Adrenal gland disorders - adrenal carcinoma
Description
- Rare, aggressive malignancy of the adrenal cortex
- ~60% are hormonally functional at diagnosis
- Cortisol alone ~50-80% of functional tumours
- Cortisol + androgen mixed secretion is highly suggestive of ACC (an adenoma rarely does both)
- Androgen alone -> virilisation in women
- Oestrogen -> gynaecomastia in men (near-diagnostic of ACC)
- Aldosterone rarely
- Any adrenal mass >4 cm is ACC until proven otherwise
Size and imaging thresholds
| <4 cm, HU <=10, homogeneous | Almost certainly a benign adenoma |
| >4 cm | ~70% of ACCs; malignancy risk rises steeply |
| >6 cm | Resect |
| Unenhanced CT >10 HU + absolute washout <60% / relative <40% | Lipid-poor -> ACC, phaeo or metastasis |
Epidemiology
- 0.7-2 per million per year - among the rarest adult cancers
- Bimodal: small peak in childhood (<5 yr), main peak 40-50s
- F>M ~1.5:1 (women more often functional)
- ~50-70% present with stage III-IV
- Southern Brazil: markedly higher paediatric incidence from a founder TP53 R337H mutation
Aetiopathogenesis
Molecular
- TP53 loss (somatic and germline), CTNNB1/Wnt-beta-catenin activation, IGF2 overexpression (11p15 loss of imprinting - the commonest event)
- ZNRF3 deletion, MEN1, CDKN2A
Hereditary syndromes - always ask
- Li-Fraumeni (TP53) - offer germline testing to all paediatric and young-adult ACC
- Beckwith-Wiedemann (11p15)
- Lynch syndrome (MMR) - up to 3% of ACC; test MMR/MSI
- MEN1, FAP, Carney complex, neurofibromatosis type 1
Steroid pattern as a clue
- Inefficient, disordered steroidogenesis -> precursor excess
- Raised DHEAS, 17-OH-progesterone, androstenedione, 11-deoxycortisol
- Urine steroid metabolomics (LC-MS/MS) can discriminate ACC from adenoma
- A very high DHEAS with a suppressed ACTH points to ACC, not an adenoma
Diagnosis
Hormonal workup - before any biopsy or surgery
- Exclude phaeochromocytoma FIRST: plasma free or 24-hr urinary metanephrines
- Operating on an unblocked phaeo is lethal
- Cortisol autonomy: 1 mg overnight dexamethasone suppression (fail if cortisol >50 nmol/L), ACTH, midnight salivary cortisol, 24-hr UFC
- Androgens: DHEAS, testosterone, androstenedione, 17-OH-progesterone; oestradiol in men/postmenopausal women
- Aldosterone:renin ratio if hypertensive or hypokalaemic
Imaging
- CT adrenal protocol with washout - the key test
- MRI with chemical shift; FDG PET for staging (ACC is FDG-avid)
- Look for: size >4 cm, irregular margins, heterogeneity, necrosis/haemorrhage, calcification, local invasion, IVC tumour thrombus, lymph nodes, liver/lung metastases
Do NOT biopsy
- Biopsy is contraindicated unless metastatic disease needs histology and phaeo is excluded
- Cannot distinguish adenoma from carcinoma (that requires the intact capsule)
- Risks tumour seeding along the needle tract
Histology
- Weiss score >=3 of 9 = carcinoma (high nuclear grade, mitoses >5/50 HPF, atypical mitoses, <25% clear cells, diffuse architecture, necrosis, venous/sinusoidal/capsular invasion)
- Ki-67 is the key prognostic index (and drives adjuvant decisions)
- IHC: SF-1 positive (confirms adrenocortical origin), inhibin, melan-A; chromogranin negative
Staging - ENSAT
| I | <=5 cm, confined |
| II | >5 cm, confined |
| III | Local invasion, positive nodes, or tumour thrombus |
| IV | Distant metastases |
Management
1. Surgery - the only curative option
- Open en-bloc R0 resection by a high-volume adrenal surgeon
- Laparoscopic approach risks capsular rupture and peritoneal seeding - avoid if ACC suspected or tumour >6 cm
- Resect locally invaded organs and IVC thrombus as needed
- Post-operatively, cortisol-secreting tumours need glucocorticoid replacement - the contralateral adrenal is suppressed for months
2. Adjuvant therapy - by recurrence risk
- Low/intermediate risk (R0, stage I-III, Ki-67 <=10%) -> surveillance
- ADIUVO showed no clear survival benefit from adjuvant mitotane in this group - a change from earlier practice
- High risk (R1/Rx resection, stage III, Ki-67 >10%) -> adjuvant mitotane for ~2 years
- +/- adjuvant radiotherapy to the tumour bed for R1/Rx
3. Advanced/metastatic disease
- Mitotane - adrenolytic; targets zona fasciculata/reticularis
- Therapeutic range 14-20 mg/L - narrow, takes weeks to reach; measure levels
- Causes adrenal insufficiency in everyone -> obligatory glucocorticoid replacement at 2-3x the usual dose (mitotane induces CYP3A4 and raises CBG), plus fludrocortisone if needed
- Toxicity: GI, neurological (ataxia, confusion), hepatic, hypercholesterolaemia, hypothyroidism, hypogonadism
- Potent CYP3A4 inducer - reduces the efficacy of many co-prescribed drugs
- EDP-M (etoposide, doxorubicin, cisplatin + mitotane) - first-line for progressive metastatic disease (FIRM-ACT)
- Second-line: streptozocin-mitotane, gemcitabine-capecitabine, trials
- Immunotherapy responses are modest; check MMR/MSI and TMB
4. Control the hypercortisolism - it kills before the tumour does
- Steroidogenesis inhibitors: metyrapone (11-beta-hydroxylase), ketoconazole (multiple steps, hepatotoxic), osilodrostat, etomidate infusion in crisis
- Mifepristone - a glucocorticoid RECEPTOR antagonist, not a steroidogenesis inhibitor
- For hypercortisolism from ACC or ectopic ACTH, especially with diabetes
- *Cortisol levels are useless for monitoring* - titrate to clinical effect and glucose
- Hypokalaemia (cortisol spillover onto MR), endometrial thickening, abortifacient
- Treat the consequences: hypokalaemia, hyperglycaemia, hypertension, VTE prophylaxis, PJP prophylaxis if UFC very high or on prolonged steroid excess
Follow-up
- CT chest/abdomen/pelvis every 3 months for 2 years, then less often, to 5-10 years
- Repeat hormonal markers that were elevated at diagnosis
Associations
- Li-Fraumeni syndrome (TP53) - germline testing in all young patients
- Beckwith-Wiedemann syndrome
- Lynch syndrome, MEN1, FAP, Carney complex, neurofibromatosis type 1
- Cushing syndrome, virilisation, feminisation, hyperaldosteronism
- Adrenal incidentaloma (the usual route to diagnosis)
- Paraneoplastic hypoglycaemia from IGF-2 secretion
Natural history & complications
- 5-year overall survival ~35-40%, strongly stage-dependent
| ENSAT stage | 5-yr survival |
|---|---|
| I-II | ~60-80% |
| III | ~35-50% |
| IV | <15% (median ~12-15 months) |
- Recurrence after R0 resection ~50-70%, usually within 2 years
- Prognostic drivers: stage, resection margin, Ki-67, cortisol secretion (functional tumours do worse)
Complications
- Metastases: liver, lung, bone, peritoneum
- Uncontrolled hypercortisolism -> infection (the commonest cause of death in secretory ACC), VTE, myopathy, psychosis, fracture
- Post-operative and mitotane-induced adrenal insufficiency - lifelong education, sick-day rules, emergency hydrocortisone
- IVC obstruction, local recurrence with retroperitoneal invasion
🔒
6 more sections, plus exam facts
Premium unlocks every note across every specialty, and the full exam fact library behind it.
Get premium access