Adrenocortical carcinoma (ACC) is an aggressive cancer originating in the cortex (steroid hormone-producing tissue) of the adrenal gland.
Adrenocortical carcinoma is remarkable for the many hormonal syndromes that can occur in patients with steroid hormone-producing ("functional") 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.
Adrenocortical carcinoma can occur at any age, with the highest incidence between 40 and 60 years of age. Women are more frequently affected (55 to 60%) than men (40 to 45%). Adrenocortical carcinomas usually occur sporadically in adults. However, they sometimes occur as part of hereditary syndromes, such as:
- Li-Fraumeni syndrome
- Lynch syndrome
- Multiple endocrine neoplasia (MEN)
- Familial adenomatous polyposis (see also adenomatosis) Nonfunctional tumors (about 40%, authorities vary) usually present with abdominal or flank pain, varicocele, and renal vein thrombosis or they may be asymptomatic and detected incidentally.
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.
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
Incidental discovery
Approximately 30% of adrenal gland carcinomas are diagnosed incidentally (incidentalomas). However, the probability that an adrenal gland incidentaloma is a carcinoma of the adrenal cortex is very low. Adenomas are much more common in this situation. Other benign or malignant tumors can also be the underlying cause. Online open-access datasets of adrenocortical carcinoma CT examinations are available.
On MRI, it shows low intensity on T1-weighted images, and high T2 signal with strong heterogeneous contrast enhancement and slow washout. Haemorrhagic areas may show high T1-signal. <sup>11</sup>C-labelled metomidate binds to enzymes expressed in adrenocortical cells and has been used as a radiotracer with high specificity for adrenal tumors.
Pathology
thumb|right|[[gross pathology|Gross view of a large ACC]]
thumb|Cell-block preparation from a fine-needle aspiration biopsy of a large ACC shows tumor cells with compact, eosinophilic cytoplasm and a mild degree of nuclear pleomorphism.
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. with adrenocortical carcinoma at top.]]
Differential diagnosis includes:
- Adrenocortical adenoma
- Renal cell carcinoma
- Pheochromocytoma
- Hepatocellular carcinoma
Adrenocortical carcinomas are most commonly distinguished from adrenocortical adenomas (their benign counterparts) by the Weiss system, as follows:
{|class="wikitable"
! Characteristic || 1
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| More mitoses than 5/50 high power fields || 1
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| Atypical mitoses || 1
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| Eosinophilic cytoplasm in >75% of tumor cells || 1
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| Diffuse architecture of >33% of tumor || 1
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| Necrosis || 1
|-
| Venous invasion || 1
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| Sinusoidal invasion (no smooth muscle in wall) || 1
|-
| Capsular invasion || 1
|}
Total score indicates: with an overall 5-year survival rate of about 50%. For outcomes such as all-cause mortality, early morbidity, socioeconomic effects, and operative and postoperative parameter, the evidence is uncertain about the effects of either interventions over the other. 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 (EDP) + 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. The prognosis is poor. There are currently no established standards for diagnosis and treatment. Therefore, the "ENSAT kids" study group was established for children with adrenocortical carcinoma within ENSAT. While only a proportion of adrenocortical carcinomas in adults are hormonally active, almost all of these carcinomas are hormonally active in affected children. Cushing's syndrome, precocious puberty, or virilization usually occur. As with the treatment of adult patients, the tumor is completely removed surgically. If an advanced stage is present, lymph nodes are also removed in children, and chemotherapy and mitotane therapy are administered.
State of research
Approximately 70% of affected children are female. Of these, about 90% are hormone-active carcinomas.
- 50% androgens
- 30% mixed
- 10% steroids
- 10% hormone-inactive
The average time from the onset of symptoms to diagnosis is six months. Approximately 70% of tumors can be completely removed surgically.
The current state of research is considered insufficient. The few available comparisons between adrenocortical carcinomas in adults and children indicate significant differences. Therefore, findings obtained so far in adults cannot be readily applied to children. To close these knowledge gaps and to be able to determine suitable therapies for children, a better molecular biological understanding of the prognosis and tumor biology of adrenocortical tumors in children is needed.
Currently, the main research questions are:
- Clinical: International assessment of diagnostics and therapy with the aim of improving clinical understanding and treatment procedures.
- Clinical-translational: Analysis of the significance of plasma and urine steroid profiles / liquid biopsy with the aim of identifying suitable tumor markers.
- Experimental: Identification of immunohistochemical characteristics and DNA sequencing with the aim of identifying drugable targets, i.e., targets for the drug treatment of tumor cells. This should ensure that healthy cells are spared from the drug as much as possible.