Adrenal: Malignant Tumours

Adrenal cortical carcinoma (ACC)

Pathogenesis

• Classification: genetic vs. sporadic
• Sporadic
  • Cause of sporadic ACC remains unknown
• Genetic
  • Syndromes associated with ACC (6):
    1. Li-Fraumeni syndrome
    2. Beckwith-Wiedemann syndrome
    3. Lynch syndrome
    4. Carney complex
    5. MEN-1
    6. McCune-Albright syndrome

Diagnosis and Evaluation

History and Physical Exam

• History
  • Symptoms can be secondary to local or systemic disease burden and/or hypersecretion of adrenal hormones.
    • ACCs associated with hypersecretion of adrenal hormones are characterized as being functional.
      • Most ACCs will be functional at the time of presentation and the most common hormone secreted is cortisol

Laboratory

• Evaluating the functional status of adrenal tumors suspicious for ACC is essential, not only for making the diagnosis of ACC but also for consideration of postoperative cortisol replacement and the potential use of tumor-secreted hormones as markers during postoperative surveillance.
• When considering the functional status of a tumor that raises suspicion for ACC, glucocorticoid, mineralocorticoid, catecholamine, sexual steroid, and steroid precursor excesses should be evaluated

Imaging

• In incidentally detected adrenal tumors, size is a relative indicator of malignancy
  • Risk of malignancy based on tumour size:
    • < 4 cm: 5%
    • > 4 cm: 10%
    • > 6 cm: 25%
    • Given the relationship between size and malignancy, it is currently recommended that adrenal tumors > 4-6 cm be surgically excised
  • ACCs tend to be larger than benign adrenal tumors, with an average size of 10-12 cm on presentation
• Radiographic characteristics of ACCs on CT imaging (5):
  1. Irregular borders
  2. Heterogenous enhancement
  3. Increased enhancement (mean 39 HU) compared to adenoma (8 HU)
  4. Calcifications
  5. Necrotic areas with cystic degeneration
• MRI§
  • Normal adrenal gland
    • TI: uniform intermediate signal intensity that is slightly less intense than that of the liver and renal cortical tissue
    • T2: difficult to distinguish from retroperitoneal adipose tissue because of the presence of intracellular lipid with the gland
  • Myelolipoma
    • T1: bright
    • T2: intermediate
  • ACCs
    • T1: isointense relative to the liver or spleen
    • T2: intermediate to increased intensity
    • Marked contrast uptake on gadolinium-enhanced images
  • Pheochromocytoma
    • Classically, bright signal intensity on T2-weighted imaging (best seen on fat suppression sequences)—termed the “light bulb” sign—was believed to be diagnostic. It is now clear that this imaging characteristic is neither specific nor sensitive enough to secure a diagnosis and must be interpreted with caution

Other

• Percutaneous needle biopsy is usually not performed before surgical excision owing to a clinically unacceptable risk of needle-tract seeding.
  • In cases of surgically resectable disease, the information obtained from biochemical and radiographic evaluation should be enough to justify extirpation.

Pathology

• Modified Weiss criteria (5):§ Necrotic ACC Metastasizes
  1. Necrosis
  2. Abnormal mitoses
  3. Cytoplasm (clear cells comprising ≤25% of the tumor)
  4. Capsular invasion
  5. Mitotic rate > 5 per 50 high power fields
  • Calculate: 2x mitotic rate criterion + 2x clear cytoplasm criterion + abnormal mitoses + necrosis + capsular invasion (score of 3 or more suggests malignancy)
• Traditional Weiss criteria:
  • Abnormal mitoses
  • Mitotic rate >5/hpf
  • Diffuse Architecture of tumor cells
  • Clear cells ≤25%
  • Capsular/sinusoidal/venous invasion
  • Furman grade (3 to 4)
  • Necrosis

Management

• Multimodal treatment, surgical resection, radiation therapy, and systemic chemotherapy are often necessary
• Systemic chemotherapy
  • Mitotane
    • Oral synthetic derivative of the insecticide dichlorodiphenyltrichloroethane (DDT)
    • Mechanism of action: inhibits several enzymes of the adrenal cortex including 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
    • Most commonly used chemotherapeutic agent in the treatment of adrenal cortical carcinoma

Prognosis

• Despite aggressive surgical resection, adrenal carcinoma is associated with a high rate (60-80%) of recurrent disease
• Factors associated with recurrence-free survival
  • Tumor size
  • Nodal status
  • T stage
  • Functional activity
  • Capsular invasion
• Local and systemic adjuvant therapy is often administered despite any clear evidence demonstrating improved survival
• Factors associated with overall survival
  • Margins status (most important)
  • Tumor size
  • Nodal status

Metastases

• Metastatic disease to the adrenals is common
• In patients with a history of a previous malignancy, >50% of newly discovered adrenal lesions are metastatic; nevertheless, metabolic workup in these patients 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 tumor.

Questions

1. List syndromes associated with increased risk of adrenal cortical carcinoma
2. What percentage of adrenal tumours >4cm are malignant? >6cm?
3. List radiographic characteristics of ACC on CT imaging
4. What is the most common hormone secreted by ACC?

Answers

1. List syndromes associated with increased risk of adrenal cortical carcinoma
2. What percentage of adrenal tumours >4cm are malignant? >6cm?
3. List radiographic characteristics of ACC on CT imaging
4. What is the most common hormone secreted by ACC?
   • Cortisol

References

• Wein AJ, Kavoussi LR, Partin AW, Peters CA (eds): CAMPBELL-WALSH UROLOGY, ed 11. Philadelphia, Elsevier, 2015, chap 65