Adrenocortical tumors develop in the adrenal glands (also known as suprarenal glands). The adrenal glands are triangular-shaped organs that measure about 1.5 inches in height and 3 inches in length above your kidneys.
These glands are made up of a number of different layers that directly influence the structure and function of the glands. The adrenal cells, using cholesterol as a starting material, produce and secrete a variety of steroid hormones vital to life, such as cortisol, aldosterone and sex steroids.
Each gland is comprised of two distinct structures: an outer adrenal cortex consisting of steroid-producing cells surrounding a core of medulla. The adrenal cortex is divided into three zones, and each one is responsible for producing specific hormones. There are three classes of these hormones:
The mineralocorticoid aldosterone is produced in the zona glomerulosa. It is important for regulation of blood pressure and electrolyte balance. Mineralocorticoids are mediated by signals triggered by the kidney.
Glucocorticoids, such as cortisol, are produced in the zona fasciculata. They are important for regulation of metabolism, cardiovascular function and immune response. The release of glucocorticoids is triggered by the hypothalamus and pituitary gland.
Androgens and estrogens are produced by the zona reticularis, the most inner zone of the adrenal cortex. The adrenal cortex releases small amounts of male and female sex hormones. However, their impact is usually overshadowed by the greater amounts of hormones, such as estrogen and testosterone, released by the ovaries or testes, respectively.
The hormones of the adrenal medulla (adrenaline and noradrenaline) are released from the sympathetic nervous system. This helps the body deal with physical and emotional stress. The hormones of the adrenal medulla contribute to this response by increasing the heart rate and blood pressure. As a response to stress, the hormones also convert glycogen to glucose.
Tumors affecting the cortex of the adrenal gland (ACT) are very common. These tumors occur in 3% to 10% of the human population. The vast majority of these are small, non-malignant and nonfunctional adrenocortical adenomas (ACA).
Adrenocortical carcinomas (ACC), in contrast, are very rare and aggressive. These tumors usually occur in adults, affecting one to two people for every million persons. In children, ACT is even more rare, affecting 0.3 to 0.4 per year out of every million persons younger than 15. The United States Surveillance, Epidemiology, and End Results (SEER) database estimates that there are about 25 to 30 new cases per year in children and adolescents. In Southern Brazil, the incidence of pediatric ACT is 10 times higher than that observed worldwide.
Adrenocortical tumors have three peaks of incidence, the first between two and five years of age, and the second in the fifth decade of life. A small peak is also observed in the adolescent age. ACT is more prevalent in females (range, 1.5-2.5:1). Clinical manifestations and outcomes, as well as molecular findings, differ between childhood and adult ACT.
Adrenocortical tumors are remarkable for the many hormonal syndromes that can occur in patients with steroid hormone-producing ("functional") tumors. Many patients will seek medical attention because the bodily changes due to excessive hormone secretion. Individual tumors can secrete one or more hormone types such as androgens (male hormones), cortisol, aldosterone and estrogen (female hormone). However, the initial manifestations depend on the patient’s age and gender.
After puberty, when excess estrogen and progesterone is produced in a female, ACT may not be suspected because the signs and symptoms can mimic normal sexual maturation. The same is true for excess testosterone in males after puberty.
When excess adrenal hormones occur in pre-pubertal children of any sex, the clinical manifestations will be considered abnormal by parents and physicians. For example, if a female begins to develop male characteristics (deeper voice, excess body hair) or when a boy develops enlarged breasts, pubic hair or virilization (increased testosterone), a medical condition may be suspected.
About 80% of children with ACT present with signs and symptoms associated with virilization syndromes, caused by high levels of androgen hormone secretion. In addition to androgens, other patients with ACT could experience an excess of cortisol or aldosterone.
In about 5% to 10% of children and 50% of adults with ACT, signs and symptoms associated with an increase hormonal secretion are not present. In these cases, ACT is generally discovered during clinical exams because a sizable mass, abdominal pain or discomfort from pressure applied to the abdominal organs occurs. A small portion of cases are incidentally discovered by imaging studies for different reasons. ACT can also be detected during routine fetal ultrasonography or at birth.
Virilization is caused by excessive secretion of adrenal androgen hormones. This leads to high levels of the male hormone testosterone. Virilization includes early onset of facial and body hair, called hirsutism, body odor, acne, deepening of the voice, enlarged muscles, growth acceleration and an increase in genital size. In about 40% of patients, virilization is observed by itself. In about 45% of cases, it is accompanied by clinical manifestations of the overproduction of other adrenocortical hormones, including glucocorticoids (cortisol), aldosterone or estrogens.
Cushing syndrome is caused by excessive secretion of cortisol (glucocorticoids). Symptoms of cortisol excess include obesity, high blood pressure, edema, thin skin, easy bruising, muscle weakness, purple lines on the abdomen, a fatty “buffalo hump” on the neck and a “moonlike” face. Isolated Cushing's syndrome is relatively rare in children with ACT and most commonly affects the adult counterpart (ages 20 to 50).
Aldosterone-producing tumors are caused by excessive production of aldosterone. When deregulated, aldosterone is pathogenic and contributes to the development and progression of heart and kidney disease. High aldosterone levels can cause high blood pressure and low potassium levels. Low potassium levels may cause weakness, tingling, muscle spasms and periods of temporary paralysis. Aldosterone-producing tumors, also called Conn’s syndrome, occurs very rarely in pediatric ACT.
Feminization is caused by increased estrogen production. The most frequent sign of feminization is breast enlargement in males, called gynecomastia. It can also occur in females.
At the time of diagnosis, the initial evaluation includes a careful physical examination with a focus on symptoms and signs of increased hormone levels. Patients are required to have an initial basic biochemical and hormonal evaluation. The patient’s plasma and free urinary cortisol, DHEA-S, testosterone, androstenedione, 17-hydroxyprogesterone, aldosterone, renin activity, deoxycorticosterone and other 17-deoxysteroid precursors should be measured. Simultaneous elevation of glucocorticoid and androgen levels is a strong indication of an adrenocortical tumor.
The patients will be required to perform a computed tomography (CT) scan and magnetic resonance imaging (MRI). Because the liver and lungs are the most common sites of metastasis at the time of diagnosis, CT scan of the chest and MRI of the abdomen are recommended for all patients with newly diagnosed ACT.
Doppler ultrasonography of the abdomen and lower extremities is recommended to evaluate the presence of tumor thrombus. Over the past few years, F-18/fluorodeoxyglucose-positron emission tomography (FDG-PET) use has increased. FDG-PET/CT has not been proven to be superior to CT/MRI in pediatric ACT.
Because children with ACT usually carry a germline TP53 mutation, they are at high-risk of developing second cancers, so radiation exposure should be minimized. The new integrated PET/MR scanners have the advantage to reduce radiation exposure. It may become a preferable imaging modality in the near future. Bone scintigraphy is reserved for cases of advanced-stage disease when skeletal metastasis is suspected.
The definitive diagnosis of ACT is made on the basis of the gross and histologic appearance of tissue obtained from surgical resection. Based on the presence of several histopathologic features, these tumors can be classified as adenoma, carcinoma, or when the features are not clear, as having indeterminate biologic potential. This classification system utilizes tumor size, tumor weight and histologic findings including mitotic activity, the presence of atypical mitotic figures, tumor extension into adjacent tissues or the inferior vena cava, necrosis, venous invasion and capsular infiltration.
Adrenocortical adenoma (ACA) in children accounts for 20% of cases. The remaining cases are classified as carcinoma (70%) or undetermined histology (10%). For those cases difficult to classify, pathologists have used a variety of terms, such as atypical adenoma, adrenocortical neoplasm and adrenocortical neoplasm of uncertain malignant potential or uncertain biological behavior.
There are several staging criteria for pediatric ACT. We use the criteria proposed by investigators from the Children’s Oncology Group’s (COG).
Adrenocortical Tumor Staging Criteria
Stage Definition I Completely resected, small tumors (< 100 grams or < 200 cubic centimeters) with normal postoperative hormone levels II Completely resected, large tumors (≥ 100 grams or ≥ 200 cubic centimeters) with normal postoperative hormone levels III
Unresectable, gross or microscopic residual disease
Patients with stage I and II tumors who fail to normalize hormone levels after surgery
Patients with retroperitoneal lymph node involvement
IV Presence of metastatic disease
However, defining classification schemes or disease staging systems that guide therapy for pediatric ACT is an evolving process. Histologic features in pediatric ACT are not included among the staging criteria, although nearly all cases of adenoma have stage I/II disease.
Surgery is the single most important procedure in the successful treatment of ACT. It is performed by a transabdominal approach. Laparoscopic resection should be avoided in children.
Sometimes, it is necessary to do an en bloc resection, which may include the kidney, portions of the pancreas or liver, spleen, diaphragm or other adjacent structures. Because of tumor frailty, rupture of the capsule and tumor spillage is frequent. It occurs in approximately 20% of cases during the initial procedure and in 43% after local recurrence).
Infiltration of the vena cava may make surgery difficult and may require a radical resection that might include removing the thrombus from the IVC or together with the IVC. In some cases, complete removal of the tumor thrombus may require the use of cardiopulmonary bypass.
The role of lymph node dissection in the treatment of pediatric ACT was studied in the recent COG ARAR0332 protocol, and the results are still pending. You can learn more about the study at clinicaltrials.gov.
Surgical resection of recurrent local and distant disease is also important. Multiple surgical resections may be necessary to render patients free of disease. This aggressive approach is associated with prolonged survival, particularly when combined with chemotherapy.
Chemotherapy is commonly administered, particularly for children with advanced disease. For children with completely resected tumors, the role of adjuvant therapy has not been established. The combination of chemotherapy used most often in pediatrics consists of mitotane, cisplatin, etoposide and doxorubicin.
Mitotane remains the only drug approved by the U.S. Food and Drug Administration and European Medicine Executive Agency for treatment of ACT. Mitotane leads, with relative specificity, to a destruction of the inner zones of the adrenal cortex, the zona fasciculata and zona reticularis. It has been used extensively in adults with ACT, but its efficacy in children is not known.
Mitotane has been used to treat metastatic ACT. It is given prior to surgery in cases of inoperable tumors or after surgery in patients at high risk of relapse (adjuvant chemotherapy). Mitotane is combined with other agents and used to control symptoms associated with increased production of adrenal hormones. Objective responses to mitotane are obtained in 15% to 60% of treated adult patients.
The wide variation in response rates may, in part, reflect the pharmacokinetics of mitotane. There has been evidence of greater tumor response when the plasma concentration of mitotane is above 14 mg/L. The most important common toxicities of mitotane are nausea, vomiting, diarrhea and abdominal pain. Less frequent reactions include sleepiness, lethargy, ataxic gait, depression and vertigo. Of interest, prepubertal patients can develop breast engorgement. Another shortcoming of mitotane treatment is it significantly alters steroid hormone metabolism. Blood and urine steroid measurements cannot be used as markers of tumor relapse when mitotane is administered. Mitotane should be considered an experimental agent in the treatment of children with ACT.
Radiation therapy to treat ACT is controversial, but has been advocated by some investigators. Radiation therapy is associated with an increased cancer risk. Tumor development within radiotherapy fields has been observed in 30% of TP53-mutation carriers. This provides strong clinical arguments suggesting radiation therapy contributes to the development of secondary tumors in patients with Li-Fraumeni syndrome. This hypothesis can be explained by the key role of TP53 in response to DNA damage.
Complete tumor resection is the single most important prognostic indicator. Based on the IPACTR data series, of the 254 patients with known outcomes, the five-year event-free survival was 54.2% (95% CI, 48.2–60.2%). The overall survival estimate is 54.7% (95% CI, 48.7–60.7%).
Patients who have metastatic disease or gross residual disease after surgery have a poor prognosis. However, among cases with advanced stage disease, there is marked individual variation in disease progression and length of survival. Survival in these children ranges from a few months to several years.
Among 192 children with complete tumor resection, tumor weight was independently associated with outcome. Those children with tumors weighing more than 200 grams had an event-free survival rate of 39% compared with 87% for those with smaller tumors.
Tumor size has been consistently associated with prognosis in several studies of ACT. Children whose tumors produce excess glucocorticoid appear to have a worse prognosis than those who have pure virilizing manifestations. It is likely that prognostic factor analysis can be further refined by adding other clinical and biological and/or molecular factors.