Adrenocortical carcinoma (ACC) is a rare but often aggressive endocrine malignancy that may present with symptoms of hormone secretion, as a symptomatic nonfunctional abdominal mass, or as an incidental imaging finding. The first known successful adrenal cancer resection was performed by Knowsley Thornton in 1890.^1,2 In the same year, Otto Ramsay published a small case series of patients with malignant adrenal tumors.³ However, prognosis was poor as tumor excision offered only temporarily relief with the majority of patients suffering from severe adrenal insufficiency. In 1949, discovery of cortisone, derived from an adrenocortical extract developed by the Mayo group, significantly improved survival from adrenalectomy.⁴ Other milestones include the introduction of mitotane, a pesticide derivative, which was first used in 1960 to treat inoperable or recurrent ACC.⁵

Adrenocortical carcinoma is rare with an annual incidence of 1 to 2 per million people.^6,7 Higher incidence of ACC is seen in the pediatric population in southern Brazil who are at higher risk due to an inherited germline p53 mutation.⁸ Adrenal tumors are found incidentally in over 4% of abdominal imaging studies.⁹ From a retrospective review from the Mayo Clinic, ACC constitutes 1.2% of all incidentalomas.¹⁰ There is a preponderance of women, ranging from 55% to 60% of those affected by ACC. The age distribution is bimodal with peaks in children under the age of five and in adults in the fourth and fifth decades of life.¹¹

Though most ACC are sporadic in nature, it is associated with several hereditary syndromes.¹² Li–Fraumeni syndrome, caused by germline mutations of the tumor suppressor gene, TP53, is found in 50% to 80% of children and about 4% of adults with ACC.^13,14 Patients with Beckwith–Wiedemann syndrome have 11p15 mutations and are predisposed to Wilms’ tumor, neuroblastoma, hepatoblastoma, and ACC. Inactivating mutations of the menin gene causes multiple endocrine neoplasia type 1 (MEN1) syndrome, which is commonly associated with parathyroid, pancreatic neuroendocrine, and pituitary tumors. Adrenal tumors occur in about 5% of patients with MEN1; most are adenomas, but rarely can be ACC.

Somatic mutations have been found in sporadic ACC. Loss of heterozygosity (LOH) at the 17p13 locus, TP53, is found in more than 50% of ACC in adult patients and is associated with an aggressive phenotype.¹⁵ Overexpression of IGFII due to LOH at 11p15 is also associated with malignancy in sporadic ACC.¹⁶ Inhibition of the IGF pathway in vitro leads to decreased cell proliferation in ACC.¹⁷ Wnt/beta-catenin signaling is another important pathway during embryonic adrenal development, and the constitutive activation through mutation of the CTNNB1 gene has been implicated in adrenal tumorigenesis.¹⁸ Mutations in CTNNB1 in animal models have shown to induce adrenal hyperplasia and predispose to ACC.¹⁹ Activation of the Wnt/beta-catenin pathway is found in both adrenal adenomas and ACC and is associated with decreased overall survival.^20,21 Steroidogenic factor-1 (SF1) is another factor involved in adrenal development and is associated with increased tumor proliferation and poor survival in ACC.²²

The original Weiss histopathologic system was developed in 1984 as a scoring system to differentiate between benign and malignant adrenal tumors in the absence of local invasion and distant metastasis.²³ It has since been revised in 2002. Two points are assigned to the presence of greater than six mitotic figures per 50 high power fields, and to the presence of less than or equal to 25% clear or vacuolated tumor cells. One point is assigned to having abnormal mitoses, necrosis, and capsular invasion. Three or more points in the total score indicate malignancy.²⁴

Steroidogenic factor-1 is used as an immunohistochemical marker as protein staining can be detected in 98% of ACC samples and strong expression is correlated with a poor prognostic outcome.²⁵ Staining for Ki67 is used as a marker for proliferation in ACC.

Patients diagnosed with ACC most commonly present with overt clinical syndrome of hormonal hypersecretion and it is found in about 60% of cases. Young women are most likely affected by excess hormone production. Hormone-secreting ACC will present as Cushing’s alone in 45% of patients with rapidly developing symptoms over 3 to 6 months. Both glucocorticoid and androgen excess present as a mixed Cushing’s and virilization syndrome in 25%. Less than 10% will present with virilization alone. Less commonly feminization and hyperaldosteronism are seen in fewer than 10% of patients.¹¹ Virilization syndrome is much more common in children (84%) while isolated Cushing’s is less common (6%).²⁶ Nonfunctioning tumors or subclinical production of steroids manifest as a mass syndrome in 30% of adult patients diagnosed with ACC. Flank pain or constitutional symptoms such as weight loss, fever, and anorexia may also be present. The remaining 10% of ACC are diagnosed from incidentally found adrenal mass on abdominal imaging for unrelated reasons.

In 2009, the TNM staging system for ACC was presented by the American Joint Committee on Cancer. However, a revised classification was proposed by the European Network for the Study of Adrenal Tumors (ENSAT) as follows—stage I: size ≤5 cm; stage II: size >5 cm; stage III: involvement of surrounding tissue, positive regional lymph nodes, or inferior vena cava (IVC)/renal thrombus; stage IV: distant metastases. These correspond to 5-year survival of 82%, 61%, 50%, and 13%, respectively.²⁷ This updated system has been validated to offer superior prognostication in patients with distant metastasis.²⁸

The most important prognostic factors include disease stage and completeness of resection.²⁹ Patients with incomplete resection have a median survival of less than 1 year.³⁰ In a study of the national cancer database, 5-year survival rates in ACC patients were as follows: 46% in those with a negative margin, 21% in those with a microscopically positive margin, and 10% in those with a macroscopically positive margin.³¹ In a study from Memorial Sloan-Kettering, histopathologic factors such as venous, capsular, and adjacent organ invasion, tumor necrosis, high mitotic rate, atypical mitoses, and overexpression of mdm-2 were found to be significant predictors of poor disease-specific survival.³²

A focused history and physical exam should be performed in all patients diagnosed with adrenal tumor to evaluate for signs and symptoms of pheochromocytoma, Cushing’s syndrome, hyperaldosteronism, and virilization.

Laboratory Evaluation

Laboratory workup should include diagnostic tests for hypercortisolism: plasma cortisol, adrenocorticotropic hormone (ACTH), 24-hour urinary free cortisol, 1-mg dexamethasone suppression test, or midnight salivary cortisol. Evaluation for hyperandrogenism should be performed including, dehydroepiandrosterone (DHEA), androstenedione, testosterone, and 17-OH progesterone. Serum estradiol may be obtained in men and postmenopausal women. Plasma and/or urinary metanephrines and catecholamines should be obtained to rule out pheochromocytoma. Plasma aldosterone and renin levels are helpful in hypokalemic or hypertensive patients.³³

Computed Tomography