Excerpt from Adrenal Carcinoma

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Background

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 (approximately 1%) 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 who do not fit either of these classes 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 and 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.

Pathophysiology

While some reports suggest an increased predilection for the left adrenal, most reports suggest no side preference. The exact etiopathogenesis of sporadic AC is unclear, but analysis of syndromic variants of the condition gives some insight.

The role of tumor suppressor gene mutations is suggested by their association with Li-Fraumeni syndrome, which is characterized by inactivating germline mutations of the TP53 gene (a vital tumor suppressor gene or antioncogene) on chromosome 17. This syndrome also is associated with a predisposition to other malignancies, including breast carcinoma, leukemias, osteosarcomas, and soft-tissue sarcomas. A few reports describe an association between AC and familial adenomatous polyposis, which also is due to a germline inactivating mutation of a tumor suppressor gene (in this case, the adenomatous polyposis coli gene, APC). However, such mutations have not been found in sporadic APC cases. Others studies report the following:

Suggestions have been made that adrenal hyperplasia predisposes patients to develop AC. A few cases of congenital adrenal hyperplasia are associated with functional adrenocortical adenomas but not carcinoma.

A few cases of AC are associated with primary hyperaldosteronism, in which the adrenal tissue has portions showing adrenocortical hyperplasia.

A definitive proof for a hyperplasia-to-adenoma-to-carcinoma sequence, which occurs with colonic neoplasms, is lacking, although a multistep tumor progression model has been suggested as a possible etiologic basis for sporadic AC. The association of AC with the Carney triad (GI stromal tumor, pulmonary chondromas, and extra-adrenal paraganglioma) is far less defined. Since the Carney triad is so rare, there are very few reported cases. In some, paragangliomas have been described, but the numbers are too few to be able to definitely state that it is an associated tumor typical of the syndrome.

Among the putative pathogenetic mechanisms that may function in concert are alterations in intercellular communication, paracrine and autocrine effects of various growth factors, cytokines elaborated by the tumor cells, and promiscuous expression of various ligand receptors on the cell membranes of the cells that cause them to be in a state of perpetual hyperstimulation. This is presumed to lead to clonal adrenal cellular hyperplasia, autonomous proliferation, tumor formation, and hormone elaboration.

Some molecular studies of adrenocortical tumor cells show in situ mutations of the TP53 and TP57 genes (both antioncogenes) and increased production of insulin-like growth factor 2. P53 gene mutations are the most common mutant genes in human cancer. A potential role for this in sporadic AC is suggested by the frequent finding of loss of heterozygosity (LOH) at the 17p13 locus in cases of sporadic AC. Definite germ cell mutations of the P53 gene have also been demonstrated in more than 90% of children with AC from southern Brazil, which has the highest prevalence of sporadic AC in the world. Amplification of steroidogenic factor-1 expression has also been described in this population.

Another genetic locus of interest is the 11-p region that may also harbor a tumor suppressor gene and has been implicated in linkage studies in subjects with the Beckwith-Wiedemann syndrome. LOH at band 11p15 and overexpression of IGF-2, whose gene is carried on this genetic locus, have been described in cases of sporadic AC.

Other studies demonstrate that some of these tumor cells express menin (the aberrant gene product in patients with multiple endocrine neoplasia type I [MEN-1]); in others, the hybrid gene is associated with glucocorticoid-responsive aldosteronism (GRA).

Several reports suggest that, while benign adrenal tumors retain expression of the type 2 MHC antigens, these are lost in adrenocortical carcinoma cells. Furthermore, while adrenal adenomas can be monoclonal (43%), polyclonal (28%), or mixed (28%), virtually all ACs are monoclonal.

The fact that the normal adrenal cortex has multiple areas of adrenomedullary cells (often forming large cell nests) and that adrenocortical cells also are scattered in the adrenal medulla suggest a close interaction between the 2 groups of cells, despite their distinct phylogenetic and embryonic origins. The relevance of the paracrine interactions of these cells in the etiopathogenesis of AC and adrenal tumors as a whole is still being actively investigated.

Frequency

International

AC tumors are uncommon. The incidence is approximately 0.6-1.67 cases per million persons per year. Some reports suggest an inordinately high frequency (up to 10-fold higher) of cases among children in southern Brazil, for unknown reasons. Overall, AC accounts for 0.02-0.2% of all cancer-related deaths; therefore, it is relatively rare.

Race

AC has no specific racial predilection.

Sex

The female-to-male ratio is approximately 2.5-3:1. Male patients tend to be older and have a worse overall prognosis than female patients. Female patients are more likely than male patients to have an associated endocrine syndrome. Nonfunctional ACs are distributed equally between the sexes.

Age

AC occurs in 2 major peaks: in the first decade of life and again in the fourth to fifth decades. Approximately 75% of the children with AC are younger than 5 years. Functional tumors also are more common in children, while nonfunctional tumors are more common in adults.

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