OVERVIEW: What every practitioner needs to know
Adrenocortical tumors can be divided into benign or malignant, as well as “functional” or “nonfunctional” in reference to whether or not they secrete hormones. The most common adrenocortical tumor is a benign adenoma or “incidentaloma,” which is nonfunctional.
Adrenocortical carcinoma is a rare, malignant tumor that can be associated with hormone secretion or can be nonfunctional. When it occurs in children, it is more common when they are less than 5 years of age. Approximately 60% of adrenocortical carcinomas are functional and can produce androgens, cortisol, or both. Pheochromocytomas are tumors that arise from the adrenal medulla and thus are not considered adrenocortical tumors.
Are you sure your patient has an adrenocortical tumor? What are the typical findings for this disease?
The most common presenting symptom in children is virilization, followed by symptoms related to hypercortisolism, whereas in adults, the majority of tumors are nonfunctional and are discovered incidentally.
Nonfunctional adenoma: These tumors are typically discovered incidentally on radiographic imaging performed for another indication.
Functional adenoma: Patients typically present with signs/symptoms of hormone excess secondary to overproduction of cortisol (e.g., weight gain, striae, thinning skin, acne), androgens (precocious puberty, gynecomastia, virilization, or feminization), or rarely aldosterone (hypertension, hypokalemia).
Adrenocortical carcinoma: Symptoms associated with glucocorticoid excess, such as rapid weight gain, hypertension, or striae, or symptoms associated with androgen excess, such as virilization and precocious puberty. Virilization is the most common presenting symptom in children. Symptoms can also be associated with mass effect of the tumor, such as flank pain or abdominal pain, or constitutional symptoms such as weight loss or fatigue.
Staging system for adrenocortical carcinomas in children
Stage I: completely resected tumors weighing less than 200 g
Stage II: completely resected larger tumors weighing more than 200 g
Stage III: residual or distant metastatic disease
What other disease/condition shares some of these symptoms?
Adrenal hemorrhage, infection, or abscess causing enlargement
Metastatic disease, e.g., renal cell carcinoma, hepatocellular carcinoma, melanoma, or other carcinoma
What caused this disease to develop at this time?
Adenoma: Most tumors are sporadic, but genetic alterations in adrenal signaling pathways have been implicated in the formation of benign adenomas, both functional and nonfunctional.
β-Catenin mutations: the β-catenin pathway is involved in the embryonic development of the adrenal glands. Activating somatic mutations in the
β-catenin gene have been implicated in a number of benign adenomas as well as adrenal carcinomas.
PRKAR1A: germline mutations in a regulatory subunit of the cyclic adenosine monophosphate (cAMP) signaling pathway have been implicated in a form of bilateral adrenal hyperplasia—primary pigmented nodular adrenocortical disease.
Aberrant receptor expression: genes encoding the adrenocorticotropic hormone (ACTH) receptor, gastrointestinal inhibitory peptide, vasopressin, β-adrenergic receptors, serotonin, as well as estrogen and luteinizing hormone can cause disease to develop.
Carcinoma: Many tumors are sporadic but ACC has also been associated with hereditary syndromes.
Sporadic adrenocortical carcinoma: This is associated with the tumor suppressor gene TP53, which has been implicated in the higher rate of adrenocortical carcinoma in children from southern Brazil. Other genes include the IGF1Rgene and the SF-1 gene.
Li-Fraumeni syndrome: an inactivating mutation in the TP53 tumor suppressor gene causes this syndrome.
Multiple endocrine neoplasia, type 1 (MEN 1): a mutation in the MEN1 gene causes MEN 1.
Beckwith-Wiedemann syndrome: microduplication of chromosome 11p15 is the cause of this syndrome.
SBLA (sarcoma, breast, leukemia, and adrenal gland) syndrome: It is not yet known what genetic abnormality causes this syndrome.
What laboratory studies should you request to help confirm the diagnosis? How should you interpret the results?
Hormone evaluation should be performed to determine if the tumor is functional.
Androgens: DHEA-S, testosterone, androstenedione, 17-OH progesterone, serum estradiol (high-sensitivity assay), estrone, as well as urinary 17-ketosteroids, which tend to be elevated in the majority of patients with adrenocortical tumors, and urinary total estrogens should be evaluated. In prepubertal children, serum estradiol levels will be undetectable by assays; however, in an estrogen-secreting tumor, levels may be high enough for detection using the high-sensitivity assay.
An initial evaluation should consist of 24-hour urinary free cortisol, 17-ketosteroids, and 17-hydroxysteroids at a minimum. If any of these tests are even slightly abnormal, DHEA-S, androstenedione, testosterone, and high-sensitivity estradiol should be obtained. Further testing may be needed if there is indication of increased steroid production, at which point 17-OH progesterone, estrone, and free testosterone may be tested.
Cortisol: screening tests include a 24-hour urinary free cortisol evaluation, serum cortisol and ACTH levels, a 1-mg dexamethasone suppression test with an 8 AM serum cortisol or an 11 pm salivary cortisol level. If one screening test is positive, a different screening test should be obtained as a repeat.
Aldosterone: plasma renin activity and serum aldosterone levels should be evaluated; serum potassium levels should be obtained in a hypertensive patient.
Catecholamines: plasma metanephrines and normetanephrines should also be obtained in a hypertensive patient.
Would imaging studies be helpful? If so, which ones?
Computed tomography: This is the imaging modality of choice for the adrenal glands. Precontrast Hounsfield units (HU) are helpful in differentiating a benign adenoma from a malignant carcinoma. Typically, lipid-rich adenomas have a HU measurement of less than 10, although some adenomas that do not contain large amounts of lipid can have higher HU measurements. Adenomas tend to have a smooth, round, and homogeneous density and measure less than 4 cm. In contrast, adrenal carcinomas and metastases have readings of greater than 20 HUs, have irregular shapes, may display tumor calcifications, appear inhomogeneous, and typically measure greater than 4 cm.
Magnetic resonance imaging (MRI): Although CT is the preferred imaging technique for the adrenal glands, MRI is an alternative to CT when there is concern for radiation exposure. Adenomas appear isointense with the liver on T1- and T2-weighted images, whereas carcinomas and metastases appear hypointense compared with the liver.
Ultrasonography: This modality is useful in evaluating for potential tumor extension into the inferior vena cava.
Positron emission tomography (PET): if there is a high suspicion for malignancy, PET can be helpful, and malignant masses such as carcinomas have a high standardized uptake value.
When should a biopsy be performed?
Fine-needle aspiration (FNA) should be performed for a nonfunctional mass if there is suspicion of a metastatic tumor to the adrenal gland, or for staging purposes if there is a previous history of cancer. It should be used to evaluate for lymphoma of the adrenal gland or suspected infectious causes. FNA cannot distinguish between adrenal adenomas and carcinomas and should never be performed if there is suspicion for pheochromocytoma.
Confirming the diagnosis
Any tumor with suspicious radiologic features, functional tumors, or tumors measuring greater than 4 cm should be surgically removed. Tumors smaller than 4 cm and with a HU measurement greater than 10 may be reimaged in 3-6 months and if there is growth of at least 0.8 cm, or if there are indeterminant radiologic features, surgical resection should be considered.
If you are able to confirm that the patient has an adrenocortical tumor, what treatment should be initiated?
Initial treatment: surgical resection is the initial treatment of choice, as it offers the potential for cure. If invasion of adjacent organs is present, extensive surgery involving en bloc resection may be required. Even if full resection is not possible, debulking surgery may offer symptom relief if the tumor is secreting hormone and may improve survival. Open adrenalectomy is preferred to a laparascopic procedure because of risk of tumor spillage and the likely requirement of en bloc resection.
Mitotane: This agent acts to inhibit steroidogenesis and causes adrenocortical necrosis, thus acting as an adrenolytic agent. Additionally, it alters the metabolism of glucocorticoids, and thus higher doses of replacement glucocorticoids are required, as it results in adrenal insufficiency.
Mitotane should be used in all patients after surgical resection, since occult micrometastases may be present at the time of diagnosis and as primary therapy if the tumor is not resectable or if the tumor has recurred. Mitotane should be administered up to maximally tolerated doses. Additionally, it may also be used in combination with other chemotherapeutic agents, such as etoposide, doxorubicin, and cisplatin. The efficacy of mitotane in children, however, is unknown, as there are no studies to date, but given the high mortality in children and its efficacy in adults, it is reasonable to treat with mitotane.
Radiation: This modality may be used as adjuvant therapy for incomplete resections or for advanced stages of disease. Its efficacy has not been evaluated in children.
Radiofrequency ablation: This may be used as adjuvant therapy to provide short-term control and palliation for obstructive symptoms and may also be used to treat liver metastases. Its efficacy has not been evaluated in children.
if the tumor is functional, measures greater than 4 cm, or displays suspicious characteristics on radiologic imaging, it should be surgically removed. A laparoscopic approach is recommended, particularly if the tumor is smaller than 6 cm.
Medical therapy: medications to block cortisol, aldosterone, or androgens may be used for patients who are not surgical candidates or before surgery if symptoms from excess hormone secretion are severe. Although there are no studies, all of the medications listed below have been used in children, with ketoconazole being used most frequently, followed by mitotane.
Cortisol: ketoconazole, metyrapone, or mitotane
Aldosterone: spironolactone is most commonly used in children. In addition, eplerenone, amiloride, or triamterene can also be used.
What are the adverse effects associated with each treatment option?
Mitotane: the most common adverse effects are gastrointestinal (nausea, vomiting, anorexia, diarrhea). It also can cause central nervous system effects, including lethargy and sedation, dizziness, and ataxia. Hepatoxicity can occur, but significant liver function test abnormalities are rare. In children, it may cause reversible growth arrest, and prepubertal children demonstrate gynecomastia or thelarche. It also causes glucocorticoid and, less frequently, mineralocorticoid deficiency, which can be avoided by replacement therapy.
All tumors are cured by surgery; however, the patient may require replacement glucocorticoid therapy for a time because of contralateral adrenal gland suppression for functional tumors. Patients with Cushing syndrome may require supratherapeutic doses of glucocorticoids in the first few weeks after surgery, with a slow taper.
Medication to block cortisol (ketoconazole, metyrapone, or mitotane) can cause adrenal insufficiency, and patients may require replacement glucocorticoid therapy.
Medication to block aldosterone (spironolactone) may cause gynecomastia, whereas eplerenone, which is specific for the aldosterone receptor, does not. Both amiloride and triamterene can cause gastrointestinal side effects.
Flutamide may cause nausea, vomiting, and transaminitis, which is typically mild and transient
What are the possible outcomes of adrenocortical tumors?
Despite the poor prognosis for adults, children with adrenocortical carcinoma have a better survival rate. Good prognostic signs include age less than 3 years, stage I disease, and virilization as the sole presenting symptom. Survival rates are greater than 90% for stage I disease and greater than 50% for stage II disease. Stage III disease, which indicates residual disease or distant metastasis, is associated with a poor prognosis. The outcome of adrenal adenomas is good, and the survival rate is 100%. Children with functional adenoma may have some permanent disturbance in growth, although this is controversial.
What causes this disease and how frequent is it?
The overall incidence of adrenocortical tumors, which includes both benign adenomas and malignant carcinomas, is 0.3/1 million population and constitutes less than 0.2% of all pediatric neoplasms.
Adrenal adenomas: the majority are sporadic, although several genetic mutations have been associated with adenoma development.
Adrenocortical carcinomas: These are rare tumors; the overall incidence is 0.4/million population during the first 4 years of life, with a second peak during the late teens of 0.2/million population. In the United States, only 25 new cases are diagnosed each year in children, although the frequency is higher in southern Brazil, where the incidence is estimated to be 15 times higher than the rest of the world because of the presence of a germline mutation. It is either sporadic or associated with several hereditary syndomes.
Sporadic adrenocortical carcinoma: Adrenocortical carcinoma associated with loss of heterozygosity in the tumor suppressor gene TP53 and a germline mutation has been implicated in the higher rate of adrenocortical carcinoma in children from southern Brazil. Other genes implicated include the IGF1R gene, which is overexpressed in some tumors, as well as the SF1 gene, which is a transcription factor that has been shown to have increased copy numbers in some adrenocortical carcinoma tumors.
Li-Fraumeni syndrome: This syndrome can include sarcomas of the bone and soft tissue, cancers of the brain and breast, and adrenocortical carcinoma. It is caused by an inactivating mutation in the TP53 tumor suppressor gene.
MEN 1: Adenomas of the parathyroids, pituitary, pancreas, and adrenals, and rarely adrenocortical carcinoma can be seen in MEN 1. It is caused by an inactivating mutation in the MEN1 gene.
Beckwith-Wiedemann syndrome: Wilms tumor, neuroblastoma, hepatoblastoma, and adrenocortical carcinoma can be seen in this syndrome. It is associated with a microduplication of chromosome 11p15.
SBLA syndrome: This syndrome can include cancer of the breast and lung, sarcoma, and adrenocortical carcinoma. It is not yet known what genetic abnormality causes this syndrome.
What complications might you expect from the disease or treatment of the disease?
Complications from hormone production include early closure of the growth plates from androgen, as well as cortisol exposure. Hypertensive complications, such as encephalopathy, can occur from aldosterone oversecretion as well as from excess cortisol and androgens.
Adrenocortical carcinomas can metastasize locally to lymph nodes, as well as to distant sites, including lung, liver, and the inferior vena cava. Recurrence of disease is rapidly fatal, with average survival time less than 48 months.
How can adrenocortical tumors be prevented?
There is no current prevention for adrenocortical tumors.
What is the evidence?
Ciftci, AO, Senocak, ME, Tanyel, FC. “Adrenocortical tumors in children”. J Pediatr Surg. vol. 36. 2001. pp. 549-54.
Faria, AM, Almeida, MQ. “Differences in the molecular mechanisms of adrenocortical tumorigenesis between children and adults”. Mol Cell Endocrinol. 2011 Oct 14.
Lau, SK, Weiss, LM. “The Weiss system for evaluating adrenocortical neoplasms: 25 years later”. Hum Pathol. vol. 40. 2009. pp. 757-68.
Ribeiro, RC, Michalkiewicz, EL, Figueiredo, BC. “Adrenocortical tumors in children”. Braz J Med Biol Res. vol. 33. 2000. pp. 1225-34.
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- OVERVIEW: What every practitioner needs to know
- Are you sure your patient has an adrenocortical tumor? What are the typical findings for this disease?
- What other disease/condition shares some of these symptoms?
- What caused this disease to develop at this time?
- What laboratory studies should you request to help confirm the diagnosis? How should you interpret the results?
- Would imaging studies be helpful? If so, which ones?
- Confirming the diagnosis
- If you are able to confirm that the patient has an adrenocortical tumor, what treatment should be initiated?
- What are the adverse effects associated with each treatment option?
- What are the possible outcomes of adrenocortical tumors?
- What causes this disease and how frequent is it?
- What complications might you expect from the disease or treatment of the disease?
- How can adrenocortical tumors be prevented?
- What is the evidence?