Adrenal carcinoma is a rare, aggressive malignancy characterised by pleomorphic cells with a high mitotic rate and atypical mitoses and appearing as a large invasive, heterogeneous mass with irregular borders.
Description
Adrenal carcinoma is a rare and aggressive malignancy originating from the adrenal cortex. The prognosis is generally poor due to the late stage at diagnosis and aggressive nature.
Pathogenesis
Adrenal carcinomas may be functional (producing hormones) or non-functional. The majority are sporadic, but some cases have genetic predispositions, including Li-Fraumeni syndrome, Beckwith-Wiedemann syndrome, familial adenomatous polyposis, and Lynch syndrome.
Epidemiology, Risk Factors & Associations
Adrenal carcinoma is rare, with an incidence of 1-2 per million population per year. There is a slight female predominance (60%). It has a bimodal age distribution with peaks in childhood and the 4th to 5th decade.
Genetic predispositions are seen in a small number of cases:
- Beckwith-Wiedemann syndrome (5-10%)
- Li-Fraumeni syndrome (1%)
- Familial adenomatous polyposis (<1%)
- Lynch syndrome (<1%)
Subtypes
Adrenal carcinomas may be classified based on their hormonal activity into functional or non-functional types.
- Functional tumours, which account for about 60% of all adrenal carcinomas, produce excess amounts of hormones.
- Non-functional tumours do not produce hormones and often present later due to their larger size or the presence of metastasis.
Clinical Features
The clinical manifestations of adrenal carcinoma can range widely based on the functional status of the tumour.
- Cushing syndrome (50-60% of functional tumours): Characterised by excessive cortisol production leading to weight gain, moon face, abdominal striae, and hypertension.
- Virilisation (20-30% of functional tumours): Occurs due to excess androgen production, causing male-pattern hair growth, deepening of the voice, and menstrual irregularities in females.
- Feminisation (~1% of functional tumours): This is due to excess estrogen production, leading to gynaecomastia and testicular atrophy in males.
- Conn syndrome (~1% of functional tumours): Resulting from excessive aldosterone production, causing hypertension and hypokalemia.
- Non-functional tumours (40%): These tumours do not produce hormones and often present late with non-specific symptoms like abdominal pain or fullness, or with symptoms related to metastatic disease.
Complications
Adrenal carcinoma is associated with a high rate of metastasis at the time of diagnosis. The most common sites of metastasis are the lungs (60%), liver (50%), and lymph nodes (30%). The disease is also associated with significant morbidity due to hormone excess states, local invasion of adjacent organs, and systemic spread.lis
Pathological Features
Histopathology
- Gross: Adrenal carcinomas are often large (mean size 10-12 cm), necrotic tumours with heterogeneous cut surfaces.
- Microscopic: Exhibit high mitotic rates, atypical mitoses, clear evidence of venous invasion, and capsular invasion.
Biochemistry
- In functional adrenal carcinomas, hormone levels such as cortisol, androgens, aldosterone, or oestrogens may be elevated. The specific hormone that is increased often correlates with the patient’s clinical presentation.
Genetics
- IGF2 (Insulin-like Growth Factor 2): Overexpression occurs in up to 90% of cases. A target for therapeutic intervention.
- TP53: Mutations found in approximately 20-25% of adult ACC cases. Associated with aggressive ACC and poorer outcomes.
- CTNNB1 (Cyclin-Dependent Kinase Inhibitor 2A): Mutations detected in about 15-20% of ACCs.
- SF1 (Steroidogenic Factor 1: Amplification observed in 5-10% of cases.
- CDKN2A: Inactivation or deletion is present in around 5% of ACCs.
- MEN1, PRKAR1A, DAXX/ATRX: Alterations are less common, exact percentages vary, more relevant in specific familial syndromes (MEN 1, Carney Complex) or subsets of ACC.
Radiological Features
General Features
- Unilateral adrenal mass with invasive margins. May be bilateral in 10% of cases.
- Functioning tumours: Usually 5 cm at presentation
- Nonfunctioning tumours: ≥ 10 cm
- May demonstrate necrosis, haemorrhagic, cystic areas, calcification.
- May invade renal vein, IVC, adjacent renal parenchyma
- Displaces the splenic vein anteriorly or superiorly
- Masses that displace the splenic vein posteriorly &/or inferiorly are likely of pancreatic or gastric origin.
- Masses that displace the splenic vein anteriorly or superiorly are likely of adrenal, renal, or other retroperitoneal origin.
CT
- Large mass (>4 cm) with heterogeneous enhancement
- Necrosis, haemorrhage, and calcification may be seen
- Typically have high unenhanced CT attenuation (>10 HU)
- Assess IVC for invasion
MRI
- T1: Hypointense adrenal mass relative to liver. Heterogenous signal may indicate necrosis and haemorrhage
- T2: Hyperintense adrenal mass relative to liver. Heterogenous signal may indicate necrosis and haemorrhage
- Contrast enhancement: Heterogeneous enhancement due to tumour necrosis
- In/Out-of-phase: Typically no significant loss of signal on out-of-phase imaging to suggest adrenal adenoma
US
- Heterogeneous appearance due to necrosis, haemorrhage, and cystic degeneration within the tumour
- Hyperechoic or mixed echogenicity
- Poorly defined borders due to invasive nature
NM
- FDG-PET: Given the typically high metabolic rate of adrenal carcinomas, FDG-PET can be useful in detecting metastatic disease. Lesions with high FDG uptake may suggest malignancy.
- MIBG (metaiodobenzylguanidine) scintigraphy: Adrenal carcinomas are generally less avid for MIBG than benign adrenal tumours, although exceptions exist. Therefore, a positive MIBG scan does not exclude the diagnosis of adrenal carcinoma.
- Octreotide scintigraphy: It is used less commonly and might be used when other more specific nuclear medicine studies are non-diagnostic. It might show increased uptake in the tumour due to somatostatin receptor expression.
- Ga-68 DOTATATE PET/CT: This form of imaging is based on the expression of somatostatin receptors and might be used when other forms of imaging are non-diagnostic or inconclusive.
Grading and Staging
The most commonly used staging system for adrenal carcinoma is the TNM system.
Diagnosis
- The definitive diagnosis of ACC is made post-surgically based on histopathological criteria, including the Weiss criteria, which assess architectural and cytological features of the tumour.
- Percutaneous biopsy is unreliable due to necrosis and not recommended due to the risk of needle track seeding. It may be considered for metastatic disease.
Differential Diagnosis
- Adrenal adenoma: Adenomas are typically smaller (mean size <4 cm), homogeneous, and exhibit lower unenhanced CT attenuation (<10 HU). Can degenerate but mimic ACC.
- Adrenal metastasis: Metastases should be suspected in patients with a history of malignancy, especially if the adrenal lesion is bilateral.
- Pheochromocytoma: This condition often presents with symptoms of catecholamine excess and shows a high signal on T2-weighted MRI images. A neoplastic lesion with large cystic region favours pheochromocytoma over adrenal carcinoma.
Management
- The management of adrenal carcinoma typically involves surgery for localised disease.
- For those with complete resection, adjuvant therapy with mitotane may improve outcomes.
- For patients with metastatic or unresectable disease, systemic therapies including mitotane, chemotherapy, and targeted therapy may be used.
- Given the complexity of this disease, patients should be managed by a multidisciplinary team experienced in adrenal malignancies.