
Positive MIBG scan
Typical clinical presentation or elevated catecholamines
Extra-adrenal pheoparaganglioma
Primary adrenocortical carcinoma
Large heterogeneous aggressive tumor with
necrosis and hemorrhage
Often locally invasive
May metastasize
May be hyperfunctional
Metastatic disease
Large heterogeneous mass
Often bilateral masses
Most commonly from lung, breast,
gastrointestinal, renal, pancreas
114 Cancer Control
April 2011, Vol 18, No. 2
When an adrenal mass is detected, characterization
can be performed by several different imaging techniques (Table). The technique employed is usually determined 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 specificity of 98% and a sensitivity of 71%.11 Lipidrich adrenal adenomas demonstrate unenhanced attenuation values < 10 Hounsfield units (HU) due to the presence 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 opposedphase 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 field 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, defined as:
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 fluid attenu-
A
(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% specificity.13 Unenhanced and
contrast-enhanced CT with percentage washout calculation 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 defined as:
B
(E – D) / (E – U) × 100
Greater than 60% washout yields 96% sensitivity and
88% specificity for adrenal adenomas.14
Several other common adrenal masses have specific
imaging characteristics that allow for a confident diagnosis (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 accumulate MIBG on nuclear medicine scans. Adrenal hemorrhage demonstrate increased attenuation on CT and
April 2011, Vol 18, No. 2
C
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.
Cancer Control 115
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 adrenocortical 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 configuration, and demonstrate internal homogeneity. Conversely, malignant masses are often much larger,
exceeding 5 cm with irregular margins and internal heterogeneity. Aside from adrenal cysts, most benign and
malignant lesions enhance following the administration
of iodinated or gadolinium-based contrast agents; therefore, 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, surveillance to ensure stability may be a reasonable management strategy. As the most common adrenal mass, adrenal
adenoma should lead the differential diagnosis of an incidental adrenal mass, and imaging should be performed
to confirm 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 identified.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 first
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 hyperfunctional 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-defined 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.
116 Cancer Control
April 2011, Vol 18, No. 2
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 specificity of 98% at a threshold SUV of 3.1.16
Metabolic Studies
All patients with adrenal masses should undergo biochemical evaluation for cortical or medullary hyperfunction, particularly prior to biopsy or therapy.17 Patients
should be questioned for signs and symptoms of a metabolically active primary adrenal tumor such as hyperten-
A
sion, tachycardia, headache, palpitations, hirsutism, gynecomastia, sudden weight gain, change in body habitus
(particularly truncal obesity), and progressive myopathy.6
A complete metabolic workup is necessary to identify a pheochromocytoma and any functional adrenal
mass. Functional adrenal tumors effectively rule out a
metastatic lesion. Anywhere from 26% to 94% of adrenocortical carcinomas are hyperfunctioning,3 and when
multiple adrenal hormones are elevated, a primary adrenocortical carcinoma should be suspected.18 A metabolic
evaluation should be performed to determine excess
cortisol, aldosterone, and androgens as well as metanephrines. 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 estrogens 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 catecholamines, however, are less specific than a urinary test.
Spontaneous hypokalemia (≤ 3.5 mmol/L) combined
with hypertension is highly suspicious for mineral corticoid excess. However, more than 50% of patients with primary aldosteronism are normokalemic. Although plasma
potassium should be checked, a normal level does not
exclude an aldosterone-secreting mass.19 The most effective 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
B
Fig 3. — Contrast-enhanced CT through the right adrenal. (A) A large, heterogeneous, irregular mass and (B) an ill-defined mass proven to be primary
adrenocortical carcinoma presenting with rib metastasis are shown.
April 2011, Vol 18, No. 2
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.
Cancer Control 117
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 specificity
of 91%.20 Kidney failure, beta blockers, antisympathetic
agents, and calcium channel blockers all interfere with
the aldosterone-renin pathway and may alter plasma aldosterone and renin levels.3 Additional testing with the
25-mg captopril test, salt-loading or saline infusion tests,
or fludrocortisone suppression test should be used to confirm 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 confirms lateralization of production
and subsequent correction after adrenalectomy. At least
60% of Conn’s syndrome is bilateral, even with imaging
that identifies 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 urinary free cortisol level or a fasting a.m.cortisol level, with
an adrenocorticotropic hormone (ACTH) level and a
dexamethasone suppression test to confirm 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-negative results in patients who were not identified by the
urinary free cortisol test. Failure to suppress the cortisol
level to < 1.8 mg/dL identifies 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
confirm compliance with taking the medication, particularly with equivocal results.
We recommend that all functioning adrenal lesions
be removed, if practical (Fig 5).
Biopsy
In 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 fine needle aspiration (FNA) to diagnose malignancy
ranged from 81% to 100% and specificity ranged from 83%
to 100%.3 However, in patients with an already known
118 Cancer Control
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/cytoplasmic ratio in intact cells.6 A skilled cytopathologist who
can confirm the adequacy of a specimen is critical in the
accuracy of fine 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 adrenal range from 0% to 3%, most of which are self-limited.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 complications, 9 of which required hospitalization.3
In general, FNA is highly accurate in distinguishing between adrenal cortical lesions and metastases in
patients with a known malignancy. FNA can also help
define a primary malignancy of unknown origin.6 Histologic distinction between benign adrenal lesions and
primary malignant ones, however, is much less accurate,
with sensitivity ranging from 54% to 86%.17
Indications for Resection
In 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 reasonable 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. Critics 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 nonsurgically.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 chemotherapy 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
April 2011, Vol 18, No. 2
Adrenal neoplasm in the extra-adrenal cancer patient
Hormonal evaluation for
excess adrenal function1
Positive
Negative
No,
multiple
metastasis
Isolated adrenal neoplasm
Systemic
therapy
for
primary
cancer
Yes
No,
synchronous
presentation
Metachronous presentation
(> 6 months from diagnosis)
Yes
Surgical
resection2
Yes
Size > 4 cm
No
Imaging typical for
lipid-rich adenoma
Yes
No
Positive for
metastasis
Yes
Negative for
metastasis
FNA
Change in malignant potential3
Interval
surveillance
imaging every
3-6 months
No
2
Autonomous production of cortisol, aldosterone, metanephrines, and estradiol/testosterone.
In all cancer patients, consideration for surgery must include an overall assessment of prognosis and
alternate treatments as influenced by the primary cancer.
3
Change in size (> 4 cm or 1 cm/year); progression of features not consistent with lipid-rich adenoma.
1
Fig 5. — Algorithm for evaluation and treatment of an adrenal neoplasm in the extra-adrenal cancer patient.
April 2011, Vol 18, No. 2
Cancer Control 119
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 debulking 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 studies 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 Resection
Laparoscopy is the accepted approach of choice for benign 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 associated with less pain, lower blood loss, reduced morbidity, 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 recurrence 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 confined within 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 approaches. 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 significant, favoring the open adrenalectomy group. Microscopic margins were positive in
29% of the open adrenalectomy group and in 22% of
the laparoscopic group without statistical significance.
Laparoscopy was associated with fewer complications,
less blood loss, reduced operative times, and shorter
hospital stay.
120 Cancer Control
Castillo et al36 performed 34 laparoscopic adrenalectomies in 32 patients for suspected adrenal metastases.
Patients with tumors > 10 cm with evidence of periadrenal infiltration, 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 conversions or port site recurrences were reported. Similarly,
in another series of 13 patients who underwent laparoscopic 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 spillage, 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 resections 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.
Outcomes
In 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 diseasefree 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 underwent a combination of laparoscopic and open adrenalectomies for metastatic disease,28 the only predictors 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 majority of these patients had NSCLC as their primary tumor.
Similarly, Lo et al39 demonstrated a median survival of
April 2011, Vol 18, No. 2
13 months and a 2-year survival rate of 40%. The majority 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 survival 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 defined
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 significantly different (P = .62). On the other hand, in a pooled analysis
of the literature of patients with NSCLC and isolated
adrenal metastases who underwent resection,Tanvetyanon et al41 found that the median overall survival was
lower for patients with synchronous metastases compared 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 significant (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 benefit, 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 Resection
Not all patients are candidates for surgical resection due
to medical comorbidities, local tumor invasion of surrounding 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 palliate symptoms.
April 2011, Vol 18, No. 2
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 guidance 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 Ablation
RFA 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 literature 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 metastatic 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 insufficiency. 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 significant. None of the
patients who were completely treated had recurrent
tumor or tumor progression, indicating adequate local
control. Also, none of the patients developed hypertension. Complications included a self-resolving hematoma
in a thrombocytopenic patient, shortness of breath that
resolved with diuretics, and adrenal insufficiency in a
Cancer Control 121
patient with bilateral metastases treated at separate sessions. 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 patients as posttreatment adrenal insufficiency 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 reported 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 placement include bleeding, infection, and tumor seeding.
The reported rate of needle track seeding is approximately 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 field was able to avoid significant dose to preserve function.
122 Cancer Control
April 2011, Vol 18, No. 2
spleen, pancreas, stomach, and colon. Complications
from thermal ablation include damage to nontarget tissues, grounding pad burns, and metabolic complications
such as acute malignant hypertension.53,54 Occurrence of
malignant hypertension can be minimized by preoperative alpha blockade followed by beta blockade.55
Radiotherapy
Technological advances in radiation planning and delivery have now expanded this noninvasive modality as another potential form of local therapy. Historically, external beam radiotherapy (EBRT) has been associated with
the treatment of large target volumes with significant
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 challenging. First, with the location of the tumor in the upper abdomen, tumor motion associated with respiration
is possible.56-58 In fact, these studies of upper abdominal
structures have shown potential for significant respiration-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 treatment position is uncertain since organ motion (gastrointestinal tract filling, 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 opportunities for local control with minimal toxicity. Data
on how best to exploit the benefits of EBRT in this setting continue to emerge. One potential role for radiation 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 metachronous metastasis, overall 1- 2-, and 5-year survival rates
were 83%, 56%, and 56%, respectively.
Another consideration for EBRT is its role as definitive 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.
April 2011, Vol 18, No. 2
Cancer Control 123
plications, stereotactic body radiation therapy (SBRT) is
now available.61 This treatment differs from that of conventional 5- to 6-week therapy since it compresses the
course to 5 days or less with a significantly more biologically potent dose strategy. Timmerman et al62 reported
the confirmation of efficacy based on multiple prospective 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 significant
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 highdose, 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 advantageous. 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 defined.
Arterial Embolization
Arterial 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 angiography and decreased CT enhancement and by normalization of adrenal hormone. The mean duration of success
was 45 months, and most patients required multiple
124 Cancer Control
procedures.70 Complications included back or flank
pain, mild fever, labile blood pressure, and pleural effusion. Hypertensive crisis has been reported with ethanol
injection into the adrenal artery.71,72 Arterial embolization 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 influenced by
blood flow. 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 adrenal HCC metastases that were managed with combinedmodality 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 initially 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 difficult 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 chemoembolization offers a safe, feasible treatment option
for patients with HCC adrenal metastasis who are not
surgical candidates.
Chemical Ablation
Xiao et al76 reported on the largest series of patients in
the literature undergoing percutaneous chemical ablation 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.
April 2011, Vol 18, No. 2
Percutaneous ethanol ablation was first 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 fibrosis can impede effective distribution of ethanol
within the target tumor.
Shibata et al78 reported on 7 patients with 9 metastatic HCC adrenal lesions treated with percutaneous
ethanol ablation. The patients required two to four sessions, with adequacy of treatment judged by lack of tumor 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 Therapies
Cryoablation 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 efficacious
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 laserinduced 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.
Conclusions
Although the adrenal gland is a common site of metastasis 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 identification of isolated
adrenal lesions. Stratifying these tumors based on risk of
malignancy and hypersecretion allows for appropriate
treatment planning. Complete biochemical and radiologic workup should be completed prior to initiating
treatment for metastatic disease to assess for hypersecretion of cortical hormones and metanephrines and to
determine the risk of malignancy. Hypersecreting tumors
should be surgically resected. Benign adenomas by imaging criteria can be followed by serial, cross-sectional
imaging. Tumors with higher malignant potential should
be resected. Resection of solitary metastases, specifically
metachronous lesions, can improve long-term survival
and should be considered as primary treatment. Synchronous adrenal metastasis or metastasis associated
April 2011, Vol 18, No. 2
with additional metastatic disease should be treated with
systemic therapy and may be considered for palliative ablative 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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