Adrenocortical carcinoma
Adrenocortical carcinoma is an aggressive cancer originating in the cortex of the adrenal gland.
Adrenocortical carcinoma is remarkable for the many hormonal syndromes that can occur in patients with steroid hormone-producing tumors, including Cushing's syndrome, Conn syndrome, virilization, and feminization. Adrenocortical carcinoma has often invaded nearby tissues or metastasized to distant organs at the time of diagnosis, and the overall 5-year survival rate is about 50%.
Adrenocortical carcinoma is a rare tumor, with incidence of one to two per million population annually. It has a bimodal distribution by age, with cases clustering in children under 5 and in adults 30–40 years old. The widely used angiotensin-II-responsive steroid-producing cell line H295R was originally isolated from a tumor diagnosed as adrenocortical carcinoma.
Signs and symptoms
Adrenocortical carcinoma may present differently in children and adults. Most tumors in children are functional, and virilization is by far the most common presenting symptom, followed by Cushing's syndrome and precocious puberty. Among adults presenting with hormonal syndromes, Cushing's syndrome alone is most common, followed by mixed Cushing's and virilization. Feminization and Conn syndrome occur in less than 10% of cases. Rarely, pheochromocytoma-like hypersecretion of catecholamines has been reported in adrenocortical cancers. Nonfunctional tumors usually present with abdominal or flank pain, varicocele, and renal vein thrombosis or they may be asymptomatic and detected incidentally.All patients with suspected ACC should be carefully evaluated for signs and symptoms of hormonal syndromes. For Cushing's syndrome, these include weight gain, muscle wasting, purple lines on the abdomen, a fatty "buffalo hump" on the neck, a "moon-like" face, and thinning, fragile skin. Virilism is most obvious in women, and may produce excess facial and body hair, acne, enlargement of the clitoris, deepening of the voice, coarsening of facial features, cessation of menstruation. Conn syndrome is marked by high blood pressure, which can result in headache and hypokalemia, low plasma renin activity, and high serum aldosterone. Feminization is most readily noted in men, and includes breast enlargement, decreased libido, and impotence.
Pathophysiology
The main etiologic factor of ACC is unknown, although families with Li–Fraumeni syndrome, caused by an inherited inactivation mutation in TP53, have increased risk. Several genes have been shown to be recurrently mutated, including TP53, CTNNB1, MEN1, PRKAR1A, RPL22, and DAXX. The telomerase gene TERT is often amplified while ZNRF3 and CDKN2A are often homozygously deleted. The genes h19, insulin-like growth factor II, and p57kip2 are important for fetal growth and development. They are located on chromosome 11p. Expression of the h19 gene is markedly reduced in both nonfunctioning and functioning adrenal cortical carcinomas, especially in tumors producing cortisol and aldosterone. Also, a loss occurs of activity of the p57kip2 gene product in virilizing adenomas and adrenal cortical carcinomas. In contrast, IGF-II gene expression has been shown to be high in adrenal cortical carcinomas. Finally, c-myc gene expression is relatively high in neoplasms, and it is often linked to poor prognosis.Bilateral adrenocortical tumors are less common than unilateral. The majority of bilateral tumours can be distinguished according to size and aspect of the nodules: primary pigmented nodular adrenocortical disease, which can be sporadic or part of Carney complex, and primary bilateral macro nodular adrenal hyperplasia.
Metastasis is most commonly to the liver and lung.
Diagnosis
Laboratory findings
Hormonal syndromes should be confirmed with laboratory testing. Laboratory findings in Cushing syndrome include increased serum glucose and increased urine cortisol. Adrenal virilism is confirmed by the finding of an excess of serum androstenedione and dehydroepiandrosterone. Findings in Conn syndrome include low serum potassium, low plasma renin activity, and high serum aldosterone. Feminization is confirmed with the finding of excess serum estrogen.Radiology
Radiological studies of the abdomen, such as CT scans and magnetic resonance imaging are useful for identifying the site of the tumor, differentiating it from other diseases, such as adrenocortical adenoma, and determining the extent of invasion of the tumor into surrounding organs and tissues. CT scans of the chest and bone scans are routinely performed to look for metastases to the lungs and bones, respectively. These studies are critical in determining whether or not the tumor can be surgically removed, the only potential cure at this time.Pathology
Adrenal tumors are often not biopsied prior to surgery, so diagnosis is confirmed on examination of the surgical specimen by a pathologist. Grossly, ACCs are often large, with a tan-yellow cut surface, and areas of hemorrhage and necrosis. On microscopic examination, the tumor usually displays sheets of atypical cells with some resemblance to the cells of the normal adrenal cortex. The presence of invasion and mitotic activity help differentiate small cancers from adrenocortical adenomas.Several relatively rare variants of ACC include:
- Oncocytic adrenal cortical carcinoma
- Myxoid adrenal cortical carcinoma
- Carcinosarcoma
- Adenosquamous adrenocortical carcinoma
- Clear cell adrenal cortical carcinoma
Differential diagnosis
Adrenocortical carcinomas are most commonly distinguished from adrenocortical adenomas by the Weiss system, as follows:
| Characteristic | Score |
| High nuclear grade | 1 |
| More mitoses than 5/50 high power fields | 1 |
| Atypical mitoses | 1 |
| Eosinophilic cytoplasm in >75% of tumor cells | 1 |
| Diffuse architecture of >33% of tumor | 1 |
| Necrosis | 1 |
| Venous invasion | 1 |
| Sinusoidal invasion | 1 |
| Capsular invasion | 1 |
Total score indicates:
- 0-2: Adrenocortical adenoma
- 3: Undetermined
- 4-9: Adrenocortical carcinoma
Treatment
Chemotherapy regimens typically include the drug mitotane, an inhibitor of steroid synthesis, which is toxic to cells of the adrenal cortex, as well as standard cytotoxic drugs. A retrospective analysis showed a survival benefit for mitotane in addition to surgery when compared to surgery alone.
The two most common regimens are cisplatin, doxorubicin, etoposide + mitotane, and streptozotocin + mitotane. The FIRM-ACT trial demonstrated higher rates of response and longer progression-free survival with EDP + mitotane than with streptozotocin + mitotane.
Prognosis
ACC, generally, carries a poor prognosis, with an overall 5-year survival rate of about 50%. Five-year disease-free survival for a complete resection of a stage I–III ACC is about 30%. The most important prognostic factors are age of the patient and stage of the tumor. Poor prognostic factors include mitotic activity, venous invasion, weight of 50 g or more, diameter of 6.5 cm or more, Ki-67/MIB1 labeling index of 4% or more, and p53 positive.In its malignancy, adrenocortical carcinoma is unlike most tumours of the adrenal cortex, which are benign and only occasionally cause Cushing's syndrome.