Perrin C. White
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 (<10%) secrete high levels of estrogens as a result of 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 (see Chapter 597 ). Whereas isolated virilization occurs relatively frequently, children with adrenal tumors usually do not have Cushing syndrome alone.
Serum levels of dehydroepiandrosterone, dehydroepiandrosterone 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.
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 597 . For virilizing signs, the differential includes virilizing forms of adrenal hyperplasia (see Chapter 594 ) and factitious exposure to androgens, such as topical testosterone preparations. The differential diagnosis for hormonally inactive adrenocortical adenomas includes pheochromocytomas, adrenocortical carcinoma, and metastasis from an extraadrenal 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.
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. Treatment with higher doses of mitotane for more than 6 mo is associated with improved 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 one 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.