Pathogenesis
Adrenal cortical carcinoma (ACC) is classified as sporadic or genetic.
- Sporadic — the cause remains unknown.
- Genetic — syndromes associated with ACC (6): Li-Fraumeni, Beckwith-Wiedemann, Lynch, Carney complex, MEN-1, and McCune-Albright.
Diagnosis and Evaluation
History and Physical Exam
Symptoms can be secondary to local or systemic disease burden and/or hypersecretion of adrenal hormones; ACCs with hormone hypersecretion are characterized as functional. Most ACCs are functional at presentation, and the most common hormone secreted is cortisol.
Laboratory
Evaluating the functional status of tumours suspicious for ACC is essential — for making the diagnosis, for considering postoperative cortisol replacement, and for using tumour-secreted hormones as markers during postoperative surveillance. Assess for excesses of glucocorticoid, mineralocorticoid, catecholamine, sexual steroid, and steroid precursor.
Imaging
In incidentally detected adrenal tumours, size is a relative indicator of malignancy:
| Tumour size | Risk of malignancy |
|---|---|
| < 4 cm | 5% |
| > 4 cm | 10% |
| > 6 cm | 25% |
Given this relationship, adrenal tumours > 4–6 cm are currently recommended for surgical excision. ACCs tend to be larger than benign adrenal tumours, averaging 10–12 cm at presentation.
Radiographic characteristics of ACC on CT (5): irregular borders, heterogeneous enhancement, increased enhancement (mean 39 HU vs 8 HU for adenoma), calcifications, and necrotic areas with cystic degeneration.
MRI signal characteristics:
| Lesion | T1 | T2 |
|---|---|---|
| Normal adrenal gland | Uniform intermediate signal, slightly less intense than liver and renal cortex | Difficult to distinguish from retroperitoneal fat (intracellular lipid in the gland) |
| Myelolipoma | Bright | Intermediate |
| ACC | Isointense to liver or spleen; marked uptake on gadolinium-enhanced images | Intermediate to increased intensity |
| Pheochromocytoma | — | Classically bright ("light bulb" sign, best on fat-suppression sequences) — now known to be neither specific nor sensitive enough to be diagnostic; interpret with caution |
Other
Percutaneous needle biopsy is usually not performed before surgical excision, owing to a clinically unacceptable risk of needle-tract seeding. In surgically resectable disease, biochemical and radiographic evaluation should be enough to justify extirpation.
Pathology
Modified Weiss criteria (5) — mnemonic "Necrotic ACC Metastasizes":
- Necrosis
- Abnormal mitoses
- Cytoplasm (clear cells comprising ≤25% of the tumour)
- Capsular invasion
- Mitotic rate > 5 per 50 high-power fields
Score = (2× mitotic-rate criterion) + (2× clear-cytoplasm criterion) + abnormal mitoses + necrosis + capsular invasion; a score of 3 or more suggests malignancy.
Traditional Weiss criteria: abnormal mitoses, mitotic rate >5/hpf, diffuse architecture of tumour cells, clear cells ≤25%, capsular/sinusoidal/venous invasion, Fuhrman grade 3–4, and necrosis.
Management
Multimodal treatment — surgical resection, radiation therapy, and systemic chemotherapy — is often necessary.
- Mitotane — an oral synthetic derivative of the insecticide dichlorodiphenyltrichloroethane (DDT) and the most commonly used chemotherapeutic agent for ACC. It inhibits several adrenal-cortex enzymes: the cholesterol side-chain cleavage enzyme (P450scc, CYP11A1), 11β-hydroxylase (CYP11B1), 18-hydroxylase (aldosterone synthase, CYP11B2), and 3β-hydroxysteroid dehydrogenase (3β-HSD) to a lesser extent.
Prognosis
Despite aggressive surgical resection, ACC carries a high rate (60–80%) of recurrent disease.
- Factors associated with recurrence-free survival: tumour size, nodal status, T stage, functional activity, and capsular invasion. Local and systemic adjuvant therapy is often administered despite no clear evidence of improved survival.
- Factors associated with overall survival: margin status (most important), tumour size, nodal status, and metastases.
Metastatic disease to the adrenals is common: in patients with a history of previous malignancy, >50% of newly discovered adrenal lesions are metastatic — nevertheless, metabolic work-up is recommended. Bilateral and bulky disease (>4 cm) is necessary to produce biochemical evidence of adrenal insufficiency. Current imaging modalities, supplemented by adrenal biopsy when necessary, can frequently differentiate metastases from a primary adrenal tumour.
Self-Test
1. List syndromes associated with an increased risk of adrenal cortical carcinoma. Li-Fraumeni, Beckwith-Wiedemann, Lynch, Carney complex, MEN-1, and McCune-Albright.
2. What percentage of adrenal tumours >4 cm are malignant? >6 cm? About 10% of tumours >4 cm, and about 25% of tumours >6 cm.
3. List the radiographic characteristics of ACC on CT. Irregular borders, heterogeneous enhancement, increased enhancement (mean 39 HU vs 8 HU for adenoma), calcifications, and necrotic areas with cystic degeneration.
4. What is the most common hormone secreted by ACC? Cortisol.