Adrenocortical carcinoma (ACC) is an exceedingly rare and aggressive form of cancer, with an annual incidence estimated at one to two cases per million people. ACC is considered an “orphan” malignancy, meaning focused research and clinical trials are limited. Identifying definitive, widespread causes is challenging due to this rarity. Known risk factors generally fall into two categories: non-inherited population statistics and, more significantly, inherited genetic syndromes.
Defining Adrenocortical Carcinoma
The adrenal glands are small, triangle-shaped organs situated atop each kidney, playing a significant part in the endocrine system. Each gland is composed of two distinct regions: the inner medulla and the outer cortex. The cortex produces steroid hormones, including cortisol, aldosterone, and androgens.
Adrenocortical carcinoma is a malignant tumor that originates specifically in the adrenal cortex. This cancer is often aggressive and can be functional, meaning the tumor secretes excessive amounts of steroid hormones, leading to various hormonal syndromes. Unlike common, benign adrenal adenomas, ACC is a serious diagnosis requiring specialized treatment. The extreme infrequency of ACC makes the study of its underlying causes difficult.
Statistical and Population Risk Factors
When ACC does not have a clear genetic link, it is classified as a sporadic case, and the exact cause remains largely unknown. Population-based data reveal certain demographic patterns and non-inherited factors associated with increased risk. The disease exhibits a bimodal age distribution, clustering in two distinct periods: children under five years and adults primarily between 40 and 60 years.
There is also a noticeable sex difference, with women more frequently affected by ACC than men, accounting for 55% to 65% of cases. The average age of diagnosis for adults is around 45 to 47 years. Researchers have investigated environmental and lifestyle factors, but the results are mixed and these are not considered primary causes.
A family history of cancer in general, even without a specific known syndrome, is associated with an increased risk of ACC. Exposure to cigarette smoking has been linked to a higher risk in men. Due to the rarity of this cancer, the influence of common environmental and lifestyle factors is challenging to isolate from the background of sporadic genetic mutations.
Key Inherited Genetic Syndromes
The most significant known causal links for ACC are inherited genetic syndromes, which account for a substantial proportion of pediatric cases, sometimes up to 80%. These conditions involve germline mutations that predispose individuals to cancer development by disrupting normal cell growth and division pathways. The presence of these syndromes elevates the risk of ACC far beyond that of the general population.
Li-Fraumeni Syndrome
Li-Fraumeni Syndrome (LFS) is a highly penetrant inherited cancer predisposition disorder that significantly increases the lifetime risk of developing various cancers, including ACC. This syndrome is caused by a germline mutation in the TP53 tumor suppressor gene. The TP53 gene is responsible for repairing DNA damage or initiating programmed cell death if the damage is too severe.
When one copy of the TP53 gene is inherited in a non-functional state, the cell loses this checkpoint, allowing damaged cells to proliferate and form tumors. A distinct mutation, R337H, is particularly associated with a high incidence of childhood ACC in certain populations, such as Southern Brazil. Although ACC accounts for a smaller percentage of all LFS-associated cancers, about 50% of ACC patients have a TP53 mutation, highlighting the strong causal link.
Beckwith-Wiedemann Syndrome
Beckwith-Wiedemann Syndrome (BWS) is a congenital overgrowth disorder involving genetic and epigenetic changes on chromosome 11p15. BWS is characterized by features like an enlarged tongue, overgrowth of one side of the body, and an increased risk for several embryonal tumors, including ACC, typically in early childhood. The cancer predisposition is linked to the dysregulation of growth-controlling genes in this region, particularly those related to insulin-like growth factor II (IGF-II).
The increased risk of ACC in BWS is pronounced in children with certain molecular subtypes, such as those with Paternal Uniparental Disomy (UPD) of the 11p15 region. This molecular change results in two copies of the paternal chromosome 11p15 region, which can lead to the overexpression of growth-promoting genes. The estimated incidence of early-onset ACC in individuals with BWS is low (less than 1%), but their risk is substantially higher than that of the general population.
Multiple Endocrine Neoplasia Type 1
Multiple Endocrine Neoplasia Type 1 (MEN1) is an inherited condition that predisposes individuals to tumors in several endocrine glands, including the parathyroid, pituitary, and pancreas. The syndrome is caused by a mutation in the MEN1 gene, which is a tumor suppressor gene.
While adrenal tumors associated with MEN1 are most often benign adenomas, ACC has been reported in patients with this syndrome. The MEN1 gene mutation leads to the loss of the menin protein, disrupting its functions in cell growth regulation and DNA repair. Although ACC is a rare manifestation of MEN1, the underlying genetic defect creates a permissive environment for tumor development in endocrine tissues.
Familial Adenomatous Polyposis
Familial Adenomatous Polyposis (FAP) is primarily known for causing hundreds to thousands of precancerous polyps in the colon, leading to a near 100% lifetime risk of colorectal cancer if untreated. FAP is caused by an inherited mutation in the APC (Adenomatous Polyposis Coli) gene, which functions as a tumor suppressor.
Although ACC is not a common cancer associated with FAP, it is included among the extracolonic malignancies that patients with APC mutations have an increased, small risk of developing. The disruption of the APC protein affects the Wnt signaling pathway, a major regulator of cell fate, proliferation, and migration. This disruption contributes to the formation of various tumors, including the rare occurrence of ACC.