Adrenal Cortical Carcinoma
Are you sure the patient has adrenal cortical carcinoma?
- What else could the patient have?
Key laboratory and imaging tests
Other tests that may prove helpful diagnostically
Management and treatment of the disease
- ACC therapy
- Primary treatment for local or locoregional disease, stage 1-3
- Recurrent disease
- Stage 4 ACC
- Practical guide to mitotane therapy
- Therapy of hormone excess
- Therapy of hypercortsolism
- Therapy of hyperaldosteronism / increased mineralocorticoid activity:
- Therapy of hyperandrogenism:
- Therapy of hyperestrogenism:
What’s the evidence?/references
Are you sure the patient has adrenal cortical carcinoma?
Adrenocortical carcinoma (ACC) is a rare disease with an incidence of < 1/million/year, a female predominance (M:F = 1:1.5), and peak occurrence in the 4th-5th decade of life. However, ACC can occur in children and is most often part of Li-Fraumeni syndrome.
Patients present in one of three ways: 1) symptoms of hormone excess (40%), 2) abdominal pain/fullness or flank pain (40%), or 3) as an incidental finding as part of an unrelated workup (20%). Symptoms due to hormone secretion depend on the hormones secreted (glucocorticoids, androgens, estrogens or mineralocorticoids). Most hormonally active ACCs secrete androgens (DHEAS or testosterone) or cortisol or a combination of both.
The main symptoms of glucocorticoid production are Cushing's syndrome with diabetes, weight gain, muscle weakness, decreased libido, psychiatric symptoms, and osteoporosis. Androgen production in male patients is usually clinically silent; in female patients androgen excess often results in hirsutism, increased body hair growth, loss of scalp hair, menstrual abnormalities, and acne. Rare estrogen production causes gynecomastia in men and menstrual irregularities in women. Hypertension and hypokalemia can commonly be observed and are due to either aldosterone production (rare), secretion of mineralocorticoid precursors (11- deoxycorticosterone) or high levels of glucocorticoids overwhelming the renal 11-beta -HSD system leading to mineralocorticoid effects. Other paraneoplastic syndromes or general tumor-related symptoms, such as weight loss, night sweats and fever are rare with ACC.
Major signs on physical exam, if present, are hormone excess and rarely a palpable tumor. The main signs of cortisol excess are plethora, truncal obesity, supraclavicular fat pads, nuchal fat deposition ('buffalo hump'), rounded face ('moon face'), skin thinning, acne, muscle weakness (patient is unable of squatting or getting up from a low chair without using their arms) and muscle atrophy. Women with androgen excess will often present with loss of scalp hair but overall increased body hair (hirsutism), specifically in the area of the chin, abdomen, chest.
When presenting as an adrenal mass, essential laboratory findings aim to determine if the mass is a primary "functional" adrenal cortical or medullary tumor (i.e., with autonomous adrenal hormone production). Initial screening for hypercortisolism is accomplished by measuring morning cortisol and ACTH (usually < 10pg/ml), 1mg dexamethasone suppression (detects subtle hypercortisolism) and 24-hr urine collection for cortisol. Androgens are measured in serum as DHEAS and total or bioavailable testosterone. Mineralocorticoid production is evaluated by serum measurement of aldosterone, plasma renin activity and possibly 11-deoxycorticosterone. Plasma metanephrines must be measured in order to exclude (or rule in / diagnose) pheochromocytoma and prevent intraoperative hypertensive crisis.
A key imaging finding with adrenocortical carcinoma is often a large (usually >4 cm) heterogeneous mass on CT or MRI scan. When patients present with signs or symptoms of hormone excess, biochemical workup is always pursued first and followed by imaging if biochemical disease is established. Seventy percent of ACC patients present at stage 2 or stage 3 with a large tumor (>5 cm) in the adrenal bed. Twenty-five percent of patients present at stage 4 (i.e., distant metastasis). Staging with abdomen/pelvis and chest CT is the minimal work-up for ACC patients. Only a vanishing number (<4%) will present at stage 1 (tumor <5 cm).
What else could the patient have?
Depending on how a patient presents (abdominal pain versus symptoms of hormone excess), the differential diagnosis varies. In the absence of signs or symptoms of hormone excess, the differential diagnosis of a large adrenal tumor includes a primary tumor of the adrenal gland, a metastatic lesion of a non-adrenal neoplasm or other non-neoplastic lesions (i.e., infection, hemorrhage, cyst, etc.) .
The main other malignant tumors mimicking ACC are neuroblastomas, lymphomas, retroperitoneal sarcomas and renal cell cancer arising from the superior pole of the kidney, and occasionally hepatocellular carcinoma. Benign tumors in the adrenal gland include myelolipomas, pheochromocytomas, adenomas, neuronal tumors such as gangliocytomas and ganglioneuromas, adrenal cysts and occasionally bronchogenic cysts. The main tumors that classically metastasize to the adrenal glands are lung cancer, melanoma and breast cancer. Rarely, infections, such as tuberculosis or histoplasmosis, may mimic adrenal tumors.
Often the final diagnosis can be determined (or greatly facilitated) by imaging findings. A lipid-rich adrenal lesion (<10 H.U. on non-contrast CT scan) is consistent with a benign adrenocortical adenoma. Bilateral tumors suggest metastasis, although up to 5% of ACCs may be bilateral or at some point metastasize to the contralateral adrenal gland. The presence of another primary cancer of the lung or a melanoma on physical exam or patient history often indicates metastasis.
In order to differentiate these possibilities, other investigations are helpful (patient age, laboratory workup, prior history of malignancy, family history).
Biopsy of adrenal tumors is generally not recommended, because of the possibility of hypertensive crisis with a pheochromocytoma and possible needle track metastasis with ACC. The only exception to this rule is in the setting of suspicion of a metastasis of another histologically proven primary tumor (i.e., lung cancer) to the adrenal gland, when this would change tumor stage and therapy. In general, even in the setting of another primary tumor, an adrenal nodule is more likely to be a benign adenoma.
Differential diagnosis of adrenal tumors
Benign differential diagnosis:
Pheochromocytoma: Patients may have episodic hypertension, headache, pallor, tachycardia and often a personal or family history of pheochromocytoma or paraganglioma or other related conditions (e.g., multiple endocrine neoplasia type 2 (MEN2), Von Hippel-Lindau syndrome (VHL), familial paraganglioma syndrome). On laboratory evaluation, most patients have increased plasma or urine metanephrines or normetanephrines. Metanephrines should generally be measured in order to exclude possible pheochromocytoma and prevent intraoperative hypertensive crisis.
Myelolipoma: Myeloplipomas have a very specific imaging appearance on CT scan. Due to the fat content, they appear dark on unenhanced and enhanced scans with areas of more compact tissues and often calcifications. They can be very large; sizes range from 2-20 cm.
Adenoma: Most adenomas will have a homogeneous appearance on CT scan and do not infiltrate surrounding tissues. Lipid-rich adenomas have unenhanced CT scan densities of < 10 HU. Adenomas, including non-lipid-rich adenomas, have specific washout characteristics on delayed enhanced CT scan of >60% (absolute) or >40% (relative). Usually, adenomas are smaller than ACCs, but there is a significant overlap. Large adenomas with degenerative changes (inhomogeneous on imaging, degenerative necrosis) are the main differential diagnosis of ACC; the final diagnosis can often only be established after surgery. Adenomas can produce cortisol, aldosterone and androgens. However, androgen production should always raise suspicion of a malignant tumor. Cortisol production is usually proportional to tumor size and becomes increasingly clinically relevant from sizes >2-3cm. Aldosterone-producing tumors are generally small (<2 cm).
Cysts: The differential diagnosis of adrenal cysts is broad and includes simple adrenal cysts, cystic ACC, cystic pheochromocytomas and bronchogenic cysts.
Malignant differential diagnosis:
Pheochromocytoma: see above. Roughly 10% of all pheochromocytomas are malignant.
Neuroblastoma: Most often diagnosed in children at a young age. Extremely rare in adults, much less common than ACC. On CT imaging, neuroblastomas are heterogeneous and little enhancing. Areas of calcifications are often present. Usually homovanillic acid (HVA), vanillylmandelic acid (VMA) and ferritin are elevated. Hypertension generally does not occur because catecholamine synthesis is often defective. Work-up should also include metanephrines and catecholamines (plasma and urine). Patients may have paraneoplastic opsoclonus.
Lymphoma: Lymphoma can arise in the adrenal gland, usually appears as plum size round adrenal gland, often bilateral, fairly homogenous adrenal tumors.
Retroperitoneal sarcoma: This can arise in the adrenal gland or near the adrenal gland and often mimics ACC.
Renal cell cancer (RCC): If a RCC arises from the upper pole of the kidney, it can be difficult to differentiate from an ACC. A search for the native adrenal gland may be helpful in order to establish whether this is separate or connected to the mass.
Metastasis: Lung cancer, melanoma, renal cell cancer and breast cancer are notorious for forming adrenal metastases. These can be very large and often are fast growing. Because an adrenal metastasis from a non-adrenal malignancy often changes the stage and treatment of the primary tumor, a biopsy of the adrenal tumor can be conducted in this setting. However, this should only occur after biochemical workup for ACC or pheochromocytoma.
Differential diagnosis of hormone excess
In general, most ACCs will produce some steroid hormone. However, often an ACC will produce more precursors or metabolites than classical steroid hormones. Most of these non-classical steroids are usually not measured and do not have biologic activity. Overall, steroid production correlates well with tumor size in individual patients. However, steroid production in ACC is relatively ineffective, with low production rates per tumor volume when compared to the very efficient hormone production of the small native adrenal cortex.
Cortisol is only produced by adrenocortical cells; therefore, the source of hypercortisolism is always the adrenal cortex. However, cortisol release can be autonomous (ACC, adrenal adenoma) or can be adrenocorticotropic hormone (ACTH) -dependent. The source of ACTH is most commonly a pituitary adenoma (i.e., autonomous ACTH production). Less commonly, ACTH is produced ectopically by a non-pituitary tumor such as a bronchial carcinoid, small cell lung cancer, neuroendocrine tumor, medullary thyroid cancer or other epithelial carcinoma.
Hypercortisolism is established by the 1-mg dexamethasone suppression test and/or the 24-hr urine free cortisol test. In the case of primary adrenal hypercortisolism, spontaneous morning ACTH is usually low or completely suppressed. Therefore, the differential diagnosis between primary adrenal hypercortisolism and secondary hypercortisolism is usually fairly straightforward. ACTH-dependent hypercortisolism can be more difficult to differentiate and is discussed elsewhere.
Dexamethasone suppression test: The patient is given 1 mg dexamethasone at 11 PM, and serum cortisol is measured the next morning at 8 AM. The dexamethasone suppression test has a higher sensitivity than the 24-hour urine free cortisol test, especially when choosing a cut-off value of >1.8 microg/dl. Therefore, this test will identify more patients with subclinical hypercortisolism. While this plays a significant role in determining hormone production by adrenal adenomas, it is of little help in patients with ACC, who usually present with frank hypercortisolism rather than subclinical hormone excess.
24-hr urine free cortisol: This test has a higher specificity than the 1-mg dexamethasone suppression test. In most ACC patients with cortisol excess, 24-hr urine free cortisol will be well elevated above the normal range. It is often used to follow disease progression.
Testosterone and DHEAS are the main androgens elevated in androgen-secreting ACCs. Elevated serum DHEAS or testosterone levels in the setting of an adrenal tumor should always raise the suspicion for a malignant adrenocortical neoplasm. In male patients, elevated adrenal androgen production is usually only clinically evident due to the peripheral conversion to estrogen. DHEAS can serve as a tumor marker, however. In female patients, elevated androgen levels lead to menstrual irregularities, hirsutism and acne.
The main differential diagnosis is polycystic ovary syndrome (PCOS) or ovarian hyperthecosis. The primary distinguishing feature differentiating ACC from these entities is a much more rapid onset of symptoms with ACC compared with the insidious course in the benign ovarian conditions.
Key laboratory and imaging tests
The minimal essential laboratory work-up for any adrenal mass includes an 8 AM cortisol, ACTH and DHEAS. In addition, testosterone and luteinizing hormone (LH) and follicle-stimulating hormone (FSH) (specifically, female patient with hirsutism), aldosterone, 11-deoxycorticosterone and renin (patient with hypertension and hypokalemia), and estradiol (patient with menstrual irregularities, gynecomastia) can be helpful in determining autonomous hormone production. Hypercortisolism may also be worked up via a 24-hr urine free cortisol and 1-mg dexamethasone suppression test. Metanephrine and normetanephrine should always be measured to exclude a pheochromocytoma and prevent perisurgical problems.
Standard imaging is done by CT or MRI scan. Both are equally good in distinguishing a benign from a malignant adrenal neoplasm. On occasion, a positron emission tomography (PET) scan can be helpful, but certainly is not a standard modality for the initial workup. An octreotide scan does not have a role in evaluating ACCs. Once the diagnosis of ACC is likely or confirmed, a staging MRI or CT abdomen/pelvis and CT chest should be obtained. A brain MRI or CT is not necessary as ACC very rarely metastasizes to the brain (<1%). The most common organs for metastatic disease include the lung, liver, peritoneum/pelvis, and less commonly bone and the contralateral adrenal gland.
CT: ACC are usually > 4 cm in size, heterogeneous on unenhanced scan, showing areas of necrosis and heterogeneous contrast uptake. ACCs often displace adjacent structures and may extend into the renal vein and inferior vena cava (IVC) with a tumor thrombus. Calcifications and cystic areas may be present. In a homogeneous lesion. In order to differentiate benign from malignant, unenhanced density and delayed wash-out are helpful. ACC usually measure >10 HU and show a slow washout on delayed imaging (absolute wash-out <60%, relative wash-out <40%).
MRI: ACC are usually > 4 cm in size, heterogeneous on T1 and T2 weighted images. On T1 weighted images, tumor tissue is usually hypointense or isointense to normal liver, but may be hyperintense in areas of necrosis and hemorrhage. On T2 weighted images, ACC is usually hyperintense to liver. MRI may be superior to CT in order to determine intravascular (IVC) extension of tumor.
PET: Virtually all ACCs are fluorodeoxyglucose (FDG)-PET avid. However, adrenal metastasis and roughly 10% of adrenal adenomas are FDG-PET avid too, giving FDG-PET a high sensitivity, but little specificity. There are emerging imaging methods, such as 11C-metomidate imaging. This substance binds to 11-beta-hydroxylase and may be more specific in identifying adrenal tumors and ACC metastasis. This method is not yet widely available.
Other tests that may prove helpful diagnostically
The pathology report is of significant importance in determining diagnosis and prognosis. The pathology report should contain all elements of the Weiss score. A Weiss score > 3 is considered to be an ACC, while < 3 is a benign tumor. A Weiss score of 3 is somewhat indeterminate. Especially when in doubt, review of pathology by an experienced endocrine pathologist is recommended.
The number of mitoses (<20 mitoses/HPF = low grade and >20 mitoses/HPF = high grade) predicts the prognosis of a patient with ACC, with high-grade tumors showing a significantly reduced tumor-free survival and more aggressive biological behavior. A special challenge is the presence of oncocytomas, tumors that can be fairly large, show very little mitosis, degenerative, rather than tumor necrosis and are of undetermined malignant behavior, unless metastasis is clearly present. A different pathological classification system can be used for these tumors.
Management and treatment of the disease
Due to the extreme rarity of ACC, patients are often best served by being referred to a tertiary center specializing in ACC. This can facilitate preoperative care and surgical management together with necessary endocrinologic and oncologic care, often in the context of a clinical trial managed by a specialized network of ACC teams across the world.
Even "standard" treatments are not well established and are currently undergoing evaluation in prospective trials (e.g., ADIUVO for adjuvant mitotane in completely resected low-grade disease).
There are two general considerations with regards to ACC therapy: antineoplastic therapy and therapy of hormone excess. Cortisol production is an adverse risk factor, and survival of patients with cortisol production is decreased. Therefore, control of hormone excess may be beneficial to decrease morbidity.
Primary treatment for local or locoregional disease, stage 1-3
The only curable approach for stage 1-3 ACC is surgery. The surgical approach should be open adrenalectomy. We generally discourage the use of laparoscopic and specifically robotic adrenalectomy. Surgery should include lymphadenectomy whenever possible. Surgery should take place at a center that has extensive experience in adrenal surgery and should be done by a surgeon who regularly performs adrenalectomies for malignant adrenal tumors. In case of incomplete resection or isolated local recurrence, repeat surgery can be curative.
Mitotane: The mainstay of adjuvant treatment is pharmacotherapy with mitotane. Retrospective analysis suggests that mitotane therapy prolongs progression-free and overall survival, at least in a subset of patients. Mitotane therapy should be initiated as early after surgery as possible and can be started concurrently with possible radiation therapy. A plasma level of 14-20 mg/l has been determined to be therapeutic in retrospective analyses. For a detailed outline of mitotane pharmacotherapy together with laboratory and clinical monitoring, see Mitotane Therapy (below). Tumor recurrence, either local or with distant metastasis, should be interpreted as a treatment failure.
XRT: Data on adjuvant radiation therapy is not entirely conclusive, but is suggested to benefit patients in preventing local recurrence without significantly impacting overall survival. Usually doses of a total of ~50 Gy are administered in 20-30 single treatment settings.
Surgery: Surgery for locally recurrent disease should always be considered. However, in the setting of distant metastasis, surgery is of limited value. In case of hormone excess, surgery has traditionally been considered to be of potential benefit if ~90% of the tumor can be removed.
Cytotoxic chemotherapy: In case of progression with inoperable local recurrence or distant metastasis, treatment with mitotane should be considered in patients who did not receive mitotane prior to recurrence. In addition, cytotoxic chemotherapy can be used. First-line therapy as evaluated by the FIRM-ACT trial is a combination therapy of etoposide, doxorubicin and cisplatin with mitotane. As a second-line cytotoxic therapy, streptozocin plus mitotane (less effective in FIRM-ACT) can be tried. Currently, additional chemotherapy regimens that include a variety of cytotoxic agents and targeted approaches are being evaluated.
Stage 4 ACC
Cytotoxic chemotherapy: In case of progression with inoperable local recurrence or distant metastasis, treatment with mitotane should be considered in patients who did not receive mitotane prior to recurrence. In addition, cytotoxic chemotherapy can be used. The standard therapy as evaluated by the FIRM-ACT trial is a combination therapy of etoposide, doxorubicin and cisplatin with mitotane. As a second-line cytotoxic therapy, streptozocin plus mitotane (less effective in FIRM-ACT) can be tried. Currently, additional chemotherapy regimens that include a variety of cytotoxic agents and targeted approaches are being evaluated.
Surgery: Surgery for metastatic disease has not been shown to improve survival. However, especially in low-grade disease with single or oligo-metastases, this option should be considered. Long-term survival and even cure have been reported.
XRT: Radiation to metastatic sites, such as liver, bone or even lung, can be considered to prevent local complications of tumor growth, provide pain control or to treat hormone excess symptoms.
Surveillance should include initially imaging every three months with chest CT and abdomen/pelvis MRI or CT for detection of local recurrence and distant metastasis. Occasionally, a PET scan can be helpful in determining the biology of suspicious lesions. Every patient should also have a complete history and physical exam for symptoms and signs of excess hormone production. Usually, hormone production of recurrent disease will be in accordance with the initial hormone excess at the time of diagnosis. However, changes in hormone production can occur. When patients present with initial hormone excess, these hormone levels should be followed. They can also serve as tumor markers. If there is clinical suspicion of new additional hormones being produced, appropriate testing is warranted.
Practical guide to mitotane therapy
Mitotane therapy has been shown to be effective as an adjuvant therapy as well as an antitumor therapy in up to 20%-30% of ACC patients. It has significant side effects, especially gastrointestinal, neurological and endocrine side effects, and leads to several laboratory abnormalities that need to be monitored during therapy. In general, gastrointestinal side effects are dependent on the actual amount of mitotane pills taken, while neurological and endocrine effects seem to be dependent on the actual mitotane level. The therapeutic goal is to keep mitotane blood levels in the range of 14-20 microg/l. Often this is achieved by having the patient take as many mitotane tablets as tolerated. The occurrence of side effects varies significantly between individual patients, with young patients tolerating therapy much better than elderly patients.
Gastrointestinal side effects, mainly nausea and diarrhea, can be controlled by taking mitotane with lipid-rich foods or beverages (e.g., milk, peanut butter) and concurrent therapy with antidiarrheal medications such as loperamide. Often, spacing doses over the day to BID, TID or even QID dosing can be helpful.
Neurological symptoms, specifically dysphasia, balance disturbances and mental slowing are more dependent on mitotane levels. In case of neurological side effects, mitotane levels should be measured and medication should be discontinued until symptoms resolve. Once the patient improves, mitotane therapy can be reinitiated, usually at a lower daily dose.
Endocrine and metabolic side effects are adrenal insufficiency (rarely including mineralocorticoid secretion) and occasionally impairment of sex hormone synthesis, together with lipid abnormalities. Due to the fact that mitotane is a very important inducer of CYP3A4, which also metabolizes cortisol, patients will generally need higher hydrocortisone replacement doses than with other primary adrenal insufficiencies.
Hydrocortisone doses are mainly titrated clinically, starting at 20 mg upon awakening and a second dose of 10 mg in the early afternoon. Occasionally, TID dosing with a dinner dose may become necessary. Measurement of 24-hr urine cortisol may be helpful in titrating glucocorticoid replacement. Total daily doses may reach 100 mg. Persistent adrenal insufficiency after discontinuation of mitotane is rare, but due to the long half-life (up to 150 days) and persistence of increased CYP3A4 activity, patients may need hydrocortisone replacement for several weeks to months after mitotane therapy.
Mineralocorticoid replacement rarely becomes necessary. In case of low sex hormone levels, patients may benefit from testosterone replacement therapy or estrogen replacement therapy.
Patients often develop lipid abnormalities and high cholesterol levels, which are generally treated with a statin not metabolized by CYP3A4, such as pravastatin.
It is unclear whether patients need thyroid hormone replacement therapy. Usually a decrease in TSH and fT4 is observed. While it is sometimes difficult to ascertain if the fatigue associated with mitotane therapy is in part mediated by mild hypothyroidism, thyroid hormone replacement therapy should definitely be started once patients develop symptoms and signs of hypothyroidism.
Other laboratory abnormalities include an invariable increase in GGT, which can be clinically disregarded. However a rise of liver function tests (AST, ALT) to greater than 2-3 times normal should raise the concern of hepatotoxicity, and mitotane therapy should be at least temporarily discontinued.
Laboratory evaluation should take place at least every 1-3 months and include: mitotane level (target 14-20 microg/l), TSH, fT4, total testosterone and sex hormone-binding globulin (SHBG) or bioavailable testosterone, basic metabolic profile, liver function tests, cortisol ACTH, renin, aldosterone, cholesterol, and 24-hr urine.
We usually initiate a moderate-to-slow dosage escalation, starting the patient on a dose of 1g BID, increasing the dose by 1 g weekly to a total of 6 g daily. Then we adjust doses depending on mitotane target level of 14 - 20 microg/l.
Therapy of hormone excess
Therapy of hormone excess has its greatest role for the treatment of hypercortisolism. However, antiandrogenic therapy (especially in hirsute women), antimineralocorticoid therapy and occasionally antiestrogenic therapy may become necessary (e.g., male patients with gynecomastia). In general, there are two main mechanisms to treat hormone excess: blocking hormone synthesis or using steroid hormone receptor antagonist.
Therapy of hypercortsolism
Ketoconazole: Ketoconazole is still first-line therapy for hypercortisolism at many centers. However, it is much less potent than metyrapone or mifepristone and rarely controls the high levels of hypercortisolism. It works by blocking steroid synthesis at the CYP17A1 step. Treatment is initiated with 200 - 600 mg/day in 2-3 divided doses and titrated up to 800 - 1200 mg/day. Liver enzymes need to be monitored with therapy.
Metyrapone: Metyrapone is a very effective blocker of the CYP11B1 gene and is therefore able to normalize cortisol levels in most ACC patients. While adrenal insufficiency is a concern and patients should be warned about this possibility, it is rarely observed in patients with ACC treated with metyrapone. Metyrapone has to be requested from the manufacturer for off-label compassionate use. Therapy is started at 250 mg daily or BID (with food) and can be titrated up to 2-3 g daily.
Mifepristone: Mifepristone is a very effective glucocorticoid receptor antagonist and very effectively controls the deleterious glucocorticoid effects in hypercortisolism. As with metyrapone, adrenal insufficiency is rarely a concern. Patients need to be monitored clinically, because cortisol levels cannot be used for monitoring therapy. Indeed, due to the antiglucocorticoid mechanism, cortisol levels rise to extremely high levels (>100 microg/dl). Concurrent treatment with potassium and spironolactone becomes necessary in order to prevent the mineralocorticoid effects of these high levels of cortisol, which easily overwhelm the 11-beta-HSD system that usually prevents cortisol access to the mineralocorticoid receptor in the kidney. Mifepristone is approved by the FDA for treatment of hypercortisolism.
Other hormone synthesis inhibitors, such as aminoglutethimide or low-dose infusion with etomidate, are used less commonly.
Therapy of hyperaldosteronism / increased mineralocorticoid activity:
Spironolactone/eplerenone: Spironolactone and eplerenone are used as antimineralocorticoid treatment. Spironolactone is usually the first-line therapy. It is well-tolerated in women, in whom it also exerts antiandrogenic activity, but treatment in male patients is limited by the development of gynecomastia. In case of severe side effects, therapy can be changed to eplerenone. Spironolactone is usually started at a dose of 25 mg daily , but doses up to 200 mg BID may be necessary to control mineralocorticoid effects. Eplerenone is usually used in doses starting at 50 mg daily up to 200 mg BID.
Therapy of hyperandrogenism:
Spironolactone: Spironolactone is the drug of choice to treat female patients with hirsutism.
Therapy of hyperestrogenism:
Aromatase inhibitors and estrogen receptor antagonists can be used to treat symptoms or signs of hyperandrogenism, such as gynecomastia. Gynecomastia can also be treated with radiation therapy to the breast tissue.
What’s the evidence?/references
Mansmann, G, Lau, J, Balk, E, Rothberg, M, Miyachi, Y, Bornstein, SR. " The clinically inapparent adrenal mass: update in diagnosis and management". Endocr Rev . vol. 25. 2004. pp. 309-340.(Overview on epidemiology and diagnostics of the incidentally discovered adrenal mass.)
Allolio, B, Fassnacht, M. " Clinical review: Adrenocortical carcinoma: clinical update". J Clin Endocrinol Metab. vol. 91. 2006. pp. 2027-2037.(Overview on diagnosis & therapy of ACC.)
Fassnacht, M, Allolio, B. "Clinical management of adrenocortical carcinoma". Best Pract Res Clin Endocrinol Metab. vol. 23. 2009. pp. 273-89.(Overview on diagnosis & therapy of ACC.)
Schteingart, DE, Doherty, GM, Gauger, PG. "Management of patients with adrenal cancer: recommendations of an international consensus conference". Endocr Relat Cancer. vol. 12. 2005. pp. 667-80.(Consensus recommendations.)
Terzolo, M, Angeli, A, Fassnacht, M. "Adjuvant mitotane treatment for adrenocortical carcinoma". N Engl J Med. vol. 356. 2007. pp. 2372-80.(Retrospective study on mitotane as an adjuvant therapy.)
Fassnacht, M, Terzolo, M, Allolio, B. "Combination chemotherapy in advanced adrenocortical carcinoma". N Engl J Med. vol. 366. 2012. pp. 2189-97.(Phase 3 trial for cytotoxic chemotherapy of ACC.)
Nieman, LK, Biller, BM, Findling, JW. "The diagnosis of Cushing's syndrome: an Endocrine Society Clinical Practice Guideline". J Clin Endocrinol Metab. vol. 93. 2008. pp. 1526-40.
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