Adrenocortical carcinoma (ACC) is a rare tumor with an annual incidence of 2 cases per 1 million people.[1] Although it mainly occurs in adults, children may be affected. The median age at diagnosis is 46 years. Historically, about 30% of these malignancies are confined to the adrenal gland at diagnosis.[2] However, more ACCs are being diagnosed at early stages, most likely because of the widespread use of high-quality imaging techniques.
Retrospective studies have identified the following three important prognostic factors:[3]
Patients who have low-grade tumors without evidence of invasion into local tissues or spread to lymph nodes have an improved prognosis. The role of other prognostic indicators is controversial.
In approximately 60% of patients, symptoms related to excessive hormone secretion are the main reason for seeking medical attention. Biochemical hormone testing reveals that up to 80% of tumors are functioning. The second most common symptoms at time of initial presentation are unspecific abdominal symptoms, such as abdominal pain or fullness. A small percentage of ACCs are incidentally discovered when imaging studies are conducted for reasons other than potential adrenal disease.
Initial evaluation should include careful endocrine studies to reveal any excessive hormone production by the tumor, which can serve as a tumor marker during therapy. Staging should include imaging of the primary site by computed tomography (CT) and/or magnetic resonance imaging of the abdomen. In addition, a CT of the chest is necessary to assess potential lung metastasis. Although the use of positron emission tomography may be effective in identifying unsuspected sites of metastases, its role as a staging tool is unclear. The detection of metastatic lesions may allow effective palliation of both functioning and nonfunctioning tumors.
The most common sites of metastases are the lung, liver, peritoneum, and, less commonly, the bones and major veins. Palliation of metastatic functioning tumors may be achieved by resection of both the primary tumor and metastatic lesions. Unresectable or widely disseminated tumors may be palliated by adrenolytic therapy with mitotane, antihormonal drugs (i.e., ketoconazole and metyrapone), systemic chemotherapy, and/or radiation therapy. However, 5-year survival rates for patients with stage IV tumors are usually less than 20%.[2]
Although several studies have shown partial or even complete remission, there is no convincing evidence that systemic therapy improves the survival duration of patients with adrenal cancer. Radical open surgical excision is the treatment of choice for patients with localized malignancies and remains the only method for achieving long-term disease-free survival.[4] Overall 5-year survival rates are approximately 38% to 46%.[1,2]
Adrenocortical carcinoma (ACC) can be classified into functioning and nonfunctioning tumors by clinical and biochemical assessment. Approximately 60% of ACCs produce hormones.[1] The associated clinical syndromes include:
Biochemical assessment aims to detect increased levels of cortisol (24-hour urine, 1 mg dexamethasone suppression test, serum adrenocorticotropic hormone and cortisol), androgens (dehydroepiandrosterone sulfate, testosterone), estrogens (estradiol), and mineralocorticoids (renin, aldosterone).
Pathological assessment can differentiate high-grade and low-grade tumors according to the mitotic activity of the tumor. The Weiss score can differentiate benign and malignant adrenocortical tumors, based on several histopathological criteria, including:[2]
Several staging systems for adrenocortical carcinoma (ACC) are in use.
The American Joint Committee on Cancer (AJCC) defines ACC stage by the size of the primary tumor, the degree of local invasion, and whether it has spread to regional lymph nodes or distant sites.[1] Proper staging should include computed tomography (CT) of the abdomen and chest. Magnetic resonance imaging (MRI) may add specificity to CT evaluation of an adrenal mass.[2] In-phase and out-of-phase T1-weighted imaging may be the most effective noninvasive method to differentiate benign from malignant adrenal masses. MRI may suggest evidence of extracapsular tumor invasion, extension into the vena cava, or metastases. Patency of surrounding vessels can often be demonstrated with gadolinium-enhanced sequences or flip-angle techniques.[3]
In addition to AJCC staging, the European Network for the Study of Adrenal Tumors (ENSAT) staging system is widely used internationally.[4] The ENSAT staging system is essentially the same as the AJCC system, but reserves stage IV only for tumors with distant metastasis. Other staging systems include the classical Macfarlane system, modified by Sullivan, and the Union Internationale Contre le Cancer staging system, published by the World Health Organization.[5]
The AJCC has designated staging by TNM (tumor, node, metastasis) to define ACC.[1]
| Stage | TNM | Description |
|---|---|---|
| T = primary tumor; N = regional lymph node; M = distant metastasis. | ||
| aReprinted with permission from AJCC: Adrenal Cortical Carcinoma. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp. 911–8. | ||
| I | T1, N0, M0 | T1 = Tumor ≤5 cm in greatest dimension, no extra-adrenal invasion. |
| N0 = No regional lymph node metastasis. | ||
| M0 = No distant metastasis. | ||
| Stage | TNM | Description |
|---|---|---|
| T = primary tumor; N = regional lymph node; M = distant metastasis. | ||
| aReprinted with permission from AJCC: Adrenal Cortical Carcinoma. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp. 911–8. | ||
| II | T2, N0, M0 | T2 = Tumor >5 cm, no extra-adrenal invasion. |
| N0 = No regional lymph node metastasis. | ||
| M0 = No distant metastasis. | ||
| Stage | TNM | Description |
|---|---|---|
| T = primary tumor; N = regional lymph node; M = distant metastasis. | ||
| aReprinted with permission from AJCC: Adrenal Cortical Carcinoma. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp. 911–8. | ||
| III | T1, N1, M0 | T1 = Tumor ≤5 cm in greatest dimension, no extra-adrenal invasion. |
| N1 = Metastasis in regional lymph node(s). | ||
| M0 = No distant metastasis. | ||
| T2, N1, M0 | T2 = Tumor >5 cm, no extra-adrenal invasion. | |
| N1 = Metastasis in regional lymph node(s). | ||
| M0 = No distant metastasis. | ||
| T3, Any N, M0 | T3 = Tumor of any size with local invasion but not invading adjacent organs. | |
| NX = Regional lymph nodes cannot be assessed. | ||
| N0 = No regional lymph node metastasis. | ||
| N1 = Metastasis in regional lymph node(s). | ||
| M0 = No distant metastasis. | ||
| T4, Any N, M0 | T4 = Tumor of any size that invades adjacent organs (kidney, diaphragm, pancreas, spleen, or liver) or large blood vessels (renal vein or vena cava). | |
| Any N = See descriptions in this table, T3, Any N, M0. | ||
| M0 = No distant metastasis. | ||
| Stage | TNM | Description |
|---|---|---|
| T = primary tumor; N = regional lymph node; M = distant metastasis. | ||
| aReprinted with permission from AJCC: Adrenal Cortical Carcinoma. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp. 911–8. | ||
| IV | Any T, Any N, M1 | TX = Primary tumor cannot be assessed. |
| T0 = No evidence of primary tumor. | ||
| T1 = Tumor ≤5 cm in greatest dimension, no extra-adrenal invasion. | ||
| T2 = Tumor >5 cm, no extra-adrenal invasion. | ||
| T3 = Tumor of any size with local invasion but not invading adjacent organs. | ||
| T4 = Tumor of any size that invades adjacent organs (kidney, diaphragm, pancreas, spleen, or liver) or large blood vessels (renal vein or vena cava). | ||
| Any N = See descriptions in Table 3, Stage III. | ||
| M1 = Distant metastasis. | ||
Treatment options for stage I ACC include:
Adjuvant mitotane has shown some progression-free or disease-free survival advantage, but no overall survival advantage.[1-3]
Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.
Treatment options for stage II ACC include:
Adjuvant mitotane has shown some progression-free or disease-free survival advantage, no overall survival advantage.[1-3]
Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.
Treatment options for stage III ACC include:
The role of mitotane as adjuvant therapy after complete tumor resection is still unclear but should be discussed with the patient. For patients who undergo a complete resection, the role of adjuvant mitotane and radiation therapy is the same as for patients with stage I and stage II ACC.
Many patients with functioning tumors who receive treatment experience reduced hormone production. In patients with increased hormone production, antisteroidogenic drugs, such as ketoconazole and metyrapone, and steroid receptor antagonists, such as spironolactone and mifepristone, should be considered.
Clinical trials are appropriate for newly diagnosed patients.
Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.
Treatment options for stage IV ACC include:
Temporary palliation of disseminated ACC can sometimes be achieved with the chemotherapeutic agent mitotane. Although measurable partial remissions are unusual and are reported in only 20% to 30% of patients, palliation of hormone symptoms is commonly observed. Prolonged treatment with mitotane, however, is often limited by gastrointestinal and neurological toxicity. Local recurrences and selected sites of metastatic disease can sometimes be palliated surgically or with radiation therapy.[1,2]
Two other cytotoxic chemotherapy regimens may be effective and have been compared in a phase III clinical trial:[1]
Clinical trials of other chemotherapy regimens are ongoing.
Many patients with functioning tumors who receive treatment experience reduced hormone production. In patients with increased hormone production, antisteroidogenic drugs, such as ketoconazole and metyrapone, and steroid receptor antagonists, such as spironolactone and mifepristone, should be considered.
Clinical trials, including phase I and II trials of newer chemotherapeutic and biological agents, are appropriate and should be considered.
Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.
Deciding to treat patients with recurrent adrenocortical carcinoma (ACC), and what treatment to use, depends on many factors, including previous treatment, site of recurrence, and individual patient considerations. Local recurrence and selected sites of metastatic disease can sometimes be palliated by surgery or radiation therapy. Although recurrent ACC is not considered curable, palliation of hormonal symptoms and occasional 5-year survivals can be achieved.[1] However, substantial morbidity is associated with resection of recurrent tumors.
Clinical trials, including phase I and II trials of newer chemotherapeutic and biological agents, are appropriate and should be considered.
Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.
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This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of adult adrenocortical carcinoma. It is intended as a resource to inform and assist clinicians in the care of their patients. It does not provide formal guidelines or recommendations for making health care decisions.
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PDQ® Adult Treatment Editorial Board. PDQ Adrenocortical Carcinoma Treatment. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: https://www.cancer.gov/types/adrenocortical/hp/adrenocortical-treatment-pdq. Accessed <MM/DD/YYYY>. [PMID: 26389393]
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