REVIEWS

Adrenocortical carcinoma: a clinicians update

Martin Fassnacht, Rossella Lib, Matthias Kroiss and Bruno Allolio
Abstract | Adrenocortical carcinoma is a rare heterogeneous neoplasm with an incompletely understood pathogenesis and a poor prognosis. Previous studies have identified overexpression of insulin-like growth factor 2 (IGF-2) and constitutive activation of -catenin as key factors involved in the development of adrenocortical carcinoma. Most patients present with steroid hormone excess, for example Cushing syndrome or virilization, or abdominal mass effects, but a growing proportion of patients with adrenocortical carcinoma (currently >15%) is initially diagnosed incidentally. No general consensus on the diagnostic and therapeutic measures for adrenocortical carcinoma exists, but collaborative efforts, such as international conferences and networks, including the European Network for the Study of Adrenal Tumors (ENSAT), have substantially advanced the field. In patients with suspected adrenocortical carcinoma, a thorough endocrine and imaging work-up is recommended to guide the surgical approach aimed at complete resection of the tumor. To establish an adequate basis for treatment decisions, pathology reports include the Weiss score to assess malignancy, the resection status and the Ki67 index. As recurrence is frequent, close follow-up initially every 3months is mandatory. Most patients benefit from adjuvant mitotane treatment. In metastatic disease, mitotane is the cornerstone of initial treatment, and cytotoxic drugs should be added in case of progression. Results of a large phaseIII trial in advanced adrenocortical carcinoma are anticipated for 2011 and will hopefully establish a benchmark therapy. New targeted therapies, for example, IGF-1 receptor inhibitors, are under investigation and may soon improve current treatment options.
Fassnacht, M. et al. Nat. Rev. Endocrinol. 7, 323335 (2011); published online 8 March 2011; doi:10.1038/nrendo.2010.235

Continuing Medical Education online

This activity has been planned and implemented in accordance with the Essential Areas and policies of the Accreditation Council for Continuing Medical Education through the joint sponsorship of Medscape, LLC and Nature Publishing Group. Medscape, LLC is accredited by the ACCME to provide continuing medical education for physicians. Medscape, LLC designates this Journal-based CME for a maximum of 1 AMA PRA Category 1 CreditsTM. Physicians should claim only the credit commensurate with their participation in the activity. All other clinicians completing this activity will be issued a certificate of participation. To participate in this journal CME activity: (1) review the learning objectives and author disclosures; (2) study the education content; (3) take the post-test and/or complete the evaluation at http://www.medscapecme.com/ journal/nrendo; (4) view/print certificate. Released: 8 March 2011; Expires: 8 March 2012

Introduction
In contrast to benign adrenal tumors, which belong to the most common human neoplasias with a prevalence of >4%,14 adrenocortical carcinoma is a rare malignancy. Data from the National Cancer Institute survey and the SEER (Surveillance, Epidemiology and End Results) database estimate an incidence of 0.72.0 cases per million population per year.57 The incidence in adults is maximal in those aged around 4050years, but the tumor can appear at any age.8 An unusually high incidence of adrenocortical carcinoma has been found in children in southern Brazil3.44.2 versus 0.3 per 1 million children younger than 15years worldwide. The elevated incidence is possibly related to a founder germ line mutation in TP53, the gene that encodes cellular tumor antigen p53, which is common in this subpopulation.9,10 Adrenocortical carcinoma is more frequent in women than in men (ratio 1.5). Intriguingly, several case series1113 describe an increased occurrence of adrenocortical carcinomas on the left side rather than the right side of the body, which is confirmed by data from the German adreno cortical carcinoma registry (55% versus 45%; P = 0.009; n = 603).14 However, the mechanism behind this observation is unknown.

Learning objectives
Upon completion of this activity, participants should be able to: 1 Distinguish common molecular alterations associated with adrenocortical carcinoma. 2 Evaluate the clinical presentation of adrenocortical carcinoma. 3 Apply ancillary studies effectively to diagnose adrenocortical carcinoma. 4 Treat adrenocortical carcinoma effectively.

Competing interests M. Fassnacht and B. Allolio declare an association with the following companies: HRA Pharma, OSI Pharmaceuticals. See the article online for full details of the relationships. The other authors, the journal Chief Editor V. Heath and the CME questions author C. P Vega declare no competing interests. .

Pathophysiology and genetic alterations

Progress has been made in understanding the molecular mechanisms of sporadic tumor development on the basis of studies of rare genetic syndromes associated with

Department of Internal Medicine I, Endocrine Unit, University Hospital, University of Wrzburg, Oberdrrbacher Strae6, 97080 Wrzburg, Germany (M.Fassnacht, M.Kroiss, B. Allolio). Department of Endocrinology, INCa COMETE network, Cochin Hospital, University Paris Descartes, 24 Rue du Faubourg-SaintJacques, 75014 Paris, France (R. Lib). Correspondence to: M. Fassnacht fassnacht_m@medizin. uni-wuerzburg.de

NATURE REVIEWS | ENDOCRINOLOGY

2011 Macmillan Publishers Limited. All rights reserved

VOLUME 7 | JUNE 2011 | 323

REVIEWS
Key points
Overexpression of insulin-like growth factor 2 and constitutive activation of -catenin are key molecular alterations in adrenocortical carcinoma Detailed presurgical endocrine and imaging work-up and an expert surgeon are key prerequisites for a complete resection that offers the best chance of cure Even after radical resection, recurrence rate is high and, therefore, most patients benefit from adjuvant treatment strategies (mitotane with or without radiotherapy) Mitotane is the most effective single drug for adrenocortical carcinoma, but drug monitoring is important and management of adverse events is demanding In advanced disease not amenable to surgery, mitotane is given as monotherapy or in combination with cytotoxic chemotherapy (either etoposide combined with doxorubicin and cisplatin or streptozotocin) To facilitate progress in the treatment of adrenocortical carcinoma, patients should be enrolled in clinical trials

adrenocortical carcinoma and of gene profiling studies of these tumors. Genetic alterations, such as complete or partial chromosome loss or gain, have been identified using comparative genomic hybridization or microsatellite markers. Comparative genomic hybridization determined chromosome losses at 1p, 17p, 22p, 22q, 2q and 11q in up to 62% of patients with sporadic adrenocortical carcinoma,15 whereas microsatellite markers revealed a high prevalence of loss of heterozygosity (LOH) or allelic imbalance at chromosomes 11q13 (90%), 17p13 (85%) and 2p16 (92%) in patients with this disease.16,17 These data demonstrate a large and almost constant genetic disruption in these tumors; as a consequence, genes that may have a pathophysiological role need to be identified. Most of these genes correspond either to oncogenes or to tumor suppressor genes. Moreover, some of the molecular alterations are not only pathogenetically relevant but also of diagnostic, therapeutic and prognostic value, for example insulin-like growth factor 1 (IGF-1) and steroidogenic factor 1 (SF1).

owing to maternal imprinting.18 Genetic or epigenetic defects in the imprinted 11p15 region can increase IGF2 expression (Table1), as in patients with Beckwith Wiedemann syndrome (BWS), with macro somia, organomegaly and predisposition to the development of multiple tumors, including adrenocortical carcinoma.19 High overexpression of IGF2 mRNA is observed in the vast majority of adrenocortical carcinomas.20,21 It occurs mostly through loss of the maternal allele and duplication of the paternal allele, so-called paternal isodisomy, or, less frequently, through loss of maternal imprinting.21 The autocrine and/or paracrine growth effect of IGF-2 is mediated via the IGF-1 receptor (Figure1a,b).22 Analysis of the 11p15 locus is useful in adrenocortical tumors, as 11p15 LOH is significantly more frequent in adrenocortical carcinoma than in the benign adrenocortical adenoma (78.5% versus 9.5%) and is associated with a higher risk of tumor recurrence.17
catenin Genetic alterations of the Wnt signaling pathway, which were initially identified in patients with familial adenomatous polyposis coli (APC), have been found in a variety of cancers;23 occasionally, adrenocortical tumors have been observed in familial APC (Table1).24 The Wnt signaling pathway is active during normal embryonic development, and -catenin is a key component of this signaling pathway. Constitutive activation of -catenin is the most frequent alteration in benign and malignant adrenocortical tumors.25,26 In a subset of these tumors, somatic mutations of the -catenin gene inactivate its phosphorylation site for glycogen synthase kinase 3 (GSK3).25 Wnt signaling correlates with intracellular -catenin concentration (Figure1c,d). In a transgenic mouse model, constitutive -catenin activation induces adrenal hyperplasia and promotes adrenal cancer development.27 Steroidogenic factor 1 SF1 plays an important part in adrenal development,2830 and previous studies have demonstrated SF1 overexpression in most cases of childhood onset, but also in many cases of adult onset, adrenocortical tumors.3134 In addition, elevated levels of SF1 have been shown to increase proliferation of human adrenocortical cells invitro and to induce tumorigenesis in mice.35,36 Accordingly, SF1stimulated adrenocortical cell proliferation was inhibited by SF1 inverse agonists invitro.37

Oncogenes
IGF2 IGF signaling is involved not only in the development but also in the maintenance of differentiated adrenocortical functions. In addition, a pathophysiological role for this signaling pathway has also been documented in adrenocortical tumors.17 The IGF2 gene, which is located on chromosome 11p15, encodes a fetal growth factor that is expressed exclusively from the paternally inherited allele

Table 1 | Genetic syndromes associated with adrenocortical carcinoma Syndrome

BeckwithWiedemann syndrome

Chromosomal localization
11p15

Genes
CDKN1C IGF2 H19 APC TP53

Signaling pathway
IGF

Cause of sporadic adrenocortical carcinoma

11p15 paternal isodisomy IGF2 overexpression APC mutation (rare) -catenin (CTNNB1) somatic mutation TP53 germline mutations in children TP53 somatic mutations in adults 17p13 loss of heterozygosity

Familial adenomatous polyposiscoli LiFraumeni syndrome

5q12-22 17p13

Wnt p53

324 | JUNE 2011 | VOLUME 7

2011 Macmillan Publishers Limited. All rights reserved

www.nature.com/nrendo

REVIEWS
a
IGF-1 IGF-2

b
IGF-2 IGF-2 IGF-1R IGF-2 IGF-2 IGF-2

IGF-1R

IGF-2

IGF-2 IGF-2

IGF-2

IGF-2

Paternal allele

Paternal allele

Maternal allele CDKN1C (p57kip2) IGF-2 H19 CDKN1C (p57kip2) IGF-2 H19

Paternal allele Paternal isodisomy

Wnt Wnt Wnt

-catenin -catenin Dsh Axin WTX GSK3 APC -catenin P P WTX -catenin degradation (proteasome) APC

Axin

-catenin -catenin

Dsh P GSK3 P -catenin -catenin -catenin -catenin -catenin -catenin

TCF/LEF

Figure 1 | Pathophysiologically relevant pathways in adrenocortical carcinoma. a,b | Alterations of 11p15 locus and IGF2 overexpression in adrenocortical carcinoma. The imprinted 11p15 locus contains the genes CDKN1C (p57kip2), IGF2, and H19. a | In normal differentiated tissue, only the paternal allele of the IGF2 gene and maternal alleles of CDKN1C and H19 are expressed. b | In adrenocortical carcinoma, paternal isodisomy with loss of the maternal allele at 11p15 is frequently observed, which leads to the overexpression of IGF2. IGF-2 can then act as an autocrine growth factor through binding to the IGF-1 receptor to promote proliferation of adrenocortical carcinoma cells. c,d | The Wnt signaling pathway. c|In the absence of Wnt signaling, the level of -catenin is low owing to degradation by the ubiquitinproteasome system after phosphorylation at critical NH2-terminal residues by the GSK3 kinase bound to a scaffolding complex of axin and APC. d|Wnt stimulation leads to the inactivation of GSK3 and thereby the stabilization of -catenin in the cytoplasm. After translocation to the nucleus, -catenin stimulates expression of target genes after interaction with TCF/LEF. Mutations of -catenin abolish or reduce GSK3 phosphorylation of -catenin, which leads to its accumulation by preventing its degradation by the ubiquitinproteasome system. Abbreviations: APC, adenomatosis polyposis coli; GSK3, glycogen synthase kinase 3; IGF, insulin-like growth factor; TCF/LEF, T-cell factor/lymphoid enhancer factor.

Growth factors Various growth factors and/or cytokines other than IGFs also regulate growth and function of normal fetal and adult adrenal glands, for example, basic fibroblast growth factor (FGF2), transforming growth factor (TGF) , TGF-1 and vascular endothelial growth factor (VEGF).3841 Expression of VEGF is higher in adrenocortical carcinoma than
NATURE REVIEWS | ENDOCRINOLOGY

in adrenal adenomas.41,42 However, the high expression of VEGF contrasts with a low vascularization in adrenocortical carcinoma, which indicates a dissociation of the angiogenic status and the neoangiogenic capabilities of these tumors.42 Interestingly, serum VEGF levels were significantly higher in patients with adrenocortical carcinoma than in patients with adrenal adenomas or
VOLUME 7 | JUNE 2011 | 325

2011 Macmillan Publishers Limited. All rights reserved

REVIEWS
healthy individuals.43 Data on epidermal growth factor receptor (EGFR) demonstrated that this receptor is overexpressed in most adrenocortical carcinomas but hardly expressed in adenomas. However, no mutations of the EGFR gene were found, and expression was not of prognosticrelevance.44 glands.41 Moreover, a microarray approach has shown the frequent activation of Wnt signaling target genes in adrenocortical carcinoma.52 In an unsupervised cluster analysis, two new molecular markers, DLGAP5 and PINK1, were found to be differentially expressed between recurring and non recurring adrenocortical tumors, thereby demonstrating their diagnostic usefulness.53 Moreover, independent analyses led to the discrimination of two different types of adrenocortical carcinoma, with either poor or good prognosis, which indicates that transcriptome analysis could also uncover new prognostic factors.53,54 Furthermore, a metaanalysis of gene expression microarray and comparative genomic hybridization studies revealed three major pathogenic pathways in adrenocortical tumors: first, damage of cell cycle; second, alteration in retinoid acid signaling; and third, alteration in antigen presentation and the complement system.55

Tumor suppressor genes

TP53 Germline mutations in the TP53 gene, located on 17p13 (Table1), are present in 70% of families with LiFraumeni syndrome. This syndrome confers susceptibility to breast carcinoma, soft tissue sarcoma, brain tumors, osteosarcoma, leukemia and adrenocortical carcinoma.45 These tumors have an early onset and affect mostly children and young adults. Germline mutations in TP53 have been observed in 5080% of children with apparently sporadic adrenocortical carcinoma. 46 In adults, somatic mutations of TP53 are found in 2035% of cases of sporadic adrenocortical carcinoma4749 and might be associated with more aggressive and advanced tumors.49 LOH at 17p13 has been reported more frequently in patients with adrenocortical carcinoma than in those with adrenocortical adenoma (85% versus 30%) and is an independent predictive marker of recurrence after complete surgical removal of localized tumors.17 The discrepancy between the prevalence of somatic TP53 mutations (33%) and that of 17p13 LOH (85%) is suggestive of another tumor suppressor gene in this locus. A minimal region of loss on 17p13 has been identified in adrenocortical carcinomas,50 whereas no minimal region of loss could be demonstrated for adrenocortical adenomas. Compared with adrenocortical adenomas, a significant downregulation of two genes which map to this region, ACADVL and ALOX15B, was demonstrated in adrenocortical carcinomas.50 Melanocortin 2 receptor The melanocortin 2 receptor (MC2R; also known as the ACTH receptor) belongs to the G-protein-coupled receptor superfamily, and its gene is located on chromosome 18p11.2. MC2R LOH has been observed in two of four informative adrenocortical carcinomas, but not in 15 hypersecreting adrenocortical adenomas, which suggests a role for MC2R in cellular differentiation. Accordingly, MC2R mRNA expression is upregulated in patients with functional adrenocortical adenomas but downregulated in those with nonfunctional adrenocortical adenomas or carcinomas.51

Clinical presentation
Most patients with adrenocortical carcinoma (5060% of cases) seek medical advice because of clinical evidence of adrenal steroid hormone excess.8,13,5661 In functioning adrenocortical carcinoma, signs and symptoms of Cushing syndrome are the most frequent presentation. However, rapid development of the disease often leads to an altered clinical pattern of Cushing syndrome, with little or no weight gain, profound muscle atrophy, severe hypertension and diabetes mellitus as the dominating features. Massive hypercortisolism activates mineralocorticoid receptors by overriding the inactivating capacity of corticosteroid 11-dehydrogenase isozyme 2 (HSD11B2), which consecutively causes severe hypokalemia.62 A high percentage of affected women develop signs and symptoms of androgen excess (acne, hirsutism, androgenetic effluvium, oligomenorrhea) and virilization without or with concomitant Cushing syndrome. Estrogen-secreting adrenocortical carcinoma in men leads to feminization, with gynecomastia of recent onset, loss of libido and testicular atrophy. However, of 195 men with adrenocortical carcinoma in the German adrenocortical carcinoma registry only 14 showed clinical evidence of feminization (7%).14 Aldosterone-producing adrenocortical carcinoma is rare and manifests as hypertension with profound hypokalemia.63 Tumor-induced hypoglycemia has been repeatedly described in patients with adrenocortical carcinoma and is most probably the result of increased glucose utilization induced by paracrine release of IGF-2.6466 Patients with a nonfunctioning adrenocortical carcinoma usually show symptoms of abdominal discomfort (nausea, vomiting, abdominal fullness) or back pain caused by the local mass effect of the rapidly growing neoplasia. Few cases initially present as retroperitoneal hemorrhage from spontaneous tumor rupture. By contrast, nonspecific symptoms of malignancy, such as fever, weight loss or general malaise, affect only a small minority of patients. Owing to the more frequent use of modern imaging, a growing percentage of adrenocortical carcinomas are
www.nature.com/nrendo

Gene profiling of adrenocortical carcinoma By use of large-scale analyses of gene expression, socalled transcriptome analyses, the gene expression profile of benign adrenocortical tumors was consistently shown to differ markedly from that of adrenocortical carcinomas,41,52 which suggests that this analysis could offer new diagnostic tools. Transcriptome analysis of adrenocortical tumors has confirmed that IGF2 is the most upregulated gene in adrenocortical carcinoma compared with adrenocortical adenoma or healthy adrenal
326 | JUNE 2011 | VOLUME 7

2011 Macmillan Publishers Limited. All rights reserved

REVIEWS
Table 2 | Diagnostic work-up in patients with suspected or proven adrenocortical carcinoma* Hormonal work-up
Glucocorticoid excess (minimum 3 out of 4 tests)

Tests
Dexamethasone suppression test (1 mg, 2300 h) Excretion of free urinary cortisol (24 h urine) Basal cortisol Basal ACTH (plasma) Potassium Aldosterone:renin ratio (only in patients with arterial hypertension and/or hypokalemia) DHEAS 17OH-progesterone Androstenedione Testosterone 17-estradiol (only in men and postmenopausal women) Fractionated metanephrines in 24 h urine or free plasma metanephrines CT or MRI of abdomen and CT of thorax Bone scintigraphy (if skeletal metastasis is suspected) FDG-PET (optional)

Mineralocorticoid excess Sex steroids and steroid precursors

Exclusion of a pheochromocytoma Imaging

*Recommendation of the adrenocortical carcinoma working group of the European Network for the Study of Adrenal Tumors (ENSAT). 69 Modern imaging is able to identify most adenomas correctly. However, measurement of Hounsfield units (HU), before contrast media and calculation of washout 10 min or 15 min after contrast media or MRI with chemical shift analysis is needed to provide optimal diagnostic yield. Abbreviations: ACTH, adrenocorticotropic hormone; DHEAS, dehydroepiandrosterone sulfate; FDG, fluorodeoxyglucose.

discovered incidentally. In a series from the German adrenocortical carcinoma registry, 17.7% of 581 patients were found to have an adrenal incidentaloma.14

Diagnostic procedures
A comprehensive diagnostic work-up in patients with suspected or proven adrenocortical carcinoma has been recommended by the European Network for the Study of Adrenal Tumors (ENSAT; Table2).6769

Laboratory work-up A thorough initial hormonal work-up is needed, as demonstration of autonomous steroid hormone excess establishes the adrenocortical origin of the tumor and excludes relevant other differential diagnosis, for example, pheochromocytoma or lymphoma. In fact, the hormone profile is often already highly suggestive of an adrenocortical carcinoma before surgery, for example, owing to evidence of co-secretion of glucocorticoids, sex steroids and steroid precursors. Importantly, the preoperative steroid hormone pattern can serve as a fingerprint of the tumor and may be used for early detection of recurrence. Demonstration of glucocorticoid excess before surgery is essential to prevent postoperative adrenal crisis. Thus, all patients with suspected adrenocortical carcinoma undergo a standard 1 mg dexamethasone overnight test for exclusion of hypercortisolism, even in the absence of clinical evidence of Cushing syndrome. Early exclusion of a pheochromocytoma is mandatory to avoid misdiagnosis and unexpected intraoperative complications. Imaging Imaging plays a key part in the differential diagnosis of an adrenal mass, with CT and MRI being equally effective. Typically, adrenocortical carcinomas are inhomogeneous tumors with evidence of necrosis or hemorrhage and irregular margins. At the time of diagnosis, the median tumor size is >10 cm, with size a valuable parameter to indicate malignancy.70
NATURE REVIEWS | ENDOCRINOLOGY

Figure 2 | Imaging studies performed in a patient with adrenocortical carcinoma. a | Computerized tomography that shows a tumor of 17 14 18 cm, indicated by a circle. b | 18F-fluorodeoxyglucose-PET, in which the tumor is indicated by an arrow, demonstrated a high tracer uptake with SUVmax of 10.2 and an SUV adrenal:liver ratio of 2.4. After surgery, adrenocortical carcinoma was confirmed by histopathology with a Weiss score of 5. Abbreviation: SUV, standardized uptake value.

Thin collimation CT Thin collimation CT offers high spatial resolution and detection of invasion into the surrounding structures. Measurement of Hounsfield units (HU) in unenhanced CT has been helpful to differentiate benign from malignant adrenal lesions. By use of a threshold value of 10 HU, sensitivity and specificity for characterizing an adrenal mass as a benign adenoma in unenhanced CT are 71% and 98%, respectively.70 In adrenal masses with an unenhanced HU value of >10, delayed postcontrast CT typically shows an enhancement washout of <50% and a delayed attenuation of >35 HU in malignant lesions.7177
VOLUME 7 | JUNE 2011 | 327

2011 Macmillan Publishers Limited. All rights reserved

REVIEWS
Table 3 | ENSAT staging for adrenocortical carcinoma Stage
I II III IV

ENSAT tumor stage 2008

T1, N0, M0 T2, N0, M0 T12, N1, M0 T34, N01, M0 T14, N01, M1

T1, tumor size 5 cm; T2, tumor size >5 cm; T3, tumor infiltration in surrounding tissue; T4, tumor invasion in adjacent organs or venous tumor thrombus in vena cava or renal vein. N0, no positive lymph nodes; N1, positive lymph node(s); M0, no distant metastases; M1, presence of distant metastasis. Abbreviations: ENSAT, European Network for the Study of Adrenal Tumors; M, metastasis; N, lymph node; T, tumor. Permission obtained from John Wiley and Sons Fassnacht, M. etal. Cancer 115, 243250 (2009).

100

adrenocortical carcinomas demonstrate high uptake of 18 F-FDG, with an adrenal to liver maximum standardized uptake value (SUV) ratio >1.45 (Figure2). In a prospective study of 77 operated patients, the sensitivity and specificity to distinguish adenomas from adrenocortical carcinomas were 100% and 88%, respectively.79 Thus, in indeterminate cases, 18F-FDG-PET is highly useful to define the malignant potential of an adrenal mass. However, not CT, MRI, nor FDG-PET can reliably differentiate an adrenocortical carcinoma from a pheochromocytoma or adrenal metastasis. To answer this question, metomidate is emerging as a new radiotracer. Metomidate specifically binds to adrenal 11-hydroxylase and aldosterone synthase; therefore, uptake indicates the adrenocortical origin of a lesion.80 Metomidate can be given as 11C-metomidate for PET81,82 or as 123I-iodometomidate for single photon emission CT (SPECT) imaging.80

80 Disease-speci c survival (%)

60

40

20

0 0 1 2 3 4 5 6 Time (years) 7 8 9 10

ENSAT I (n = 29) ENSAT II (n = 227)

ENSAT III (n = 144) ENSAT IV (n = 166)

Figure 3 | Disease-specific survival according to tumor stage data from the European Network for the Study of Adrenal Tumors (ENSAT), which includes follow-up data from 566 patients derived from the German adrenocortical carcinoma registry in July 2010. Adapted with permission from John Wiley and Sons Fassnacht, M. etal. Cancer 115, 243250 (2009).

Multiplanar MRI Multiplanar MRI is well-suited to separate adrenal masses from surrounding structures, such as liver or spleen, and extremely useful to guide the surgical approach to the tumor. Adrenocortical carcinomas typically produce the same signal intensity as liver on T1-weighted images and show an increase in intensity in T2-weighted sequences. A clear enhancement after administration of gadolinium is followed by a slow wash-out. By use of modern technology, including chemical shift MRI, the sensitivity for differentiating benign from malignant adrenal lesions has been around 8189%, with a specificity of 9299%.75,78 Ffluorodeoxyglucose PET A major diagnostic advance represents 18F-fluorodeoxyglucose (18F-FDG) PET, as virtually all patients with
18

Histopathology The pathological differential diagnosis of adrenal neoplasias is still largely based on morphological features that require an experienced pathologist who is also familiar with rare tumor subtypes, such as pediatric or oncocytic adrenal tumors. Several markers have been introduced to establish the adrenocortical origin of an adrenal mass. Already in 1995, Sasano etal.83 suggested SF1 as a marker to differentiate between tumors of adreno cortical and nonadrenocortical origin. The value of this marker has been confirmed in a large cohort, in which SF1 immunohistochemistry was positive in >95% of all adrenocortical tumors but none of the nonsteroidogenic tumors. 34 In addition, SF1 provides prognostic information that is independent of tumor stage.34 For the diagnosis of carcinoma versus adenoma, different diagnostic scores84,85 have been introduced; the Weiss score86,87 is the most popular and consists of parameters related to tumor structure, cytology and evidence of tumor invasion. Important information is provided by immunohistochemistry with the Ki67 index, which can help differentiate carcinomas from adenomas. In addition, our experience with Ki67 staining in over 320 cases, together with smaller previous studies, indicates that a high Ki67 index is associated with shortened disease-free and overall survival.88,89 Of further importance is the careful definition of the resection status: R0 (complete resection), R1 (microscopic residual tumor) or R2 (macroscopic residual tumor), which is a major predictor of prognosis. Similarly, violation of the tumor capsule is associated with early recurrence and needs to be reported.
Percutaneous fine needle biopsy The use of percutaneous fine needle biopsy before surgery remains a matter of debate. Substantial complications, such as hemorrhage and tumor rupture, have been reported. On the other hand, in some small series, high diagnostic sensitivity, specificity and positive predictive values have been demonstrated.9093 However, real world data from one study indicates limited diagnostic yield and relevant adverse effects.94 From our experience, therefore, only two indications for biopsy of an adrenal mass (after
www.nature.com/nrendo

328 | JUNE 2011 | VOLUME 7

2011 Macmillan Publishers Limited. All rights reserved

REVIEWS
exclusion of a pheochromocytoma) seem reasonable: first, to establish the diagnosis in an already metastasized adrenal tumor in which surgery is not intended; second, to exclude or demonstrate metastatic disease in a patient with a history of an extra-adrenal malignancy, provided the result may affect treatment.
Table 4 | Radiotherapy for adrenocortical carcinoma Setting
Adjuvant

Indication
Strongly recommended after R1 resection in ENSAT stage IIII tumors Recommended after Rx resection in ENSAT stage IIII tumors Individualized decision: R0 resection in high-risk patients* Not recommended: R2 resection and ENSAT stage IV tumors Bone metastasis with spinal cord compression Thoracic or abdominal metastasis with venacava obstruction Painful thoracic or abdominal metastasis Symptomatic cerebral metastasis

Dosage
>40 Gy (1.82.0 Gy per fraction) Limited boost volume (tumor bed) to reach 5060 Gy

Staging Tumor staging is a widely used tool to assess prognosis in patients with cancer. For adrenocortical carcinoma, the tumornodemetastasis (TNM) classification proposed by ENSAT is recommended (Table3). 95 This staging system, which represents a modification of the Lee system,96 defines stage I and stage II as strictly localized tumors with a size of 5 cm or >5 cm, respectively. Stage III tumors are characterized by infiltration in surrounding tissue, positive regional lymph nodes or a tumor thrombus in the vena cava and/or renal vein, whereas stage IV is defined by the presence of distant metastasis. The high prognostic potential of the ENSAT staging system has been established in the large cohort of the German adreno cortical carcinoma registry (Figure3)95 and has been confirmed in the independent SEER cohort,97 which demonstrates its superiority to the staging system published by the Union Internationale Contre Le Cancer (UICC). To detect metastatic disease early, careful staging investigations, including chest CT, are required before surgery, as removal of the primary tumor is often of questionable value in metastatic adrenocortical carcinoma (stage IV). Follow-up investigations Even in patients with seemingly localized adrenocortical carcinoma, recurrence after surgery is frequent. Early detection is important, as local recurrence or limited metastatic disease may be amenable to complete resection (R0), often followed by a long period of diseasefree survival. Furthermore, limited evidence supports the theory that surgery for tumor recurrence may also prolong overall survival. Thus, for detection of recurrence, imaging (CT of the chest and CT and/or MRI of the abdomen) should be performed every 3months, together with monitoring of initially elevated steroid levels. After the first 2years of follow-up, intervals may be gradually increased. However, follow-up in patients without evidence of disease is recommend ed over a minimum of 10years after surgery.

Palliative

30 Gy in 10 fractions Alternatively, short-term fractionations (up to single treatment with 8 Gy)

*Arguments for radiotherapy: microscopic tumor invasion of blood vessels and Ki67 score 10%. Argument against radiotherapy: tumor size 8 cm. Consider re-surgery by an expert surgeon. Abbreviations: R0, complete resection; R1, microscopic residual tumor; R2, macroscopic residual tumor; Rx, unknown resection status.

ACC amenable to complete resection 1

Complete resection (R0) Ki67 10% 3 Ki67 >10% Lowintermediate risk High risk

Rx/R1 resection

Consider adjuvant mitotane

5 Adjuvant mitotane Consider additional therapy

Adjuvant mitotane plus irradiation of the tumor bed

Follow-up every 3 months Imaging and tumor markers

Tumor free

Recurrence

Within 6 months* or not resectable

>12 months plus complete resection feasible

Therapy
Until now, no single randomized trial in adrenocortical carcinoma has been published. The levels of evidence for treatment recommendations are, therefore, at best level 2, but mostly level 34.98 Thus, all patients should be enrolled in clinical trials, which are increasingly available.

Tumors amenable to radical resection Complete surgical resection is the treatment of choice in adrenocortical carcinoma, as it is virtually the only option to achieve cure. For localized tumors, a key question concerns the optimal surgical approach. In patients
NATURE REVIEWS | ENDOCRINOLOGY

Figure 4 | Treatment of adrenocortical carcinoma amenable to complete resection. (1) Adrenocortical carcinomas amenable to complete resection include all patients with stage I and II tumors, most patients with stage III tumors and selected patients with stage IV tumors. Consider enrolling patient into a clinical trial. (2) In patients with R2 resection, consider re-surgery by an expert surgeon or see Figure5. (3) If Ki67 staining is not available, a high proliferative index (>5 mitoses per 50 high-power fields) may be used for risk stratification. Patients with stage IV or recurrence are judged high-risk patients independent of Ki67 index. (4) The following factors are suggestive of a low risk of recurrence: tumor size <8 cm, no microscopic evidence of invasion of blood vessels or tumor capsule. If all these factors are fulfilled, observational follow-up may be justified. (5) Parameters favoring additional radiotherapy of the tumor bed: microscopic tumor invasion of blood vessels and capsule and a Ki67 index 20%. A tumor thrombus in the vena cava favors additional streptozotocin therapy. (6) After 2years, the time intervals are gradually extended. *For treatment of advanced adrenocortical carcinoma not amenable to radical surgery see Figure5. Abbreviations: ACC, adrenocortical carcinoma; R1, microscopic residual tumor; Rx, unknown resection status. Adapted with permission from John Wiley and Sons Fassnacht, M. & Allolio, B. Clin. Endocrinol. (Oxf.) 73, 561565 (2010).

with an infiltrating tumor or suspected lymph nodes (presumable stage III), open adrenalectomy is required. However increasing evidence supports the hypothesis
VOLUME 7 | JUNE 2011 | 329

2011 Macmillan Publishers Limited. All rights reserved

REVIEWS
Box 1 | Recommended medical treatment in advanced adrenocortical carcinoma Mitotane monotherapy*
Start with 1.5 g daily and increase dose within 46days to 6.0 g per day After 3weeks, adapt dosage according to tolerability and blood level; ifmitotane concentration is <7 mg/l, consider adding cytotoxic chemotherapy Maximum dose 12 g per day, but most patients do not tolerate >8 g daily Target a mitotane blood level of 1420 mg/l. With this regimen, about 50% of patients achieve target levels within 3 months

Etoposide, doxorubicin and cisplatin plus mitotane*

Every 28days: Day 1: 40 mg/m2 doxorubicin Day 2: 100 mg/m2 etoposide Day 3 and 4: 100 mg/m2 etoposide plus 40 mg/m2 cisplatin Plus oral mitotane aiming at a blood level between 1420 mg/l

Streptozotocin plus mitotane*

Induction (day 15): 1 g streptozotocin per day Afterwards: 2 g streptozotocin every 21days Plus oral mitotane aiming at a blood level between 1420 mg/l

Gemcitabine plus capecitabine||

800 mg/m2 gemcitabine on day 1 and 8 (repeated every 3weeks) 1,500 mg capecitabine orally per day in a continuous fashion
*Available data suggest a response rate for mitotane of 26%,119 for etoposide, doxorubicin, cisplatin and mitotane of 49%117 and for streptozotocin and mitotane of 36%.118 However, CIs overlap, thus not allowing a direct comparison. In patients suffering from impaired health status, a slower increase of dosage is recommended. During right-sided radiotherapy, we do not recommend to administer >3 g daily. These regimens are currently compared in a randomized phaseIII trial, the results of which are expected in 2011.121 ||Alternative regimen for second or third-line therapy. Results of a phaseII trial reported that 13 of 28 patients had stable disease for more than 4months.121

that stage I and II adrenocortical carcinomas can be removed as safe by laparoscopic adrenalectomy as by open surgery,99,100 although this notion remains a matter of debate.101,102 Nevertheless, a laparoscopic approach for adrenal tumors judged preoperatively as only potentially malignant (for example, endocrine inactive incidentaloma with evidence of tumor growth) is justified on the basis of current data.99,100 Given that complete resection is the single most important therapeutic measure, surgery for adrenocortical carcinoma should be performed by a specialized surgeon who is aware of the pitfalls of this operation (for example, vulnerable tumor capsule, tumor thrombus in the large veins). As outcome depends on surgical volume in adrenal surgery,103 operations on patients with suspected adrenocortical carcinoma should be limited to centers with >20 adrenalectomies per year and experience in surgery for adrenocortical carcinoma.

reduced by adjuvant use of the adrenolytic agent mitotane (median recurrence-free survival 42months versus 10 and 25months in the two control groups; P < 0.01). Although this study was not a randomized trial, the fact that the decision for or against mitotane was centerdriven rather than patient-driven reduced the selection bias in this study comparison with prior reports.67 Most but not all centers, therefore, now recommend adjuvant mitotane after complete resection.68,105107 In patients with incomplete resection (R1) or uncertain resection status (Rx), adjuvant radiotherapy should be offered in addition to mitotane as an approach to reduce the high risk of local recurrence (Table4).108110 In some patients, adjuvant streptozotocin in combination with mitotane might be justified. Guidance for risk stratification is given in Figure4. Almost all published case series suffer from a marked selection bias, as was recently demonstrated by an analysis from the German adrenocortical carcinoma registry.111 This study demonstrated that patients who remain free of disease after surgery rarely contact a specialized center. Hence, patients with high risk of recurrence are clearly overrepresented in most reports. Thus, the overall prognosis of early-stage adrenocortical carcinoma might be substantially better than previously reported, and the need for adjuvant therapy in all patients with adrenocortical carcinoma is no longer obvious. To address this important issue, the ADIUVO (Efficacy of Adjuvant Mitotane Treatment) study, a randomized trial in low-tointermediate risk patients (mitotane versus observation only) has been initiated and is currently recruiting.112 Surgery is also recommended in patients with metastatic disease, but only if radical resection seems feasible. In some patients, a second surgery (for example, for resection of lung metastases) is needed to remove all tumoral lesions. Radiofrequency ablation is an alternative for selected metastases <5 cm.113,114 However, even after removal of all tumor manifestations, these patients with stage IV tumors suffer from systemic disease and require postoperative medical treatment.

Adjuvant treatment Most published data indicate a high rate of recurrence even after complete resection, which clearly suggests a need for adjuvant treatment concepts. The best evidence for a role of adjuvant treatment derives from a large retrospective study by Terzolo and colleagues. 104 In this multicenter study with two independent control groups, the risk of recurrence and death was significantly
330 | JUNE 2011 | VOLUME 7

Recurrent disease Reports on treatment of recurrent adrenocortical carcinoma are scarce.115118 Although most reports favor a surgical approach, surgery should only be performed if the time between a first operation and recurrence is 612months, and complete resection is achievable,119 as only then can a clinically relevant period of disease-free survival be expected. After surgery for recurrence, adjuvant therapy must be started as soon as possible. In patients with recurrent disease despite adjuvant mitotane therapy, addition of another drug, such as streptozotocin,120 or radiotherapy for local recurrence should be considered. Advanced disease In advanced disease, debulking surgery is only of benefit in patients with severe hormone excess that cannot be controlled otherwise. Instead, medical therapy should be initiated as soon as the diagnosis is established. Until the results of the FIRM-ACT trial121 become available, the
www.nature.com/nrendo

2011 Macmillan Publishers Limited. All rights reserved

REVIEWS
recommended first-line treatment regimens are mitotane monotherapy; etoposide, doxorubicin, cisplatin plus mitotane;122 or streptozotocin plus mitotane120 (Box1). The treatment is chosen on the basis of the clinical judgment of the speed of tumor progression (Figure5) and on local preferences. For mitotane monotherapy, we currently use the following approach: after initiation of mitotane, the dose is increased to 6 g per day within a few days, and mitotane blood levels are then determined after 3weeks of treatment. Mitotane is continued as monotherapy in patients with a mitotane concentration >7 mg/l. Otherwise we consider adding cytotoxic drugs without delay. All drugs harbor clinically relevant toxicity; especially mitotane treatment requires management by an experienced physician (Table5).123,124 During treatment with mitotane, virtually all patients will experience adrenal insufficiency and gastrointestinal symptoms that both have to be treated actively (Box1). Supportive treatment that includes high-dose hydrocortisone replacement therapy is invariably needed. In patients with tumor progression despite first-line medical therapy, alternative first-line regimes are reasonable choices as second-line treatment. An additional interesting option that consists of metronomic capecitabine plus gemcitabine has also been published (Box 1).125 Increasing evidence supports the notion that adrenocortical carcinoma is not radiotherapy-resistant,109,126 and palliative radiotherapy has been successfully used to treat symptomatic metastatic lesions (Table4). Hypersecretion of adrenal steroids frequently contributes to disease burden and can severely affect quality of life. If mitotane alone is not able to control hormone excess, additional adrenostatic drugs, such as ketoconazole, metyrapone or etomidate or the glucorticoid receptor antagonist mifepristone (RU486) should be given.127131 New targeted therapies have also been tested in patients with adrenocortical carcinoma. However, the results of these studies were rather disappointing. Neither inhibition of EGFR nor targeting of VEGF in adrenocortical carcinoma resulted in a substantial benefit in advanced disease.132135 By contrast, preliminary results of phaseI trials with an orally available IGF-1 receptor inhibitor (OSI-906) are promising. In five of 16 patients, stabilization of progressive adrenocortical carcinoma for >12weeks was achieved, including one patient with a >80% reduction of tumor mass.136 A phaseIII trial on this drug as second-line or third-line therapy is now recruiting in several countries. As the field has been moving forward rapidly over the past years, physicians should contact an expert center for advice on salvage therapies.
ACC not amenable to complete resection 1 Debulking surgery 2 No prior systemic therapy After failure of adjuvant mitotane

High dose mitotane monotherapy

Rapidly progressing tumor

Mitotane level at 3 weeks >7 mg/l Continue monotherapy

<5 mg/l 4

Mitotane plus EDP or streptozotocin

Follow-up every 2 months

Tumor regression or stable disease

Progressive disease

In case of severe localized symptoms

Consider surgery Continue therapy

Add or switch 5 chemotherapy

Consider radiotherapy or radioablation

Figure 5 | Treatment of advanced adrenocortical carcinoma not amenable to radical surgery. (1) Consider enrolment of patient in a clinical trial. (2) Debulking surgery should only be performed in patients with otherwise uncontrollable hormone excess. (3) Speed of tumor progression is assessed by clinical judgment, for example, rapidly progressing symptoms within <3months, recurrence within 3months after radical surgery or lactate dehydrogenase level >1,000U/l suggest a rapidly progressing tumor. (4) If mitotane concentration at 3weeks is <5mg/l, consider adding cytotoxic chemotherapy without delay, because it is improbable that this patient will reach a level >14mg/l within the first 12weeks of treatment. (5)Consider enrolment in a clinical trial. For the best currently available cytotoxic regimens see Box 1. Contact specialized center. Abbreviations: ACC, adrenocortical carcinoma; EDP etoposide, doxorubicin and cisplatin. ,

Prognosis and predictors of clinical outcome

The overall prognosis of adrenocortical carcinoma is still poor, with a 5-year overall survival that varies between 37% and 47%.12,56,61,70 In addition to the completeness of surgery, tumor stage at the time of diagnosis remains the most relevant prognostic factor (Figure3). However, survival differs widely for any given tumor stage, which reflects the heterogeneity of the disease. Unfortunately, only limited data on clinical, histological and molecular
NATURE REVIEWS | ENDOCRINOLOGY

markers for prediction of tumor behavior are available. Functionality, age and sex have no major role.66,137139 Few studies demonstrated the value of histological markers, such as mitotic index, tumor necrosis, atypic mitotic figures, Ki67 index and mutated TP53, as predictors of poor prognosis.88,138,140 In addition, overexpression of matrix metalloproteinase 2 and the glucose transporter GLUT1 has been linked to reduced survival.141,142 Two clusters of genes that reliably grouped adrenocortical carcinomas in prognostically different subsets have been identified by gene expression studies.53,54 Of note, a French group identified a set of only two specific genes, BUB1B and PINK1, that were better predictors of outcome than tumor stage. 53 In addition, downregulation of microRNA miR-195 and upregulation of miR-483-5p were found to correlate with poor prognosis.142 These data indicate that molecular analyses may soon become part of the routine clinical management in adrenocortical carcinoma. However, from a clinical perspective, predictors of response to treatment would be even more valuable. In a
VOLUME 7 | JUNE 2011 | 331

2011 Macmillan Publishers Limited. All rights reserved

REVIEWS
Table 5 | Recommended monitoring during mitotane treatment Parameter
Mitotane blood level Adverse effects

Interval
Every 46weeks* At every visit (initially every 4weeks; after 6months, every 8weeks) Suspected glucocorticoid deficiency or excess

Comment
Target level in blood: 1420 mg/l Gastrointestinal adverse effects: use antiemetics (for example, metoclopramide or HTR3 blocker) and/or loperamide Central nervous system adverse effects (ataxia, confusion, speech or visual problems): interrupt therapy or reduce dosage Glucocorticoid status is difficult to determine Target: ACTH in the normal range (< 12 pmol/l) or slightly above Due to an increased glucorticoid clearance, high-dose glucocorticoid replacement is needed (most patients require at least 50 mg hydrocortisone per day) GGT is invariably elevated without clinical consequences If other liver enzymes increase above threefold of baseline, stop mitotane as risk of liver failure exists Disturbance of thyroid hormones is frequent Thyroid hormone replacement is recommended in patients with clinical symptoms of hypothyroidism Primary hypogonadism frequently occurs. Replacement should be initiated in patients with symptoms of hypogonadism If renin increases add fludrocortisone If LDL and HDL cholesterol increase, consider treatment with statins Check for relevant leucopenia, thrombocytopenia and anemia (rare)

ACTH

GOT, GPT, bilirubin, (GGT)

Initially every 4weeks; after 6months, every 8weeks Every 34months

TSH, free T3, free T4

Testosterone Renin Cholesterol (HDL, LDL), triglycerides Blood count

Every 34months Every 6months Every 34months (in adjuvant setting) Every 34months

*In the first 3months, mitotane blood levels should be checked every 23weeks. After reaching a plateau, the interval can be extended. Abbreviations: ACTH, adrenocorticotropic hormone; GGT, -glutamyltransferase; GOT, aspartate aminotransferase; GPT, alanine aminotransferase, HTR 3, 5-hydroxytryptamine receptor 3.

study of 45 patients treated with platinum-based chemotherapy, the expression of the DNA repair gene ERCC1 was correlated with overall survival after treatment; in a multivariate analysis, the hazard ratio for death was 2.2 (P = 0.038) for high ERCC1 expression.144 Although this result was not confirmed in a French cohort of 44 patients,145 this study represents the first attempt towards individualized medicine for adrenocortical carcinoma.

Conclusions
Within the past decade, collaborative international efforts have paved the way for unprecedented progress in the care of patients with adrenocortical carcinomas. Insights into the molecular pathogenesis of adrenocortical carcinoma have led to the first clinical trials using targeted strategies, such as IGF-1R inhibitors. The European network ENSAT has established a validated adrenocortical carcinoma staging system95 and has outlined a detailed work-up for patients with suspected adrenocortical carcinoma (Table2). Following a consensus meeting in September 2003,98 the first ever phaseIII trial in adrenocortical carcinoma was initiated

and will, in 2011, hopefully lead to a first-line treatment in advanced adrenocortical carcinoma that fulfills the standards of high-level, evidence-based medicine. More importantly, this trial has established an international structure instrumental for further clinical trials, such as ADIUVO and OSI-906. Based on these international efforts, we expect that within the coming decade the combination of basic science, translational research and clinical trials will substantially improve the clinical outcome of patients with this rare disease.
Review criteria
Original articles and reviews in English were identified using a PubMed search strategy covering the time period up until August 2010. The following search terms were used in varying combinations: adrenal, adrenocortical, cancer, carcinoma, tumor, pathophysiology, diagnosis, imaging, treatment, surgery, radiotherapy, mitotane, cytotoxic and prognosis. In addition, the reference list of selected papers served for the identification of additional publications.

1.

2.

3.

Abecassis, M., McLoughlin, M.J., Langer, B. & Kudlow, J.E. Serendipitous adrenal masses: prevalence, significance, and management. Am. J. Surg. 149, 783788 (1985). Grumbach, M.M. etal. Management of the clinically inapparent adrenal mass (incidentaloma). Ann. Intern. Med. 138, 424429 (2003). Bovio, S. etal. Prevalence of adrenal incidentaloma in a contemporary computerized

4.

5.

tomography series. J. Endocrinol. Invest. 29, 298302 (2006). Song, J.H., Chaudhry, F.S. & Mayo-Smith, W.W. The incidental adrenal mass on CT: prevalence of adrenal disease in 1,049 consecutive adrenal masses in patients with no known malignancy. AJR Am. J. Roentgenol. 190, 11631168 (2008). Cutler, S.J., Young, J.L. & Connelly, R.R. (Eds) Third national cancer survey: incidenca data (U.S.

6.

7.

Dept of Health, Education, and Welfare, Public Health Service, National Institutes of Health, National Cancer Institute, Bethesda, 1975). Kebebew, E., Reiff, E., Duh, Q.Y., Clark, O.H. & McMillan, A. Extent of disease at presentation and outcome for adrenocortical carcinoma: have we made progress? World J. Surg. 30, 872878 (2006). Golden, S.H., Robinson, K.A., Saldanha, I., Anton, B. & Ladenson, P Clinical review: .W.

332 | JUNE 2011 | VOLUME 7

2011 Macmillan Publishers Limited. All rights reserved

www.nature.com/nrendo

REVIEWS
Prevalence and incidence of endocrine and metabolic disorders in the United States: acomprehensive review. J. Clin. Endocrinol. Metab. 94, 18531878 (2009). Koschker, A.C., Fassnacht, M., Hahner, S., Weismann, D. & Allolio, B. Adrenocortical carcinomaimproving patient care by establishing new structures. Exp. Clin. Endocrinol. Diabetes 114, 4551 (2006). Ribeiro, R.C. etal. An inherited p53 mutation that contributes in a tissue-specific manner to pediatric adrenal cortical carcinoma. Proc. Natl Acad. Sci. USA 98, 93309335 (2001). Pinto, E.M. etal. Founder effect for the highly prevalent R337H mutation of tumor suppressor p53 in Brazilian patients with adrenocortical tumors. Arq. Bras. Endocrinol. Metabol. 48, 647650 (2004). Hutter, A.M. Jr & Kayhoe, D.E. Adrenal cortical carcinoma. Clinical features of 138 patients. Am. J. Med. 41, 572580 (1966). Bilimoria, K.Y. etal. Adrenocortical carcinoma in the United States: treatment utilization and prognostic factors. Cancer 113, 31303136 (2008). Wooten, M.D. & King, D.K. Adrenal cortical carcinoma. Epidemiology and treatment with mitotane and a review of the literature. Cancer 72, 31453155 (1993). Universitt Wrzburg Offizielle Homepage des Deutsche NebennierenkarzinomRegisters [online], http://www.nebennierenkarzinom.de/ (2010). Sidhu, S. etal. Comparative genomic hybridization analysis of adrenocortical tumors. J. Clin. Endocrinol. Metab. 87, 34673474 (2002). Kjellman, M. etal. Genotyping of adrenocortical tumors: very frequent deletions of the MEN1 locus in 11q13 and of a 1-centimorgan region in 2p16. J. Clin. Endocrinol. Metab. 84, 730735 (1999). Gicquel, C. etal. Molecular markers and longterm recurrences in a large cohort of patients with sporadic adrenocortical tumors. Cancer Res. 61, 67626767 (2001). DeChiara, T.M., Robertson, E.J. & Efstratiadis,A. Parental imprinting of the mouse insulin-like growth factor II gene. Cell 64, 849859 (1991). Wiedemann, H.R. etal. The proteus syndrome. Partial gigantism of the hands and/or feet, nevi, hemihypertrophy, subcutaneous tumors, macrocephaly or other skull anomalies and possible accelerated growth and visceral affections. Eur. J. Pediatr. 140, 512 (1983). Boulle, N., Logi, A., Gicquel, C., Perin, L. & Le Bouc, Y. Increased levels of insulin-like growth factor II (IGF-II) and IGF-binding protein-2 are associated with malignancy in sporadic adrenocortical tumors. J. Clin. Endocrinol. Metab. 83, 17131720 (1998). Gicquel, C. etal. Structural and functional abnormalities at 11p15 are associated with the malignant phenotype in sporadic adrenocortical tumors: study on a series of 82 tumors. J. Clin. Endocrinol. Metab. 82, 25592565 (1997). Logi, A. etal. Autocrine role of IGF-II in proliferation of human adrenocortical carcinoma NCI H295R cell line. J. Mol. Endocrinol. 23, 2332 (1999). Kikuchi, A. Tumor formation by genetic mutations in the components of the Wnt signaling pathway. Cancer Sci. 94, 225229 (2003). Naylor, E.W. & Gardner, E.J. Adrenal adenomas in a patient with Gardners syndrome. Clin. Genet. 20, 6773 (1981). 25. Tissier, F. etal. Mutations of beta-catenin in adrenocortical tumors: activation of the Wnt signaling pathway is a frequent event in both benign and malignant adrenocortical tumors. Cancer Res. 65, 76227627 (2005). 26. Tadjine, M., Lampron, A., Ouadi, L. & Bourdeau,I. Frequent mutations of beta-catenin gene in sporadic secreting adrenocortical adenomas. Clin. Endocrinol. (Oxf.) 68, 264270 (2008). 27. Berthon, A. etal. Constitutive beta-catenin activation induces adrenal hyperplasia and promotes adrenal cancer development. Hum. Mol. Genet. 19, 15611576 (2010). 28. Luo, X., Ikeda, Y. & Parker, K.L. A cell-specific nuclear receptor is essential for adrenal and gonadal development and sexual differentiation. Cell 77, 481490 (1994). 29. Hammer, G.D., Parker, K.L. & Schimmer, B.P . Minireview: transcriptional regulation of adrenocortical development. Endocrinology 146, 10181024 (2005). 30. Schimmer, B.P & White, P Minireview: . .C. steroidogenic factor 1: its roles in differentiation, development, and disease. Mol. Endocrinol. 24, 13221337 (2010). 31. Figueiredo, B.C. etal. Amplification of the steroidogenic factor 1 gene in childhood adrenocortical tumors. J. Clin. Endocrinol. Metab. 90, 615619 (2005). 32. Pianovski, M.A. etal. Mortality rate of adrenocortical tumors in children under 15years of age in Curitiba, Brazil. Pediatr. Blood Cancer 47, 5660 (2006). 33. Almeida, M.Q. etal. Steroidogenic factor 1 overexpression and gene amplification are more frequent in adrenocortical tumors from children than from adults. J. Clin. Endocrinol. Metab. 95, 14581462 (2010). 34. Sbiera, S. etal. High diagnostic and prognostic value of steroidogenic factor-1 expression in adrenal tumors. J. Clin. Endocrinol. Metab. 95, E161E171 (2010). 35. Doghman, M. etal. Increased steroidogenic factor-1 dosage triggers adrenocortical cell proliferation and cancer. Mol. Endocrinol. 21, 29682987 (2007). 36. Lichtenauer, U.D. etal. Pre-B-cell transcription factor 1 and steroidogenic factor 1 synergistically regulate adrenocortical growth and steroidogenesis. Endocrinology 148, 693704 (2007). 37. Doghman, M. etal. Inhibition of adrenocortical carcinoma cell proliferation by steroidogenic factor-1 inverse agonists. J. Clin. Endocrinol. Metab. 94, 21782183 (2009). 38. Hotta, M. & Baird, A. Differential effects of transforming growth factor type beta on the growth and function of adrenocortical cells invitro. Proc. Natl Acad. Sci. USA 83, 77957799 (1986). 39. Feige, J.J. etal. Transforming growth factor beta1: an autocrine regulator of adrenocortical steroidogenesis. Endocr. Res. 17, 267279 (1991). 40. Feige, J.J., Vilgrain, I., Brand, C., Bailly, S. & Souchelnitskiy, S. Fine tuning of adrenocortical functions by locally produced growth factors. J.Endocrinol. 158, 719 (1998). 41. de Fraipont, F. etal. Gene expression profiling of human adrenocortical tumors using complementary deoxyribonucleic Acid microarrays identifies several candidate genes as markers of malignancy. J. Clin. Endocrinol. Metab. 90, 18191829 (2005). 42. Bernini, G.P etal. Angiogenesis in human . normal and pathologic adrenal cortex. J. Clin. Endocrinol. Metab. 87, 49614965 (2002). 43. Kolomecki, K., Stepien, H., Bartos, M. & Kuzdak,K. Usefulness of VEGF, MMP-2, MMP-3 and TIMP-2 serum level evaluation in patients with adrenal tumours. Endocr. Regul. 35, 916 (2001). Adam, P etal. Epidermal growth factor receptor . in adrenocortical tumors: analysis of gene sequence, protein expression and correlation with clinical outcome. Mod. Pathol. 23, 15961604 (2010). Hisada, M., Garber, J.E., Fung, C.Y., Fraumeni,J.F. Jr & Li, F.P Multiple primary . cancers in families with Li-Fraumeni syndrome. J.Natl Cancer Inst. 90, 606611 (1998). Wagner, J. etal. High frequency of germline p53 mutations in childhood adrenocortical cancer. J.Natl Cancer Inst. 86, 17071710 (1994). Ohgaki, H., Kleihues, P & Heitz, P p53 . .U. mutations in sporadic adrenocortical tumors. Int. J. Cancer 54, 408410 (1993). Reincke, M. etal. p53 mutations in human adrenocortical neoplasms: immunohistochemical and molecular studies. J.Clin. Endocrinol. Metab. 78, 790794 (1994). Lib, R. etal. Somatic TP53 mutations are relatively rare among adrenocortical cancers with the frequent 17p13 loss of heterozygosity. Clin. Cancer Res. 13, 844850 (2007). Soon, P .S., McDonald, K.L., Robinson, B.G. & Sidhu, S.B. Molecular markers and the pathogenesis of adrenocortical cancer. Oncologist 13, 548561 (2008). Beuschlein, F., Fassnacht, M., Klink, A., Allolio, B. & Reincke, M. ACTH-receptor expression, regulation and role in adrenocortial tumor formation. Eur. J. Endocrinol. 144, 199206 (2001). Giordano, T.J. etal. Distinct transcriptional profiles of adrenocortical tumors uncovered by DNA microarray analysis. Am. J. Pathol. 162, 521531 (2003). de Reynis, A. etal. Gene expression profiling reveals a new classification of adrenocortical tumors and identifies molecular predictors of malignancy and survival. J. Clin. Oncol. 27, 11081115 (2009). Giordano, T.J. etal. Molecular classification and prognostication of adrenocortical tumors by transcriptome profiling. Clin. Cancer Res. 15, 668676 (2009). Szab, P .M. etal. Meta-analysis of adrenocortical tumour genomics data: novel pathogenic pathways revealed. Oncogene 29, 31633172 (2010). Icard, P etal. Adrenocortical carcinomas: . surgical trends and results of a 253-patient series from the French Association of Endocrine Surgeons study group. World J. Surg. 25, 891897 (2001). Crucitti, F., Bellantone, R., Ferrante, A., Boscherini, M. & Crucitti, P The Italian Registry . for Adrenal Cortical Carcinoma: analysis of a multiinstitutional series of 129 patients. The ACC Italian Registry Study Group. Surgery 119, 161170 (1996). Kendrick, M.L. etal. Adrenocortical carcinoma: surgical progress or status quo? Arch. Surg. 136, 543549 (2001). Schulick, R.D. & Brennan, M.F. Adrenocortical carcinoma. World J. Urol. 17, 2634 (1999). Dackiw, A.P Lee, J.E., Gagel, R.F. & ., Evans,D.B. Adrenal cortical carcinoma. World J. Surg. 25, 914926 (2001). Abiven, G. etal. Clinical and biological features in the prognosis of adrenocortical cancer: poor outcome of cortisol-secreting tumors in a series of 202 consecutive patients. J. Clin. Endocrinol. Metab. 91, 26502655 (2006). Stewart, P .M., Walker, B.R., Holder, G., OHalloran, D. & Shackleton, C.H. 11 beta-

44.

8.

45.

9.

46.

10.

47.

11.

48.

12.

49.

13.

50.

14.

51.

15.

52.

16.

53.

17.

54.

18.

55.

19.

56.

20.

57.

21.

58.

59. 60.

22.

23.

61.

24.

62.

NATURE REVIEWS | ENDOCRINOLOGY

2011 Macmillan Publishers Limited. All rights reserved

VOLUME 7 | JUNE 2011 | 333

REVIEWS
Hydroxysteroid dehydrogenase activity in Cushings syndrome: explaining the mineralocorticoid excess state of the ectopic adrenocorticotropin syndrome. J. Clin. Endocrinol. Metab. 80, 36173620 (1995). Seccia, T.M., Fassina, A., Nussdorfer, G.G., Pessina, A.C. & Rossi, G.P Aldosterone. producing adrenocortical carcinoma: an unusual cause of Conns syndrome with an ominous clinical course. Endocr. Relat. Cancer 12, 149159 (2005). Hyodo, T., Megyesi, K., Kahn, C.R., McLean, J.P . & Friesen, H.G. Adrenocortical carcinoma and hypoglycemia: evidence for production of nonsuppressible insulin-like activity by the tumor. J. Clin. Endocrinol. Metab. 44, 11751184 (1977). Wajchenberg, B. etal. Adrenocortical carcinoma: clinical and laboratory observations. Cancer 88, 711736 (2000). Luton, J.P etal. Clinical features of . adrenocortical carcinoma, prognostic factors, and the effect of mitotane therapy. N. Engl. J. Med. 322, 11951201 (1990). Allolio, B. & Fassnacht, M. Clinical review: Adrenocortical carcinoma: clinical update. J. Clin. Endocrinol. Metab. 91, 20272037 (2006). Lib, R., Fratticci, A. & Bertherat, J. Adrenocortical cancer: pathophysiology and clinical management. Endocr. Relat. Cancer 14, 1328 (2007). European Network for the Study of Adrenal Tumours Adrenocortical carcinomas [online], http://www.ensat.org/acc.htm (2010). Fassnacht, M. & Allolio, B. Clinical management of adrenocortical carcinoma. Best Pract. Res. Clin. Endocrinol. Metab. 23, 273289 (2009). Boland, G.W. etal. Characterization of adrenal masses using unenhanced CT: an analysis of the CT literature. AJR Am. J. Roentgenol. 171, 201204 (1998). Hamrahian, A.H. etal. Clinical utility of noncontrast computed tomography attenuation value (hounsfield units) to differentiate adrenal adenomas/hyperplasias from nonadenomas: Cleveland Clinic experience. J. Clin. Endocrinol. Metab. 90, 871877 (2005). Caoili, E.M. etal. Adrenal masses: characterization with combined unenhanced and delayed enhanced CT. Radiology 222, 629633 (2002). Ilias, I., Sahdev, A., Reznek, R.H., Grossman,A.B. & Pacak, K. The optimal imaging of adrenal tumours: a comparison of different methods. Endocr. Relat. Cancer 14, 587599 (2007). Heinz-Peer, G., Memarsadeghi, M. & Niederle, B. Imaging of adrenal masses. Curr. Opin. Urol. 17, 3238 (2007). Szolar, D.H. etal. Adrenocortical carcinomas and adrenal pheochromocytomas: mass and enhancement loss evaluation at delayed contrastenhanced CT. Radiology 234, 479485 (2005). Park, B.K., Kim, C.K., Kim, B. & Lee, J.H. Comparison of delayed enhanced CT and chemical shift MR for evaluating hyperattenuating incidental adrenal masses. Radiology 243, 760765 (2007). Hnigschnabl, S. etal. How accurate is MR imaging in characterisation of adrenal masses: update of a long-term study. Eur. J. Radiol. 41, 113122 (2002). Groussin, L. etal. 18F-Fluorodeoxyglucose positron emission tomography for the diagnosis of adrenocortical tumors: a prospective study in 77 operated patients. J. Clin. Endocrinol. Metab. 94, 17131722 (2009). Hahner, S. etal. [123I]Iodometomidate for molecular imaging of adrenocortical cytochrome P450 family 11B enzymes. J. Clin. Endocrinol. Metab. 93, 23582365 (2008). Khan, T.S. etal. 11C-metomidate PET imaging of adrenocortical cancer. Eur. J. Nucl. Med. Mol. Imaging 30, 403410 (2003). Hennings, J. etal. [11C]metomidate positron emission tomography of adrenocortical tumors in correlation with histopathological findings. J.Clin. Endocrinol. Metab. 91, 14101414 (2006). Sasano, H. etal. Transcription factor adrenal 4 binding protein as a marker of adrenocortical malignancy. Hum. Pathol. 26, 11541156 (1995). Hough, A.J., Hollifield, J.W., Page, D.L. & Hartmann, W.H. Prognostic factors in adrenal cortical tumors. A mathematical analysis of clinical and morphologic data. Am. J. Clin. Pathol. 72, 390399 (1979). van Slooten, H., Schaberg, A., Smeenk, D. & Moolenaar, A.J. Morphologic characteristics of benign and malignant adrenocortical tumors. Cancer 55, 766773 (1985). Weiss, L.M., Medeiros, L.J. & Vickery, A.L. Jr. Pathologic features of prognostic significance in adrenocortical carcinoma. Am. J. Surg. Pathol. 13, 202206 (1989). Weiss, L.M. Comparative histologic study of 43 metastasizing and nonmetastasizing adrenocortical tumors. Am. J. Surg. Pathol. 8, 163169 (1984). Morimoto, R. etal. Immunohistochemistry of a proliferation marker Ki67/MIB1 in adrenocortical carcinomas: Ki67/MIB1 labeling index is a predictor for recurrence of adrenocortical carcinomas. Endocr. J. 55, 4955 (2008). Terzolo, M. etal. Immunohistochemical assessment of Ki-67 in the differential diagnosis of adrenocortical tumors. Urology 57, 176182 (2001). Fassina, A.S., Borsato, S. & Fedeli, U. Fine needle aspiration cytology (FNAC) of adrenal masses. Cytopathology 11, 302311 (2000). Saeger, W. etal. High diagnostic accuracy of adrenal core biopsy: results of the German and Austrian adrenal network multicenter trial in 220 consecutive patients. Hum. Pathol. 34, 180186 (2003). Lumachi, F. etal. Fine-needle aspiration cytology of adrenal masses in noncancer patients: clinicoradiologic and histologic correlations in functioning and nonfunctioning tumors. Cancer 93, 323329 (2001). Lumachi, F. etal. Role and cost-effectiveness of adrenal imaging and image-guided FNA cytology in the management of incidentally discovered adrenal tumours. Anticancer Res. 25, 45594562 (2005). Quayle, F.J. etal. Needle biopsy of incidentally discovered adrenal masses is rarely informative and potentially hazardous. Surgery 142, 497502 (2007). Fassnacht, M. etal. Limited prognostic value of the 2004 International Union Against Cancer staging classification for adrenocortical carcinoma: proposal for a revised TNM classification. Cancer 115, 243250 (2009). Lee, J.E. etal. Surgical management, DNA content, and patient survival in adrenal cortical carcinoma. Surgery 118, 10901098 (1995). Lughezzani, G. etal. The European Network for the Study of Adrenal Tumors staging system is prognostically superior to the international union against cancer-staging system: a North American validation. Eur. J. Cancer 46, 713719 (2010). Schteingart, D.E. etal. Management of patients with adrenal cancer: recommendations of an international consensus conference. Endocr. Relat. Cancer 12, 667680 (2005). 99. Porpiglia, F. etal. Retrospective evaluation of the outcome of open versus laparoscopic adrenalectomy for stage I and II adrenocortical cancer. Eur. Urol. 57, 873878 (2010). 100. Brix, D. etal. Laparoscopic versus open adrenalectomy for adrenocortical carcinoma: surgical and oncologic outcome in 152 patients. Eur. Urol. 58, 609615 (2010). 101. Miller, B.S. etal. Laparoscopic resection is inappropriate in patients with known or suspected adrenocortical carcinoma. World J. Surg. 34, 13801385 (2010). 102. Leboulleux, S. etal. Adrenocortical carcinoma: is the surgical approach a risk factor of peritoneal carcinomatosis? Eur. J. Endocrinol. 162, 11471153 (2010). 103. Murphy, M.M. etal. Trends in adrenalectomy: a recent national review. Surg. Endosc. 24, 25182526 (2010). 104. Terzolo, M. etal. Adjuvant mitotane treatment for adrenocortical carcinoma. N. Engl. J. Med. 356, 23722380 (2007). 105. Huang, H. & Fojo, T. Adjuvant mitotane for adrenocortical cancera recurring controversy. J.Clin. Endocrinol. Metab. 93, 37303732 (2008). 106. Terzolo, M., Fassnacht, M., Ciccone, G., Allolio,B. & Berruti, A. Adjuvant mitotane for adrenocortical cancer--working through uncertainty. J. Clin. Endocrinol. Metab. 94, 18791880 (2009). 107. Berruti, A. etal. Adjuvant therapy in patients with adrenocortical carcinoma: a position of an international panel. J. Clin. Oncol. 28, e401e402 (2010). 108. Fassnacht, M. etal. Efficacy of adjuvant radiotherapy of the tumor bed on local recurrence of adrenocortical carcinoma. J. Clin. Endocrinol. Metab. 91, 45014504 (2006). 109. Polat, B. etal. Radiotherapy in adrenocortical carcinoma. Cancer 115, 28162823 (2009). 110. Sabolch, A. etal. Adjuvant and definitive radiotherapy for adrenocortical carcinoma. Int. J. Radiat. Oncol. Biol. Phys. doi:10.1016/ j.ijrobp.2010.04.030. 111. Fassnacht, M. etal. Improved survival in patients with stage II adrenocortical carcinoma followed up prospectively by specialized centers. J. Clin. Endocrinol. Metab. 95, 49254932 (2010). 112. US National Institutes of Health Clinicaltrials.gov [online], http://clinicaltrials.gov/ct2/show/ NCT00777244 (2010). 113. Bauditz, J., Quinkler, M. & Wermke, W. Radiofrequency thermal ablation of hepatic metastases of adrenocortical cancera case report and review of the literature. Exp. Clin. Endocrinol. Diabetes 117, 316319 (2009). 114. Wood, B.J., Abraham, J., Hvizda, J.L., Alexander,H.R. & Fojo, T. Radiofrequency ablation of adrenal tumors and adrenocortical carcinoma metastases. Cancer 97, 554560 (2003). 115. Jensen, J.C., Pass, H.I., Sindelar, W.F. & Norton,J.A. Recurrent or metastatic disease in select patients with adrenocortical carcinoma. Aggressive resection vs chemotherapy. Arch. Surg. 126, 457461 (1991). 116. Pommier, R.F. & Brennan, M.F. An eleven-year experience with adrenocortical carcinoma. Surgery 112, 963970 (1992). 117. Bellantone, R. etal. Role of reoperation in recurrence of adrenal cortical carcinoma: results from 188 cases collected in the Italian National Registry for Adrenal Cortical Carcinoma. Surgery 122, 12121218 (1997). 118. Schulick, R.D. & Brennan, M.F. Long-term survival after complete resection and repeat resection in patients with adrenocortical

81.

63.

82.

83.

64.

84.

65.

85.

66.

86.

67.

68.

87.

69.

88.

70.

89.

71.

90.

72.

91.

73.

92.

74.

93.

75.

76.

94.

77.

95.

78.

96.

97.

79.

80.

98.

334 | JUNE 2011 | VOLUME 7

2011 Macmillan Publishers Limited. All rights reserved

www.nature.com/nrendo

REVIEWS
carcinoma. Ann. Surg. Oncol. 6, 719726 (1999). 119. Erdogan, I. etal. Impact of surgery on clinical outcome in patients with recurrence of adrenocortical carcinoma. Endocrine Abstracts (10th European Congress of Endocrinology), 20, P194 (2009). 120. Khan, T.S. etal. Streptozocin and o,pDDD in the treatment of adrenocortical cancer patients: long-term survival in its adjuvant use. Ann. Oncol. 11, 12811287 (2000). 121. First International Randomized Trial in locally advanced and Metastatic Adrenocortical Cancer Treatment (FIRM-ACT) [online], http://www.firmact.org/ (2010). 122. Berruti, A. etal. Etoposide, doxorubicin and cisplatin plus mitotane in the treatment of advanced adrenocortical carcinoma: a large prospective phaseII trial. Endocr. Relat. Cancer 12, 657666 (2005). 123. Hahner, S. & Fassnacht, M. Mitotane for adrenocortical carcinoma treatment. Curr. Opin. Investig. Drugs 6, 386394 (2005). 124. Daffara, F. etal. Prospective evaluation of mitotane toxicity in adrenocortical cancer patients treated adjuvantly. Endocr. Relat. Cancer 15, 10431053 (2008). 125. Sperone, P etal. Gemcitabine plus metronomic . 5-fluorouracil or capecitabine as a second-/thirdline chemotherapy in advanced adrenocortical carcinoma: a multicenter phaseII study. Endocr. Relat. Cancer 17, 445453 (2010). 126. Hermsen, I.G., Groenen, Y.E., Dercksen, M.W., Theuws, J. & Haak, H.R. Response to radiation therapy in adrenocortical carcinoma. J. Endocrinol. Invest. doi:10.3275/6904. 127. Miller, J.W. & Crapo, L. The medical treatment of Cushings syndrome. Endocr. Rev. 14, 443458 (1993). 128. Schulte, H.M., Benker, G., Reinwein, D., Sippell,W.G. & Allolio, B. Infusion of low dose etomidate: correction of hypercortisolemia in patients with Cushings syndrome and doseresponse relationship in normal subjects. J. Clin. Endocrinol. Metab. 70, 14261430 (1990). 129. Fassnacht, M. etal. New mechanisms of adrenostatic compounds in a human adrenocortical cancer cell line. Eur. J. Clin. Invest. 30 (Suppl. 3), 7682 (2000). 130. Johanssen, S. & Allolio, B. Mifepristone (RU 486) in Cushings syndrome. Eur. J. Endocrinol. 157, 561569 (2007). 131. Castinetti, F. etal. Merits and pitfalls of mifepristone in Cushings syndrome. Eur. J. Endocrinol. 160, 10031010 (2009). 132. Quinkler, M. etal. Treatment of advanced adrenocortical carcinoma with erlotinib plus gemcitabine. J. Clin. Endocrinol. Metab. 93, 20572062 (2008). 133. Wortmann, S. etal. Bevacizumab plus capecitabine as a salvage therapy in advanced adrenocortical carcinoma. Eur. J. Endocrinol. 162, 349356 (2010). 134. Fassnacht, M., Kreissl, M.C., Weismann, D. & Allolio, B. New targets and therapeutic approaches for endocrine malignancies. Pharmacol. Ther. 123, 117141 (2009). 135. Berruti, A. etal. Emerging drugs for adrenocortical carcinoma. Expert Opin. Emerg. Drugs 13, 497509 (2008). 136. Carden, C.P etal. PhaseI study of intermittent . dosing of OSI-906, a dual tyrosine kinase inhibitor of insulin-like growth factor-1 receptor (IGF-1R) and insulin receptor (IR) in patients with advanced solid tumors. J. Clin. Oncol. 28 (Suppl.), abstr 2530 (2010). 137. Venkatesh, S., Hickey, R.C., Sellin, R.V., Fernandez, J.F. & Samaan, N.A. Adrenal cortical carcinoma. Cancer 64, 765769 (1989). 138. Vassilopoulou-Sellin, R. & Schultz, P .N. Adrenocortical carcinoma. Clinical outcome at the end of the 20th century. Cancer 92, 11131121 (2001). 139. Stojadinovic, A. etal. Adrenocortical carcinoma: clinical, morphologic, and molecular characterization. J. Clin. Oncol. 20, 941950 (2002). 140. Assi, G. etal. Prognostic parameters of metastatic adrenocortical carcinoma. J. Clin. Endocrinol. Metab. 92, 148154 (2007). 141. Volante, M. etal. Matrix metalloproteinase type2 expression in malignant adrenocortical tumors: Diagnostic and prognostic significance in a series of 50 adrenocortical carcinomas. Mod. Pathol. 19, 15631569 (2006). 142. Fenske, W. etal. Glucose transporter GLUT1 expression is an stage-independent predictor of clinical outcome in adrenocortical carcinoma. Endocr. Relat. Cancer 16, 919928 (2009). 143. Soon, P etal. Microarray gene expression .S. and immunohistochemistry analyses of adrenocortical tumors identify IGF2 and Ki-67 as useful in differentiating carcinomas from adenomas. Endocr. Relat. Cancer 16, 573583 (2009). 144. Ronchi, C.L. etal. Expression of excision repair cross complementing group 1 and prognosis in adrenocortical carcinoma patients treated with platinum-based chemotherapy. Endocr. Relat. Cancer 16, 907918 (2009). 145. Malandrino, P etal. Prognostic markers of . survival after combined mitotane- and platinumbased chemotherapy in metastatic adrenocortical carcinoma (ACC). Endocr. Relat. Cancer 17, 797807 (2010). Acknowledgments Work described in this Review was supported by grants of the Deutsche Krebshilfe (grant #107111 to M.Fassnacht), the German Ministry of Research BMBF (grant #01KG0501 to M. Fassnacht and B.Allolio) and the German Research Foundation DFG (grant #FA466/3-1 to M. Fassnacht). C.P. Vega, University of California, Irvine, CA, is the author of and is solely responsible for the content of the learning objectives, questions and answers of the Medscape, LLC-accredited continuing medical education activity associated with this article. Author contributions All authors researched the data for the article, provided a substantial contribution to discussions of the content, wrote the review and reviewed and edited the manuscript before submission.

NATURE REVIEWS | ENDOCRINOLOGY

2011 Macmillan Publishers Limited. All rights reserved

VOLUME 7 | JUNE 2011 | 335