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Adrenocortical carcinoma


Table of Contents

GENERAL INFORMATION
CELLULAR CLASSIFICATION
STAGE INFORMATION
TNM definitions
Stage I
Stage II
Stage III
Stage IV
TREATMENT OPTION OVERVIEW
STAGE I ADRENOCORTICAL CARCINOMA
STAGE II ADRENOCORTICAL CARCINOMA
STAGE III ADRENOCORTICAL CARCINOMA
STAGE IV ADRENOCORTICAL CARCINOMA
RECURRENT ADRENOCORTICAL CARCINOMA

GENERAL INFORMATION

Adrenocortical carcinoma is a rare tumor afflicting only one to two persons per one million population. It usually occurs in adults, and the median age at diagnosis is 44 years. Although potentially curable at early stages, only 30% of these malignancies are confined to the adrenal gland at the time of diagnosis.[1] Approximately 60% of patients present with symptoms related to excessive hormone secretion, but hormone testing reveals that 60%-80% of tumors are functioning.[2,3] Nonfunctioning carcinomas may be heralded by symptoms of local invasion by tumor or by metastases. The most common sites of metastases are the peritoneum, lung, liver, and bone. Initial evaluation should include, in addition to appropriate endocrine studies, computed tomography and/or magnetic resonance imaging of the abdomen. Selective angiography and adrenal venography may be helpful for smaller lesions and for distinguishing tumors of the adrenal gland from tumors of the upper pole of the kidney. The detection of metastatic lesions may allow effective palliation of both functioning and nonfunctioning lesions.

Adrenal carcinoma may be curable if treated at an early stage. Radical surgical excision is the treatment of choice for localized malignancies and remains the only method by which long-term disease-free survival may be achieved. Overall 5-year survival for tumors resected for cure is approximately 40%. Retrospective studies have identified two important prognostic factors: completeness of resection and stage of disease. Patients without evidence of invasion into local tissues or spread to lymph nodes have an improved prognosis.[4] The role of DNA ploidy as a prognostic indicator is controversial, with some [5] studies showing correlation between aneuploidy and prognosis, and other studies [4,6] showing no correlation.

The most common organ sites for distant metastases are the liver and lung. 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 antihormonal therapy with mitotane, systemic chemotherapy, or (for localized lesions) radiation therapy. However, survival for patients with stage IV tumors is usually less than 9 months unless a complete remission is achieved.[3,7-9] To date, there is no convincing evidence that systemic therapy will improve the survival duration of patients with adrenal cancer.

References:

  1. Norton JA: Adrenal tumors. In: DeVita VT Jr, Hellman S, Rosenberg SA, eds.: Cancer: Principles and Practice of Oncology. Philadelphia, Pa: Lippincott-Raven Publishers, 5th ed., 1997, pp 1659-1677.

  2. Icard P, Chapuis Y, Andreassian B, et al.: Adrenocortical carcinoma in surgically treated patients: a retrospective study on 156 cases by the French Association of Endocrine Surgery. Surgery 112(6): 972-979, 1992.

  3. Luton JP, Cerdas S, Billaud L, et al.: Clinical features of adrenocortical carcinoma, prognostic factors, and the effect of mitotane therapy. New England Journal of Medicine 322(17): 1195-1201, 1990.

  4. Lee JE, Berger DH, El-Naggar AK, et al.: Surgical management, DNA content, and patient survival in adrenal cortical carcinoma. Surgery 118(6): 1090-1098, 1995.

  5. Camuto P, Schinella R, Gilchrist K, et al.: Adrenal cortical carcinoma: flow cytometric study of 22 cases, an ECOG study. Urology 37(4): 380-384, 1991.

  6. Haak HR, Cornelisse CJ, Hermans J, et al.: Nuclear DNA content and morphological characteristics in the prognosis of adrenocortical carcinoma. British Journal of Cancer 68(1): 151-155, 1993.

  7. Brennan MF: Adrenocortical carcinoma. Ca-A Cancer Journal for Clinicians 37(6): 348-365, 1987.

  8. Cohn K, Gottesman L, Brennan M: Adrenocortical carcinoma. Surgery 100(6): 1170-1177, 1986.

  9. Wooten MD, King DK: Adrenal cortical carcinoma: epidemiology and treatment with mitotane and a review of the literature. Cancer 72(11): 3145-3155, 1993.


CELLULAR CLASSIFICATION

Differentiated: Functioning tumors are usually differentiated.

Anaplastic: Production of hormones by anaplastic tumors is rare.

Hormonal: Approximately 60% of adrenocortical carcinomas produce hormones. The associated clinical syndromes include the following:[1-3]

hypercortisolism (Cushing's syndrome)
adrenogenital syndrome
virilization
feminization
precocious puberty
hyperaldosteronism
primary hyperaldosteronism (Conn's syndrome)

References:

  1. Javadpour N, Woltering EA, Brennan MF: Adrenal neoplasms. Current Problems in Surgery 17(1): 5-52, 1980.

  2. Nader S, Hickey RC, Sellin RV, et al.: Adrenal cortical carcinoma: a study of 77 cases. Cancer 52(4): 707-711, 1983.

  3. Norton JA: Adrenal tumors. In: DeVita VT Jr, Hellman S, Rosenberg SA, eds.: Cancer: Principles and Practice of Oncology. Philadelphia, Pa: Lippincott-Raven Publishers, 5th ed., 1997, pp 1659-1677.


STAGE INFORMATION

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.[1-4] Proper staging should include computed tomography (CT) of the abdomen. Magnetic resonance imaging (MRI) may add specificity to CT evaluation of an adrenal mass.[5] In-phase and out-of-phase T1-weighted imaging may be the most effective noninvasive method to differentiate benign from malignant adrenal masses. MRI can also often clearly demonstrate any 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.[6] Vena caval contrast studies and angiography may provide additional staging information and allow for more complete preoperative assessment. Review of published data from 608 patients revealed the following stage distribution at diagnosis: 3% stage I, 29% stage II, 20% stage III, and 49% stage IV.[7]

Stages are defined by TNM classification.[8]


TNM definitions

Primary tumor (T)

T1: Primary tumor no more than 5 cm in size; no local invasion
T2: Primary tumor greater than 5 cm in size; no invasion
T3: Primary tumor of any size, locally invading to but not involving
adjacent organs
T4: Tumor any size, locally invading adjacent organs

Nodal involvement (N)
N0: No regional positive nodes
N1: Positive regional nodes

Distant metastasis (M)
MX: Minimum requirements to assess the presence of distant metastasis cannot
be met
M0: No (known) distant metastasis
M1: Distant metastasis present


Stage I

Stage I adrenocortical carcinoma is defined by the following TNM grouping:

T1, N0, M0


Stage II

Stage II adrenocortical carcinoma is defined by the following TNM grouping:

T2, N0, M0


Stage III

Stage III adrenocortical carcinoma is defined by the following TNM groupings:

T3, N0, M0
T1 or T2, N1, M0


Stage IV

Stage IV adrenocortical carcinoma is defined by the following TNM groupings:

T3 or T4, N1, M0
any T, any N, M1

References:

  1. Cerfolio RJ, Vaughan ED, Brennan TG, et al.: Accuracy of computed tomography in predicting adrenal tumor size. Surgery, Gynecology and Obstetrics 176(4): 307-309, 1993.

  2. Brennan MF: Adrenocortical carcinoma. Ca-A Cancer Journal for Clinicians 37(6): 348-365, 1987.

  3. Cohn K, Gottesman L, Brennan M: Adrenocortical carcinoma. Surgery 100(6): 1170-1177, 1986.

  4. Nader S, Hickey RC, Sellin RV, et al.: Adrenal cortical carcinoma: a study of 77 cases. Cancer 52(4): 707-711, 1983.

  5. Doppman JL, Reinig JW, Dwyer AJ, et al.: Differentiation of adrenal masses by magnetic resonance imaging. Surgery 102(6): 1018-1025, 1987.

  6. Brown ED, Semelka RC: Magnetic resonance imaging of the adrenal gland and kidney. Topics in Magnetic Resonance Imaging 7(2): 90-101, 1995.

  7. Wooten MD, King DK: Adrenal cortical carcinoma: epidemiology and treatment with mitotane and a review of the literature. Cancer 72(11): 3145-3155, 1993.

  8. Henley DJ, Van Heerden JA, Grant CS, et al.: Adrenal cortical carcinoma: a continuing challenge. Surgery 94(6): 926-931, 1983.


TREATMENT OPTION OVERVIEW

The designations in PDQ that treatments are "standard" or "under clinical evaluation" are not to be used as a basis for reimbursement determinations.


STAGE I ADRENOCORTICAL CARCINOMA

Treatment options:

Standard:

Complete surgical removal of the tumor is the treatment of choice for
patients with stage I adrenocortical carcinomas. The long-term survival
with nonfunctioning tumors is comparable to that with functioning tumors.
Removal of regional lymph nodes that are not clinically enlarged is not
indicated.[1-5]

Under clinical evaluation:
Adjuvant radiation or chemotherapy with mitotane has not been proven to be
of value in improving survival.[5,6]

References:

  1. Javadpour N, Woltering EA, Brennan MF: Adrenal neoplasms. Current Problems in Surgery 17(1): 5-52, 1980.

  2. Brennan MF: Adrenocortical carcinoma. Ca-A Cancer Journal for Clinicians 37(6): 348-365, 1987.

  3. Cohn K, Gottesman L, Brennan M: Adrenocortical carcinoma. Surgery 100(6): 1170-1177, 1986.

  4. Icard P, Chapuis Y, Andreassian B, et al.: Adrenocortical carcinoma in surgically treated patients: a retrospective study on 156 cases by the French Association of Endocrine Surgery. Surgery 112(6): 972-979, 1992.

  5. Luton JP, Cerdas S, Billaud L, et al.: Clinical features of adrenocortical carcinoma, prognostic factors, and the effect of mitotane therapy. New England Journal of Medicine 322(17): 1195-1201, 1990.

  6. Vassilopoulou-Sellin R, Guinee VF, Klein MJ, et al.: Impact of adjuvant mitotane on the clinical course of patients with adrenocortical cancer. Cancer 71(10): 3119-3123, 1993.


STAGE II ADRENOCORTICAL CARCINOMA

Treatment options:

Standard:

Complete surgical removal of the tumor is the treatment of choice for
patients with stage II adrenocortical carcinomas. The long-term survival
with nonfunctioning tumors is comparable to that with functioning tumors.
Removal of regional lymph nodes that are not clinically enlarged is not
indicated.[1-5]

Under clinical evaluation:
Adjuvant radiation or chemotherapy with mitotane has not been proven to be
of value in improving survival.[5,6]

References:

  1. Javadpour N, Woltering EA, Brennan MF: Adrenal neoplasms. Current Problems in Surgery 17(1): 5-52, 1980.

  2. Brennan MF: Adrenocortical carcinoma. Ca-A Cancer Journal for Clinicians 37(6): 348-365, 1987.

  3. Cohn K, Gottesman L, Brennan M: Adrenocortical carcinoma. Surgery 100(6): 1170-1177, 1986.

  4. Icard P, Chapuis Y, Andreassian B, et al.: Adrenocortical carcinoma in surgically treated patients: a retrospective study on 156 cases by the French Association of Endocrine Surgery. Surgery 112(6): 972-979, 1992.

  5. Luton JP, Cerdas S, Billaud L, et al.: Clinical features of adrenocortical carcinoma, prognostic factors, and the effect of mitotane therapy. New England Journal of Medicine 322(17): 1195-1201, 1990.

  6. Vassilopoulou-Sellin R, Guinee VF, Klein MJ, et al.: Impact of adjuvant mitotane on the clinical course of patients with adrenocortical cancer. Cancer 71(10): 3119-3123, 1993.


STAGE III ADRENOCORTICAL CARCINOMA

Treatment options:

Standard:

Complete surgical removal of the tumor, with or without regional lymph node
dissection. 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 high risk for disease recurrence and
should be considered for enrollment in a clinical trial.

Under clinical evaluation:
1. Clinical trials are appropriate for newly diagnosed patients when possible.

2. Radiation therapy: 4,200-5,000 rads given for a period of 4 weeks to localized but unresectable tumors.[1]

3. For patients unable to undergo complete resection, mitotane in doses up to 10-12 grams/day can be considered. This antitumor drug produces useful clinical responses that average 10 months in duration in about 30% of patients with measurable metastases. Responses in patients who achieve complete remission can be durable. Approximately 80% of treated patients with functioning tumors will show substantial diminution in hormone production. The drug is not usually used unless either radiologically evaluable metastases are present or the residual tumor is producing measurable levels of hormone.[2,3] There does not appear to be a role for mitotane as adjuvant therapy if the patient has undergone complete resection of the tumor.[3,4]

References:

  1. Percarpio B, Knowlton AH: Radiation therapy of adrenocortical carcinoma. Acta Radiologica 15(4): 288-292, 1976.

  2. Lubitz JA, Freeman L, Okun R: Mitotane use in inoperable adrenal cortical carcinoma. Journal of the American Medical Association 223(10): 1109-1112, 1973.

  3. Luton JP, Cerdas S, Billaud L, et al.: Clinical features of adrenocortical carcinoma, prognostic factors, and the effect of mitotane therapy. New England Journal of Medicine 322(17): 1195-1201, 1990.

  4. Vassilopoulou-Sellin R, Guinee VF, Klein MJ, et al.: Impact of adjuvant mitotane on the clinical course of patients with adrenocortical cancer. Cancer 71(10): 3119-3123, 1993.


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 19%-34% of cases, excellent palliation of hormone symptoms is commonly observed.[1] 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.[2] Clinical trials are appropriate and should be considered whenever possible, especially phase I and II trials that evaluate newer chemotherapeutic and biologic agents.[3-6] Palliative chemotherapy with cisplatin-based regimens has produced short-term objective responses in approximately 30% of patients treated.[4,5,7,8] One study reported that doxorubicin produced objective responses in 3 of 16 patients with poorly-differentiated, non-hormone-producing tumors but no responses in 15 patients whose disease did not respond to mitotane.[3]

Treatment options:

Standard:

1. Chemotherapy with mitotane.[1]

2. Radiation therapy to bone metastases.[9]

3. Surgical removal of localized metastases, particularly those that are functioning.[2]

Under clinical evaluation:
Cisplatin has been reported to produce beneficial effects in some selected
patients with metastatic disease.[7,8,10]

Clinical trials of other chemotherapy regimens.[3-6] Refer to PDQ
and to CancerNet (http://cancernet.nci.nih.gov) for information on clinical
trials.

References:

  1. Lubitz JA, Freeman L, Okun R: Mitotane use in inoperable adrenal cortical carcinoma. Journal of the American Medical Association 223(10): 1109-1112, 1973.

  2. Pommier RF, Brennan MF: An eleven-year experience with adrenocortical carcinoma. Surgery 112(6): 963-971, 1992.

  3. Decker RA, Elson P, Hogan TF, et al.: Eastern Cooperative Oncology Group study 1879: mitotane and adriamycin in patients with advanced adrenocortical carcinoma. Surgery 110: 1006-1013, 1991.

  4. Bukowski RM, Wolfe M, Levine HS, et al.: Phase II trial of mitotane and cisplatin in patients with adrenal carcinoma: a Southwest Oncology Group study. Journal of Clinical Oncology 11(1): 161-165, 1993.

  5. Hesketh PJ, McCaffrey RP, Finkel HE, et al.: Cisplatin-based treatment of adrenocortical carcinoma. Cancer Treatment Reports 71(2): 222-224, 1987.

  6. Schlumberger M, Ostronoff M, Bellaiche M, et al.: 5-fluorouracil, doxorubicin, and cisplatin regimen in adrenal cortical carcinoma. Cancer 61(8): 1492-1494, 1988.

  7. Tattersall MH, Lander H, Bain B, et al: Cis-platinum treatment of metastatic adrenal carcinoma. Medical Journal of Australia 1(9): 419-421, 1980.

  8. Chun HG, Yagoda A, Kemeny N, et al.: Cisplatin for adrenal cortical carcinoma. Cancer Treatment Reports 67(5): 513-514, 1983.

  9. Percarpio B, Knowlton AH: Radiation therapy of adrenocortical carcinoma. Acta Radiologica 15(4): 288-292, 1976.

  10. Haq MM, Legha SS, Samaan NA, et al.: Cytotoxic chemotherapy in adrenal cortical carcinoma. Cancer Treatment Reports 64(8-9): 909-913, 1980.


RECURRENT ADRENOCORTICAL CARCINOMA

The question and selection of further treatment of 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. Although none of these patients can be considered curable, palliation of hormonal symptoms and occasional 5-year survivals can be achieved.[1,2] Substantial morbidity, however, is associated with resection of these recurrent tumors.[2] Clinical trials are appropriate and should be considered whenever possible, especially phase I and II trials that evaluate newer chemotherapeutic and biological agents.[3-6]

References:

  1. Pommier RF, Brennan MF: An eleven-year experience with adrenocortical carcinoma. Surgery 112(6): 963-971, 1992.

  2. Jensen JC, Pass HI, Sindelar WF, et al.: Recurrent or metastatic disease in select patients with adrenocortical carcinoma: aggressive resection vs chemotherapy. Archives of Surgery 126(4): 457-461, 1991.

  3. Decker RA, Elson P, Hogan TF, et al.: Eastern Cooperative Oncology Group study 1879: mitotane and adriamycin in patients with advanced adrenocortical carcinoma. Surgery 110: 1006-1013, 1991.

  4. Bukowski RM, Wolfe M, Levine HS, et al.: Phase II trial of mitotane and cisplatin in patients with adrenal carcinoma: a Southwest Oncology Group study. Journal of Clinical Oncology 11(1): 161-165, 1993.

  5. Hesketh PJ, McCaffrey RP, Finkel HE, et al.: Cisplatin-based treatment of adrenocortical carcinoma. Cancer Treatment Reports 71(2): 222-224, 1987.

  6. Schlumberger M, Ostronoff M, Bellaiche M, et al.: 5-fluorouracil, doxorubicin, and cisplatin regimen in adrenal cortical carcinoma. Cancer 61(8): 1492-1494, 1988.

Date Last Modified: 02/1999



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