Adrenocortical carcinoma (ACC) is a rare and heterogeneous malignancy with incompletely understood pathogenesis and poor prognosis. Patients present with hormone excess (e.g. virilization, Cushing’s syndrome) or a local mass effect (median tumor size at diagnosis > 10 cm). This paper reviews current diagnostic and therapeutic strategies in ACC.

Evidence Acquisition: Original articles and reviews were identified using a PubMed search strategy (http://www.ncbi.nlm.nih.gov/entrez/query.fcgi) covering the time period up until November 2005. The following search terms were used in varying combinations: adrenal, adrenocortical, cancer, carcinoma, tumor, diagnosis, imaging, treatment, radiotherapy, mitotane, cytotoxic, surgery.

Evidence synthesis: Tumors typically appear inhomogeneous in both computerized tomography and magnetic resonance imaging with necroses and irregular borders and differ from benign adenomas by their low fat content. Hormonal analysis reveals evidence of steroid hormone secretion by the tumor in the majority of cases, even in seemingly hormonally inactive lesions. Histopathology is crucial for the diagnosis of malignancy and may also provide important prognostic information. In stages I–III open surgery by an expert surgeon aiming at an R0 resection is the treatment of choice. Local recurrence is frequent, particularly after violation of the tumor capsule. Surgery also plays a role in local tumor recurrence and metastatic disease. In patients not amenable to surgery, mitotane (alone or in combination with cytotoxic drugs) remains the treatment of choice. Monitoring of drug levels (therapeutic range 14–20 mg/liter) is mandatory for optimum results. In advanced disease, the most promising therapeutic options (etoposide, doxorubicin, cisplatin plus mitotane, and streptozotocin plus mitotane) are currently being compared in an international phase III trial (www.firm-act.org). Adjuvant treatment options after complete tumor removal (e.g. mitotane, radiotherapy) are urgently needed because postoperative disease-free survival at 5 yr is only around 30%, but options have still not been convincingly established. National registries, international cooperations, and trials provide important new structures for patients but also for researchers aiming at systematic and continuous progress in ACC. However, future advances in the management of ACC will mainly depend on a better understanding of the molecular pathogenesis facilitating the use of modern cancer treatments (e.g. tyrosine kinase inhibitors).

ADRENOCORTICAL TUMORS ARE common tumors with a prevalence of at least 3% in a population over the age of 50 yr (1, 2). In contrast, adrenocortical carcinoma (ACC) is a rare malignancy (incidence 1–2 per 1 million population) with a heterogeneous presentation and a variable but generally poor prognosis (3, 4, 5). However, data on incidence are mainly based on the National Cancer Institute survey from the early 1970s and probably underestimate the true incidence. An exceptionally high annual incidence of ACC has been reported for children in southern Brazil (3.4–4.2 per 1 million children vs. an estimated worldwide incidence of 0.3 per 1 million children younger than 15 yr) and is related to a TP53 tumor suppressor gene mutation (6, 7, 8). Women are more often affected than men (ratio 1.5) (9, 10, 11, 12). The age distribution is reported as bimodal with a first peak in childhood and a second higher peak in the fourth and fifth decade (4, 12).

The molecular pathogenesis of ACC has been the topic of recent reviews (13, 14, 15, 16) but is still poorly understood. It is unclear whether ACCs evolve from adrenal adenomas after a second hit paradigm. Although such a sequence has been observed in occasional cases (17, 18), long-term follow-up data of incidentally discovered adrenal neoplasms suggest otherwise (19, 20, 21). Inactivating mutations at the 17p13 locus including the TP53 tumor suppressor gene and alterations of the 11p15 locus leading to IGF-II overexpression are frequently observed. In vitro experiments suggest that overexpressed IGF-II acting via the IGF-I receptor is relevant for adrenal cancer cell proliferation (22, 23, 24). Thus, the IGF-II IGF-I receptor pathway is a promising target for future therapies in ACC (25).

Patients present with evidence of adrenal steroid hormone excess in approximately 60% of cases. Rapidly progressing Cushing’s syndrome with or without virilization is the most frequent presentation. In patients from the German ACC Registry, autonomous cortisol secretion, either alone or in combination with other steroids, was detectable in 60% of the cases in which hormonal analysis had been performed prior to surgery (12). However, not in all of these cases was autonomous cortisol secretion clinically suspected. Androgen-secreting ACCs in women induce hirsutism and virilization with deepening of the voice, male pattern baldness, and oligoamenorrhea. Estrogen-secreting adrenal tumors in males lead to gynecomastia and testicular atrophy and are almost invariably malignant (26). High concentration of dehydroepiandrosterone sulfate (DHEA-S) is another clue suggesting ACC, whereas decreased serum DHEA-S concentrations are suggestive of a benign adenoma (26). Aldosterone-producing adrenocortical carcinomas present with hypertensionand pronounced hypokalemia (mean serum potassium 2.3 ± 0.08 mmol/liter) (27). However, severe hypokalemia is more likely caused by grossly elevated cortisol secretion, leading to insufficient renal cortisol inactivation by 11ß-hydroxysteroid dehydrogenase type 2 with consecutive activation of the mineralocorticoid receptor.

In many patients with a seemingly hormonally inactive ACC, high concentrations of steroid precursors like androstenedione or 17-hydroxyprogesterone can often be demonstrated, thereby establishing the adrenocortical origin of the tumor.

Hormonally inactive ACCs usually present with abdominal discomfort (nausea, vomiting, abdominal fullness) or back pain caused by a mass effect of the large tumor. In the Italian survey on adrenal incidentaloma, the occurrence of pain was significantly associated with ACC and was not fully explained by large tumor size per se (28). However, an increasing percentage of ACCs is discovered as incidentaloma during abdominal imaging (28, 29, 30, 31).

Only occasionally patients present with fever, weight loss, and anorexia, and it is a remarkable feature of non-cortisol-producing ACC that well-being is often little affected by even a large tumor burden.

Hormonal work-up

Careful endocrine assessment is mandatory prior to surgery in ACC (Table 1). The pattern of hormone secretion may point to the malignant potential of the lesion (e.g. estradiol in males, high concentration of serum DHEA-S, or secretion of steroid precursors) and may thus affect surgical strategy (open instead of minimal invasive surgery). In addition, autonomous cortisol secretion by the tumor is associated with the risk of postoperative adrenal insufficiency. Due to the variable hypercortisolemia and the rapid development of ACC, clinical features of Cushing’s syndrome are often incomplete or even missing (atypical or subclinical Cushing’s syndrome). To establish tumor markers for monitoring of tumor recurrence, a thorough hormonal work-up is essential. Finally, it is important to exclude a pheochromocytoma prior to surgery because imaging often cannot reliably differentiate between ACC and pheochromocytoma (26).

Imaging

Both size and appearance of an adrenal mass on computerized tomography (CT), magnetic resonance imaging (MRI), and more recently ¹⁸F-fluorodeoxyglucose positron emission tomography (FDG-PET) have been used to distinguish between benign and malignant lesions. The size of the adrenal mass, as measured by CT or MRI remains one of the best indicators of malignancy. In the German Adrenal Cancer Registry (n = 215), the mean tumor size at diagnosis was 11.5 ± 4.7 cm (range 3–28 cm). However, ACCs smaller than 6 cm have been increasingly reported (5), and it is intuitively obvious that during early development ACCs are small, and surgical intervention would be most beneficial at this stage. According to the National Institutes of Health consensus conference, tumors larger than 6 cm are highly suspicious for malignancy and will be removed (1, 2). Therefore, tumors between 3 and 6 cm represent the main diagnostic challenge. To avoid misclassification of a small ACC as benign neoplasia, follow-up imaging is mandatory to detect early tumor growth and should be performed initially every 3–12 months (depending on tumor size and radiological appearance).

Thin-collimation CT. ACCs are inhomogeneous with irregular margins and irregular enhancement of solid components after iv contrast media. Sometimes calcifications are visible. Local invasion or tumor extension into the inferior vena cava as well as lymph node or other metastases (lung and liver) are often found in advanced ACC (Fig. 1). Measurement of Hounsfield units (HU) in unenhanced CT is of great value in differentiating malignant from benign adrenal lesions. Using a threshold value of 10 HU sensitivity and specificity for characterization an adrenal lesion as a benign adenoma in unenhanced CT was 71 and 98%, respectively, in a metaanalysis of 10 studies (32). However, in a recent series from Cleveland including 151 adrenal masses with histologically confirmed diagnosis, the median unenhanced HU was 19 (range: – 19 to 43) for adenomas and 36 (31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43) for carcinomas, indicating overlap between both groups (33). For better discrimination of lipid-poor adenomas from ACC, a delayed contrast-enhanced CT can be used, analyzing washout of contrast medium. Adrenal lesions with an attenuation value of more than 10 HU in unenhanced CT or an enhancement washout of less than 50% and a delayed attenuation of more than 35 HU (on 10- to 15-min delayed enhanced CT) are suspicious for malignancy (34, 35, 36, 37, 38, 39, 40).

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