Adrenocortical Oncocytic Carcinoma

Adrenocortical oncocytic carcinoma is a rare variant of adrenocortical carcinoma in which over 90% of tumour cells are oncocytic (eosinophilic and mitochondria rich).

Most are hormonally inactive, and they are often large when found. They are malignant by modified histological criteria, and behaviour is variable but generally better than conventional adrenocortical carcinoma when confined to the gland.

Adrenocortical carcinoma has an incidence of about 0.7 to 2 cases in 1,000,000 people each year. Oncocytic tumours form about 2% to 5% of adrenocortical tumours, mostly in adults in the 40s to 60s, with a slight female predominance. Many tumours are found incidentally on imaging.

Associations are Li-Fraumeni syndrome, Lynch syndrome, multiple endocrine neoplasia type 1, Beckwith-Wiedemann syndrome and familial adenomatous polyposis.

Pathophysiology

Oncocytic change reflects mitochondrial accumulation. Pathogenic mitochondrial DNA variants, TP53 mutation and CTNNB1 or other cell cycle alterations are described. Malignancy is judged by modified criteria for oncocytic tumours (a large size over 10 cm or 200 g, mitoses over 5 in 50 high power fields, atypical mitoses, venous invasion), since the Weiss score over calls oncocytic tumours.

Prognosis

Localised tumours confined to the adrenal have a 5-year survival of about 60% to 80%. Advanced disease with metastasis carries survival under 20%. Ki-67 index over 10%, positive margins, rupture and stage are the main prognostic factors.

• Many are asymptomatic and incidental. Large tumours cause flank or abdominal pain, early satiety and a palpable mass.
• Hormone excess in a minority: Cushing syndrome (weight gain, hypertension, striae, proximal myopathy), virilisation, feminisation or hyperaldosteronism with hypertension and hypokalaemia.
• Constitutional symptoms (fever, weight loss) and metastases to lung, liver, bone and lymph nodes.

Red flags.

• Hypercortisolism with hypokalaemia, severe hypertension or infection.
• Tumour rupture or haemorrhage, and inferior vena cava involvement.

• Unenhanced CT of the adrenal: heterogeneous mass often over 4 cm, attenuation over 10 Hounsfield units, delayed washout, with necrosis and calcification. MRI or FDG-PET-CT help characterise indeterminate masses and stage disease.
• Hormonal workup before surgery: overnight 1 mg dexamethasone suppression test (with morning cortisol over 50 nmol/L, or 1.8 micrograms/dL, indicating autonomous cortisol), ACTH, DHEA sulphate, androgens, oestradiol, 17-hydroxyprogesterone, plasma aldosterone with renin when hypertension or hypokalaemia is present, and plasma metanephrines to exclude phaeochromocytoma. Urinary steroid profiling (mass spectrometry) when available.
• Staging with CT of the chest, abdomen and pelvis, and bone scan or PET.
• Percutaneous biopsy is avoided for a mass suspected to be resectable (risk of seeding), unless to confirm metastasis. Diagnosis is made on the resected specimen.
• Genetic testing (TP53, Lynch genes, MEN1) and counselling.

Differential diagnosis.

• Adrenocortical adenoma and oncocytoma
• Conventional adrenocortical carcinoma
• Phaeochromocytoma and adrenal metastasis
• Renal cell carcinoma and retroperitoneal sarcoma
• Adrenal lymphoma

Surgery. Open adrenalectomy with en bloc resection of adherent structures and regional lymphadenectomy (an oncological technique avoiding capsule rupture) by a high volume surgeon, for localised disease. Laparoscopic surgery is reserved for small tumours (under 6 cm) without invasion. Perioperative glucocorticoid cover is used when there is cortisol excess.

Adjuvant therapy. Adjuvant mitotane is considered for tumours with higher recurrence risk (Ki-67 over 10%, stage III, positive margins, rupture, large size).

• Mitotane: mitotane 1.5 g orally in 2 to 3 divided doses with fat rich meals, increased every 3 to 7 days to 4 to 6 g daily as tolerated (starting more slowly with gastrointestinal symptoms) to a plasma level of 14 to 20 mg/L, continued for at least 2 to 5 years after surgery for adjuvant treatment; maximum 6 g daily usually (up to 12 g in selected patients); monitoring: plasma mitotane level every 4 to 6 weeks until stable then every 3 months, liver tests, lipids, thyroid function, adrenal insufficiency, gastrointestinal and neurological toxicity; adjustment: reduce the dose or pause for level over 20 mg/L or neurotoxicity, replace glucocorticoid and mineralocorticoid (cover given at the start), expect increased clearance of CYP3A4 substrates (warfarin, many chemotherapy drugs), use non-hormonal contraception, avoid pregnancy for at least 2 years after stopping
• Glucocorticoid replacement during mitotane: hydrocortisone 30 to 50 mg orally daily in 2 to 3 divided doses (for example 20 mg on waking, 10 mg at midday and 10 mg in the late afternoon), started with mitotane because mitotane increases cortisol clearance; maximum about 60 mg daily in routine replacement (double or triple the dose for fever or illness and give intramuscular or IV 100 mg for vomiting or collapse); monitoring: symptoms of adrenal insufficiency or excess, blood pressure, potassium, weight; adjustment: increase the dose with rising mitotane levels, give stress dose cover for surgery and illness, provide a steroid emergency card
• Mineralocorticoid replacement when needed: fludrocortisone 0.05 to 0.2 mg orally once daily, titrated to blood pressure, potassium and plasma renin; maximum 0.3 mg daily; monitoring: seated and standing blood pressure, potassium, oedema, renin; adjustment: reduce for hypertension, hypokalaemia or oedema, increase with salt loss

Radiotherapy. Radiotherapy (about 50 to 60 Gy) to the tumour bed after positive margins or for local control of recurrence, and palliative radiotherapy for bone and symptomatic metastases.

Advanced and metastatic disease.

• Etoposide, doxorubicin and cisplatin with mitotane: etoposide 100 mg/m2 IV on days 2 to 4, doxorubicin 40 mg/m2 IV on day 1 and cisplatin 40 mg/m2 IV on days 3 and 4, every 4 weeks, with mitotane continued at the target level; maximum doxorubicin cumulative 450 mg/m2 and cisplatin 100 mg/m2 each cycle; monitoring: FBC, creatinine, magnesium, echocardiography, audiometry, neuropathy; adjustment: reduce doxorubicin by 50% when bilirubin is 26 to 51 micromol/L and avoid it over 51 micromol/L, give cisplatin only when creatinine clearance is 60 mL/min or more, etoposide 75% of the dose when creatinine clearance is 15 to 50 mL/min and 50% when under 15, expect lower exposure of drugs metabolised by CYP3A4 with mitotane
• Metastasectomy, ablation or embolisation for limited disease. Mitotane may be used alone for slowly progressive disease.

Hormone excess. Medical control of cortisol excess before surgery with steroidogenesis inhibitors is directed by an endocrinologist.

Monitoring. CT of the chest, abdomen and pelvis every 3 months for 2 years, then every 6 months to year 5 (and 10 years in high risk disease). Mitotane level, liver tests, lipids, thyroid function, adrenal function and symptoms of adrenal insufficiency.

Referral and escalation.

• Referral to an adrenal tumour centre on suspicion, before any biopsy or surgery.
• Same day assessment for adrenal insufficiency, hypercortisolism complications or tumour rupture.

Special groups.

• Li-Fraumeni and other syndromes: genetic counselling and surveillance, with avoidance of radiation where possible.
• Pregnancy: mitotane is contraindicated, and management is individualised.
• Women of childbearing age: avoid pregnancy during mitotane and for at least 2 years after it is stopped.