Epidemiology

Adrenocortical tumors are rare in childhood, with an incidence of 0.3-0.5 cases per million child-years. They occur in all age groups but most commonly in children younger than 6 yr of age, and are more frequent (1.6-fold) in girls. In 2-10% of cases, the tumors are bilateral. Symptoms of endocrine hyperfunction are present in more than 90% of children with adrenal tumors (see Table 571-1). Tumors may be associated with hemihypertrophy, usually occurring during the 1st few years of life. They are also associated with other congenital defects, particularly genitourinary tract and central nervous system abnormalities and hamartomatous defects.

Etiology

Germline mutations in p53 (on chromosome 17p13.1) have been found in patients with isolated adrenal carcinoma as well as in patients with familial clustering of unusual malignancies; this latter condition is termed Li-Fraumeni syndrome. A 15-fold increased incidence of childhood adrenocortical tumors is found in southern Brazil, associated with a R337H mutation in p53. Overexpression of IGF2 (chromosome 11p15.5) occurs in 80% of sporadic childhood adrenocortical tumors, as well as in those associated with Beckwith-Wiedemann syndrome, in which there is loss of the normal imprinting of genes in this chromosomal region.

Clinical Manifestations

Virilization is the most common presenting symptom in children with adrenocortical tumors, occurring in 50-80%. In males, the clinical picture is similar to that of simple virilizing congenital adrenal hyperplasia: accelerated growth velocity and muscle development, acne, penile enlargement, and the precocious development of pubic and axillary hair. In females, virilizing tumors of the adrenal gland cause masculinization of a previously normal female with clitoral enlargement, growth acceleration, acne, deepening of the voice, and premature pubic and axillary hair development.

Conversely, adrenal tumors can occasionally (7%) secrete high levels of estrogens due to overexpression of CYP19 (aromatase). Gynecomastia in males or premature thelarche in girls is often the initial manifestation. Growth and development may be otherwise normal, or concomitant virilization may occur.

In addition to virilization, 15-40% of children with adrenocortical tumors also have Cushing syndrome (Chapter 571). Although virilization may occur alone, children with adrenal tumors usually do not have Cushing syndrome alone.

In adults, adrenal tumors are frequently detected incident to CT or MRI imaging of the abdomen for other reasons; these are often referred to as incidentalomas. There are no published data on the frequency of the occurrence of such tumors in childhood. They are likely to be infrequent, being found in approximately 7% of autopsies of persons over 70 yr old, but <1% of those younger than 30 yr.

Laboratory Findings

Serum levels of dehydroepiandrosterone (DHEA), DHEA sulfate, and androstenedione are usually elevated, often markedly. Serum levels of testosterone are often increased, usually as a result of peripheral conversion of androstenedione, but infants with predominantly testosterone-secreting adenomas have been reported. Levels of estrone and estradiol are elevated in tumors from patients with feminizing signs. Urinary 17-ketosteroids (sex steroid metabolites) are also increased but are no longer routinely measured. Many adrenocortical tumors have a relative deficiency of 11β-hydroxylase activity and secrete increased amounts of deoxycorticosterone; these patients are hypertensive, and their tumors are often malignant.

Tumors can usually be detected by ultrasonography, CT, or MRI. Preoperatively, the presence of metastatic disease should be determined by MRI or CT of the chest, abdomen, and pelvis. Radiochemical imaging of these tumors by positron emission tomography with ¹¹C-metomidate or single-photon emission computed tomography (SPECT) with ¹²³I-iodometomidate have been proposed but are not routinely available.

Pathologic Findings

Differentiation between benign and malignant tumors by histologic criteria (architecture, cytologic atypia, mitotic activity, atypical mitotic figures) is usually not possible; almost all pediatric adrenocortical tumors would be classified as malignant by the criteria used to classify adult tumors. Size is a useful prognostic factor, with tumors weighing less than 200 g, 200-400 g and greater than 400 g being classified as low, intermediate, and high risk. Incomplete resection, and gross local invasion or metastasis is also associated with poor prognosis. However, most tumors occurring in children less than 4 yr of age fall into favorable prognostic categories.

Differential Diagnosis

For functioning tumors, the differential diagnoses are those of the main presenting signs and symptoms. The differential diagnosis for Cushing syndrome is discussed in Chapter 571. For virilizing signs, the differential includes virilizing forms of adrenal hyperplasia (Chapter 570) and factitious exposure to androgens, such as topical testosterone preparations. Most are benign hormonally inactive adrenocortical adenomas, but the differential diagnosis includes pheochromocytomas, adrenocortical carcinoma, and metastasis from an extra-adrenal primary carcinoma (very rare in children). Careful history, physical examination, and endocrine evaluation must be performed to seek evidence of autonomous cortisol, androgen, mineralocorticoid, or catecholamine secretion. Not infrequently, a low level of autonomous cortisol secretion is detected that does not cause clinically apparent symptoms; this condition is sometimes referred to as “subclinical” Cushing syndrome.

Treatment

Functioning adrenocortical tumors should be removed surgically. There are no data on which to base a recommendation regarding nonfunctioning childhood incidentalomas; in adults, such tumors may be closely observed with imaging and repeat biochemical studies if smaller than 4 cm in diameter, but it is not certain that this is prudent in small children. Adrenalectomy may be performed either transperitoneally or laparoscopically. Some adrenocortical neoplasms are highly malignant and metastasize widely, but cure with regression of masculinizing or Cushingoid features may follow removal of less malignant, encapsulated tumors. Postoperatively, patients should be closely monitored biochemically, with frequent determinations of adrenal androgen levels and imaging studies. Recurrent symptoms or biochemical abnormalities should prompt a careful search for metastatic disease. Metastases primarily involve liver, lung, and regional lymph nodes. The majority of metastatic recurrences appear within 1 yr of tumor resection. Repeat surgical resection of metastatic lesions should be performed if possible and adjuvant therapy instituted. Radiation therapy has not been generally helpful. Antineoplastic agents, such as cisplatin and etoposide, ifosfamide and carboplatin, and 5-fluorouracil and leucovorin have had limited use in children, and their success is not established. Therapy with o,p′-DDD (mitotane), an adrenolytic agent, may relieve the symptoms of hypercortisolism or virilization in recurrent disease but does not appear to improve survival. Other agents that interfere with adrenal steroid synthesis, such as ketoconazole, aminoglutethimide, and metyrapone, may also relieve symptoms of steroid excess but do not improve survival.

A neoplasm of 1 adrenal gland may produce atrophy of the other because excessive production of cortisol by the tumor suppresses adrenocorticotropic hormone stimulation of the normal gland. Consequently, adrenal insufficiency may follow surgical removal of the tumor. This situation can be avoided by giving 10-25 mg of hydrocortisone every 6 hr, starting on the day of operation and weaned over 3-4 days postoperatively. Adequate quantities of water, sodium chloride, and glucose also must be provided.