Adrenocortical carcinoma
Adrenocortical carcinoma is a rare and aggressive cancer of the adrenal cortex. It affects one or two people per million each year, with peaks in early childhood and in the fourth and fifth decades. Its rarity is itself a clinical problem: it is frequently not considered, and it is frequently managed outside centres that see it regularly. The two decisions that most influence outcome — whether a complete, capsule-intact resection is achieved at the first operation, and whether the patient is referred to a specialist centre — are both made early, often before the diagnosis is confirmed.
How it forms
The tumour arises from the steroid-producing cells of the adrenal cortex. Most cases are sporadic, and the characteristic molecular events are:
- Loss of TP53 — the principal tumour suppressor
- Activation of Wnt/β-catenin signalling, through CTNNB1 or ZNRF3 alterations, driving proliferation
- Alterations at the 11p15 locus, causing overexpression of IGF-2 (insulin-like growth factor 2) in the great majority of tumours. This is one of the most consistent features of the disease, and it also explains the hypoglycaemia that occasionally occurs, since IGF-2 has insulin-like activity.
A minority arise within hereditary syndromes, and this is important to recognise because the implications extend to the family:
- Li-Fraumeni syndrome (germline TP53) — responsible for a high proportion of childhood cases. In some populations, particularly southern Brazil, a specific founder mutation makes paediatric adrenocortical carcinoma relatively common. Germline TP53 testing is recommended in all children with this tumour and considered in adults.
- Beckwith-Wiedemann syndrome — involving the same 11p15 locus
- Lynch syndrome, familial adenomatous polyposis, and multiple endocrine neoplasia type 1
Most tumours are functioning, producing steroid hormones — most often cortisol, frequently combined with androgens. A characteristic feature is that their steroidogenesis is inefficient: the malignant cells produce large quantities of steroid precursors as well as finished hormones. This has diagnostic value, since a urinary steroid profile showing excess precursors is highly suggestive of malignancy rather than a benign adenoma.
Symptoms
Presentations fall into three groups:
Hormone excess (around 60%)
- Cushing's syndrome, characteristically of rapid onset — weight gain, weakness, bruising, diabetes, hypertension developing over months rather than years
- Virilisation in women — hirsutism, deepening voice, male-pattern balding, clitoromegaly, menstrual cessation. The combination of rapidly progressive Cushing's features with virilisation is highly suggestive of adrenocortical carcinoma, because benign adenomas rarely produce both.
- feminisation in men — gynaecomastia, testicular atrophy — rare but almost always malignant
- mineralocorticoid excess with hypertension and hypokalaemia
- in children, precocious puberty and rapid growth with virilisation
Mass effect
- abdominal or flank pain, a palpable mass, early satiety
- these tumours are often large at presentation, frequently above 6cm
Incidental
Found on imaging performed for another reason — an increasing proportion, and the group with the best outlook because they are found smaller.
How the diagnosis is made
- Full hormonal assessment before any intervention — dexamethasone suppression test, plasma and urinary metanephrines (to exclude phaeochromocytoma, which is essential before surgery), DHEAS, testosterone and oestradiol, 17-hydroxyprogesterone and androstenedione, aldosterone-renin ratio, and potassium. A urinary steroid metabolite profile by mass spectrometry is increasingly used and is a sensitive discriminator between benign and malignant.
- CT of chest, abdomen and pelvis with contrast — assessing size, heterogeneity, necrosis, calcification, irregular margins, local invasion, tumour thrombus in the renal vein or inferior vena cava, and metastases to liver, lung and bone. Unenhanced attenuation above 10 Hounsfield units and delayed contrast washout are features of malignancy.
- MRI — for assessing vascular involvement and tumour thrombus, and in pregnancy and children.
- FDG PET-CT — helpful in staging and in distinguishing malignant from benign lesions.
- Biopsy is generally contraindicated. It cannot reliably distinguish adrenocortical carcinoma from adenoma, it risks tumour seeding along the needle track, and it is hazardous if a phaeochromocytoma has not been excluded. It is reserved for suspected metastatic disease from another primary, or for unresectable disease where tissue is needed to plan systemic treatment — and then only after biochemical exclusion of phaeochromocytoma.
- Histology — diagnosis rests on the Weiss criteria (nuclear grade, mitotic rate, atypical mitoses, clear cell proportion, architecture, necrosis, and venous, sinusoidal and capsular invasion), supported by a high Ki-67 index, which is the strongest single prognostic marker and guides adjuvant treatment.
Treatment
Surgery
Complete resection is the only curative treatment, and its quality determines everything.
Open adrenalectomy is the standard approach for suspected or confirmed adrenocortical carcinoma. This deserves explaining, because it runs against the general trend toward minimally invasive surgery. The reason is that capsular rupture and tumour spillage during laparoscopic removal seeds the peritoneum and dramatically worsens the outcome, and the risk of this is higher laparoscopically for a large, friable tumour. Series consistently show higher rates of local and peritoneal recurrence after laparoscopic resection of these tumours.
The operation involves en bloc resection with adjacent involved structures — kidney, spleen, tail of pancreas, liver segment, diaphragm — and removal of tumour thrombus from the renal vein or inferior vena cava where present, which may require vascular reconstruction. Lymphadenectomy of the locoregional nodes improves staging and probably outcome.
Where the tumour is small, clearly localised, without local invasion, and being removed in an expert centre, laparoscopic resection may be considered — but the default is open surgery.
Adjuvant treatment
- Mitotane — an adrenolytic drug that selectively destroys adrenocortical cells and inhibits steroidogenesis. It is used as adjuvant treatment after resection in patients at high risk of recurrence (incomplete resection, stage III, Ki-67 above 10%). It requires therapeutic drug monitoring, has a narrow therapeutic window, and causes substantial side effects — nausea, diarrhoea, fatigue, ataxia, cognitive slowing, gynaecomastia and hyperlipidaemia. It also causes adrenal insufficiency, so glucocorticoid replacement at higher-than-usual doses is mandatory, because mitotane accelerates steroid metabolism.
- Radiotherapy to the tumour bed, considered where the resection margin is involved or close.
Advanced disease
- Mitotane with EDP chemotherapy (etoposide, doxorubicin, cisplatin) — the standard first-line regimen, established by the FIRM-ACT trial.
- Surgical resection of isolated metastases or local recurrence in selected patients with a long disease-free interval.
- Control of hormone excess with steroidogenesis inhibitors — metyrapone, osilodrostat, ketoconazole — which materially improves quality of life and reduces infection and thrombotic risk.
- Immunotherapy and targeted agents have shown limited benefit to date; clinical trial participation is particularly valuable in this rare disease and should be discussed.
Recovery
Open adrenalectomy with en bloc resection involves a hospital stay of around a week and a recovery of two to three months, longer where vascular reconstruction or nephrectomy has been performed.
Patients whose tumour produced cortisol require glucocorticoid replacement after surgery, because the opposite gland is suppressed, and recovery of the axis takes many months. Those on mitotane need higher replacement doses and careful education about sick-day rules, a steroid card and an emergency injection, since adrenal crisis is a real risk.
Follow-up
Intensive and long-term: CT of chest, abdomen and pelvis every three months initially, with hormonal markers where the tumour was functioning, extending over at least five to ten years. Recurrence is common, and early detection of isolated recurrence allows further resection, which is worthwhile in selected patients.
When to seek an opinion
Referral to a specialist adrenal centre should precede surgery, not follow it. Features that should prompt it: an adrenal mass above 4cm, particularly above 6cm; an adrenal mass with heterogeneous, irregular or invasive appearances or attenuation above 10 HU; rapidly progressive Cushing's features; virilisation in a woman or feminisation in a man; and any adrenal mass in a child.
Common questions
Why is open surgery recommended rather than keyhole?
Because this tumour is often large and fragile, and if its capsule tears during removal, cells spread through the abdominal cavity and the outlook worsens substantially. Open surgery allows the tumour to be removed intact with the surrounding tissue. This is one of the situations where the older approach remains the better one, and it is a deliberate decision rather than an outdated one.
Why not take a biopsy to confirm it first?
Because a biopsy cannot reliably tell this tumour apart from a harmless adrenal growth — that distinction depends on examining the whole tumour — and putting a needle into it risks spreading cells along the needle track. The diagnosis is made from the hormone tests and the scan appearances, and confirmed after removal.
I have both Cushing's features and increased hair growth and voice changes. What does that mean?
That combination — rapidly developing features of steroid excess together with masculinising features — is characteristic of this tumour, because benign adrenal growths rarely produce both types of hormone. It is a reason for prompt specialist assessment rather than for alarm on its own, but it should not be investigated slowly.
What is mitotane and why does it have so many side effects?
It is a drug that selectively destroys adrenal cortex cells, including tumour cells. Because it acts on a whole tissue rather than a single molecular target, it also affects normal adrenal function and has widespread effects — nausea, tiredness, unsteadiness and slowed thinking are common. Its level in the blood is monitored to keep it within a narrow effective range, and steroid replacement is essential while taking it, at higher doses than usual because it speeds up steroid breakdown.
Why do I need steroid tablets after the tumour is removed?
Because if your tumour was producing cortisol, your other adrenal gland has effectively shut down and will take many months to recover. Without replacement in the meantime you would become dangerously unwell. You will be given clear instructions about increasing the dose if you become ill, and should carry a card and an emergency injection.
Should my children be tested?
Possibly. A proportion of these tumours — and a high proportion of those occurring in children — are linked to an inherited gene fault, most often in the TP53 gene, which also raises the risk of several other cancers. Genetic testing is recommended for all affected children and considered for adults, and it has significant implications for relatives, so it comes with genetic counselling.
What is the outlook?
It depends heavily on the stage and on whether the tumour was removed completely and intact. Tumours confined to the adrenal gland and removed completely carry a considerably better outlook than those that have spread or were removed incompletely. It is an aggressive cancer and the figures are sobering, but they vary substantially by stage, and your own situation is what matters rather than an average.
Why does it matter where I am treated?
Because this cancer is rare — one or two people per million each year — so most surgeons see very few. The completeness of the first operation is the strongest factor within anyone's control, and outcomes are better in centres with an experienced adrenal surgeon, endocrinologist, pathologist and oncologist working together. Asking for that referral before surgery is entirely reasonable.
Related conditions
Other conditions of the adrenal glands covered on this site:
- Adrenal incidentaloma
- Primary aldosteronism (Conn's syndrome)
- Cushing's syndrome
- Phaeochromocytoma and paraganglioma
- Adrenal metastases
This page provides general information and does not replace an individual medical consultation. Adrenocortical carcinoma should be managed in a specialist adrenal centre.