Disease Overview

Epidemiology and pathogenesis

What is ACC?

The adrenal gland plays a crucial role in the endocrine system. Adrenal tumours are very common, affecting 3‒10% of the population (Else et al., 2014). They are normally small, benign, non-functioning adenocarcinomas (ACAs) (Else et al., 2014). The adrenal glands are also a common metastatic site for lung and other cancers. ACC arising from the adrenal cortex is one of two primary adrenal malignancies, the other being phaeochromocytoma arising from the medulla (Berruti et al., 2012).

Anatomy of the adrenal gland (National Cancer Institute, 2019)

Figure 1. Anatomy of the adrenal gland (National Cancer Institute, 2019).

ACC is rare with an incidence of between 0.7‒2.0 per million per year. It can occur at any age, with a peak in incidence between 40 and 60 years (Fassnacht et al., 2018). It is responsible for 1.3% of all childhood cancers and 0.02‒0.2% of all adult cancers (Else et al., 2018). Women are the most often affected (55‒60%) (Libé 2015).

ACC is most frequently presented as a sporadic tumour. However, it can occur as part of hereditary syndromes such as Li-Fraumeni syndrome (TP53 germline and somatic mutations), Lynch syndrome, multiple endocrine neoplasia (MEN) 1, familial adenomatous polyposis (b-catenin somatic mutations) and Beckwith–Wiedeman syndromes (IGF-2 overexpression) (Puglisi et al., 2018).

In recent years, several multicentre studies have shed light on the pathogenesis of ACC, but ‘multi-omic’ studies reveal that only a minority of ACC cases have pathogenic driver mutations (Fassnacht et al., 2018).

ACC is an aggressive disease (Creemers et al., 2016) and patients often present with advanced disease and distant metastases (Else et al., 2014). Although most patients have resectable diseases at presentation, the majority relapse following radical resection (Kassi et al., 2016).

ACC is associated with poor prognosis (Creemers et al., 2016). The more advanced the cancer stage, the worse the five-year survival rate (Libé 2015).

Table 1. Clinical presentations of ACC (Fassnacht et al., 2018)

Clinical presentations of ACC


Key facts

  • Sex: Women are more frequently affected than men (55‒60%) (Libé 2015).
  • Age: It can occur at any age but is more common in children and in adults between 40‒50 years of age (Libé 2015).
  • Family history: Most ACCs occur sporadically but they can also be associated with hereditary syndromes including the Beckwith-Wiedmann syndrome (Else et al., 2014).
  • Risk factors: Genetic predisposition is the only fully established risk factor but smoking in men and contraceptive use in women, especially under the age of 25, have also been suggested as risk factors (Else et al., 2014).
  • Location: ACCs are usually unilateral: they are only bilateral in 2‒10% of cases (Else al., 2014).
  • Tumour functionality: Estimates range between 25‒80% (Kassi et al., 2016). It is important to check for steroid precursors to avoid inappropriately classifying a tumour as non-functional (Benassai et al., 2014).
  • Metastatic disease: 25‒45% of ACC patients have metastases at presentation. The most common metastatic sites are the liver, lung and bones. Metastases of the skin and brain are less common (Else et al., 2014).
  • Differential diagnosis: ACC must be differentially diagnosed from benign ACAs and adrenal medullary tumours (such as phaeochromocytomas). In cases of multiple tumours, it must be determined if it is the primary tumour or a metastatic state (Duregon et al., 2015).

Clinical presentation

ACC presentation:
Patients typically present with ACC in the following ways:

  • 50‒60% present with symptoms of hormone excess (Fassnacht et al., 2018).
  • 10‒15% are incidentally discovered by imaging purposes (Fassnacht et al., 2018).
  • 30‒40% present with symptoms from an abdominal mass (Fassnacht et al., 2018).

In patients with hormone excess (Fassnacht et al., 2018):

  • 50‒70% present with hypercortisolism, giving rise to rapidly developing Cushing’s syndrome (specifically muscle weakness, hypokalaemia, wasting and constitutional symptoms).
  • 20‒30% present with androgen excess, resulting in virilisation in females.
  • 5% present with oestrogen excess, resulting in feminisation in females.
  • 2‒3% present with mineralocorticoid excess, causing hypertension and pronounced hyperkalaemia.
  • Multiple types of hormone excess may be present.
  • Abdominal masses can produce non-specific symptoms like abdominal discomfort (nausea, vomiting, abdominal fullness) or back pain.

ACC patients rarely have classic tumour symptoms such as weight-loss, fever, fatigue or night sweats (Fassnacht et al., 2018).

Prognosis

The prognosis for ACC is variable and surgical resection is the only means of cure (Fassnacht et al., 2018).

Mean survival rate:

  • 3‒4 years.

Five-year survival:

  • 60‒80% for tumour confined to adrenal space.
  • 35‒50% for totally advanced disease.
  • 0‒28% for metatstatic disease.
     
ESE Diagnosis recommendations References
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