Patients with Beckwith-Wiedemann and hemihypertrophy syndromes have a predisposition to cancer, and as many as 16% of their neoplasms are adrenocortical tumors. Hypomethylation of the KCNQ1OT1 gene has also been associated with the development of adrenocortical tumors in patients without the phenotypic features of Beckwith-Wiedemann syndrome. However, less than 1% of children with adrenocortical tumors have these syndromes. The distinctive genetic features of pediatric adrenocortical carcinoma have been reviewed.
Unlike adult adrenocortical tumors, histologic differentiation of adenomas and carcinomas is difficult. However, approximately 10% to 20% of pediatric cases are adenomas.[2,9] The distinction between benign (adenomas) and malignant (carcinomas) tumors can be problematic. In fact, adenoma and carcinoma appear to share multiple genetic aberrations and may represent points on a continuum of cellular transformation. Macroscopically, adenomas tend to be well defined and spherical, and they never invade surrounding structures. They are typically small (usually <200 cm3), and some studies have included size as a criterion for adenoma. By contrast, carcinomas have macroscopic features suggestive of malignancy; they are larger, and they show marked lobulation with extensive areas of hemorrhage and necrosis. Microscopically, carcinomas comprise larger cells with eosinophilic cytoplasm, arranged in alveolar clusters. Several authors have proposed histologic criteria that may help to distinguish the two types of neoplasm.[21,22] However, morphologic criteria may not allow reliable distinction of benign and malignant adrenocortical tumors. Mitotic rate is consistently reported as the most important determinant of aggressive behavior.IGF2 expression also appears to discriminate between carcinomas and adenomas in adults, but not in children.[24,25] Other histopathologic variables are also important, and risk groups may be identified on the basis of a score derived from characteristics, such as venous, capsular, or adjacent organ invasion; tumor necrosis; mitotic rate; and the presence of atypical mitoses.
Because pediatric adrenocortical tumors are almost universally functional, they cause endocrine disturbances, and a diagnosis is usually made 5 to 8 months after the first signs and symptoms emerge.[3,9] Virilization (pubic hair, accelerated growth, enlarged penis, clitoromegaly, hirsutism, and acne) due to excess of androgen secretion is seen, alone or in combination with hypercortisolism, in more than 80% of patients. Hyperestrogenism can also occur. Isolated Cushing syndrome is very rare (5% of patients), and it appears to occur more frequently in older children.[3,9,12,27] Likewise, nonfunctional tumors are rare (<10%) and tend to occur in older children. Because of the hormone hypersecretion, it is possible to establish an endocrine profile for each particular tumor, which may facilitate the evaluation of response to treatment and monitor for tumor recurrence.