Adrenocortical carcinoma

Adrenocortical carcinoma (ACC) is a rare endocrine malignancy arising from the cortex of the adrenal gland. It has an incidence of 0.7–2.0 cases per million habitants per year and presents most frequently with signs and symptoms related to steroid excess. It is an aggressive cancer with a generally poor prognosis. The five-year survival rate ranges from 10%–60%, mostly reflecting the primary tumour stage, the Ki67 proliferation index and the resection status.

Clinical features of ACC are listed below.

• Symptoms related to steroid hormone excess (glucocorticoids, androgens, mineralocorticoids and oestrogens), seen in 40%–60% of patients:
  • Cushing syndrome (including localised weight gain, muscle weakness, purple skin stretch marks, easy bruising, moon face, hypertension and hyperglycaemia);
  • hyperandrogenism (virilisation in women: hirsutism, acne, menstrual irregularities and so on); and
  • rarely, symptoms related to excess of aldosterone or oestrogens.
• Symptoms related to abdominal mass (seen in 30% of patients) – that is, abdominal or lower back pain and a feeling of fullness in the abdomen.
• Symptoms related to cancer: weight loss, loss of appetite.
• No symptoms: 15%–20% of patients with ACC are initially diagnosed incidentally.

The diagnosis of ACC relies on careful investigations of clinical, biological and imaging features before surgery, and pathological examination after tumor removal.

ACC is generally a sporadic disease, but approximately 5%–10% of cases can be associated with constitutional (germline) pathogenic variants typically associated with familial cancer syndromes. These include the following.

• Heritable TP53-related cancer syndromes, including Li-Fraumeni syndrome.
  • These conditions are caused by constitutional (germline) pathogenic variants in the gene TP53.
  • They are cancer predisposition syndromes associated with high risk of a diverse spectrum of childhood- and adult-onset malignancies.
  • Approximately 6% of adults and 50%–80% of children with ACC will be found to carry an underlying constitutional (germline) pathogenic variant in TP53. For this reason, all patients diagnosed with ACC should be offered genomic testing irrespective of age, concomitant presence of other cancer types and positive family history.
• Lynch syndrome.
  • This condition is caused by pathogenic constitutional (germline) variants in genes affecting DNA mismatch repair (MLH1, MSH2, MSH6, PMS2 and EPCAM).
  • Lynch syndrome is characterised by an increased risk of colorectal cancer, endometrial cancer and multiple other solid cancer types.
  • The condition should be considered in patients diagnosed with ACC if they have a personal or family history of Lynch syndrome-associated cancers (colorectal cancer, endometrial cancer, epithelial ovarian cancer, ureteric cancer, transitional cell cancer of renal pelvis, cholangiocarcinoma, small bowel cancer, glioblastoma, endocervical cancer, multiple sebaceous tumours).
  • Tumour-based assessment of mismatch repair by immunohistochemistry or microsatellite instability analysis is the first step at which Lynch syndrome is suspected.
  • Confirmation of Lynch syndrome or somatic mismatch repair deficiency may have therapeutic implications, as MMR-deficient cancers are more likely to demonstrate response to checkpoint inhibitors.
  • Multiple endocrine neoplasia type 1 (MEN1).
    • This condition occurs due to constitutional (germline) pathogenic variants in the MEN1 gene.
    • MEN1 is a hereditary syndrome associated with more than 20 endocrine and non-endocrine tumours.
    • Information about which patients should be offered genomic testing for MEN1 can be found in Presentation: Patient with endocrine neoplasia and Presentation: Patient with possible multiple endocrine neoplasia type 1.
• For further information about genomic testing in the context of adrenocortical carcinoma, see Presentation: Adult with possible adrenocortical carcinoma.

Li-Fraumeni syndrome, Lynch syndrome and MEN1 are all inherited in an autosomal dominant pattern, so that each child and each sibling (brother or sister) of an affected individual has a 50% (one-in-two) chance of inheriting the condition.

The management of patients with confirmed ACC is complex and should be delivered via a multidisciplinary team following available European guidelines. In the case of localised tumours, surgical resection is the first therapeutic option; however, disease recurrences are frequent. Patients at high risk of relapse benefit from adjuvant mitotane treatment. In advanced disease, mitotane is the cornerstone of initial treatment, and cytotoxic drugs should be added in case of progression. First-line chemotherapy usually consists of a combination of etoposide, doxorubicin and cisplatin (EDP regimen), with cisplatin plus gemcitabine as a second-line chemotherapy option.

There are currently no genomically targeted therapies for ACC approved or licenced for use within the UK. Phase II clinical trials of the immune checkpoint inhibitor pembrolizumab have reported responses in both MSI-H and non MSI-H metastatic ACC; further studies are currently in progress.

For clinicians

• European Network for the Study of Adrenal Tumors
• Genomics England: GMS signed off panels
• NHS England: National Genomic Test Directory

References:

• Else T. ‘Association of adrenocortical carcinoma with familial cancer susceptibility syndromes’. Molecular and Cellular Endocrinology 2012: volume 351, issue 1, pages 66–70. DOI: 1016/j.mce.2011.12.008
• Fassnacht M, Assie G, Baudin E and others. ‘Adrenocortical carcinomas and malignant phaeochromocytomas: ESMO–EURACAN Clinical Practice Guidelines for diagnosis, treatment and follow-up’. Annals of Oncology 2020: volume 31, issue 11, pages 1,476–1,490. DOI: 1016/j.annonc.2020.08.2099
• Fassnacht M, Dekkers OM, Else T and others. ‘European Society of Endocrinology Clinical Practice Guidelines on the management of adrenocortical carcinoma in adults, in collaboration with the European Network for the Study of Adrenal Tumors’. European Journal of Endocrinology 2018: volume 179, issue 4, pages G1–G46. DOI: 10.1530/EJE-18-0608

For patients

• ACC Support UK
• Association for Multiple Endocrine Neoplasia Disorders (AMEND)
• European Network for the Study of Adrenal Tumours