What Is Adrenocortical Carcinoma (Adrenal Gland Cancer)? How Is It Treated?

The adrenal glands are endocrine (hormone-producing) glands above the kidneys. They produce important hormones such as cortisol, aldosterone and sex hormones. Adrenocortical carcinomas are rare cancers arising from cells in these glands.

Tumors or masses affecting one adrenal gland are common. They are classified as functioning (hormone-secreting) or silent, and benign or malignant.

• Most adrenocortical tumors are benign, nonfunctioning adenomas found incidentally during abdominal imaging.
• These benign adenomas can secrete hormones, causing Cushing syndrome, primary aldosteronism or, much less commonly, virilization (increased hair growth).
• Adrenocortical carcinomas (adrenal gland cancers) are rare, often aggressive tumors. They may be functioning and cause Cushing syndrome and/or virilization, or cause no symptoms and be found incidentally on abdominal imaging.
• Pheochromocytomas are catecholamine-secreting tumors arising from chromaffin cells in the medulla, the adrenal gland’s central region. They may be benign or malignant (cancerous).

Note: Virilization means the development of masculine physical features not typically present in women, caused by increased levels of male hormones, or androgens.

What Is Adrenocortical (Adrenal Cortical) Carcinoma?

Adrenocortical carcinoma (ACC) is a rare, biologically aggressive cancer beginning in the adrenal cortex, or outer layer. It can affect production of cortisol, one of the gland’s hormones. ACC is generally found incidentally during imaging for another reason. Pathology reports may also call it adrenal cortical cancer.

Approximately one to two people per million are diagnosed with ACC annually. Incidence is around 10 times higher in children in southern Brazil, where certain environmental and genetic risk factors have been identified.

ACC can occur at any age, but peaks before age five and in the fourth to fifth decades of life (the 40s and 50s). In general, it progresses faster in adults than children.

Women develop ACC more frequently than men, by a factor of 1.5 to 2.5.

Causes

Most adrenocortical carcinomas occur spontaneously, but some form part of hereditary cancer syndromes, including Li-Fraumeni syndrome, Beckwith-Wiedemann syndrome and multiple endocrine neoplasia type 1 (MEN1). Li-Fraumeni is autosomal dominant and associated with TP53 tumor-suppressor mutations on chromosome 17p. Beckwith-Wiedemann is associated with abnormalities at 11p15. MEN1 is associated with inactivating MEN1 mutations on chromosome 11q.

The molecular mechanisms of sporadic (nonhereditary) adrenocortical carcinoma are less well characterized than those of most hereditary syndromes mentioned above. However, a multistep tumor-progression model described for colorectal cancer has also been proposed for adrenocortical carcinoma.

TP53 is among the genes most frequently mutated in human cancers. Frequent loss of heterozygosity at the 17p13 locus in sporadic adrenocortical carcinoma suggests a role for the TP53 tumor suppressor. However, only around one-third of heterozygosity loss at 17p13 occurs with a TP53 mutation, suggesting another, as yet unidentified suppressor gene at this locus.

Abnormalities at 11p15, as in Beckwith-Wiedemann syndrome, may also contribute to some adrenocortical carcinomas. Activating CTNNB1 mutations and mutations in genes including ZNRF3, PRKAR1A, RPL22, TERF2, CCNE1 and NF1 have also been observed.

Symptoms

Around 60% of ACC patients present with a hormone-excess syndrome. Adults with hormone-secreting tumors generally have Cushing syndrome alone (45%) or a mixed Cushing and virilization syndrome from excessive glucocorticoid and androgen production (25%). Treating patients with Cushing syndrome by surgery or chemotherapy increases the risk of infection and metabolic or vascular complications.

Clinical signs of glucocorticoid excess, such as weight gain, weakness and insomnia, generally develop rapidly, within 3-6 months. Patients also secreting excessive androgens may not experience typical glucocorticoid-related catabolic effects, such as muscle and skin atrophy.

Most ACC symptoms arise from growing tumors, such as abdominal or flank pain, or the disease presents as an adrenal mass found incidentally on imaging for another reason.

Diagnosis

In more than 50% of patients, ACC is found incidentally during imaging for other reasons.

Hormonal assessment is recommended for ACC diagnosis.

Hormonal evaluations may include:

1. Serum cortisol: high levels may indicate Cushing syndrome, and some ACCs secrete cortisol.
2. Serum aldosterone and renin: high aldosterone and low renin may indicate Conn syndrome, and some ACCs secrete aldosterone.
3. Serum androgens: assess levels in patients with virilization symptoms. Some ACCs secrete androgens.
4. Serum estrogen and progesterone: some ACCs also secrete these hormones.

Some ACCs do not secrete hormones, so hormone tests may be normal. Diagnosis can then be confirmed by tumor biopsy and histopathological examination.

Radiographic imaging, particularly PET-CT, can be used to stage ACC.

ACC biopsy can use different methods according to tumor location, size and the patient’s condition. These include fine-needle aspiration (FNA), core-needle (tru-cut) biopsy and open or closed surgical biopsy. FNA is the most commonly used method and particularly useful for diagnosing small tumors. Open surgical biopsy or resection may be preferred for large tumors or when the entire tumor needs removal.

Histopathological examination provides diagnostic assessment of a biopsy. Features indicating malignancy may include a high mitotic index, nuclear atypia, necrosis and arterial invasion. Hormone-producing cells also have diagnostic importance and can be identified by immunohistochemistry.

ACC histopathological classification depends on structural features and malignancy grade. The most commonly used system is called the Weiss score and is based on tissue characteristics. It helps estimate malignancy grade and prognosis.

ACC biopsy is therefore important for accurate diagnosis and classification. Biopsy technique and histopathological assessment are determined by tumor size, location and malignancy grade. Examination can establish the grade and prognosis.

Staging

Different staging systems are available for adrenocortical cancer.

Adults are staged using the 8th tumor, node, metastasis (TNM) system revised by the American Joint Committee on Cancer (AJCC)/Union for International Cancer Control (UICC) for implementation in 2018. Its definitions are the same as those originally proposed by UICC/World Health Organization (WHO) in 2004. In the eighth edition, compared with the previous 2004 AJCC/UICC classification, stage IV is restricted to distant metastasis. Local invasion or invasion of adjacent organs (T3 or T4) without distant metastasis is classified as stage III. These changes agree with those originally proposed by ENSAT.

ENSAT is part of the European Network in Adrenocortical Carcinoma and is a classification system used to determine disease extent.

ENSAT is a variation of TNM, incorporating tumor size (T), lymph node involvement (N) and distant metastasis (M). It can be summarized as follows:

• T1: Tumor smaller than 5 cm
• T2: Tumor larger than 5 cm
• T3: Invasion of adjacent organs, or contact with major blood vessels without invasion
• T4: Invasion of distant organs or tissues
• N0: No lymph node spread
• N1: Lymph node spread
• M0: No distant metastasis
• M1: Distant metastasis

ENSAT combines with TNM to determine stage. For example, T2N0M0 is stage II when the tumor is larger than 5 cm without lymph node or distant metastasis.

The system can help doctors predict disease course and determine treatment options.

Based on ENSAT classification, in 416 adult ACC cases reported from Germany, 5-year disease-specific survival rates were as follows:

• Stage I – confined to the adrenal gland, without local invasion or distant metastasis; maximum size ≤5 cm (T1N0M0): 82%
• Stage II – the same as stage I except for size >5 cm, without risk factors (T2N0M0): 61%
• Stage III – any tumor size with at least one of the following: infiltration of surrounding tissues (T3), tumor thrombus and invasion in the vena cava or renal veins (T4), or positive lymph nodes (N1), without distant metastasis: 50%
• Stage IV – distant metastases: 13%

Pediatric staging differs somewhat from adult systems. It divides disease into groups based on three factors: completely removed small tumors (200 g or less), completely removed large tumors (more than 200 g), and residual or distant metastatic disease.

Treatment

ACC treatment is complete surgical removal. For potentially resectable stage I-III disease, complete resection is recommended initially. All patients need full hormonal assessment before surgery to determine secretory activity. This is particularly important for cortisol-producing tumors. Even with mild hypercortisolism, these patients have some hypothalamic-pituitary-adrenal (HPA) axis suppression and need glucocorticoid cover to prevent postoperative adrenal insufficiency. Surgery should be performed by surgeons at a specialized referral center.

For resectable tumors, a specialized surgical team should prevent tumor dissemination and ensure complete removal. Full hormonal evaluation is needed before surgery. Because lymphatic drainage is the main route of ACC spread, suspicious lymph nodes should be removed.

Postoperative Treatment

Approach to adjuvant (postoperative preventive) systemic therapy – Although resection is technically possible in most stage I to III cases, it is not curative for many, probably because occult micrometastases already exist at presentation. Our approach to adjuvant therapy after complete ACC resection is based on recurrence risk:

• Low recurrence risk – For most patients at low risk after complete resection (stage I to III, microscopically complete [R0] resection, Ki-67 ≤10 percent), we recommend observation rather than adjuvant mitotane. In a randomized trial, adjuvant mitotane did not significantly improve recurrence-free or overall survival in this group. It is recommended for patients meeting low-risk criteria but with features suggesting potential recurrence, such as low-grade stage III disease or a large (>20 cm) stage II tumor with a borderline mitotic rate or Ki-67 score.
• High recurrence risk – For high recurrence risk after complete resection, adjuvant mitotane alone, without chemotherapy, is recommended over observation. High-risk features include high-grade disease (Ki-67 >10 percent and <20 percent, or a mitotic rate above 20 per 50 high-power fields); incompletely resected disease; intraoperative tumor spillage or rupture; and large, low-grade tumors with vascular or capsular invasion.
• Very high recurrence risk – In selected patients at very high risk of early recurrence, such as very high Ki-67 staining (≥20 percent) and extensive vascular invasion/vena cava thrombus, adding cisplatin-based chemotherapy is typically recommended.

Indications for adjuvant radiation therapy – Adjuvant radiation therapy (RT) is recommended for all patients with incompletely resected ACC, other high-risk stage III disease, tumor spillage during resection or high-grade disease (>20 mitotic figures per 50 HPF).

What Is Mitotane? How Does It Work?

Mitotane is used to treat ACC and is among the most effective options. It inhibits tumor growth and reduces hormone production by cancer cells.

ACC tumors often produce hormones such as cortisol, causing symptoms. Mitotane suppresses cortisol production and relieves related symptoms. It may also prevent progression by slowing or stopping tumor growth.

Mitotane is frequently used during treatment. An initial dose is determined by disease severity and tumor size. Higher doses are given early, then reduced. Regular monitoring is needed. The drug requires careful use because of side effects including drowsiness, depression, elevated liver enzymes and reduced thyroid function.

How Long Should Adjuvant Mitotane Continue? The optimal duration is unknown and depends on recurrence risk, tolerability and the maximum period at target therapeutic levels. Observation is preferred for most patients with resected low-risk ACC. Where adjuvant treatment is indicated, at least two years of mitotane is targeted.

• Patients with resected high-risk ACC receive three to five years of adjuvant therapy.

Target mitotane levels – Adjuvant doses vary between patients. The usual recommended starting dose is 2-4 grams daily. If possible, blood mitotane levels should be monitored to reach therapeutic concentrations and avoid toxicity. Levels should be maintained between 14 and 20 mcg/mL.

Glucocorticoid replacement for adrenal insufficiency – Replacement is required after resecting cortisol-secreting ACC. It should also begin with adjuvant mitotane in non-cortisol-secreting tumors because the drug’s adrenolytic action causes insufficiency in most patients. Hydrocortisone is used rather than dexamethasone. Supraphysiological doses become necessary as mitotane progressively accelerates cortisol metabolism by inducing the P450 system.

Treating aldosterone deficiency – Mitotane can eventually cause aldosterone deficiency. We recommend checking blood pressure at every visit, serum potassium every three months and plasma renin every six months. When clinical and biochemical signs develop, fludrocortisone is added at 0.1 to 0.3 mg daily and adjusted to restore normal parameters.

Post-Treatment Surveillance

Imaging – Surveillance includes chest and abdominal computed tomography (CT) every three months for two years, then every six months for five years. The value of fluorodeoxyglucose (FDG)-positron emission tomography (PET) is controversial, and practice varies.

Biochemical monitoring – After complete resection of steroid-producing ACC, some groups monitor steroid tumor markers every three months for two years: cortisol, measured in the morning before hydrocortisone, dehydroepiandrosterone sulfate (DHEAS) and androstenedione. Testosterone, estradiol or mineralocorticoids may be followed according to the original tumor’s steroid profile. Other groups do not routinely screen for hormone excess unless recurrence is evident.

Treating Advanced ACC

Unresectable, recurrent or progressive disease – Complete resection followed by mitotane is recommended for isolated, locally recurrent ACC that can be removed surgically. Surgery may also be considered in rare patients with limited, potentially resectable liver or lung metastases and selected patients with uncontrolled symptoms and hormone excess.

• For most patients with unresectable disease, mitotane plus chemotherapy is recommended rather than either alone. However, mitotane alone is reasonable for low-grade, slowly progressive disease with a limited tumor burden.
• For combination treatment, mitotane with etoposide, doxorubicin and cisplatin (EDP) is recommended.
• Indications for radiofrequency ablation – Percutaneous radiofrequency ablation (RFA) may provide short-term local control of an unresectable primary tumor, particularly if its diameter is <5 cm.
• Medical treatment of hormone excess – For patients with hypercortisolism who are not taking mitotane or whose excess cortisol is not controlled by it, ketoconazole is recommended, with combined ketoconazole and mitotane if needed for control. Appropriate management of glucose, potassium, blood pressure and infections is also important.
• Indications for palliative RT – Palliative radiation is recommended to relieve symptoms from locally advanced or distant metastatic disease, such as bone metastases.

New Approaches Under Investigation for Advanced ACC

Several new approaches, many molecularly targeted, are being investigated for advanced ACC. These have been evaluated only in clinical trials, generally after progression on standard treatments such as mitotane or EDP-mitotane.

Immunotherapy — Programmed cell death ligand (PD-L1) is expressed in some ACCs and associated tumor-infiltrating lymphocytes, raising interest in checkpoint inhibitors. Outside high microsatellite instability (MSI-H) or high tumor mutational burden (TMB-H), immunotherapy for ACC requires further investigation.

Pembrolizumab has shown a favorable safety profile and response rates ranging from 14 to 50 percent in phase II studies in adults and children:

• In an open-label, single-arm phase II study, 39 adults with advanced ACC received pembrolizumab, most after prior systemic treatment with mitotane or platinum-based chemotherapy. At around 18 months’ median follow-up, objective response was 23 percent (9 patients); median progression-free and overall survival were 2 and 24 months. Two of six patients with MSI-high/mismatch repair-deficient (MSI-H/MMR-D) tumors responded. Grade ≥3 toxicity was uncommon, at 13 percent.
• Another open-label, single-arm phase II study found similar results. It treated 16 adults with resistant ACC, around half with cortisol-producing tumors, using the programmed death 1 (PD-1) inhibitor pembrolizumab. At around seven months’ follow-up, two patients (14 percent) had objective responses and seven (50 percent) stable disease. Grade ≥3 toxicity was uncommon, at 13 percent; only one patient stopped because of pulmonary toxicity.
• In an open-label phase I-II pembrolizumab study enrolling 154 children with various recurrent solid tumors (KEYNOTE-051), two of four patients with adrenocortical carcinoma had partial responses.

Other approaches

IGF1R inhibitors – Around 80 percent of ACCs overexpress insulin-like growth factor (IGF) type 2 (IGF-2), known to signal mainly through the IGF-1 receptor (IGF1R).

Preclinical and early-phase studies of antibodies or small molecules inhibiting IFG1R were initially promising, but a subsequent phase I-II trial of the anti-IGF1R antibody cixutumumab showed limited overall efficacy. A placebo-controlled phase III trial of linsitinib, an oral small molecule targeting both IGF1R and insulin receptors, also failed to improve disease-free or overall survival in advanced ACC. Nevertheless, partial responses and disease stabilization occurred in some patients with these drugs alone or combined with agents such as temsirolimus.

Although IGF1R inhibitors may be considered in advanced ACC, further research could identify molecular markers predicting which patients might benefit.

VEGF inhibitors – Vascular endothelial growth factor (VEGF) is upregulated in ACC tissue. Some studies found significantly higher circulating levels in ACC than adrenal adenoma.

Case reports suggested activity from antiangiogenic thalidomide, sorafenib and sunitinib. Subsequent phase II trials found limited efficacy for VEGF inhibitors alone, such as axitinib or sunitinib, or combined with chemotherapy, such as bevacizumab plus capecitabine or sorafenib plus weekly paclitaxel.

EGFR inhibitors – EGFR expression in more than 80 percent of ACCs provides a rationale for targeted agents. Unfortunately, salvage erlotinib, a small-molecule EGFR inhibitor, with gemcitabine provided little benefit in a study of 10 evaluable patients whose advanced ACC had failed at least two systemic chemotherapy regimens. Only one had a minor response, while eight progressed.

Radionuclide therapy – ACC can also be targeted with therapeutic radionuclides. Examples include iodine-131-metomidate and agents targeting 11-beta-hydroxylase, such as (R)-1-[1-(4-[131-I]iodophenyl)ethyl]-1H-imidazole-. 5-carboxylic acid azetidinyl ([iodine-131]-IMAZA).

What Is the Disease Course?

ACC generally behaves aggressively, with low 5-year survival. Five-year survival is around 45% to 60% in early-stage disease and 10% to 25% in advanced disease. However, reports suggest overall survival has improved in recent years.

• Among 139 adults treated at MD Anderson Cancer Center over 20 years, five-year survival was 60%, despite 34% having distant metastases at diagnosis.
• In a second series of 113 patients at Memorial Sloan-Kettering Cancer Center, those with complete resection of primary, nonrecurrent disease (68 patients) had five-year survival of 55%, with a median of 74 months.

Adrenocortical carcinomas are rare, often aggressive tumors that may secrete hormones, causing Cushing syndrome and/or virilization, or be nonfunctioning and present as an abdominal mass or incidental finding. Most adrenal adenomas are smaller than 4 cm, whereas most ACCs are larger than 4 cm when found. The lipid-rich nature of cortical adenomas helps distinguish benign tumors from carcinomas on CT. Around 50 percent of adult ACC patients have relatively advanced disease at diagnosis.