Adrenocortical carcinomas (ACs) are uncommon malignancies that can have protean clinical manifestations. A majority of cases are metastatic at the time of diagnosis, with the most common sites of spread being the local periadrenal tissue, lymph nodes, lungs, liver, and bone. AC is relatively rare, however, accounting for just 0.02-0.2% of all cancer-related deaths. Detection of tumors at an early clinical stage is crucial for curative resection. See the image below.

Signs and symptoms

Physical examination findings in patients with hormonally active AC include the following:

• Virilization
• Cushing syndrome
• Feminization (rare)Patients with nonfunctional AC typically present with any of the following:

  • Fever
  • Weight loss
  • Abdominal pain and tenderness
  • Back pain
  • Abdominal fullness
  • Symptoms related to metastases

    Diagnosis

    Laboratory studies

    These include the following:

    • Serum glucose
    • Serum cortisol
    • Serum adrenal androgen
    • Urine adrenal hormone
    • Urine vanillylmandelic acid (VMA)
    • Urine homovanillic acid (HVA) levels

    Imaging studies

    Adrenal computed tomography (CT) scanning and magnetic resonance imaging (MRI) are the imaging studies of choice in AC. The typical case is characterized by a large unilateral adrenal mass with irregular edges. The presence of contiguous adenopathy serves as corroborating evidence.

    Histologic examination

    Some of the macroscopic features of an AC that suggest malignancy include a weight of more than 500 g, the presence of areas of calcification or necrosis, and a grossly lobulated appearance. Histologic findings also include numerous mitoses, scant cytoplasm, and none of the rosettes observed in neuroblastoma.

    Management

    When feasible, total resection remains the management modality of choice for the definitive treatment of AC. It also remains the only potentially curative therapeutic modality. While open laparotomy for adrenalectomy represents the standard of care, several reports suggest a role for laparoscopic resection if the adrenal tumor is small and there is no preoperative evidence of metastatic disease.

    Medical care in patients with AC, which can be supportive or adjuvant to surgical resection, encompasses the following:

    • Treatment of endocrine excess syndromes
    • Use of mitotane or several multiagent chemotherapy regimens
    • Treatment and prevention of potential complications
    • Strategies for palliative and terminal care issues, including symptom relief and manageme

      Approach Considerations

      A full evaluation is advised in all patients with a distinct adrenal nodule or tumor larger than 1 cm in order to determine whether the tumor is functional. The general agreement is that all functional masses should be removed.

      Laboratory results may also help in distinguishing between a neoplasm of the adrenal cortex and a neuroblastoma. Adrenocortical tumors should not be confused with adrenal medullary tumors, also known as pheochromocytomas, which, similar to neuroblastomas, secrete catecholamines.

      In a comparison of imaging findings in pediatric patients with adrenocortical carcinoma (AC), carcinoma was highly suspected when adrenal lesions had a thin tumoral capsule, a stellate zone of central necrosis, and evidence of the production of adrenocortical hormone.

      The following are the major imaging features that serve as red flags for a possible AC on adrenal imaging:

      • Irregular shape
      • Large size (larger than 4 cm in diameter)
      • Intralesional calcification
      • Tumor heterogeneity on both plain and contrast enhancement, which may indicate intralesional hemorrhage, necrosis, or both (Inhomogeneous density estimates by CT in various parts of the tumor on both plain and contrast-enhanced images may also indicate intralesional hemorrhage.)
      • Unilateral location
      • High CT attenuation values (especially with >20 HU)
      • Evidence of tumor invasion of local structures or extension into major vessels

        Laboratory Studies

        Laboratory studies for AC include determinations of the following:

        • Serum glucose
        • Serum cortisol
        • Serum adrenal androgen
        • Urine adrenal hormone
        • Urine vanillylmandelic acid (VMA)
        • Urine homovanillic acid (HVA) levels

        Include screening tests that can exclude excess hormone production when evaluating all primary adrenal masses.

        Cushing syndrome

        The best screening tests for Cushing syndrome are the standard 1-mg dexamethasone suppression test and the 24-hour urinary cortisol excretion test. The recognition of the relatively high prevalence of subclinical Cushing syndrome in adrenal incidentalomas (some reports suggest a prevalence as high as 5-8%) that may otherwise appear hormonally silent informs the policy of some experts to perform more in-depth testing of the hypothalamic-pituitary-adrenal axis in patients with identified adrenal masses. Such testing would include the screening tests mentioned, as well as diurnal rhythm evaluation with 8 am and midnight serum or salivary cortisol estimations, corticotropin-releasing hormone (CRH) stimulation test, serum adrenocorticotropic hormone (ACTH) estimations (generally found to be low), and serum dehydroepiandrosterone (DHEAS) levels (also generally found to be suppressed). Alternatively, 24-hour urinary cortisol and its metabolites can be measured.

        Pheochromocytoma

        The evaluation of adrenal masses must also include screening for possible pheochromocytoma, including, at a minimum, a 24-hour urinary estimation of catecholamines (epinephrine, norepinephrine, dopamine) and metabolites (particularly metanephrines and normetanephrines). In addition, plasma metanephrines and catecholamines can be assayed.

        Other screens

        Evaluation of adrenal masses also includes screens for the following:

        • Hyperaldosteronism: Screen for hyperaldosteronism by using simultaneous aldosterone and renin levels to compute aldosterone-to-renin ratios
        • Virilization syndromes: Screen for virilization syndromes using serum adrenal androgens (androstenedione, dehydroepiandrosterone, dehydroepiandrosterone sulfate), serum testosterone, and 24-hour urinary 17-ketosteroids.
        • Feminization syndromes: Plasma estradiol and/or estrone tests can help to screen for feminization syndromes

          Imaging Studies

          CT scanning and MRI

          Adrenal CT scanning and MRI are the imaging studies of choice in AC. The typical case is characterized by a large unilateral adrenal mass with irregular edges. The presence of contiguous adenopathy serves as corroborating evidence. (See the image below.)

          The National Italian Study Group review of adrenal incidentalomas demonstrated that 90% of AC cases had diameters of 4 cm or larger on radiologic imaging. This study, based on a cohort of 887 patients, showed that using the 4 cm cutoff resulted in 90% sensitivity but poor specificity. ^[8]

          Targeted CT scans of the adrenal using 3- to 5-mm sections offer the best resolution and are particularly useful in detecting tumors that are 1 cm or smaller.

          Intravenous contrast generally is not necessary for localization of adrenal masses but is useful for demonstrating vascularity and clarifying sites of metastases. Some reports have also shown that in comparison with ACs, adrenal adenomas have a much earlier washout of contrast enhancement and that this may be of diagnostic utility. The contrast washout at 5 minutes postinjection is approximately 50% in adenomas, versus 8% in nonadenomas; at 15 minutes, the contrast washout is approximately 70% versus 20%, respectively.

          Accumulating evidence suggests that low attenuation values on unenhanced CT scans can distinguish benign adrenal adenomas from AC or metastatic adrenal deposits that have attenuation values generally greater than 20 Hounsfield units (HU). Authorities suggest that adenomas have HU values of 10 or less. (However, many caveats significantly limit the clinical utility of this.)

          Authorities also suggest using norms for HU values in intravenous contrast studies to assist in distinguishing adrenal adenomas from AC. A study by Hamrahian et al found that the sensitivity and specificity for the 10- and 20-HU cutoffs in distinguishing adenomas from nonadenomas, including AC and pheochromocytoma, were 40.5% and 100% for adenomas and 58.2% and 96.9% for nonadenomas. ^[9] These numbers suggest that, while limited as a screening instrument, the HU score has considerable utility in making definitive diagnoses when the scores are either less than 10 HU or greater than 20 HU.

          MRI, in particular, shows significant utility in distinguishing AC from nonfunctional adenomas and pheochromocytomas. The malignant lesions tend to be of intermediate to high density on T2 imaging, while the nonfunctional adenomas are low intensity, and pheochromocytomas have a very high signal intensity. On gadolinium–diethylenetriamine penta-acetic acid (DTPA) contrast-enhanced MRI scans, adenomas generally demonstrate mild enhancement with rapid contrast washout, while ACs show rapid and intense enhancement with sluggish washout. The relatively higher fat content of adrenal adenomas compared with ACs has been used in the new chemical shift imaging (CSI) MRI protocols to further enhance the distinguishing capacity of these studies.

          Approach Considerations

          Because adrenocortical carcinomas (ACs) are so rare, clinical series are small and there has been only limited prospective evaluation of treatment strategies. Therefore, significant controversy over therapy exists, and very few, if any, universally accepted treatment standards have been determined. Current practices are strongly influenced by expert consensus opinion from a few medical centers that specialize in ACs.

          When feasible, total resection remains the management modality of choice for the definitive treatment of AC. It also remains the only potentially curative therapeutic modality.

          Medical care in patients with AC, which can be supportive or adjuvant to surgical resection, encompasses the following:

          • Treatment of endocrine excess syndromes
          • Use of mitotane or several multiagent chemotherapy regimens
          • Treatment and prevention of potential complications
          • Strategies for palliative and terminal care issues, including symptom relief and management

          Management of nonfunctional tumors

          Virtually all authorities agree that because of the significant potential cancer risk, all nonfunctional adrenal tumors of 6 cm or greater should be removed. Authorities also generally agree that nonfunctional adrenal tumors of 3 cm or less have a very low probability of being adrenal cancer; therefore, they can be observed 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.

          Chemotherapy

          Mitotane

          This drug remains the major chemotherapeutic option for the management of AC because it is a relatively specific adrenocortical cytotoxin. It is used as primary therapy, as adjuvant therapy, and as therapy in recurrent or relapsing disease. ^[17]

          Mitotane apparently causes adrenal inhibition without cellular destruction. The exact mechanism of action is unknown. It inhibits cholesterol side-chain cleavage and 11-beta-oxyhydrase reactions. It also appears to reduce the peripheral metabolism of steroids. Alteration of extra-adrenal metabolism of cortisol reduces measurable 17-hydroxy corticosteroid while stimulating the formation of 6-beta-hydroxy cortisol. Plasma levels of corticosteroids do not fall.

          This drug may be considered in the treatment of inoperable adrenal cortical carcinoma (functional, nonfunctional). It controls endocrine hypersecretion in 70-75% of patients. While objective tumor responses often are cited in as many as 20-25% of patients, a study has yet to be conducted with modern imaging techniques and response criteria accepted by clinical oncologists. Tumor response has been reported to correlate with serum levels and often requires several months of continuous therapy. Assaying mitotane levels during therapy is valuable because therapeutic efficacy depends on achieving serum levels of at least 15 mcg/mL.

          Approximately 40% of the drug is absorbed, and approximately 10% of the dose is recovered in the urine as a water-soluble metabolite. Active metabolite excreted in the bile varies from 1-17%. The balance apparently is stored in tissues. Autopsy data indicate that fat tissue is the primary storage site, but the active metabolite is found in most tissues. After therapy, plasma terminal half-life varies from 18-159 days.

          Experience suggests that the best approach is continuous treatment with the maximum possible dosage. If the dose is tolerated and an improved clinical response appears possible, increase the dose until adverse reactions interfere. The aim is to achieve doses as high as 10-20 g/day.

          Efficacy

          Mitotane’s major beneficial effect is on symptoms; treatment benefits are generally short-lived, and long-term survivors on this therapy are rare.

          El Ghorayeb et al.reported a rapid and complete remission of metastatic ACC with mitotane monotherapy 2 years after a right adrenalectomy for stage III nonsecreting ACC. The patient remained disease-free with good quality of life on low maintenance dose of mitotane during the following 10 years