What is adrenocortical carcinoma

Adrenocortical carcinoma also called cancer of the adrenal cortex, is a rare cancer affecting the outside of the adrenal glands (adrenal cortex). The adrenal glands are on top of each kidney and are responsible for producing certain hormones and keeping blood pressure at normal levels. A tumor of the adrenal cortex may be functioning (makes more hormones than normal) or nonfunctioning (does not make more hormones than normal). Most adrenocortical tumors are functioning. The hormones made by functioning tumors may cause certain signs or symptoms of disease. Adrenocortical carcinoma is a rare tumor that affects only 0.72 persons per one million population ¹. Adrenocortical carcinoma is relatively frequent in children compared to many other cancers, although the adrenal cortex carcinoma may also affect adults in their 40s and 50s. Girls are more often affected than boys. The median age at diagnosis is 46 years. Symptoms of adrenocortical carcinoma may include pain in the abdomen, hypertension, weight gain, frequent urination and possibly deepening of the voice. These symptoms are due to the tumors causing excess secretion of hormones from the adrenal glands ². 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 adrenocortical carcinomas is incidentally discovered by imaging studies conducted for reasons other than potential adrenal disease.

Adrenocortical carcinoma may develop by chance alone, but at least 50% of the cancers are thought to be hereditary. There are a number of genes that have changes (mutations) that can cause an adrenocortical carcinoma, including TP53 and IGF2. There have been reports of both autosomal dominant inheritance and autosomal recessive inheritance ³.

An adrenocortical carcinoma is diagnosed based on urine tests for abnormal levels of cortisol, the hormone released by the adrenal glands. Blood tests can also be conducted to measure levels of potassium and sodium in the blood. A CT scan or MRI may be used to search for a visible tumor in the adrenal cortex. Historically, only about 30% of adrenocortical cancers are confined to the adrenal gland at the time of diagnosis ⁴. However, recently, more adrenocortical carcinomas have been diagnosed at early states, most likely due to the widespread use of high-quality imaging techniques.

Treatment options include surgical removal of the tumor, which is important to achieve a good long-term outlook. Chemotherapy, specifically a drug called mitotane, can be used to try to remove any remaining cancer after surgery ³.

Adrenocortical carcinoma causes

Adrenocortical carcinoma is very rare and the cause is unknown. Adrenocortical carcinoma may develop by chance alone, but at least 50% of the cancers are thought to be hereditary. There are a number of genes that have changes (mutations) that can cause an adrenocortical carcinoma, including TP53 and IGF2. There have been reports of both autosomal dominant inheritance and autosomal recessive inheritance.

In the past, progress in identifying genes involved in adrenocortical carcinoma came mainly from the study of familial diseases ⁵. Adrenocortical carcinoma were frequently associated to the Li–Fraumeni syndrome, due to germline TP53 mutations and the Beckwith–Wiedemann syndrome, due to alterations of the insulin-like growth factor IGF2. At somatic level, inactivating mutations of TP53 and activating mutations of the proto-oncogene β-catenin (CTNNB1) were the most frequent mutations identified in adrenocortical carcinoma. Recently, thanks to genomic approaches, including exome sequencing, not only TP53 and CTNNB1 were confirmed as implicated in adrenocortical carcinoma tumorigenesis, but also ZNRF3 (Zinc and ring finger protein 3) was the most frequently altered gene (21%) ⁶. Interestingly, ZNRF, as CTNNBI, belong to the WNT pathway and it seems that the mutations in the two genes are mutually exclusive.

Moreover, by comparative genomic hybridization, chromosomal gains at 5, 7, 12, 16, 19, and 20 and losses at 13 and 22 were observed in adrenocortical carcinoma. Concerning the epigenetic changes, a specific CpG island methylator phenotype was identified in adrenocortical carcinoma associated to the hypermethylation of the promoters of specific genes as H19, PLAGL1, G0S2, and NDRG2. In addition, some studies identified a significant up-regulation of miR-483 associated to a downrefulation of miR-195 and miR-335 in adrenocortical carcinoma ⁷.

Adrenocortical carcinoma symptoms

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 adrenocortical carcinomas is incidentally discovered by imaging studies conducted for reasons other than potential adrenal disease.

Symptoms of increased cortisol or other adrenal gland hormones may include:

• Fatty, rounded hump high on the back just below the neck (buffalo hump)
• Flushed, rounded face with pudgy cheeks (moon face)
• Obesity
• Stunted growth (short stature)
• Virilization — the appearance of male characteristics, including increased body hair (especially on the face), pubic hair, acne, deepening of the voice, and enlarged clitoris (females)

Symptoms of increased aldosterone are the same as symptoms of low potassium, and include:

• Muscle cramps
• Weakness
• Pain in the abdomen

Adrenocortical carcinoma 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.

Endocrine work-up

The diagnosis of malignancy relies on careful investigations of clinical, biological, and imaging features before surgery and pathological examination after tumor removal. Most patients (40–60%) present steroid hormone excess (glucocorticoids, mineralocorticoids, androgens) or abdominal mass effects (30%), but 15–20% of patients with adrenocortical carcinoma are initially diagnosed incidentally ⁵.

The European Network for the Study of Adrenal Tumors (ENSAT) suggests a pre-operative hormonal workup for suspected adrenocortical carcinoma. In particular, the assessment of basal cortisol, ACTH, dehydroepiandrostenedione sulfate, 17-hydroxyprogesterone, testosterone, androstenedione, and estradiol as well as a dexamethasone suppression test and urinary free cortisol are recommended. In the last years, it seems more evident that some adrenocortical carcinoma, previously considered as non-secreting, in fact can secrete some urine steroid metabolites and recently urine steroid metobolomic analysis have been introduced in routine use ⁸.

Imaging

Traditional and functional imagings are able to diagnose correctly an adrenal mass as adrenocortical carcinoma in most of the cases. The risk for adrenocortical carcinoma increases with tumor size, with the index of suspicion increasing for tumors >4 cm (sensitivity, 97%; specificity, 52%) and >6 cm (sensitivity, 91%; specificity, 80%) ⁹. Unfortunately, masses from 1 to 4 cm in diameter are diagnostically challenging. Generally, most of the adrenocortical carcinoma are large, heterogeneous with irregular margins. Necrosis, hemorrhage or calcification can be associated.

Currently, no single imaging method can characterize a localized adrenal mass as adrenocortical carcinoma. Regarding traditional imaging, abdominal computed tomography (CT) scan is mandatory in suspicion of adrenocortical carcinoma: many studies have established a threshold of ≤10 Hounsfield Unit (HU) in unenhanced CT for the diagnosis of benign lesion. When the basal density is >10 UH, the contrast media washout is helpful to discriminate the benign adrenal lesions from the adrenocortical carcinoma. An absolute washout >50% suggests a benign adrenal lesion. As well as CT scan is fundamental to define the disease staging ¹⁰, all patients with adrenocortical carcinoma must perform a chest CT scan in order to detect pulmonary metastases before surgery.

The state of art of the Magnetic Resonance Imaging (MRI) is less known. In case of suspicion of adrenocortical carcinoma, when the CT scan cannot perfectly characterize the adrenal lesion, three major characteristics of MRI are helpful in the adrenocortical carcinoma diagnosis: the presence of isointense to hypointense signal on T1-weighted images, a hyperintense signal on T2-weighted images and an heterogeneous signal drop on chemical shift ¹¹.

Regarding functional imaging, adrenocortical carcinoma showed high 18F-fluorodeoxyglucose (FDG) uptake ¹² with a cut-off value > 1.45 for adrenal to liver maximum standardized uptake value (SUV), as reported in a series of 77 patients with surgical proven diagnosis of adrenal adenoma or adrenocortical carcinoma ¹³. As the chest and abdominal CT scan, FDG-PET is important for disease staging and prognosis (Leboulleux et al., 2006), but its routine use still needs validation.

In recent years, a new tracer, the metomidate ([11C]MTO) can be useful to prove the adrenocortical origin because it specifically binds to adrenocortical CYP11B enzymes, which catalyze the final steps of steroid synthesis. In a study of 11 patients, adrenocortical carcinoma showed a higher tracer uptake at [11C]MTO-PET compared to normal adrenal gland and liver ¹⁴.

Adrenocortical carcinoma staging

The process used to find out if adrenocortical carcinoma has spread within the adrenal gland or to other parts of the body is called staging. The information gathered from the staging process determines the stage of the disease. It is important to know the stage in order to plan treatment. The following tests and procedures may be used in the staging process:

• CT scan (CAT scan): A procedure that makes a series of detailed pictures of areas inside the body, such as the abdomen or chest, taken from different angles. The pictures are made by a computer linked to an x-ray machine. A dye may be injected into a vein or swallowed to help the organs or tissues show up more clearly. This procedure is also called computed tomography, computerized tomography, or computerized axial tomography.
• MRI (magnetic resonance imaging) with gadolinium: A procedure that uses a magnet, radio waves, and a computer to make a series of detailed pictures of areas inside the body, such as the abdomen. A substance called gadolinium may be injected into a vein. The gadolinium collects around the cancer cells so they show up brighter in the picture. This procedure is also called nuclear magnetic resonance imaging (NMRI).
• PET scan (positron emission tomography scan): A procedure to find malignant tumor cells in the body. A small amount of radioactive glucose (sugar) is injected into a vein. The PET scanner rotates around the body and makes a picture of where glucose is being used in the body. Malignant tumor cells show up brighter in the picture because they are more active and take up more glucose than normal cells do.
• Ultrasound exam: A procedure in which high-energy sound waves (ultrasound) are bounced off internal tissues or organs, such as the vena cava, and make echoes. The echoes form a picture of body tissues called a sonogram.
• Adrenalectomy: A procedure to remove the affected adrenal gland. A tissue sample is viewed under a microscope by a pathologist to check for signs of cancer.

Several staging systems for adrenocortical carcinoma (adrenocortical carcinoma) are in use. The American Joint Committee on Cancer (AJCC) staging system for is based on the following assessment ¹⁵:

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 ¹⁶. 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 ¹⁷.

In addition to the above-mentioned American Joint Committee on Cancer (AJCC) staging, the European Network for the Study of Adrenal Tumors (ENSAT) staging system is widely used internationally ¹⁸. 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 ¹⁹.

Stage 1

• In stage 1, the tumor is 5 centimeters or smaller and is found in the adrenal gland only.
  • T1 = Tumor ≤5 cm in greatest dimension, no extra-adrenal invasion.
  • N0 = No regional lymph node metastasis.
  • M0 = No distant metastasis.

Stage 2

• In stage 2, the tumor is larger than 5 centimeters and is found in the adrenal gland only.
  • T2 = Tumor >5 cm, no extra-adrenal invasion.
  • N0 = No regional lymph node metastasis.
  • M0 = No distant metastasis.

Stage 3

• In stage 3, the tumor is any size and has spread:
  • to nearby lymph nodes; or
  • to nearby tissues or organs (kidney, diaphragm, pancreas, spleen, or liver) or to large blood vessels (renal vein or vena cava) and may have spread to nearby lymph nodes.

Stage 4

• In stage 4, the tumor is any size, may have spread to nearby lymph nodes, and has spread to other parts of the body, such as the lung, bone, or peritoneum.

Adrenocortical carcinoma treatment

There are different types of treatment available for patients with adrenocortical carcinoma.

Three types of standard treatment are used:

• Surgery: Surgery to remove the adrenal gland (adrenalectomy) is often used to treat adrenocortical carcinoma. Sometimes surgery is done to remove the nearby lymph nodes and other tissue where the cancer has spread.
• Radiation therapy: Radiation therapy is a cancer treatment that uses high-energy x-rays or other types of radiation to kill cancer cells or keep them from growing. There are two types of radiation therapy:
  • External radiation therapy uses a machine outside the body to send radiation toward the cancer.
  • Internal radiation therapy uses a radioactive substance sealed in needles, seeds, wires, or catheters that are placed directly into or near the cancer.
  • The way the radiation therapy is given depends on the type and stage of the cancer being treated. External radiation therapy is used to treat adrenocortical carcinoma.
• Chemotherapy: Chemotherapy is a cancer treatment that uses drugs to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. When chemotherapy is taken by mouth or injected into a vein or muscle, the drugs enter the bloodstream and can reach cancer cells throughout the body (systemic chemotherapy). When chemotherapy is placed directly into the cerebrospinal fluid, an organ, or a body cavity such as the abdomen, the drugs mainly affect cancer cells in those areas (regional chemotherapy). Combination chemotherapy is treatment using more than one anticancer drug. The way the chemotherapy is given depends on the type and stage of the cancer being treated.

New types of treatment are being tested in clinical trials. A treatment clinical trial is a research study meant to help improve current treatments or obtain information on new treatments for patients with cancer. When clinical trials show that a new treatment is better than the standard treatment, the new treatment may become the standard treatment. Patients may want to think about taking part in a clinical trial. Some clinical trials are open only to patients who have not started treatment.

• Biologic therapy: Biologic therapy is a treatment that uses the patient’s immune system to fight cancer. Substances made by the body or made in a laboratory are used to boost, direct, or restore the body’s natural defenses against cancer. This type of cancer treatment is also called biotherapy or immunotherapy.
• Targeted therapy: Targeted therapy is a type of treatment that uses drugs or other substances to identify and attack specific cancer cells without harming normal cells.

Treatment Options by Stage

Stage 1 Adrenocortical Carcinoma

Treatment of stage 1 adrenocortical carcinoma may include the following:

• Surgery (adrenalectomy). Nearby lymph nodes may also be removed if they are larger than normal.
• A clinical trial of a new treatment.

Stage 2 Adrenocortical Carcinoma

Treatment of stage 2 adrenocortical carcinoma may include the following:

• Surgery (adrenalectomy). Nearby lymph nodes may also be removed if they are larger than normal.
• A clinical trial of a new treatment.

Stage 3 Adrenocortical Carcinoma

Treatment of stage 3 adrenocortical carcinoma may include the following:

• Surgery (adrenalectomy). Nearby lymph nodes may also be removed if they are larger than normal.
• A clinical trial of a new treatment.

Stage 4 Adrenocortical Carcinoma

Treatment of stage 4 adrenocortical carcinoma may include the following as palliative therapy to relieve symptoms and improve the quality of life:

• Chemotherapy or combination chemotherapy.
• Radiation therapy to bones or other sites where cancer has spread.
• Surgery to remove cancer that has spread to tissues near the adrenal cortex.
• A clinical trial of chemotherapy, biologic therapy, or targeted therapy.

Adrenocortical carcinoma survival rate

Prognostic Factors

Retrospective studies have identified the following three important prognostic factors ²⁰:

• 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.

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 4 tumors is usually less than 20% ⁴.

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 ¹⁹. Overall 5-year survival is approximately 38% to 46% ¹.

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