Adrenocortical Carcinoma

DEFINITION, ETIOLOGY, PATHOGENESISTop

Adrenocortical carcinoma (ACC) is a rare epithelial malignancy originating in the adrenal cortex, prone to local invasion and distant metastases. Steroidogenesis disorders are quite common in this condition. Tumors may overproduce mainly cortisol and androgens but sometimes also estrogens and mineralocorticoids. The tumor’s ability to synthesize biologically active glucocorticoids depends on its cellular differentiation; less differentiated tumors are less likely to be functioning. Signs or symptoms of increased hormonal activity may be absent.

CLINICAL FEATURES AND NATURAL HISTORYTop

The peak incidence of ACC usually has a bimodal age distribution, with the disease peaking at <5 years of age and in the fourth to fifth decade of life. ACC is more common in women and, although sporadic in most cases, it can occur as part of hereditary syndromes such as Li-Fraumeni syndrome, Carney complex, Lynch syndrome, multiple endocrine neoplasia type 1 (MEN 1), and familial adenomatous polyposis. Clinical features and natural history depend on whether the tumor is hormonally active (functioning) (50%-60%) or nonfunctioning. Functioning tumors typically cause Cushing syndrome, often with concomitant features of androgenization/virilism in women. Arterial hypertension and secondary amenorrhea are common in women, and in men excess estrogen may cause gynecomastia and other feminizing features, such as changes in the distribution of body fat.

Manifestations of nonfunctioning carcinoma appear late, usually with abdominal discomfort, other obstructive gastrointestinal (GI) symptoms, progressive weight loss, and symptoms associated with distant metastases. Besides regional lymph nodes, the tumor most often metastasizes to the lungs, liver, and bones. These features can also be present in functioning carcinomas.

DIAGNOSISTop

Diagnostic Tests

1. Basic biochemical tests: Hypokalemia, hyperglycemia; in extensive liver metastases: elevated transaminase, alkaline phosphatase, and bilirubin levels.

2. Hormonal tests: If overt clinical manifestations of a functioning ACC are present, perform hormonal testing to assess for glucocorticoid excess (Cushing syndrome): free cortisol in 24-hour urine collection, 1-mg dexamethasone suppression test, or late-night salivary cortisol, in addition to serum adrenocorticotropic hormone (ACTH). Sex hormone excess can be assessed with 17-hydroxyprogesterone (17-OHP), androstenedione, testosterone; and dehydroepiandrosterone sulfate (DHEAS) in women and estradiol in men. Elevated serum DHEAS or androstenedione levels may be an early finding. Aldosterone excess can be assessed with potassium measurements (with hypokalemia expected), high aldosterone, and low renin (to be checked only in patients with arterial hypertension and/or hypokalemia). For clinically silent, incidentally detected neoplastic tumors, the results of standard hormonal tests may be within normal limits. However, seemingly hormonally silent ACCs may still produce steroid hormone precursors, so there should be a low index of suspicion to perform hormonal testing, at least as a baseline. Of note, in addition to the above-mentioned investigations, pheochromocytoma must be excluded, which can be done by measuring 24-hour urinary fractionated metanephrines or plasma metanephrines.

3. Imaging: Computed tomography (CT) or magnetic resonance imaging (MRI) of the abdominal cavity and pelvis usually allow for the differentiation of benign disease from malignancy, along with chest CT, which is used to assess for metastases. 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG-PET/CT), bone scintigraphy, bone MRI/CT, and/or brain MRI can be performed for staging if other metastases are suspected. Imaging enables assessment of tumor size, extent of local invasion, lymph node involvement, and metastases, and is necessary for staging. Staging is typically performed based on the European Network for the Study of Adrenal Tumors (ENSAT) classification and the very similar tumor, node, metastasis (TNM) classification (2017).

The simplest staging method is the one provided by the National Institutes of Health (NIH):

1) Local disease: No invasion.

2) Regional disease: Infiltration of the surrounding tissues or involvement of regional lymph nodes.

3) Metastatic disease: Distant metastases. Metastases from other malignancies to the adrenal glands are also possible and are ranked fourth in terms of frequency, following metastases to the lungs, liver, and bones.

Typical CT and MRI features of adrenal masses: Table 1.

Genetic Testing

Patients with ACC should be referred for genetic evaluation for associated hereditary syndromes including Li-Fraumeni syndrome, Carney complex, Lynch syndrome, multiple endocrine neoplasia type 1 (MEN 1), and familial adenomatous polyposis.

Diagnostic Criteria

Imaging is crucial and serves as the basis for deciding whether surgery is needed; suspected ACC is a contraindication to biopsy of the adrenal mass due to the risk of tumor seeding. The final diagnosis is established based on histologic examination following surgical tumor removal, as this allows for unequivocal diagnosis of ACC or adrenal metastasis from other cancers.

TREATMENTTop

1. Surgical treatment: The method of choice is removal of the tumor and metastases to the greatest extent possible. In tumors sized >6 to 8 cm and if local invasion or metastases to regional lymph nodes are suspected, open surgery is usually preferred to laparoscopy. Preoperatively patients with severe symptoms of hypercortisolemia should receive a steroidogenesis inhibitor (see Cushing Syndrome).

2. Systemic treatment: Mitotane (an adrenolytic agent) is used as adjuvant therapy in certain cases and is administered as soon as possible after tumor resection. It is usually used in patients at high risk of recurrence, that is, with ENSAT stage III or IV ACCs or with ACC with a high Ki-67 proliferation index (>10%), or in the case of incomplete tumor resection. In patients at low risk for recurrence, decisions are made on a case-by-case basis, considering the adverse effect profile. Ideally mitotane should be monitored with serum drug concentration measurements (target: 14-20 mg/L); in situations where it is not available in a timely manner, the drug should be dosed to manageable toxicity. Adverse effects include bone marrow suppression, rashes, liver enzyme elevations, GI side effects, and central nervous system (CNS) symptoms. Gynecomastia may develop in men (sex hormone–binding globulin [SHBG] elevation and thus lower free sex hormone levels), along with hypogonadism. Dyslipidemia may also occur. In most cases mitotane reduces thyroid-stimulating hormone (TSH) secretion and thus free thyroxine (FT4), leading to secondary hypothyroidism (requiring levothyroxine [L-T4] replacement therapy with monitoring FT4 rather than TSH levels). Since mitotane has an adrenolytic effect on the remaining adrenal gland function, replacement therapy is needed. The doses of hydrocortisone are usually higher than in the treatment of typical primary adrenal insufficiency (30-60 mg/d, divided into 2-3 doses, with the highest dosing in the morning), as mitotane accelerates its metabolism in the liver and increases the concentration of corticosteroid-binding globulin (CBG). Avoid using dexamethasone since it is metabolized by mitotane to a higher extent. Some patients also require fludrocortisone treatment in the case of hypotension, hyperkalemia, and/or high renin levels. Given the potential teratogenic effects of mitotane, women should be using contraceptive measures while on therapy, until drug plasma levels become undetectable. In regionally or systemically advanced cancer, specialized oncology centers use systemic treatment in addition to mitotane, which may include cisplatin, etoposide, and doxorubicin; other options include gemcitabine with capecitabine or streptozotocin with mitotane. Patients may also be enrolled in clinical trials.

3.  Radiotherapy is mainly used to treat symptomatic metastases, especially in the bones.

4. Interventional treatment may be considered, such as transarterial chemoembolization (TACE) of the tumor, or local treatment of unresectable liver metastases (eg, thermoablation, radioembolization, chemoembolization). These treatment considerations are often consulted in a tertiary care center in a multidisciplinary setting with a medical oncologist, surgeon, endocrinologist, radiation oncologist, and, most importantly, the patient.

FOLLOW-UPTop

Clinical follow-up every 3 to 6 months is important to detect recurrence and metastasis based on hormonal profiles (see above), along with ultrasonography or CT/MRI of the abdomen, pelvis and chest; and occasionally 18F-FDG-PET/CT. Patients also need to be monitored for complications of Cushing syndrome including hypertension, diabetes mellitus, venous thromboembolism, opportunistic infections (eg, Pneumocystis jirovecii pneumonia, tuberculosis), osteoporosis, fractures, and adverse neuropsychiatric effects (see Cushing Syndrome), and may require treatment and prophylaxis if applicable. Patients are also clinically monitored for Cushing syndrome, virilization/feminization, and primary aldosteronism, and also with steroid tumor markers depending on whether the tumor is functioning or nonfunctioning at the time of diagnosis (eg, 24-h urinary free cortisol, 1-mg dexamethasone suppression test, or late-night salivary cortisol; DHEAS, testosterone, estradiol, aldosterone, and renin). In those on mitotane, complications of treatment are monitored with complete blood count (CBC), liver enzymes, electrolytes, creatinine, free thyroid hormones, lipid profile, and sex hormones as clinically indicated. As mitotane causes a strong induction of cytochrome P450 3A4 (CYP3A4), medications should be checked for drug–drug interactions. 

PROGNOSISTop

Approximately 20% of patients survive 5 years after diagnosis. The 5-year survival rate in patients with tumors confined to the adrenal gland is 60% to 80%; however, in those with metastatic disease, it is reported to range between 0% and 28%. In local disease, complete recovery is possible, but metastases or local recurrence (especially within 1 year of the first treatment trial) make the prognosis significantly worse, with cure being very rare. Good prognostic factors include complete tumor resection, Ki-67 <10%, stage I disease, and absence of Cushing syndrome.

TABLESTop

Figure 6.1-1. Right adrenocortical carcinoma with features of necrosis (arrow) in a 41-year-old woman with hyperandrogenism.