Overview

Definition of adrenocortical carcinoma (ACC)

Adrenocortical carcinoma (ACC) is a rare type of malignant cancer which affects the adrenal gland.¹ The National Institutes of Health Office of Rare Diseases research defines a rare disease as a disease which affects less than 200,000 patients, ACC is regarded as extremely rare.²

Background

The adrenal glands and their functions

The human body comprises  two adrenal glands, also known as the suprarenal glands, which are located on top of the kidneys on each side of the body.

The adrenal glands are fundamental, bilateral organs within the human body comprising of a medulla and cortex, each of which has its own function to regulate the endocrine system and have significant involvement in the body’s fight-or-flight response. The medulla develops from the neurectoderm and is involved in the sympathetic nervous system by producing epinephrine (adrenaline) and norepinephrine (noadrenaline) hormones, while the cortex develops from the mesoderm and is surrounded by the adrenal capsule.³ 

The endocrine system involves hormone production and release from glands, such as the stress hormones, into the bloodstream to control bodily functions such as growth, development, and metabolism, and enable the body to respond to external environmental stimuli. Additionally, the endocrine system acts as the body’s way of communicating between organs to maintain homeostasis, such as temperature and electrolytes.⁴

Difference between benign and malignant tumours in the adrenal cortex

It is important for clinicians to be able to differentiate between benign (noncancerous) and malignant types of adrenal cortex tumours due to differences in treatment strategies, as well as important for patients to understand the implications associated with each type of adrenocortical tumour due to their clinical differences.⁵

75-90% of tumours affecting the adrenal cortex are adrenal adenomas, which are benign growths which are localised in the adrenal cortex and classified as either functional or non-functional.⁶ Functional adrenal adenomas secrete adrenal cortical hormones such as cortisol and aldosterone, and present with symptoms associated with Cushing syndrome, primary hyperaldosteronism and hyperandrogenism. The treatment strategy for patients with functional adrenal adenomas involves correcting hormonal imbalances and surgical intervention. Non-functional adrenal adenomas which do not secrete hormones are usually asymptomatic and usually do not require treatment.

Conversely, 5% of tumours are attributed to the formation of adrenocortical carcinoma and pheochromocytomas, which are types of malignant tumours originating from the adrenal cortex and are capable of metastasising beyond the adrenal glands around the body. Although malignant tumours are less commonly diagnosed, they are associated with a poorer prognosis in patients.^{6, 7}

Incidence and prevalence of ACC

The prevalence of adrenocortical carcinoma is suggested to increase with age, with the incidence rate at approximately 10% around 70 years of age.⁵ The incidence of ACC is rare, being reported to affect 0.5-2 patients per million populations per year, but found to be increasing with the development in imaging techniques used when making diagnoses.⁸

Causes and risk factors

Genetic predisposition

Next-generation sequencing has led to the discovery of mechanisms which contribute to the formation of ACC. Mutations in genes such as insulin-like growth factor 2, B-catenin and TP53 have been implicated in driving ACC tumour development, and additionally associated with familial tumour syndromes such as Beckwith-Wiedemann syndrome, familial adenomatous polyposis and Li-Fraumeni syndrome which pose as risk factors for the disease.⁶ ACC is more common in children, where 80% of ACC diagnosed during childhood is attributed to a mutation of the TP53 gene, it is assumed children have a genetic predisposition to inheriting ACC.⁹

Signs and symptoms

Typical signs of ACC may include abdominal pain, lumps in the abdomen/back as well as feeling full. As a result of an excess amount of hormones in the body due to functional adenomas, patients may experience a variety of symptoms depending on the type of hormone being overproduced.

Increased cortisol:

• Weight gain
• Hair growth
• Deep voice
• Weak muscles
• High blood pressure

Increased aldosterone:

• High blood pressure
• Weak muscles
• Frequent urination
• Feeling dehydrated

Increased testosterone (in people assigned female at birth (AFABs)):

• Hair growth
• Acne
• Deep voice
• Loss of menstruation

Increased oestrogen (in AFABs):

• Irregular periods
• Weight gain

Increased oestrogen (in people assigned male at birth):

• Decreased libido
• Erectile dysfunction
• Growth of breast tissue

Diagnosis

Imaging

More than one imaging technique is used to identify ACC tumours. Abdominal computed tomography (CT) scans are routinely used for staging, while the use of Magnetic Resonance Imaging (MRI) is more useful to characterise the tumour in greater detail.¹⁰

Hormone tests

As 40-60% of patients present with increased levels of steroid hormones, The European Network for the Study of Adrenal Tumours suggests blood tests to assess the levels of cortisol, adrenocorticotropic hormone (ACTH), androgens, hydroxyprogesterone and testosterone amongst others.¹⁰

Biopsy and histopathological examination

Histological testing is essential to confirm the diagnosis of ACC by macroscopic and microscopic evaluation. Macroscopically, ACC is identified as a large brown or yellow-coloured surface with areas of necrosis. Microscopically, the Weiss scoring system is used to assess the architecture, nucleus and type of invasion, with the incidence of each item scoring 1, and the sum determining the final score. A Weiss score of more than 3 defines an ACC, whereas a score between 0 and 2 is classified as a benign adrenal adenoma.¹⁰

Cancer Staging

Tumour-node-metastasis staging system

The tumour-node-metastasis (TNM) classification system is used for the diagnosis of ACC. According to this system, stage I is defined as a localised tumour less than 5cm in size, while stage II is a localised tumour greater than 5cm in size. Stage III is defined as the infiltration of the tumour into surrounding tissue, with positive regional lymph nodes. Stage IV is defined as distant metastasis of the tumour from the site of origin.¹⁰

Prognostic factors

Staying healthy without any symptoms for stage I-III and overall survival (with or without symptoms) for stage IV ACC is assessed based on staging, resection (surgical tumour removal) status and grading.¹⁰

Five-year stage-dependent survival is defined as:

• Stage I: 66-82%
• Stage II: 58-64%
• Stage III: 24-50%
• Stage IV: 0-17%

This is based on the resection status:

• R0: complete resection (no tumour left) which correlates with a better prognosis
• R1: microscopic resection (microscopic tumour residue left)
• R2: incomplete macroscopic resection (macroscopic tumour residue left)
• Rx: unknown resection (unknown amount of tumour left) is associated with the worst overall survival at 15%

Grading is also done with accordance to Ki67.Ki67 is a protein molecular marker identified as the crucial factor which predicts recurrence of ACC in patients following R0 resection.

Treatment

Surgery

Open surgery is the gold standard approach for highly suspected or confirmed cases of ACC. An entire tumour resection, including further removal of fat tissue near the tumour,  abdominal wall fat and surrounding healthy tissue, is recommended. An individualised approach should be taken by a multidisciplinary team to assess each patient on a case-by-case basis when the tumour has metastasised into larger vessels to determine the next step in the surgical plan.¹¹

Adjuvant therapies

Adjuvant therapy (secondary cancer treatment) is recommended for patients without macroscopic identification of residual tumours following surgery. Mitotane is an anticancer agent which is the most routinely prescribed adjuvant therapy for ACC, being specifically cytotoxic (cell-damaging/lethal) to the adrenal tissue and functions by altering the metabolism of cortisol in the adrenal glands. Patients who are treated with mitotane are susceptible to side effects such as anorexia, nausea and vomiting.¹¹

Chemotherapy

Metronomic chemotherapy, also known as anti-angiogenic chemotherapy, is described as frequent administration of doses lower than the maximum tolerated dose over a prolonged period which aims to inhibit tumour angiogenesis. This strategy is advantageous in reducing resistance to drugs, as well as improving drug efficacy and tolerability.

Targeted therapies

Bevacizumab is a monoclonal antibody which has been developed to prevent vascular endothelial growth factor (VEGF) from binding to VEGF receptors. This factor promotes angiogenesis and tumour cell proliferation (increase in number of cancerous cells)  and correspondingly is elevated in ACC, Similarly, Erlotinib and Gefitinib are both endothelial growth factor receptor (EGFR) tyrosine kinase inhibitors, developed to reduce the expression of EGFR, which is commonly increased in ACC.

Clinical trials

Currently, several clinical trials are in place to develop additional targeted therapies for the treatment of ACC to improve patient prognosis.  For example, agents have recently been targeted to the Wnt signalling pathway, which has been proven to promote tumourigenesis in the adrenal glands, although have not been specifically targeted to the adrenal cortex. Additionally, trials are in motion for inhibitors of acetyl-coA cholesterol acetyltransferase (ACAT1), an enzyme which regulates cholesterol.¹²

Summary

Adrenocortical carcinoma (ACC) is a rare malignant tumour affecting the adrenal glands and associated with a poor prognosis in patients.  As the adrenal glands are normally responsible for regulating hormonal balance and therefore have a fundamental role in the endocrine system, patients presenting with ACC have been found to have increased levels of steroid hormone secretion. 

Although the incidence of ACC is low, it is more prevalent in children, which has been attributed to the genetic predisposition to inheriting familial syndromes such as Beckwith-Wiedemann syndrome, familial adenomatous polyposis and Li-Fraumeni syndrome which have gene mutations for insulin-like growth factor 2, B-catenin and TP53, which have been implicated with driving ACC tumour development.

Abdominal symptoms involve feeling a lump in your abdomen or feeling full, while a variety of symptoms such as weight gain, a deeper voice, weakening of the muscles, and high blood pressure among others are associated with increased levels of hormones like cortisol, aldosterone, testosterone and oestrogen. 
ACC can be diagnosed through a series of blood tests to assess hormone balance, imaging techniques and histology testing. Following diagnosis, ACC is staged according to the TNM staging system, while disease-free survival for patients with stage I-III and overall survival for stage IV ACC is assessed based on staging, resection status and grading.

ACC is primarily treated by surgical resection, but other treatment strategies include a series of adjuvant therapies, chemotherapies and targeted therapies, with active clinical trials currently testing a range of novel therapeutics to improve patient prognosis.