Adrenocortical Carcinoma
Epidemiology
Benign adrenal tumors belong to the most common human neoplasias, with a prevalence of >4% in computed tomography (CT) studies1–3 and an even higher prevalence in autopsy series.4 In contrast, adrenocortical carcinoma (ACC) is a rare malignancy with an incidence of only 1 to 2 per million population per year,5,6 leading to 0.2 % of cancer deaths according to U.S. data. However, these data may underestimate the true incidence of ACC. An unusually high incidence of ACC has been found in children in southern Brazil (3.4 to 4.2 per 1 million children versus an estimated worldwide incidence of 0.3 per 1 million children younger than 15 years) related to a founder germline p53 tumor-suppressor gene mutation.7 ACC is more frequent in women than in men (ratio: 1.5). The incidence shows a maximum around the 4th and 5th decade, but the tumor can appear at any age.8
Molecular Pathology
The molecular pathogenesis of adrenocortical tumors is incompletely understood.9,10 Important insights come from hereditary tumor syndromes associated with the development of ACC. In the Li-Fraumeni syndrome,11 the frequency of ACC is up to 4%,12 and 70% of patients with Li-Fraumeni syndrome have germline mutations of the p53 tumor-suppressor gene located at the 7p13 locus.13 A second variant is caused by a heterozygous germline mutation in the hCHK2 gene.14 In children in southern Brazil, a specific germline mutation of p53 encoding an R337H amino acid substitution has been demonstrated. This mutation leads to a pH-sensitive and temperature-dependent alteration in the function of the p53 protein.15 Somatic mutations in the p53 gene have also been found in tumors of patients with sporadic ACC.16 Another hereditary syndrome associated with ACC is the Beckwith-Wiedemann Syndrome (BWS), a congenital overgrowth syndrome characterized by exomphalos, macroglossia, gigantism, and the development of childhood tumors.17 BWS has been mapped to the 11p15.5 region and is associated also with Wilms tumor and hepatoblastoma. Genes located at 11p15 and implicated in the pathogenesis of BWS are insulin-like growth factor 2 (IGF-2), H19, and cyclin-dependent kinase inhibitor 1C (CDKN1C, p57kip2). IGF-2 is maternally imprinted, whereas H19 and p57kip2 are both paternally imprinted. Uniparental paternal isodisomy for this locus associated with IGF-2 overexpression has been observed in BWS. In sporadic ACC, rearrangement at the 11p15 locus, with overexpression of IGF-2, is frequently observed. These are caused either by duplications of the paternal 11p15 allele or by loss of the maternal allele containing the H19 gene. In fact, increased IGF-2 expression is a hallmark of adrenocortical carcinoma and has been consistently described in a variety of studies, including microarray analyses.18–21 These observations indicate that IGF-2 overexpression is of particular importance in the pathogenesis of ACC. Accordingly, inhibition of IGF-2 action by blocking the IGF-1 receptor leads to reduced growth of ACC cells in vitro.22
An important observation relates to phosphodiesterase 11a (PDE11a) and the genetic predisposition to adrenocortical tumors.23 PDE11a inactivating germline mutations are more frequent in patients harboring adrenocortical tumors, including ACC, than in age- and sex-matched controls (odds ratio 3.53), suggesting that PDE11a alterations predispose to adrenocortical tumors.
In sporadic ACC, a variety of somatic mutations have been identified. In both benign and malignant adrenocortical tumors, β-catenin accumulation has been frequently observed, indicating activation of the Wnt-signaling pathway. This is explained in a subset of these tumors by somatic mutations of the β-catenin gene (CTNNB1) which may contribute to tumor progression.24
No activating mutations were found in the ACTH receptor in adrenal tumors.25 In fact, in ACC a loss of heterozygosity of the ACTH receptor, with reduced expression of ACTH receptor mRNA, was observed, supporting the view that ACTH is mainly a differentiating factor for adrenocortical cells and that growth-promoting activities of pro-opiomelanocortin (POMC) may reside in the N-terminus of POMC.26,27
Chromosomal instability has been described in malignant adrenal tumors, indicating defects in the mitogenic machinery.28 Using comparative genomic hybridization analysis, a significantly higher number of changes in ACCs compared to adrenocortical adenomas (mean of 7.6 to 14 changes versus 1.1 to 2 changes) have been demonstrated.29,30 The likelihood of chromosomal changes increased with tumor size. Similarly, loss of heterozygosity (LOH) analysis has found LOHs of 17p13, 11p15, 11q13, 17q22-24, and 2p16 in sporadic ACC.10 It has been shown that the number of somatic aberrations in ACC also predicts prognosis.31
Furthermore, telomere maintenance mechanisms are critical for the malignant phenotype in ACC. It has been demonstrated that telomerase activity is the major mechanism for telomere maintenance, but subsets of ACCs also show evidence of alternative telomere lengthening.32
Clinical Presentation
Most patients with ACC (60%) present with signs and symptoms of adrenal steroid excess. Rapidly progressing Cushing’s syndrome with or without virilization is the most frequent presentation.8,33 Androgen-secreting ACCs in women present with hirsutism and virilization, with male-pattern baldness and oligo/amenorrhea of recent onset. Estrogen-secreting tumors in males lead to gynecomastia and testicular atrophy. Rare aldosterone-producing adrenocortical carcinomas present with severe hypertension and profound hypokalemia (mean serum potassium 2.3 ± 0.08 mmol/L).34 However, low serum potassium is more often the result of excessive cortisol production leading to incomplete renal inactivation by 11-β-dehydrogenase type 2, with consecutive mineralocorticoid excess. Careful search for abnormal adrenal steroid secretion will often reveal increased dehydroepiandrosterone sulfate (DHEAS) concentrations or elevation of androstenedione or 17α-hydroxyprogesterone, thereby confirming the adrenocortical origin of the tumor and defining a marker for follow-up. Using gas chromatography/mass spectroscopy (GC-MS) for sophisticated urinary steroid analysis, hormonal activity can be demonstrated in almost all ACC cases.35 However, owing to low efficiency of intratumoral steroidogenesis or the exclusive secretion of steroid precursors, tumors may appear clinically as hormonally inactive.
Patients with a nonfunctioning ACC usually present with symptoms of abdominal discomfort (nausea, vomiting, abdominal fullness) or back pain caused by the large tumor mass. In particular, local pain may indicate invasive tumor growth and point to malignancy in a larger adrenal lesion. More frequent and improved abdominal imaging have led to an increasing percentage of ACC being discovered incidentally.36,37 Nonspecific symptoms like fever, weight loss, and loss of appetite are rare. In fact, patients may carry a large tumor burden without much evidence of systemic disease besides signs and symptoms of hormone excess.
Diagnosis
Detailed hormonal evaluation is performed prior to surgery for ACC to identify tumor markers for long-term follow-up and to guide perioperative treatment strategies (e.g., replacement of glucocorticoids after removal of a cortisol-secreting ACC).38 Guidelines for hormonal evaluation in suspected or established ACC have been provided by the ACC Working Group of the European Network for the Study of Adrenal Tumors (ENSAT; www.ensat.org) (Table 11-1). Hormone concentrations are of limited value in predicting malignancy. However, high testosterone in women, or high estradiol in men, or cosecretion of glucocorticoids and sex hormones are indicative of a malignant adrenal lesion. In addition, benign adrenocortical tumors very often show low DHEAS concentrations, whereas highly elevated DHEAS is suggestive of ACC. Similarly, high levels of steroid precursors such as 17α-hydroxyprogesterone or androstenedione are often observed in seemingly hormonally inactive ACCs. Measurement of urinary catecholamine excretion or plasma metanephrines is required prior surgery to exclude pheochromocytoma.
Imaging
Imaging plays a key role in the diagnostic workup of patients with suspected adrenal malignancy39–41 (also discussed in Chapter 10). Both size and appearance of an adrenal mass on CT, magnetic resonance imaging (MRI), and 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) are highly relevant to distinguish between benign and malignant lesions. For an adrenal mass >6 cm, the likelihood of ACC increases dramatically.42 In the German ACC Registry (n = 489), the median tumor size at diagnosis was 11.6 ± 4.7 cm (range 3 to 40 cm). Thus, in many patients, size alone is a strong indicator of malignancy. However, stage I ACC with a diameter of <5 cm has clearly the best prognosis and it is, therefore, important to identify adrenal malignancy as early as possible. Tumors between 3 and 6 cm represent a major diagnostic challenge.
Thin-collimation CT offers high spatial resolution and is fast and widely available. Large size, inhomogeneous appearance, irregular shape, and invasion into surrounding structures indicate malignancy. Frequently, tumor extension into the inferior vena cava, enlarged regional lymph nodes, and other metastases (lung and liver) are already found at presentation of ACC (Fig. 11-1). Measurement of Hounsfield units (HU) in unenhanced CT can often differentiate benign adrenal lesions from malignancy. If the density is <10 HU, diagnosis of adenoma has a sensitivity of 71% and a specificity of 98%, respectively.43 However, lipid-poor benign adenomas are frequent and show unenhanced HU values >10.44 In these cases, delayed postcontrast CT yields high sensitivity and specificity.45,46 Calculating the percentage washout for adrenal masses at 10- to 15-min-delayed enhanced CT, a washout of more than 40% to 50% is highly suggestive of a benign mass, whereas a delayed attenuation of more than 35 HU and a washout of less than 50% suggest malignancy. Delayed enhanced CT is also able to characterize some adrenal masses that cannot be characterized by chemical shift MRI.47
FIGURE 11-1 CT after contrast media of 8.5 cm in homogeneous ACC of the left adrenal gland (white arrow) and liver metastases (black arrows). (Image provided by W. Kenn, Dept. of Radiology, University of Würzburg, Germany.)
Modern MRI of adrenal tumors should include T1- and T2-weighted images plus chemical shift imaging, which consists of in-phase and out-of-phase imaging. Multiplanar MRI is particularly suited to separating adrenal masses from surrounding structures like liver, spleen, pancreas, and kidney. ACCs typically present isointense to liver on T1-weighted images and show an increase in intensity in T2-weighted sequences. Heterogeneity of signals is noted both on T1-weighted and T2-weighted images due to necrosis or hemorrhage. Enhancement after gadolinium is typical, and washout is slow. Modern MRI technology can differentiate benign from malignant adrenal lesions with a sensitivity of 81% to 89% and a specificity between 92% and 99%.41,48,49 However, the optimum MRI method (T1/T2 relaxation time, chemical shift, fast low angle shot, in vivo proton MR spectroscopy, etc.) for diagnosis of ACC remains a matter of controversy.37,50,51
In the past, adrenal scintigraphy with 131I-6β-iodomethyl-norcholesterol (NP59) has been used to characterize adrenal lesions.52 Benign hypersecretory adenomas show enhanced tracer uptake. However, NP 59 scintigraphy is time consuming and associated with a high radiation dose. In contrast, FDG-PET may be highly valuable in patients with suspected ACC. High uptake of 18F-FDG demonstrates increased glucose metabolism, and with few exceptions indicates malignancy. Thus, FDG-PET may be highly valuable for evaluation adrenal masses that are indeterminate by both CT and MRI. However, some benign adenomas or pheochromocytomas also show uptake of FDG.41,50,53 Imaging with FDG-PET has the additional advantage of simultaneously detecting metastases at other sites, but metastatic lesions <1 cm (particularly in the lung) are not easily detected by FDG-PET,54,55 indicating that PET cannot substitute for CT imaging.
None of the imaging methods mentioned can reliably differentiate ACC from a metastasis of other origin or a pheochromocytoma. In this context, a new method for adrenal imaging is promising: 11C-metomidate PET.56,57 Metomidate specifically binds to adrenal 11β-hydroxylase and aldosterone synthase, so uptake indicates the adrenocortical origin of an adrenal lesion. A potentially more widely available tracer is 123I-iodometomidate for SPECT imaging.58
Prior to surgery, high-resolution CT of chest and abdomen should be performed to detect frequent lung and liver metastases. A bone scan is only required if the patient complains of bone pain (see Table 11-1). Fine-needle biopsy of suspected ACC is rarely justified and is associated with the risk of needle-track metastasis. In our view, a biopsy should only be performed if the tumor cannot be removed surgically, and medical therapy needs to be based on clear pathologic evidence.
Histopathology
The pathologic diagnosis of ACC may be difficult because of the lack of clear-cut morphologic criteria,59 and in all cases, it is recommended to involve a specialized pathologist.
Weight and size are important criteria for malignancy. Most adenomas have a weight of <50 g, whereas most carcinomas weigh >100 g. The likelihood of an ACC increases steeply with a diameter of more than 6 cm.60
The differential diagnosis of carcinomas and adenomas is based largely on morphologic features. Different diagnostic scores61–63 have been introduced for diagnosis of malignancy. The Weiss system is most widely used and combines nine morphologic parameters, which include three parameters related to structure (description of cytoplasm, diffuse architecture, necrosis), three parameters related to cytology (atypia, atypical mitotic figures, mitotic count), and three related to invasion (veins, sinusoids, and capsule). Further morphologic parameters of importance are broad fibrous bands and hemorrhage. It has been shown that the mitotic index also has prognostic importance.64,65 In addition, periadrenal tissue infiltration and vena cava or renal vein invasion carry prognostic significance.66 Careful assessment of the resection status (R0, R1, R2) is also of great importance in that it may define further treatment strategies. For the same reason, violation of the capsule must be reported.
