Hospital Medicine

Adrenal cancer

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I. What every physician needs to know

Though adrenal tumors are relatively common in the general population, adrenocortical carcinoma (ACC) is a rare malignancy with a relatively poor prognosis.

The pathogenesis of ACC is not well understood. Mutations which inactivate the TP53 tumor suppressor gene or lead to over expression of IGF-II are frequently seen in cases of ACC, but the direct pathogenic mechanisms have not been clearly established. Though there are reports of adrenal adenomas progressing to ACC, this seems to be a very rare occurrence.

A. History Part 1: Pattern Recognition

ACCs are usually large when they are discovered, so patients may present with complaints related to local effects from tumor burden. Up to 60% of patients present with evidence of adrenal hormone excess (i.e., glucocorticoid, mineralocorticoid, or sex hormones), but a growing number of patients will present with incidentally found tumors on imaging for unrelated reasons.

Each adrenal gland is essentially two separate and distinct endocrine gland - the cortex and the medulla. The adrenal cortex consists of three concentric zones. The outer zone is the glomerulosa, which secretes mineralocorticoid; the intermediate zone is the fasciculata, which secretes glucocorticoids, most importantly cortisol; and the innermost zone is the reticularis, which secretes androgens. The adrenal medulla is part of the sympathetic nervous system and produces the catecholamines epinephrine and norepinephrine (also known as adrenaline and noradrenaline).

The most common hormonal excess state seen with ACCs is hypercortisolism with resultant Cushing’s syndrome. The symptoms of this condition may include weight gain, abdominal obesity with thin extremities, plethoric “moon face”, and interscapular fat deposition (“buffalo hump”). Easy bruising, purple striae and a proximal myopathy may also be seen.

When present, mineralocorticoid excess classically presents with hypertension and hypokalemia. In one series of functional adrenal masses, the mean serum potassium was 2.3 mmol/L, though severe hypokalemia can also be caused by excess cortisol production leading to mineralocorticoid effects, even without excess aldosterone present.

Virilization is not always present, but it is more common in ACCs than adrenal adenomas. Women may complain of hirsutism, oligomenorrhea, deepening of the voice and male pattern baldness. In men, gynecomastia and testicular atrophy have been associated with estrogen secreting tumors which are almost always malignant.

Some tumors do not produce enough hormones and will not lead to clinically apparent findings; these tumors are considered "hormonally silent". However, if tested, even patients with these tumors can have elevated levels of adrenal hormones. When the tumor is hormonally silent, abdominal discomfort may be the first sign. Patients may complain of abdominal fullness, nausea, vomiting, or even back pain caused by mass effect of a large tumor. Pain tends to occur somewhat more commonly with ACC than with adrenal adenoma, even with tumors of similar size. However, many patients will have relatively few symptoms until the tumor burden is high.

B. History Part 2: Prevalence

ACC is a relatively rare malignancy but the true incidence is not well understood and is probably understated since most of the data on incidence were collected prior to the advent of computed tomography (CT) scanning. A National Cancer Institute survey from the 1970s suggested an incidence of approximately 1-2 per 1 million population.

Women are more commonly effected than men with a ratio of 1.5:1. The age distribution of diagnosis is bimodal with the first peak being in childhood and a second, higher peak, in the fourth and fifth decades of life.

C. History Part 3: Competing diagnoses that can mimic adrenal cancer

The diagnosis which most commonly mimics ACC is adrenal adenoma. Though no single characteristic, either from imaging or biochemical testing can differentiate malignant lesions from benign, the size and radiographic density in Hounsfield Units (H.U.) are important predictors (see Table I). In addition, while either adenomas or ACCs can over produce hormones, sex hormone effects are seen more commonly in malignancy. This is especially true for estrogen secreting tumors.

Table I.

Features that may help distinguish benign from malignant lesions
Size <6 cm Size >6 cm
<10 Hounsfield units (HU) on unenhanced CT >10 HU on unenhanced CT
Smooth margins Irregular margins
Homogenous or hypodense appearance Heterogeneous appearance
CT contrast -medium washout <50% at 10 minutes CT contrast-medium washout <50% at 10 minutes

Another differentiating characteristic that has been studied is the level of dehydroepiandrosterone sulfate (DHEA-S). In ACCs, this level is frequently elevated, while in adenomas, DHEA-S is generally decreased. In addition, pain associated with an adrenal mass should raise suspicion for malignancy as this is more commonly seen with ACC than adrenal adenoma.

Hormonal imbalances from other points along the hormonal axis can present with apparent adrenal hormone excess and must be ruled out with biochemical testing. For example, pituitary lesions may cause a state of relative hormonal excess as well. It is worth noting, however, that ACC can be hormonally silent.

It is also important to differentiate primary tumor from metastatic lesion. The adrenal glands are not an infrequent location for metastatic disease to present. In fact, metastatic lesions are the most common malignancy of the adrenals. These tumors will more commonly be associated with hormonal deficiency than excess.

D. Physical Examination Findings

There are no physical exam findings that are specific to ACCs. Most of these tumors are found on imaging, often incidentally. When physical examination findings are present, they are usually a direct result of hormonal excess, with cortisol excess being the most common.

Common symptoms of hypercortisolism include weight gain, abdominal obesity with thin extremities and a plethoric face – described as “moon face”. There may be interscapular fat deposition (sometimes referred to as a “buffalo hump”). Other exam findings may include easy bruising and purple striae. Strength testing should be done on each patient as proximal muscle weakness can be seen with cortisol excess.

Mineralocorticoid excess is less common, but presents with hypertension on exam. Inappropriately elevated levels of sex hormones may lead to changes in secondary sex characteristics on exam. Virilization and hirsutism in women is found more often in ACC than in adrenal adenoma and should be noted on exam. If the tumor is estrogen secreting, gynecomastia and testicular atrophy may be found in men. If present, these findings suggest malignancy as nearly all estrogen secreting tumors are malignant.

E. What diagnostic tests should be performed?

Hormonal testing is important for both diagnosis as well as to guide perioperative management. In general, testing for glucocorticoid and mineralocorticoid excess is recommended for all, as is testing to exclude pheochromocytoma. Testing for sex hormone excess in the absence of suggestive history or physical exam findings is less clearly indicated.

Preoperatively, it is important to exclude pheochromocytoma as the perioperative management differs and imaging cannot reliably differentiate between adrenocortical carcinoma and pheochromocytoma. In addition, patients with autonomous cortisol production by the tumor are more likely to have postoperative adrenal insufficiency.

1. What laboratory studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?

Testing for cortisol excess

On standard laboratory testing, those with cortisol excess may have a leukocytosis with relative lymphopenia. Hypokalemia will be variably present.

The easiest screening test for hospitalized adults is the dexamethasone suppression test. In the standard dose version of this test, dexamethasone 1 mg is given orally at 11pm and a serum cortisol level is checked the next morning at 8am. A cortisol level of less than 1.8 mg/dL is a normal response and has a low false negative rate (less than 2%). However, false positives have been reported in up to 40% so confirmatory testing is needed with positive results. In the low dose dexamethasone suppression test, a dose of 0.5 mg is taken orally every 6 hours starting at 6am with the last dose at midnight. Cortisol is measured the next morning at 8am and the same cut-off value of 1.8 mg/dL has been shown to have an excellent sensitivity and a specificity of 98%. Certain drugs such as phenytoin, phenobarbital and rifampin increase the clearance rate of dexamethasone, resulting in false positives during the dexamethasone suppression test.

An alternative test is the measurement of a midnight salivary cortisol level as the saliva and plasma should have roughly equal concentrations of cortisol. This test requires a normal sleeping pattern for interpretation.

A 24-hour urine collection for urinary-free cortisol is the third possibility in diagnostic tests and can be used as a confirmatory test when the dexamethasone suppression test is positive. If clearance is poor (low GFR), urinary cortisol excretion will be decreased and may appear normal, even in the presence of excessive cortisol production.

Once initial testing confirms the presence of excess cortisol, an ACTH level should be measured. A suppressed ACTH is suggestive of adrenal pathology, while an elevated ACTH level would suggest that the primary lesion is in the pituitary.

Testing for mineralocorticoid excess

Routine laboratory testing may show slightly elevated serum sodium levels (less than 147mEq/L), a slight metabolic alkalosis and hyperglycemia. Hypokalemia is variably present (~40% of patients) but may be seen spontaneously or with the addition of a thiazide diuretic. This is important to note because repletion of serum potassium is imperative prior to testing for primary hyperaldosteronism.

Testing accurately is difficult as many factors can interfere with the tests. There is debate about how much effect antihypertensives have on the testing. Spironolactone, eplerenone and amiloride should be avoided (or held for at least 3 weeks prior to testing). Classical teaching is that diuretics, dihydropyridine calcium channel blockers (can normalize aldosterone secretion), and beta-blockers (can suppress plasma renin activity) should be discontinued for at least three weeks prior to testing. However, many investigators suggest that aside from spironolactone, eplerenone and amiloride, all other antihypertensives can be continued through testing.

Additionally, the patient must be on an unrestricted sodium diet during testing, should be out of bed for at least two hours and upright, and then seated for at least 10 minutes prior to the blood draw. The blood should be drawn between 8 and 10am for ideal measurement.

The best screening test is the ratio of the plasma aldosterone concentration (PAC) to plasma renin activity (PRA). A PAC/PRA ratio greater than 20 and a concomitant PAC greater than 10 ng/dL is highly suggestive of the diagnosis. Different labs will use different units for these tests and conversion may be necessary. PRA is generally high in all patients during therapy with an angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) and low or suppressed PRA in patients on these medications is suggestive of hyperaldosteronism.

Patients who have a positive initial screen should have confirmatory testing with a 24-hour urinary aldosterone level. This test is ideally done during a time of high salt load and in a state of normal potassium, and has more restrictions on antihypertensives than the PAC/PRA ratio test. Alternatively, testing of a plasma aldosterone concentration after a 2-liter isotonic saline load (over 4 hours) can be suggestive if the PAC is not suppressed. This test has fallen out of favor because of the risk of volume overload in older patients.

Once aldosterone excess has been identified, the distinction must be made between aldosterone producing adenomas and bilateral idiopathic adrenal hyperplasia. In general, patients with adenomas usually have more severe hypertension, more pronounced hypokalemia, are younger and have a discrete tumor seen on CT scan.

Additionally, a plasma 18-hydroxycorticosterone level can be obtained, which is generally greater than 100 ng/dL in patients with adenomas. Posture testing can also be used. In this test, the patient is hospitalized overnight and kept recumbent. An aldosterone level is checked in this position and then after 4 hours of upright ambulation. The normal response is a decrease in aldosterone with upright posture. No decrease or a paradoxical increase are suggestive of an adenoma.

Other testing

Testing of the sex steroids and steroid precursors includes testing dehydroepiandrosterone sulfate (DHEA-S) which is often elevated in ACC, but low in benign adenomas. Testosterone, androstenedione and 17-OH-progesterone can be checked in all patients. 17-beta-estradiol may be helpful in men and postmenopausal women but it is less useful in women of childbearing age.

2. What imaging studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?

Multiple imaging modalities have been studied in the evaluation of adrenal masses, including computed tomography (CT), magnetic resonance imaging (MRI), and F-fluorodeoxyglucose positron emission tomography (FDG-PET).

Computed tomography scan

The most well studied imaging modality is CT scan – usually done with thin cuts through the adrenals. While no single finding definitively excludes ACC, there are imaging features that suggest higher risk for malignancy (see Table I).

Tumor size is an important feature. Though there is a relationship between the risk of malignancy and adrenal tumor size, there is no clear consensus on what cut-off value should be used. Different guidelines range from 4-6 cm, but even a cut-off value of 2 cm cannot achieve a 100% specificity to rule out a malignant adrenal mass. Using a size cut-off of 4 cm resulted in a sensitivity of 90% and a specificity of 24%. Probably the most widely used guidelines come from the National Institutes of Health consensus conference, which proposed that tumors larger than 6 cm are highly suspicious for malignancy and should be removed (Figure 1).

Figure 1.

Work-up of an adrenal mass

Measurement of Hounsfield units (HU) is a promising tool in differentiating benign adrenal masses from malignant tumors. Benign masses generally have abundant intracytoplasmic fat, which is usually found in minimal amounts in malignant tumors. Therefore, malignant masses usually have higher HU values than benign masses. Using a cut-off of 10 HU, the sensitivity and specificity for characterizing an adrenal mass as a benign adenoma was 71% and 98%, respectively. Thus, a mass with a HU value of less than 10 is likely to be benign.

In adrenal masses with HU values greater than 10, there can be considerable overlap between benign and malignant tumors. One study found the median HU for adenomas was 19 versus 36 for carcinomas. Therefore, delayed enhancement washout percentage in attenuation value during CT has been used to differentiate between lipid poor adenomas and carcinomas. Adrenal lesions with a contrast washout of less than 50% are suspicious for malignancy.

Magnetic resonance imaging

Though the optimum MRI method for diagnosis of ACC remains a matter of controversy, this modality is as effective as CT in distinguishing malignant from benign lesions. Similar to CT, the fat content of the mass allows some differentiation between adenoma and carcinoma. ACCs are typically isointense to liver on T1-weighted imaging and show increased intensity on T2-weighted images. With the use of gadolinium, enhancement of the mass is present and the washout of the gadolinium is slow. The sensitivity and specificity of MRI for differentiating benign and malignant lesions ranges from 81-89% and 92-99%, respectively. Some surgeons prefer MRI for imaging as this modality is helpful in identifying invasion into adjacent structures.

Other imaging and biopsy

FDG-PET scanning has shown promise in differentiating benign from malignant lesions, but the data on this is limited thus far. There is ongoing investigation into the use of C-metomidate-PET as well. Metomidate binds to 11-beta-hydroxylase in the adrenal glands and may be particularly useful in differentiating primary adrenal tumors from metastatic tumors, as well as identification of adrenal masses that have metastasized to elsewhere in the body.

If adrenal carcinoma is suspected, staging includes high-resolution CT imaging of the chest and abdomen and whole body bone scan. The most common sites of metastasis are the lungs and the liver.

Biopsy of adrenal lesions is controversial. Concerns about needle tract metastases and the limited diagnostic value in differentiation of benign from malignant lesions have limited the enthusiasm for this procedure. Usually if suspicion is high enough for ACC, surgery is performed.

F. Over-utilized or “wasted” diagnostic tests associated with this diagnosis

Some authors suggest checking a 24-hour urine free cortisol on the day after a low dose dexamethasone suppression test; however, this probably adds little to the diagnostic accuracy of the baseline 24-hour urine free cortisol level and prolongs testing by a day.

As aldosterone and renin levels are variable throughout the day and related to position, to avoid uninterpretable tests, ensure that the test is drawn under optimal conditions.

In women of childbearing age, 17-beta-estradiol is less useful because of normal variance. Reserve this test for men and postmenopausal women.

Needle biopsy of the lesion may be of limited value in differentiating benign from malignant lesions, so it is generally not done unless surgery is not an option.

III. Default Management

A. Immediate management

Staging

Staging is generally done using the World Health Organization (WHO) model. Stages I and II are based on size, whereas stages III and IV have extra-adrenal involvement (Table II).

Table II.

Staging for adrenal cancer
Stage I Localized tumor <5 cm
Stage II Localized tumor >5 cm
Stage III Locally invasive tumors or tumors with regional lymph node metastases
Stage IV Tumors invading adjacent organs or presenting with distant metastases

In one study, the 5-year survival rates were 60% for stage I, 58% for stage II, 24% for stage III, and 0% for stage IV.

Surgery

The mainstay of therapy for stage I-III tumors is surgery. Because it is often extensive and may include lymphadenectomy, surgeons with some expertise in it should be sought. It is generally recommended that the surgeon leave the tumor capsule intact as this has been shown to decrease recurrence rates. Even with experienced surgeons, the rate of recurrence is high.

The role of laparoscopic adrenalectomy is somewhat controversial for ACC, though it is widely accepted for benign lesions less than 6 cm in size. There is concern that when laparoscopic surgery is done for ACC, there is an unduly high rate of recurrence. In general, most surgeons favor the open approach when possible.

Likewise, tumor debulking is also controversial. Incomplete resection of the primary tumor is associated with a poor prognosis, with the median survival less than 12 months in most studies. One reported benefit to debulking procedures may be to help control hormone excess, though this is not well studied.

Radiofrequency ablation has shown promise for adrenal tumors in patients with metastases. However, at this time, this method is still under investigation.

Radiation

Adrenal tumors are generally considered relatively radiation resistant. However, some studies have shown response rates up to 42%, demonstrating that ACC is not completely resistant to radiotherapy. For patients who are not surgical candidates, radiation should be considered. This is especially true of patients who develop brain or bone metastases, where radiation is the treatment of choice.

Some authors have suggested adjuvant radiotherapy after surgery. Though this treatment appears promising, further studies are needed.

Medical treatment

Mitotane

Mitotane is the first line medical treatment of ACC. This medication has a specific cytotoxic effect on adrenocortical cells, particularly in the reticular and fascicular zones. This medication is given as tablets and has a long half-life of up to 150 days. Dosing is usually between 1.5-6 grams per day, adjusted according to blood mitotane concentrations. There is a relatively narrow therapeutic window. Generally, concentrations greater than 14 mg/liter are needed for effectiveness, but concentrations greater than 20 mg/liter frequently cause central nervous system (CNS) side effects.

Complete response in patients with ACC is rare, but mitotane leads to objective tumor regression in up to 25-30% of patients with advanced ACC. A majority of patients get control of hormonal excess with this medication. The use of mitotane as an adjuvant therapy after surgery is debatable. Though some studies have shown a benefit, most studies have not.

Side effects are exceedingly common with this medication. Up to 80% of patients have at least one side effect with gastrointestinal upset and CNS effects being the most common. Adrenal insufficiency will develop on mitotane and because this medication also increases the metabolic clearance of glucocorticoids, high doses of steroid replacement are needed (up to 50 mg of hydrocortisone daily).

Cytotoxic chemotherapy

Several combinations of chemotherapy agents have been used in past studies. Perhaps the most effective was a combination of mitotane, doxorubicin, cisplatin and etoposide. In one study, the overall response rate in 72 patients was 49%, and complete response was reported in five patients. However, this regimen is often limited by significant toxicity.

Treatment of hormonal excess

While mitotane alone may be sufficient to control the hormonal excess, it has a slow onset of action and is frequently associated with dose-limiting toxicities. Some clinicians use ketoconazole 200-1200 mg/day in combination with mitotane, especially in the setting of hypercortisolism.

Novel therapy

For patients with stage III and IV disease, the discovery of new driver mutations and altered signalling pathways in ACC brings hope that new treatment concepts will become available and prove effective.

B. Physical Examination Tips to Guide Management

Patients with physical exam findings of hormone excess may experience a gradual improvement in these changes. However, the physical exam features may lag behind the improvement in hormone levels and thus are not a reliable indicator of response to therapy.

C. Laboratory Tests to Monitor Response to, and Adjustments in, Management

Hormone markers should be measured every three months for early detection of tumor recurrence.

D. Long-term management

Imaging is the most sensitive method of monitoring for tumor recurrence. For the first two years, restaging is done every three months by CT scan. Many clinicians advocate for restaging for a five-year period, though one may space out the timing of such evaluations.

Some studies suggest FDG-PET may be particularly helpful for detecting local recurrence. However, the standard remains CT for imaging follow-up.

E. Common Pitfalls and Side-Effects of Management

When patients are on mitotane, they have an increased metabolic clearance of glucocorticoids. Doses that would normally be appropriate for glucocorticoid replacement in other causes of adrenal insufficiency are inappropriate in this situation. Rather, doses upwards of 50 mg/day of hydrocortisone may be needed. This may need to be adjusted with the adjustments in mitotane dosing.

When patients on mitotane suffer systemic insults from infections or surgery, they need increased dosing of steroids. Mitotane has a long half-life, so stopping this medication will not be sufficient to compensate for loss of adrenal function.

IV. Management with Co-Morbidities

A. Renal Insufficiency

No change in standard management.

B. Liver Insufficiency

No change in standard management.

C. Systolic and Diastolic Heart Failure

No change in standard management.

D. Coronary Artery Disease or Peripheral Vascular Disease

No change in standard management.

E. Diabetes or other Endocrine issues

No change in standard management.

F. Malignancy

No change in standard management.

G. Immunosuppression (HIV, chronic steroids, etc.)

No change in standard management.

H. Primary Lung Disease (COPD, Asthma, ILD)

No change in standard management.

I. Gastrointestinal or Nutrition Issues

No change in standard management.

J. Hematologic or Coagulation Issues

No change in standard management.

K. Dementia or Psychiatric Illness/Treatment

No change in standard management.

V. Transitions of Care

A. Sign-out considerations While Hospitalized

Sign-out should make mention of the relative state of adrenal function. If the patient is pre-operative, they are often at increased risk of infections due to high circulating glucocorticoids. If high levels of mineralocorticoids are present, hypertension and potentially hypokalemia may be important to anticipate. If the patient is on mitotane or has recently had adrenal surgery, they may be at risk of adrenal insufficiency. Hypotension should prompt consideration of stress dose steroids.

B. Anticipated Length of Stay

Most of the work-up for adrenal masses can be done as an outpatient and ACC is no exception. However, patients may be hospitalized for adrenal surgery, initiation of cytotoxic chemotherapy or complication from treatment.

C. When is the Patient Ready for Discharge?

If an adrenal mass is noted on imaging done for another reason, it is important to relay this information to the patient’s providers to ensure follow-up.

D. Arranging for Clinic Follow-up

1. When should clinic follow up be arranged and with whom?

Clinic follow-up should include an evaluation with an endocrinologist well-versed in adrenal tumors to help guide the hormonal work-up. Referral to an endocrine surgeon is appropriate when there is high suspicion for ACC, though ideally hormonal testing will be completed prior to this evaluation.

2. What tests should be conducted prior to discharge to enable best clinic first visit?

Hormonal testing can be done prior to discharge to facilitate the work-up. Some of these tests may not result immediately and it is generally not imperative that the patient remain in the hospital until they do.

3. What tests should be ordered as an outpatient prior to, or on the day of, the clinic visit?

A repeat chemistry panel may be useful on the day of the clinic visit to evaluate for hypokalemia while the patient is eating their normal diet.

F. Prognosis and Patient Counseling

In one study, the 5-year survival rates were 60% for stage I, 58% for stage II, 24% for stage III, and 0% for stage IV.

VI. Patient Safety and Quality Measures

A. Core Indicator Standards and Documentation

While there are not consensus standards for inpatient evaluation of adrenal masses, if an adrenal mass is noted on imaging done for another reason, it is important to relay this information to the patient's providers to ensure follow-up. Appropriate documentation and referrals when suspicious masses are found is the standard.

B. Appropriate Prophylaxis and Other Measures to Prevent Readmission

If patients develop adrenal insufficiency and require high dose replacement steroids for a prolonged period of time, consideration should be given to antibiotic prophylaxis as well as calcium and vitamin D supplementation for bone health.

VII. What is the evidence?

Allolio, B, Fassnacht, M. "Adrenocortical Carcinoma: Clinical Update". J Clin Endocrinol Metab. vol. 91. 2006. pp. 2027-2037.

Berruti, A, Terzolo, M, Sperone, P. "Etoposide, doxorubicin and cisplatin plus mitotane in the treatment of advanced adrenocortical carcinoma: a large prospective phase II trial". Endocr Relat Cancer. vol. 12. 2005. pp. 657-666.

Caoili, EM, Korobkin, M, Francis, IR. "Delayed enhanced CT of lipid-poor adrenal adenomas". Am J Roentgenol. vol. 175. 2000. pp. 1411-1415.

Cobb, WS, Kercher, KW, Sing, RF. "Laproscopic adrenalectomy for malignancy". Am J Surg. vol. 189. 2005. pp. 405-411.

Creemers, SG, Hofland, L, Korpershoek, E. "Future directions in the diagnosis and medical treatment of adrenocortical carcinoma". Endocr Relat Cancer. 2015.

Gordon, MM, Stowasser, M, Rutherford, JC. "Primary aldosteronism: are we diagnosing and operating on too few patients". World J Surg. vol. 25. 2001. pp. 941-947.

Grumbach, MM, Biller, BM, Braunstein, GD. "Management of the clinically inapparent adrenal mass ("incidentloma")". Ann Intern Med. vol. 138. 2003. pp. 424-429.

Hamrahian, AH, Ioachimescu, Ag, Remer, EM. "Clinical utility of noncontrast computed tomography attenuation value (Hounsfield units) to differentiate adrenal adenomas/hyperplasias from nonadenomas: Cleveland Clinic experience". J Clin Endocrinol Metab. vol. 90. 2005. pp. 871-877.

Kenrick, ML, Lloyd, R, Erickson, L. "Adrenocortical carcinoma: surgical progress or status quo". Arch Surg. vol. 136. 2001. pp. 543-549.

Kirschner, LS. "Emerging treatment strategies for adrenocortical carcinoma: a new hope". J Clin endocrinol Metab. vol. 91. 2005. pp. 14-21.

"NIH state of the science statement on management of the clinically inapparent adrenal mass ("incidentaloma")". NIH Consens Sci Statements. vol. 19. 2002. pp. 1-25.

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