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.[1] 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.[2] 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:[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 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%.[2]
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.[4] Overall 5-year survival is approximately 38% to 46%.[1,2]
References
- 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.
- Fassnacht M, Allolio B: Epidemiology of adrenocortical carcinoma. In: Hammer GD, Else T, eds.: Adrenocortical Carcinoma: Basic Science and Clinical Concepts. New York, Springer, 2010, pp 23-9.
- 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.
- 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).
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:[2]
- Nuclear grade.
- Number of mitoses.
- Presence of atypical mitosis.
- Percentage of clear cells.
- Diffuse architecture.
- Necrosis.
- Venous invasion.
- Sinusoidal invasion.
- Capsular invasion.
References
- Allolio B, Fassnacht M: Clinical presentation and initial diagnosis. In: Hammer GD, Else T, eds.: Adrenocortical Carcinoma: Basic Science and Clinical Concepts. New York, Springer, 2010, pp 31-47.
- 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 [1] is based on the following assessment:
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]
| 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. | ||
References
- 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.
- Doppman JL, Reinig JW, Dwyer AJ, et al.: Differentiation of adrenal masses by magnetic resonance imaging. Surgery 102 (6): 1018-26, 1987.
- Brown ED, Semelka RC: Magnetic resonance imaging of the adrenal gland and kidney. Top Magn Reson Imaging 7 (2): 90-101, 1995 Spring.
- 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.
- Allolio B, Fassnacht M: Clinical review: Adrenocortical carcinoma: clinical update. J Clin Endocrinol Metab 91 (6): 2027-37, 2006.
Stage I Adrenocortical Carcinoma Treatment
Standard treatment options for stage I adrenocortical carcinoma (ACC)
Standard treatment options for stage I ACC include the following:
- Complete surgical removal of the tumor is the treatment of choice for patients with stage I ACCs. 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 for stage I ACC:
Although adjuvant mitotane has shown some progression-free or disease-free survival advantage, no overall survival advantage has been demonstrated thus far.[1–3]
References
- Terzolo M, Angeli A, Fassnacht M, et al.: Adjuvant mitotane treatment for adrenocortical carcinoma. N Engl J Med 356 (23): 2372-80, 2007.
- Polat B, Fassnacht M, Pfreundner L, et al.: Radiotherapy in adrenocortical carcinoma. Cancer 115 (13): 2816-23, 2009.
- 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.
Stage II Adrenocortical Carcinoma Treatment
Standard treatment options for stage II adrenocortical carcinoma (ACC)
Standard treatment options for stage II ACC include the following:
- Complete surgical removal of the tumor is the treatment of choice for patients with stage II ACCs. 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 for stage II ACC
Although adjuvant mitotane has shown some progression-free or disease-free survival advantage, no overall survival advantage has been demonstrated thus far.[1–3].
References
- Terzolo M, Angeli A, Fassnacht M, et al.: Adjuvant mitotane treatment for adrenocortical carcinoma. N Engl J Med 356 (23): 2372-80, 2007.
- Polat B, Fassnacht M, Pfreundner L, et al.: Radiotherapy in adrenocortical carcinoma. Cancer 115 (13): 2816-23, 2009.
- 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.
Stage III Adrenocortical Carcinoma Treatment
Standard treatment options for stage III adrenocortical carcinoma (ACC)
Standard treatment options for stage III ACC include the following:
- Complete surgical removal of the tumor, with or without regional lymph node dissection, is the treatment of choice for patients with stage III ACCs. 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 for stage III ACC
Treatment options under clinical evaluation for stage III ACC include the following:
- Clinical trials are appropriate for newly diagnosed patients when possible.
- Radiation therapy (approximately 50 to 70 Gy given over a period of 4 weeks) may be given to patients with localized but unresectable tumors.[1]
- For patients unable to undergo complete resection, mitotane in doses as high as 10 to 12 g per day to achieve a blood level of 14 to 20 mg/L should be considered. This adrenolytic drug produces useful clinical responses in about 20% to 30% of patients with measurable tumor burden.[2,3]
Two other cytotoxic chemotherapy regimens are suggested to be effective and have been compared in a phase III trial:[2]
- 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.
The role of mitotane as adjuvant therapy after complete tumor resection is still a matter of debate but should be discussed with the patient. In the case of complete resection, the role for adjuvant mitotane and radiation therapy is the same as for stage I and stage II ACC.
References
- Percarpio B, Knowlton AH: Radiation therapy of adrenal cortical carcinoma. Acta Radiol Ther Phys Biol 15 (4): 288-92, 1976.
- Allolio B, Fassnacht M: Clinical review: Adrenocortical carcinoma: clinical update. J Clin Endocrinol Metab 91 (6): 2027-37, 2006.
- Terzolo M, Ardito A, Zaggia B, et al.: Mitotane. In: Hammer GD, Else T, eds.: Adrenocortical Carcinoma: Basic Science and Clinical Concepts. New York, Springer, 2010, pp 369-82.
Stage IV Adrenocortical Carcinoma Treatment
Temporary palliation of disseminated adrenocortical carcinomas (ACCs) 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.[1,2]
Two other cytotoxic chemotherapy regimens are suggested to be effective and have been compared in a phase III trial:[1]
- 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 for stage IV ACC
Standard treatment options for stage IV ACC include the following:
Treatment options under clinical evaluation for stage IV ACC
Treatment options under clinical evaluation for stage IV ACC include the following new agents for unresectable ACC:
- Insulin-like growth factor 1 receptor–inhibitors.
- Gossypol.
Trials of other chemotherapy regimens are also ongoing.
References
- Allolio B, Fassnacht M: Clinical review: Adrenocortical carcinoma: clinical update. J Clin Endocrinol Metab 91 (6): 2027-37, 2006.
- Terzolo M, Ardito A, Zaggia B, et al.: Mitotane. In: Hammer GD, Else T, eds.: Adrenocortical Carcinoma: Basic Science and Clinical Concepts. New York, Springer, 2010, pp 369-82.
Recurrent Adrenocortical Carcinoma Treatment
The question of whether to further treat patients with adrenocortical carcinoma (ACC), and the selection of treatment to use, 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 patients with recurrent ACC cannot be considered curable, palliation of hormonal symptoms and occasional 5-year survivals can be achieved.[1] 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.
References
- 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.
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