General Information About Adrenocortical Carcinoma

Incidence and Mortality

Adrenocortical carcinoma (ACC) is a rare tumor with an annual incidence of 2 cases per 1 million population.[1] Although it mainly occurs in adults, children can be affected too. 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.

Prognostic Factors

Retrospective studies have identified the following three important prognostic factors:[3]

• 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 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.

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 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 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.[4] Overall 5-year survival rates are approximately 38% to 46%.[1,2]

References:

1. Bilimoria KY, Shen WT, Elaraj D, et al.: Adrenocortical carcinoma in the United States: treatment utilization and prognostic factors. Cancer 113 (11): 3130-6, 2008.
2. Fassnacht M, Allolio B: Epidemiology of adrenocortical carcinoma. In: Hammer GD, Else T, eds.: Adrenocortical Carcinoma: Basic Science and Clinical Concepts. Springer, 2010, pp 23-9.
3. Miller BS, Gauger PG, Hammer GD, et al.: Proposal for modification of the ENSAT staging system for adrenocortical carcinoma using tumor grade. Langenbecks Arch Surg 395 (7): 955-61, 2010.
4. Allolio B, Fassnacht M: Clinical review: Adrenocortical carcinoma: clinical update. J Clin Endocrinol Metab 91 (6): 2027-37, 2006.

Cellular Classification of Adrenocortical Carcinoma

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 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).

Pathological assessment 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 determined using the Weiss score, which scores several histopathological criteria, including the following:[2]

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

References:

1. Allolio B, Fassnacht M: Clinical presentation and initial diagnosis. In: Hammer GD, Else T, eds.: Adrenocortical Carcinoma: Basic Science and Clinical Concepts. Springer, 2010, pp 31-47.
2. Weiss LM, Medeiros LJ, Vickery AL: Pathologic features of prognostic significance in adrenocortical carcinoma. Am J Surg Pathol 13 (3): 202-6, 1989.

Stage Information for Adrenocortical Carcinoma

Several staging systems for adrenocortical carcinoma (ACC) are in use. The American Joint Committee on Cancer (AJCC) staging system for ACC is based on the following assessment:[1]

The stage of ACC 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.[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 the above-mentioned 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]

AJCC Stage Groupings and TNM Definitions

The AJCC has designated staging by TNM (tumor, node, metastasis) to define ACC.[1]

Table 1. Definitions of TNM Stage I^a

Stage	TNM	Description
T = primary tumor; N = regional lymph node; M = distant metastasis.
a Reprinted 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.

Table 2. Definitions of TNM Stage II^a

Stage	TNM	Description
T = primary tumor; N = regional lymph node; M = distant metastasis.
a Reprinted 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.

Table 3. Definitions of TNM Stage III^a

Stage	TNM	Description
T = primary tumor; N = regional lymph node; M = distant metastasis.
a Reprinted 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.

Table 4. Definitions of TNM Stage IV^a

Stage	TNM	Description
T = primary tumor; N = regional lymph node; M = distant metastasis.
a Reprinted 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.

References:

1. Adrenal Cortical Carcinoma. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. Springer; 2017, pp. 911–8.
2. Doppman JL, Reinig JW, Dwyer AJ, et al.: Differentiation of adrenal masses by magnetic resonance imaging. Surgery 102 (6): 1018-26, 1987.
3. Brown ED, Semelka RC: Magnetic resonance imaging of the adrenal gland and kidney. Top Magn Reson Imaging 7 (2): 90-101, 1995 Spring.
4. Fassnacht M, Johanssen S, Quinkler M, et al.: Limited prognostic value of the 2004 International Union Against Cancer staging classification for adrenocortical carcinoma: proposal for a Revised TNM Classification. Cancer 115 (2): 243-50, 2009.
5. Allolio B, Fassnacht M: Clinical review: Adrenocortical carcinoma: clinical update. J Clin Endocrinol Metab 91 (6): 2027-37, 2006.

Treatment of Stage I Adrenocortical Carcinoma

Treatment Options for Stage I Adrenocortical Carcinoma (ACC)

Treatment options for stage I ACC include the following:

1. Complete surgical removal of the tumor is the treatment of choice for patients with stage I ACC. The long-term survival of patients with nonfunctioning tumors is comparable with that of patients with functioning tumors. The removal of regional lymph nodes that are not clinically enlarged is not indicated.
2. Adjuvant mitotane (under clinical evaluation).

   Although adjuvant mitotane has shown some progression-free or disease-free survival advantage, no overall survival advantage has been demonstrated.[1,2,3]

Current Clinical Trials

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.

References:

1. Terzolo M, Angeli A, Fassnacht M, et al.: Adjuvant mitotane treatment for adrenocortical carcinoma. N Engl J Med 356 (23): 2372-80, 2007.
2. Polat B, Fassnacht M, Pfreundner L, et al.: Radiotherapy in adrenocortical carcinoma. Cancer 115 (13): 2816-23, 2009.
3. Sabolch A, Feng M, Griffith K, et al.: Adjuvant and definitive radiotherapy for adrenocortical carcinoma. Int J Radiat Oncol Biol Phys 80 (5): 1477-84, 2011.

Treatment of Stage II Adrenocortical Carcinoma

Treatment Options for Stage II Adrenocortical Carcinoma (ACC)

Treatment options for stage II ACC include the following:

1. Complete surgical removal of the tumor is the treatment of choice for patients with stage II ACC. The long-term survival of patients with nonfunctioning tumors is comparable with that of patients with functioning tumors. The removal of regional lymph nodes that are not clinically enlarged is not indicated.
2. Adjuvant mitotane (under clinical evaluation).

   Although adjuvant mitotane has shown some progression-free or disease-free survival advantage, no overall survival advantage has been demonstrated.[1,2,3]

Current Clinical Trials

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.

References:

1. Terzolo M, Angeli A, Fassnacht M, et al.: Adjuvant mitotane treatment for adrenocortical carcinoma. N Engl J Med 356 (23): 2372-80, 2007.
2. Polat B, Fassnacht M, Pfreundner L, et al.: Radiotherapy in adrenocortical carcinoma. Cancer 115 (13): 2816-23, 2009.
3. Sabolch A, Feng M, Griffith K, et al.: Adjuvant and definitive radiotherapy for adrenocortical carcinoma. Int J Radiat Oncol Biol Phys 80 (5): 1477-84, 2011.

Treatment of Stage III Adrenocortical Carcinoma

Treatment Options for Stage III Adrenocortical Carcinoma (ACC)

Treatment options for stage III ACC include the following:

1. Complete surgical removal of the tumor, with or without regional lymph node dissection, is the treatment of choice for patients with stage III ACC. 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 consider enrolling in a clinical trial.
2. Radiation therapy (approximately 50–70 Gy given over a period of 4 weeks) may be given to patients with localized but unresectable tumors (under clinical evaluation).[1]
3. Chemotherapy with mitotane in doses as high as 10 to 12 g/day to achieve a blood level of 14 to 20 mg/L should be considered for patients unable to undergo complete resection (under clinical evaluation). This adrenolytic drug produces useful clinical responses in about 20% to 30% of patients with measurable tumor burden.[2,3]

   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.

4. Chemotherapy with mitotane plus streptozotocin or mitotane plus etoposide, doxorubicin, and cisplatin may be effective and has been compared in a phase III clinical trial (NCT00924144) (under clinical evaluation).[2]

Many patients with functioning tumors who have received treatment will experience reduced hormone production. In patients who have 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.

Current Clinical Trials

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.

References:

1. Percarpio B, Knowlton AH: Radiation therapy of adrenal cortical carcinoma. Acta Radiol Ther Phys Biol 15 (4): 288-92, 1976.
2. Allolio B, Fassnacht M: Clinical review: Adrenocortical carcinoma: clinical update. J Clin Endocrinol Metab 91 (6): 2027-37, 2006.
3. Terzolo M, Ardito A, Zaggia B, et al.: Mitotane. In: Hammer GD, Else T, eds.: Adrenocortical Carcinoma: Basic Science and Clinical Concepts. Springer, 2010, pp 369-82.

Treatment of Stage IV Adrenocortical Carcinoma

Treatment Options for Stage IV Adrenocortical Carcinoma (ACC)

Treatment options for stage IV ACC include the following:

1. Chemotherapy with mitotane.
2. Chemotherapy with mitotane plus streptozotocin or mitotane plus etoposide, doxorubicin, and cisplatin, as evidenced by the NCT00924144 phase III clinical trial.[1]
3. Radiation therapy to bone metastases.
4. Surgical removal of localized metastases, particularly for tumors that are functioning.
5. Insulin-like growth factor 1 receptor–inhibitors (under clinical evaluation).
6. Gossypol (under clinical evaluation).

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]

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

Clinical trials of other chemotherapy regimens are ongoing.

Many patients with functioning tumors who have received treatment will experience reduced hormone production. In patients who have 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 biological agents.

Current Clinical Trials

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.

References:

1. Allolio B, Fassnacht M: Clinical review: Adrenocortical carcinoma: clinical update. J Clin Endocrinol Metab 91 (6): 2027-37, 2006.
2. Terzolo M, Ardito A, Zaggia B, et al.: Mitotane. In: Hammer GD, Else T, eds.: Adrenocortical Carcinoma: Basic Science and Clinical Concepts. Springer, 2010, pp 369-82.

Treatment of Recurrent Adrenocortical Carcinoma

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 patients with recurrent ACC are not considered curable, palliation of hormonal symptoms and occasional 5-year survivals can be achieved.[1] Substantial morbidity, however, is associated with resection of 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

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.

References:

1. Jensen JC, Pass HI, Sindelar WF, et al.: Recurrent or metastatic disease in select patients with adrenocortical carcinoma. Aggressive resection vs chemotherapy. Arch Surg 126 (4): 457-61, 1991.

Latest Updates to This Summary (08 / 25 / 2022)

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.

Editorial changes were made to this summary.

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® Cancer Information for Health Professionals 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 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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The lead reviewers for Adrenocortical Carcinoma Treatment are:

• Ann W. Gramza, MD (Georgetown Lombardi Comprehensive Cancer Center)
• Franco M. Muggia, MD (New York University Medical Center)
• Jaydira del Rivero, MD (National Cancer Institute)

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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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Last Revised: 2022-08-25