Bagi RP Jana, MD; Chief Editor: Jules E Harris, MD

Adrenocortical cancers (ACs) are uncommon malignancies that can have protean clinical manifestations. Adrenocortical masses are common; autopsy studies show that approximately 5-15% of the general adult population may have adrenal incidentalomas. Adrenal incidentalomas are biochemically and clinically asymptomatic adrenal masses found incidentally as a result of unrelated imaging investigations such as abdominal CT or MRI scans. Findings from abdominal CT scans suggest that the prevalence rate is 1-5%. Only a small number of adrenal tumors are functional and an even smaller number are malignant.

Regardless of size, approximately 1 per 1500 adrenal tumors is malignant. The evaluation of these incidentalomas, therefore, focuses on (1) identifying functional masses and treating them appropriately (including surgical removal); (2) identifying adrenal carcinomas early, with the intent of attempting complete surgical extirpation; and (3) reassuring the patients whose masses are neither functional nor malignant and arranging for their subsequent follow-up.

Although the means of identifying ACs from this subpopulation still are controversial, virtually all authorities agree about removing all nonfunctional adrenal tumors larger than or equal to 6 cm because of the significant potential cancer risk. Authorities also generally agree that nonfunctional adrenal tumors (≤ 3 cm) have a very low probability of being adrenal cancer; therefore, they can be removed safely.

The management strategy for adrenal masses larger than 3 cm and less than 6 cm is disputed. Some authorities suggest lowering the threshold for surgical removal of nonfunctional masses from 6 cm to 4-5 cm. Others individualize the follow-up of these patients depending on their clinical status, CT scan characteristics, and age. Particularly important is the fact that these criteria do not apply to children, who generally have smaller ACs. A review of the available data suggests that the incidence rate of malignancy is small (< 0.03%) in all adrenal incidentalomas that are 1.5-6 cm. However, this rate increases considerably with tumors larger than 6 cm (up to 15%). The smallest identified AC associated with metastasis reported in the literature was 3 cm in diameter.

Classifying adrenal tumors

Adrenal tumors are classified in several ways. One of the popular means, which has great clinical relevance, is to subclassify them as functional or nonfunctional, depending on the elaboration of adrenocortical hormones (glucocorticoids, mineralocorticoids, androgens, estrogens, rarely a host of possible peptides). Nonfunctional variants of AC were previously reported to be far less common than the functional types; older reports suggest that approximately 50-80% of ACs are functional, and patients mainly present with Cushing syndrome. More recent reports suggest that nonfunctional ACs may be more common than previously suggested. While AC accounts for only approximately 5-10% of cases of Cushing syndrome, approximately 40% of patients with both Cushing syndrome and an adrenal mass also have a malignant tumor. Virtually all feminizing adrenal tumors in men are malignant.

Another method is to subdivide ACs into sporadic and syndromic variants. The syndromic variants occur with multiple cancer predisposition syndromes, including Gardner syndrome, Beckwith-Wiedemann syndrome (associated with hemihypertrophy), multiple endocrine neoplasia type 1, the SBLA syndrome (sarcoma, breast, lung, and adrenal carcinoma and other tumors within several kindreds, which have not been clearly associated with localization to a single gene), and Li-Fraumeni syndrome. Other classification methods are dependent on the cellular origin of the neoplasm. Included here are primary adrenocortical carcinomas, primary adrenal lymphomas, soft-tissue sarcomas of the adrenal, malignant pheochromocytomas, and secondary metastatic adrenal tumors (common primaries are the breast, kidney, lung, ovary, melanoma, leukemia, lymphoma). Only the adrenocortical carcinomas typically are included in discussions of adrenal cancers, and this monograph will be restricted to those.

Authorities also report rare composite adrenal tumors, which are different histologic variant tumors of the same embryologic origin (eg, coexisting neuroblastoma and malignant pheochromocytoma) and mixed adrenal tumors (typically mixtures of pheochromocytoma, spindle cell sarcomas, and adrenocortical carcinomas). These complex tumors sometimes are called neuroendocrine carcinomas. Recognition of primary adrenal lymphomas, as distinct from AC, is important not only because these are rare (< 100 well-documented cases in the medical literature), but also because they may be associated with a better prognosis than AC because of the potential roles for standard lymphoma treatment using multiagent chemotherapy and radiotherapy.