National Cancer Institute


Expert-reviewed information summary about the treatment of adrenocortical carcinoma.

This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of adrenocortical carcinoma. It is intended as a resource to inform and assist clinicians who care for cancer patients. It does not provide formal guidelines or recommendations for making health care decisions.

This summary is reviewed regularly and updated as necessary by the PDQ Adult Treatment Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).

Adrenocortical Carcinoma Treatment

General Information About Adrenocortical Carcinoma

Incidence and Mortality

Adrenocortical carcinoma (ACC) is a rare tumor that affects only 0.72 persons per one million population. Although it mainly occurs in adults, children can be affected, too. The median age at diagnosis is 46 years. Historically, only about 30% of these malignancies are confined to the adrenal gland at the time of diagnosis. However, recently, more ACCs have been diagnosed at early states, most likely due to the widespread use of high-quality imaging techniques.

Prognostic Factors

Retrospective studies have identified the following three important prognostic factors:

  • Completeness of resection.
  • Stage of disease.
  • Pathological grade.

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.

Clinical Features

In approximately 60% of patients, symptoms related to excessive hormone secretion are the main reasons 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 is incidentally discovered by imaging studies conducted for reasons other than potential adrenal disease.

Diagnosis

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 lesions.

Prognosis and Survival

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 for patients with stage IV tumors is usually less than 20%.

Although several studies have shown partial or even complete remission, there is no convincing evidence to date that systemic therapy will improve 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 by which long-term disease-free survival may be achieved. Overall 5-year survival is approximately 38% to 46%.

Cellular Classification of Adrenocortical Carcinoma

Adrenocortical carcinoma can be classified into functioning and nonfunctioning tumors by clinical and biochemical assessment. Approximately 60% of adrenocortical carcinomas produce hormones. The associated clinical syndromes include the following:

  • Hypercortisolism (Cushing syndrome).
  • Hirsutism/virilization.
  • Feminization.
  • Precocious puberty.
  • Hyperaldosteronism.

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).

Pathology can differentiate high-grade and low-grade tumors according to the mitotic activity of the tumor. The differentiation of benign and malignant adrenocortical tumors can be achieved by determination of the Weiss score, which scores several histopathological criteria, including the following:

  • Nuclear grade.
  • Number of mitoses.
  • Presence of atypical mitosis.
  • Percentage of clear cells.
  • Diffuse architecture.
  • Necrosis.
  • Venous invasion.
  • Sinusoidal invasion.
  • Capsular invasion.

Stage Information for Adrenocortical Carcinoma

There are several staging systems in use. The American Joint Committee on Cancer (AJCC) staging system is based on the following assessment:

The stage of adrenocortical carcinoma is determined by the size of the primary tumor, the degree of local invasion, and whether it has spread to regional lymph nodes or distant sites. 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. 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.

In addition to the above-mentioned AJCC staging, the European Network for the Study of Adrenal Tumors (ENSAT) staging system is widely used internationally. 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.

Definitions of TNM

The AJCC has designated staging by TNM to define adrenocortical carcinoma.

Stage I Adrenocortical Carcinoma

Standard treatment options:

  • Complete surgical removal of the tumor is the treatment of choice for patients with stage I adrenocortical carcinomas. The long-term survival of patients with nonfunctioning tumors is comparable to that of patients with functioning tumors. The removal of regional lymph nodes that are not clinically enlarged is not indicated.

Treatment options under clinical evaluation:

Although adjuvant mitotane has shown some progression-free or disease-free survival advantage, there has been no overall survival advantage demonstrated thus far.

Current Clinical Trials

Check the list of NCI-supported cancer clinical trials that are now accepting patients with stage I adrenocortical carcinoma. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI website.

Stage II Adrenocortical Carcinoma

Standard treatment options:

  • Complete surgical removal of the tumor is the treatment of choice for patients with stage II adrenocortical carcinomas. The long-term survival of patients with nonfunctioning tumors is comparable to that of patients with functioning tumors. The removal of regional lymph nodes that are not clinically enlarged is not indicated.

Treatment options under clinical evaluation:

Although adjuvant mitotane has shown some progression-free or disease-free survival advantage, there has been no overall survival advantage demonstrated thus far.

Current Clinical Trials

Check the list of NCI-supported cancer clinical trials that are now accepting patients with stage II adrenocortical carcinoma. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI website.

Stage III Adrenocortical Carcinoma

Standard treatment options:

  • Complete surgical removal of the tumor, with or without regional lymph node dissection, is the treatment of choice for patients with stage III adrenocortical carcinomas. The treatment of patients who have tumors with local invasion, but without clinically enlarged regional lymph nodes, is complete surgical removal as for stage I and stage II tumors. For those with enlarged regional lymph nodes, a lymph node dissection should be included in the procedure. These patients are at a high risk of disease recurrence and should be considered for enrollment in a clinical trial.

Treatment options under clinical evaluation:

Current Clinical Trials

Check the list of NCI-supported cancer clinical trials that are now accepting patients with stage III adrenocortical carcinoma. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI website.

Stage IV Adrenocortical Carcinoma

Temporary palliation of disseminated adrenocortical carcinomas can sometimes be achieved with the chemotherapeutic agent mitotane. Although measurable partial remissions are unusual and are reported in only 20% to 30% of cases, palliation of hormone symptoms is commonly observed. Prolonged treatment with mitotane, however, is often limited by gastrointestinal and neurologic toxicity. Local recurrences and selected sites of metastatic disease can sometimes be palliated surgically or with radiation therapy.

Two other cytotoxic chemotherapy regimens are suggested to be effective and have been compared in a phase III trial:

  • Streptozotocin plus mitotane.
  • Etoposide, doxorubicin, and cisplatin plus mitotane.

Furthermore, a substantial number of treated patients with functioning tumors will show diminution in hormone production. In cases of 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 and should be considered whenever possible because phase I and II trials evaluate newer chemotherapeutic and biologic agents.

Standard treatment options:

Treatment options under clinical evaluation:

Several new agents are currently under investigation for unresectable adrenocortical cancer, including the following:

  • Insulin-like growth factor 1 receptor–inhibitors.
  • Gossypol.

Trials of other chemotherapy regimens are also ongoing.

Current Clinical Trials

Check the list of NCI-supported cancer clinical trials that are now accepting patients with stage IV adrenocortical carcinoma. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI website.

Recurrent Adrenocortical Carcinoma

The question and selection of further treatment for patients with adrenocortical carcinoma depends on many factors, including previous treatment and site of recurrence as well as individual patient considerations. Local recurrence and selected sites of metastatic disease can sometimes be palliated by surgery or radiation therapy. Although none of these patients can be considered curable, palliation of hormonal symptoms and occasional 5-year survivals can be achieved. Substantial morbidity, however, is associated with resection of these recurrent tumors.

Clinical trials are appropriate and should be considered whenever possible because phase I and II trials evaluate newer chemotherapeutic and biological agents.

Current Clinical Trials

Check the list of NCI-supported cancer clinical trials that are now accepting patients with recurrent adrenocortical carcinoma. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI website.

Changes to This Summary (06/02/2015)

The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.

Stage IV Adrenocortical Carcinoma

An editorial change was made to this section.

This summary is written and maintained by the PDQ Adult Treatment Editorial Board, which is editorially independent of NCI. The summary reflects an independent review of the literature and does not represent a policy statement of NCI or NIH. More information about summary policies and the role of the PDQ Editorial Boards in maintaining the PDQ summaries can be found on the About This PDQ Summary and PDQ® - NCI's Comprehensive Cancer Database pages.

About This PDQ Summary

Purpose of This Summary

This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of adrenocortical carcinoma. It is intended as a resource to inform and assist clinicians who care for cancer patients. It does not provide formal guidelines or recommendations for making health care decisions.

Reviewers and Updates

This summary is reviewed regularly and updated as necessary by the PDQ Adult Treatment Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).

Board members review recently published articles each month to determine whether an article should:

  • be discussed at a meeting,
  • be cited with text, or
  • replace or update an existing article that is already cited.

Changes to the summaries are made through a consensus process in which Board members evaluate the strength of the evidence in the published articles and determine how the article should be included in the summary.

The lead reviewer for Adrenocortical Carcinoma Treatment is:

  • Franco M. Muggia, MD (New York University Medical Center)

Any comments or questions about the summary content should be submitted to Cancer.gov through the NCI website's Email Us. Do not contact the individual Board Members with questions or comments about the summaries. Board members will not respond to individual inquiries.

Levels of Evidence

Some of the reference citations in this summary are accompanied by a level-of-evidence designation. These designations are intended to help readers assess the strength of the evidence supporting the use of specific interventions or approaches. The PDQ Adult Treatment Editorial Board uses a formal evidence ranking system in developing its level-of-evidence designations.

Permission to Use This Summary

PDQ is a registered trademark. Although the content of PDQ documents can be used freely as text, it cannot be identified as an NCI PDQ cancer information summary unless it is presented in its entirety and is regularly updated. However, an author would be permitted to write a sentence such as “NCI’s PDQ cancer information summary about breast cancer prevention states the risks succinctly: [include excerpt from the summary].”

The preferred citation for this PDQ summary is:

National Cancer Institute: PDQ® Adrenocortical Carcinoma Treatment. Bethesda, MD: National Cancer Institute. Date last modified . Available at: http://www.cancer.gov/types/adrenocortical/hp/adrenocortical-treatment-pdq. Accessed .

Images in this summary are used with permission of the author(s), artist, and/or publisher for use within the PDQ summaries only. Permission to use images outside the context of PDQ information must be obtained from the owner(s) and cannot be granted by the National Cancer Institute. Information about using the illustrations in this summary, along with many other cancer-related images, is available in Visuals Online, a collection of over 2,000 scientific images.

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Based on the strength of the available evidence, treatment options may be described as either “standard” or “under clinical evaluation.” These classifications should not be used as a basis for insurance reimbursement determinations. More information on insurance coverage is available on Cancer.gov on the Managing Cancer Care page.

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