Adrenocortical carcinoma overview

Adrenocortical carcinoma Microchapters
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Raviteja Guddeti, M.B.B.S. [2] Ahmad Al Maradni, M.D. [3] Mohammed Abdelwahed M.D[4]

Overview

Adrenocortical carcinoma (ACC) is a rare endocrine malignancy, often with an unfavorable prognosis. It originates from the adrenal cortex. In 1893, Grawitz et al was the first one who described ACC and falsely assumed it to be a hypernephroma. By 1938, the Mayo group had removed tumors successfully from 16 consecutive patients, most of whom had Cushing’s syndrome. In 1960, mitotane was first used clinically to treat inoperable or recurrent ACC. Adrenocortical carcinoma may be classified according to hormone production and histological appearance. ACCs are typically large tumors upon clinical presentation, often measuring more than 6 cm in diameter. They are bilateral in 2% to 10% of cases. Genetic basis of ACC depends on genomic aberrations that contribute to neoplastic transformation of adrenocortical cells such as clonality, gene expression arrays, microRNAs, gene mutations, chromosomal aberrations, epigenetic changes. Intracellular signaling depends on suggested three pathways: IGF pathway, WNT signaling pathway, Vascular endothelial growth factor pathway. On gross pathology, a large tan-yellow surface with areas of hemorrhage and necrosis is a characteristic finding of adrenocortical carcinoma. On microscopic histopathological analysis, sheets of atypical cells with some resemblance to the cells of the normal adrenal cortex are a characteristic finding of adrenocortical carcinoma. ACC may be associated with other neoplastic syndromes such as Lynch syndrome, Beckwith-Wiedemann syndrome (BWS), Carney complex, Neurofibromatosis type 1. There are no established causes for Adrenocortical carcinoma. Adrenocortical carcinoma must be differentiated from other diseases such as adrenocortical adenoma, adrenal metastasis, adrenal medullary tumors, and Cushing's syndrome. The incidence of adrenocortical carcinoma is believed to be 0.72 per million cases per year leading to 0.2% of all cancer deaths in the United States and 0.2 to 0.3 per million children per year worldwide but valid data are lacking. A bimodal distribution was observed, the first one in pediatrics and the second one in the fifth to the sixth decade. There is a predilection for the female gender. The relatively increased incidence in childhood is mainly explained by germline TP53 mutations, which are the underlying genetic cause of ACC in >50% to 80% of children. The most potent risk factors in the development of adrenocortical cancer are Lynch syndrome, Beckwith-Wiedemann syndrome, Carney complex, Neurofibromatosis type 1, Multiple endocrine neoplasia type 1 (MEN1), and Caney Complex. Screening is not recommended for adrenocortical carcinoma. If left untreated, patients with adrenocortical carcinoma may progress to develop hyperglycemia, osteoporosis, delayed wound healing, hypertension, Cerebrovascular disease, and local or distant metastasis. Prognosis is generally poor, and the 5-year survival rate of patients with adrenocortical carcinoma stage I-III is approximately 30%. Complications may include metastasis, Conn's syndrome and Cushing'a syndrome. According to the TNM staging system, there are four stages of adrenocortical cancer based on the tumor size, lymph nodes, and distant metastasis. Each stage is assigned a number and letter that designates the number of lymph nodes involved and presence/absence of distant metastasis. Symptoms of adrenocortical carcinoma include symptoms of androgen, glucocorticoid, mineralocorticoid, or estrogen excess. Symptoms of glucocorticoid excess include weight gain, acne, irritability. Symptoms of androgen excess symptoms include hirsutism, acne, and deepening of the voice. Symptoms of mineralocorticoid excess include headache, muscle weakness, confusion, palpitations. Common physical examination findings of Adrenocortical carcinoma include Cushing's syndrome findings such as hypertension, weakness, gynecomastia, and acne. Hyperandrogenic cases may show findings such as clitoromegaly and hirsutism. Some patients with adrenocortical carcinoma may have elevated concentrations of serum cortisol, aldosterone, testosterone or estrogen and reduced concentration of plasma renin and potassium. There are no findings associated with adrenocortical carcinoma. Adrenal CT scan may be helpful in the diagnosis of Adrenocortical carcinoma (ACC) and differentiating it from other diseases, such as adrenocortical adenoma. Signs such as Internal hemorrhage, calcifications, CT density > 10 HU or necrosis increase the chances of ACC. Contrast-enhanced CT scan is a reliable method of disease staging, identifying common metastatic sites such as regional and para-aortic lymph nodes, lungs, liver, and bones.CT imaging of the chest, liver, and bone scan are used for staging workup to detect metastasis. MRI scans are helpful in differentiating between adrenal adenoma, carcinoma, and metastatic lesions. Due to the multiplanar capability of MRI, direct invasion of adjacent organs may be better shown. MRI scans are helpful in differentiating between adrenal adenoma, carcinoma, and metastatic lesions. Due to the multiplanar capability of MRI, direct invasion of adjacent organs may be better shown. Inferior vena cava invasion has been reported in 9% to 19% of cases at presentation. Intraoperative and intravascular ultrasound may be used for metastatic deposits recognition. Adrenal angiography, venography, positron emission tomography and MIBG may be used in the diagnosis of adrenocortical carcinoma. The sensitivity of FDG PET/CT was 90% for the diagnosis of metastases as compared with 88% for diagnostic CT. FDG PET/CT is a useful modality for staging ACC and evaluating local recurrence. FNA cytology cannot distinguish a benign adrenal mass from adrenal carcinoma. Overexpression of TP53, IGF-2, and cyclin E are found in ACC but not a conclusive procedure. Chemotherapy and hormonal therapy may be required in the treatment of adrenocortical carcinoma. Mitotane is the only approved drug in the U.S. until now. Mitotane causes a destruction of the inner zones of the adrenal cortex, the zona fasciculata, and zona reticularis. Other drugs such as ketoconazole, metyrapone, aminoglutethimide, etomidate, and mifepristone can be used also. Target therapy such as sunitinib is IGF-1R antagonists that also may be effective. Surgery is the mainstay of treatment for adrenocortical carcinoma. Appropriate preoperative evaluation and operative planning are the most important to assure the best outcome. Lymph nodes should be removed as part of the en bloc resection. Recurrence in the peritoneum outside the tumor bed having the worst survival. Surgery is indicated in those patients with disease confined to one site or organ. Radiation therapyand radiofrequency ablation may be used for palliation in patients who are not surgical candidates. Recurrence is lower in the patient with adjuvant radiotherapy than in patients without radiotherapy. ACC with metastasis to bone experienced adequate pain relief after radiotherapy.

Historical perspective

In 1893, Grawitz et al was the first one who described ACC and falsely assumed it to be a hypernephroma. By 1938, the Mayo group had removed tumors successfully from 16 consecutive patients, most of whom had Cushing’s syndrome. In 1960, mitotane was first used clinically to treat inoperable or recurrent ACC.

Classification

Adrenocortical carcinoma may be classified according to hormone production and histological appearance. ACC may secrete cortisol, aldosterone, testosterone or estrogen. Other variants include oncocytic adrenal cortical carcinoma, myxoid adrenal cortical carcinoma, and carcinosarcoma.

Pathophysiology

ACCs are typically large tumors upon clinical presentation, often measuring more than 6 cm in diameter. They are bilateral in 2% to 10% of cases. Genetic basis of ACC depends on genomic aberrations that contribute to neoplastic transformation of adrenocortical cells such as clonality, gene expression arrays, microRNAs, gene mutations, chromosomal aberrations, epigenetic changes. Intracellular signaling depends on suggested three pathways: IGF pathway, WNT signaling pathway, Vascular endothelial growth factor pathway. On gross pathology, a large tan-yellow surface with areas of hemorrhage and necrosis is a characteristic finding of adrenocortical carcinoma. On microscopic histopathological analysis, sheets of atypical cells with some resemblance to the cells of the normal adrenal cortex are a characteristic finding of adrenocortical carcinoma. ACC may be associated with other neoplastic syndromes such as Lynch syndrome, Beckwith-Wiedemann syndrome (BWS), Carney complex, Neurofibromatosis type 1.

Causes

There are no established causes for Adrenocortical carcinoma. The relatively increased incidence in childhood is mainly explained by germline TP53 mutations, which are the underlying genetic cause of ACC in >50% to 80% of children.

Differentiating Adrenal Carcinoma from other Diseases

Adrenocortical carcinoma must be differentiated from other diseases such as adrenocortical adenoma, adrenal metastasis, adrenal medullary tumors, and Cushing's syndrome.

Epidemiology and Demographics

The incidence of adrenocortical carcinoma is believed to be 0.72 per million cases per year leading to 0.2% of all cancer deaths in the United States and 0.2 to 0.3 per million children per year worldwide but valid data are lacking. A bimodal distribution was observed, the first one in pediatrics and the second one in the fifth to the sixth decade. There is a predilection for the female gender.

Risk Factors

The most potent risk factors in the development of adrenocortical cancer are Lynch syndrome, Beckwith-Wiedemann syndrome, Carney complex, Neurofibromatosis type 1, Multiple endocrine neoplasia type 1 (MEN1), and Carney complex.

Screening

Screening is not recommended for adrenocortical carcinoma.

Natural History, Complications and Prognosis

If left untreated, patients with adrenocortical carcinoma may progress to develop hyperglycemia, osteoporosis, delayed wound healing, hypertension, Cerebrovascular disease, and local or distant metastasis. Prognosis is generally poor, and the 5-year survival rate of patients with adrenocortical carcinoma stage I-III is approximately 30%. Complications may include metastasis, Conn's syndrome and Cushing'a syndrome.

Diagnosis

Staging

According to the TNM staging system, there are four stages of adrenocortical cancer based on the tumor size, lymph nodes, and distant metastasis. Each stage is assigned a number and letter that designates the number of lymph nodes involved and presence/absence of distant metastasis.

History and Symptoms

Symptoms of adrenocortical carcinoma include symptoms of androgen, glucocorticoid, mineralocorticoid, or estrogen excess. Symptoms of glucocorticoid excess include weight gain, acne, irritability. Symptoms of androgen excess symptoms include hirsutism, acne, and deepening of the voice. Symptoms of mineralocorticoid excess include headache, muscle weakness, confusion, palpitations. 

Physical Examination

Common physical examination findings of Adrenocortical carcinoma include Cushing's syndrome findings such as hypertension, weakness, gynecomastia, and acne. Hyperandrogenic cases may show findings such as clitoromegaly and hirsutism.

Laboratory Findings

Some patients with adrenocortical carcinoma may have elevated concentrations of serum cortisol, aldosterone, testosterone or estrogen and reduced concentration of plasma renin and potassium.

X-ray

There are no findings associated with adrenocortical carcinoma.

MRI

MRI scans are helpful in differentiating between adrenal adenoma, carcinoma, and metastatic lesions. Due to the multiplanar capability of MRI, direct invasion of adjacent organs may be better shown. MRI scans are helpful in differentiating between adrenal adenoma, carcinoma, and metastatic lesions. Due to the multiplanar capability of MRI, direct invasion of adjacent organs may be better shown. Inferior vena cava invasion has been reported in 9% to 19% of cases at presentation.

CT

Adrenal CT scan may be helpful in the diagnosis of Adrenocortical carcinoma (ACC) and differentiating it from other diseases, such as adrenocortical adenoma. Signs such as Internal hemorrhage, calcifications, CT density > 10 HU or necrosis increase the chances of ACC. Contrast-enhanced CT scan is a reliable method of disease staging, identifying common metastatic sites such as regional and para-aortic lymph nodes, lungs, liver, and bones.CT imaging of the chest, liver, and bone scan are used for staging workup to detect metastasis.

UltraSound

Intraoperative and intravascular ultrasound may be used for metastatic deposits recognition.

Other Imaging Studies

Adrenal angiography, venography, positron emission tomography and MIBG may be used in the diagnosis of adrenocortical carcinoma. The sensitivity of FDG PET/CT was 90% for the diagnosis of metastases as compared with 88% for diagnostic CT. FDG PET/CT is a useful modality for staging ACC and evaluating local recurrence.

Biopsy

FNA cytology cannot distinguish a benign adrenal mass from adrenal carcinoma. Overexpression of TP53, IGF-2, and cyclin E are found in ACC but not a conclusive procedure.

Treatment

Medical Therapy

Chemotherapy and hormonal therapy may be required in the treatment of adrenocortical carcinoma. Mitotane is the only approved drug in the U.S. until now. Mitotane causes a destruction of the inner zones of the adrenal cortex, the zona fasciculata, and zona reticularis. Other drugs such as ketoconazole, metyrapone, aminoglutethimide, etomidate, and mifepristone can be used also. Target therapy such as sunitinib is IGF-1R antagonists that also may be effective.

Surgery

Surgery is the mainstay of treatment for adrenocortical carcinoma. Appropriate preoperative evaluation and operative planning are the most important to assure the best outcome. Lymph nodes should be removed as part of the en bloc resection. Recurrence in the peritoneum outside the tumor bed having the worst survival. Surgery is indicated in those patients with disease confined to one site or organ.

Radiation

Radiation therapyand radiofrequency ablation may be used for palliation in patients who are not surgical candidates. Recurrence is lower in the patient with adjuvant radiotherapy than in patients without radiotherapy. ACC with metastasis to bone experienced adequate pain relief after radiotherapy.