Ad Re No Cortical Carcinoma

8/3/2019 Ad Re No Cortical Carcinoma

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Department o InternalMedicine I, EndocrineUnit, UniversityHospital, University o Würzburg,Oberdürrbacher

Stra ße 6, 97080Würzburg, Germany(M. Fassnacht ,M. Kroiss, B. Allolio).Department o Endocrinology, INCaCOMETE network,Cochin Hospital,University ParisDescartes, 24 Rue duFaubourg-Saint-Jacques, 75014 Paris,France ( R. Libé).

Correspondence to:M. Fassnacht

[email protected]

Adrenocortical carcinoma: a clinician’s updateMartin Fassnacht, Rossella Libé, Matthias Kroiss and Bruno Allolio

Abstract | Adrenocortical carcinoma is a rare heterogeneous neoplasm with an incompletely understoodpathogenesis and a poor prognosis. Previous studies have identi ied overexpression o insulin-like growth

actor 2 (IGF-2) and constitutive activation o β-catenin as key actors involved in the development o adrenocortical carcinoma. Most patients present with steroid hormone excess, or example Cushing syndromeor virilization, or abdominal mass e ects, but a growing proportion o patients with adrenocortical carcinoma(currently >15%) is initially diagnosed incidentally. No general consensus on the diagnostic and therapeuticmeasures or adrenocortical carcinoma exists, but collaborative e orts, such as international con erencesand networks, including the European Network or the Study o Adrenal Tumors (ENSAT), have substantiallyadvanced the ield. In patients with suspected adrenocortical carcinoma, a thorough endocrine and imagingwork-up is recommended to guide the surgical approach aimed at complete resection o the tumor. To

establish an adequate basis or treatment decisions, pathology reports include the Weiss score to assessmalignancy, the resection status and the Ki67 index. As recurrence is requent, close ollow-up initially every3 months is mandatory. Most patients bene it rom adjuvant mitotane treatment. In metastatic disease,mitotane is the cornerstone o initial treatment, and cytotoxic drugs should be added in case o progression.Results o a large phase III trial in advanced adrenocortical carcinoma are anticipated or 2011 and willhope ully establish a benchmark therapy. New targeted therapies, or example, IGF-1 receptor inhibitors, areunder investigation and may soon improve current treatment options.

Fassnacht, M. et al. Nat. Rev. Endocrinol. 7, 323–335 (2011); published online 8 March 2011; doi:10.1038/nrendo.2010.235

IntroductionIn contrast to benign adrenal tumors, which belong tothe most common human neoplasias with a prevalenceof >4%,1–4 adrenocortical carcinoma is a rare malignancy.Data from the National Cancer Institute survey and theSEER (Surveillance, Epidemiology and End Results)database estimate an incidence of 0.7–2.0 cases permillion population per year. 5–7 The incidence in adults ismaximal in those aged around 40–50 years, but the tumorcan appear at any age. 8 An unusually high incidence of adrenocortical carcinoma has been found in children insouthern Brazil—3.4–4.2 versus 0.3 per 1 million chil-dren younger than 15 years worldwide. The elevatedincidence is possibly related to a founder germ linemutation in TP53, the gene that encodes cellular tumorantigen p53, which is common in this sub population. 9,10

Adrenocortical carcinoma is more frequent in womenthan in men (ratio 1.5). Intriguingly, several case series 11–13 describe an increased occurrence of adrenocorticalcarcinomas on the left side rather than the right side of the body, which is confirmed by data from the Germanadreno cortical carcinoma registry (55% versus 45%;P = 0.009; n = 603).14 However, the mechanism behindthis observation is unknown.

P athophysiology and genetic alterationsProgress has been made in understanding the molecu-lar mechanisms of sporadic tumor development on thebasis of studies of rare genetic syndromes associated with

Competing interestsM. Fassnacht and B. Allolio declare an association with the

ollowing companies: HRA Pharma, OSI Pharmaceuticals. Seethe article online or ull details o the relationships. The otherauthors, the journal Chie Editor V. Heath and the CME questionsauthor C. P. Vega declare no competing interests.

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Learning objectivesUpon completion o this activity, participants should be able to:1 Distinguish common molecular alterations associated with

adrenocortical carcinoma.2 Evaluate the clinical presentation o adrenocortical carcinoma.3 Apply ancillary studies e ectively to diagnose adrenocortical

carcinoma.4 Treat adrenocortical carcinoma e ectively.

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adreno cortical carcinoma and of gene profiling studiesof these tumors. Genetic alterations, such as complete orpartial chromosome loss or gain, have been identifiedusing comparative genomic hybridization or micro satellitemarkers. Comparative genomic hybridization determinedchromosome losses at 1p, 17p, 22p, 22q, 2q and 11q inup to 62% of patients with sporadic adreno cortical carci-noma, 15 whereas microsatellite markers revealed a highprevalence of loss of heterozygosity (LOH) or allelicimbalance at chromosomes 11q13 (≥90%), 17p13 (≥85%)and 2p16 (92%) in patients with this disease. 16,17 Thesedata demonstrate a large and almost constant genetic dis-ruption in these tumors; as a consequence, genes that may have a pathophysio logical role need to be identified. Mostof these genes correspond either to oncogenes or to tumorsuppressor genes. Moreover, some of the molecular altera-tions are not only pathogenetically relevant but also of diagnostic, thera peutic and prog nostic value, for exampleinsulin-like growth factor 1 (IGF-1) and steroidogenicfactor 1 (SF1).

O ncogenesIGF‑2IGF signaling is involved not only in the development butalso in the maintenance of differentiated adreno corticalfunctions. In addition, a pathophysiological role for thissignaling pathway has also been documented in adreno-cortical tumors. 17 The IGF‑2 gene, which is located onchromosome 11p15, encodes a fetal growth factor that isexpressed exclusively from the paternally inherited allele

Key points

■ Overexpression o insulin-like growth actor 2 and constitutive activation o β-catenin are key molecular alterations in adrenocortical carcinoma

■ Detailed presurgical endocrine and imaging work-up and an expert surgeon arekey prerequisites or a complete resection that o ers the best chance o cure

■ Even a ter radical resection, recurrence rate is high and, there ore, mostpatients bene it rom adjuvant treatment strategies (mitotane with or without

radiotherapy) ■ Mitotane is the most e ective single drug or adrenocortical carcinoma, but drug

monitoring is important and management o adverse events is demanding

■ In advanced disease not amenable to surgery, mitotane is given as monotherapyor in combination with cytotoxic chemotherapy (either etoposide combined withdoxorubicin and cisplatin or streptozotocin)

■ To acilitate progress in the treatment o adrenocortical carcinoma, patientsshould be enrolled in clinical trials

owing to maternal imprinting. 18 Genetic or epi geneticdefects in the imprinted 11p15 region can increase IGF‑2 expression (Table 1), as in patients with Beckwith–Wiedemann syndrome (BWS), with macro somia,organo megaly and predisposition to the develop ment of multiple tumors, including adreno cortical carcinoma. 19 High overexpression of IGF‑2 mRNA is observed in the vast majority of adrenocortical carcinomas. 20,21 It occursmostly through loss of the maternal allele and duplica-tion 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 ismediated via the IGF-1 receptor (Figure 1a,b). 22 Analysisof the 11p15 locus is useful in adrenocortical tumors,as 11p15 LOH is significantly more frequent in adreno-cortical carcinoma than in the benign adrenocorticaladenoma (78.5% versus 9.5%) and is associated with ahigher risk of tumor recurrence. 17

β ‑cateninGenetic alterations of the Wnt signaling pathway, whichwere initially identified in patients with familial adeno-matous polyposis coli (APC), have been found in a variety of cancers;23 occasionally, adrenocortical tumors have beenobserved in familial APC (Table 1). 24 The Wnt signalingpathway is active during normal embryonic develop-ment, and β-catenin is a key component of this signalingpathway. Constitutive activation of β-catenin is the mostfrequent alteration in benign and malignant adreno-cortical tumors. 25,26 In a subset of these tumors, somaticmutations of the β-catenin gene inactivate its phosphory-lation site for glycogen synthase kinase 3β (GSK3β).25 Wntsignaling correlates with intracellular β-catenin concen-tration (Figure 1c,d). In a transgenic mouse model, con-stitutive β-catenin activation induces adrenal hyperplasiaand promotes adrenal cancer development. 27

Steroidogenic factor 1SF1 plays an important part in adrenal development, 28–30 and previous studies have demonstrated SF1 over-expression in most cases of childhood onset, but also inmany cases of adult onset, adrenocortical tumors. 31–34 Inaddition, elevated levels of SF1 have been shown to increaseproliferation of human adrenocortical cells in vitro andto induce tumorigenesis in mice. 35,36 Accordingly, SF1-stimulated adrenocortical cell pro liferation was inhibitedby SF1 inverse agonists in vitro.37

Table 1 | Genetic syndromes associated with adrenocortical carcinoma

Syndrome Chromosomallocalization

Genes Signalingpathway

Cause of sporadic adrenocortical carcinoma

Beckwith–Wiedemann syndrome 11p15 CDKN1C IGF‑2H19

IGF 11p15 paternal isodisomyIGF‑2 overexpression

Familial adenomatouspolyposis coli

5q12-22 APC Wnt APC mutation (rare)β-catenin ( CTNNB1) somatic mutation

Li–Fraumeni syndrome 17p13 TP53 p53 TP53 germline mutations in childrenTP53 somatic mutations in adults17p13 loss o heterozygosity

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Growth factorsVarious growth factors and/or cytokines other than IGFsalso regulate growth and function of normal fetal and adultadrenal glands, for example, basic fibroblast growth factor(FGF2), transforming growth factor (TGF) α, TGF-β 1 and vascular endothelial growth factor (VEGF). 38–41 Expres-sion of VEGF is higher in adreno cortical carcinoma than

in adrenal adenomas. 41,42 However, the high expressionof VEGF contrasts with a low vascularization in adreno-cortical carcinoma, which indicates a dissociation of the angiogenic status and the neo angiogenic capabili-ties of these tumors. 42 Interestingly, serum VEGF levelswere significantly higher in patients with adreno corticalcarcinoma than in patients with adrenal adenomas or

Paternal allele

CDKN1C (p57kip2 )

IGF-2 H19

IGF-1R

aIGF-2

IGF-2

IGF-1

IGF-2

Paternal allele

Paternal isodisomy

Paternal allele

CDKN1C (p57kip2 )

IGF-2 H19

b

IGF-2

IGF-1R

IGF-2

IGF-2

IGF-2

IGF-2

IGF-2IGF-2

IGF-2

c d

β-catenin

β-catenin

β-catenindegradation

(proteasome)

α-catenin

β-catenin

β-catenin

β-cateninβ-catenin

β-catenin β-catenin

α-catenin

β-cateninTCF/LEF

P

PDsh

DshAxin

Axin

WTX

WTX

Wnt

Wnt

Wnt

APC

APC

GSK3 β

GSK3 β

P

P

Maternal allele

Figure 1 | Pathophysiologically relevant pathways in adrenocortical carcinoma. a,b | Alterations o 11p15 locus and IGF‑2 overexpression in adrenocortical carcinoma. The imprinted 11p15 locus contains the genes CDKN1C (p57kip2), IGF‑2, andH19 . a | In normal di erentiated tissue, only the paternal allele o the IGF‑2 gene and maternal alleles o CDKN1C and H19 are expressed. b | In adrenocortical carcinoma, paternal isodisomy with loss o the maternal allele at 11p15 is requentlyobserved, which leads to the overexpression o IGF‑2. IGF-2 can then act as an autocrine growth actor through binding tothe IGF-1 receptor to promote proli eration o adrenocortical carcinoma cells. c,d | The Wnt signaling pathway. c | In theabsence o Wnt signaling, the level o β-catenin is low owing to degradation by the ubiquitin–proteasome system a terphosphorylation at critical NH 2-terminal residues by the GSK3 β kinase bound to a sca olding complex o axin and APC.d

| Wnt stimulation leads to the inactivation o GSK3 β and thereby the stabilization o β-catenin in the cytoplasm. A tertranslocation to the nucleus, β-catenin stimulates expression o target genes a ter interaction with TCF/LEF. Mutations o β-catenin abolish or reduce GSK3 β phosphorylation o β-catenin, which leads to its accumulation by preventing itsdegradation by the ubiquitin–proteasome system. Abbreviations: APC, adenomatosis polyposis coli; GSK3 β, glycogensynthase kinase 3 β; IGF, insulin-like growth actor; TCF/LEF, T-cell actor/lymphoid enhancer actor.

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healthy indivi duals.43 Data on epidermal growth factorreceptor ( EGFR) demonstrated that this receptor isoverexpressed in most adreno cortical carcinomas buthardly expressed in adenomas. How ever, no mutationsof the EGFRgene were found, and ex pression was not of prognostic relevance. 44

Tumor suppressor genesTP53Germline mutations in the TP53 gene, located on17p13 (Table 1), are present in 70% of families withLi–Fraumeni syndrome. This syndrome confers suscep-tibility to breast carcinoma, soft tissue sarcoma, braintumors, osteo sarcoma, leukemia and adrenocorticalcarcinoma. 45 These tumors have an early onset and affectmostly children and young adults. Germline mutationsin TP53 have been observed in 50–80% of children withapparently sporadic adrenocortical carcinoma. 46 Inadults, somatic mutations of TP53 are found in 20–35%of cases of sporadic adrenocortical carcinoma 47–49 andmight be associated with more aggressive and advancedtumors. 49 LOH at 17p13 has been reported more fre-quently in patients with adreno cortical carcinoma thanin those with adrenocortical adenoma (85% versus 30%)and is an independent predictive marker of recurrenceafter complete surgical removal of localized tumors. 17

The discrepancy between the prevalence of somaticTP53 mutations (33%) and that of 17p13 LOH (85%)is suggestive of another tumor suppressor gene in thislocus. A minimal region of loss on 17p13 has been identi-fied in adrenocortical carcinomas, 50 whereas no minimalregion of loss could be demonstrated for adrenocorticaladenomas. Compared with adrenocortical adenomas, asignificant downregulation of two genes which map tothis region, ACADVLand ALOX15B, was demonstratedin adrenocortical carcinomas. 50

Melanocortin 2 receptor The melanocortin 2 receptor (MC2R; also known as theACTH receptor) belongs to the G-protein-coupled recep-tor superfamily, and its gene is located on chromosome18p11.2. MC2R LOH has been observed in two of fourinformative adrenocortical carcinomas, but not in 15hypersecreting adrenocortical adenomas, which suggestsa role for MC2R in cellular differentiation. Accordingly, MC2RmRNA expression is upregulated in patients withfunctional adrenocortical adenomas but downregulated

in those with nonfunctional adrenocortical adenomasor carcinomas. 51

G ene profiling of adrenocortical carcinomaBy use of large-scale analyses of gene expression, so-called transcriptome analyses, the gene expressionprofile of benign adrenocortical tumors was consistently shown to differ markedly from that of adrenocorticalcarcinomas, 41,52 which suggests that this analysis couldoffer new diagnostic tools. Transcriptome analysis of adreno cortical tumors has confirmed that IGF‑2 is themost upregulated gene in adrenocortical carcinoma com-pared with adrenocortical adenoma or healthy adrenal

glands.41 Moreover, a micro array approach has shownthe frequent activation of Wnt signaling target genes inadrenocortical carcinoma. 52

In an unsupervised cluster analysis, two new molecularmarkers, DLGAP5and PINK1, were found to be differen-tially expressed between recurring and non recurringadrenocortical tumors, thereby demonstrating their diag-nostic usefulness. 53 Moreover, independent analyses ledto the discrimination of two different types of adreno-cortical carcinoma, with either poor or good prognosis,which indicates that transcriptome analysis could alsouncover new prognostic factors. 53,54 Furthermore, a meta-analysis of gene expression microarray and comparativegenomic hybridization studies revealed three majorpathogenic pathways in adrenocortical tumors: first,damage of cell cycle; second, alteration in retinoid acidsignaling; and third, alteration in antigen presentationand the complement system. 55

C linical presentationMost patients with adrenocortical carcinoma (50–60% of cases) seek medical advice because of clinical evidenceof adrenal steroid hormone excess .

8,13,56–61 In function-ing adrenocortical carcinoma, signs and symptoms of Cushing syndrome are the most frequent presentation.However, rapid development of the disease often leadsto an altered clinical pattern of Cushing syndrome,with little or no weight gain, profound muscle atrophy,severe hypertension and diabetes mellitus as the domi-nating features. Massive hypercortisolism activatesmineralo corticoid receptors by overriding the inacti- vating capacity of corticosteroid 11β-dehydrogenaseisozyme 2 (HSD11B2), which consecutively causes severehypokalemia. 62 A high percentage of affected womendevelop signs and symptoms of androgen excess (acne,hirsutism, androgenetic effluvium, oligomenorrhea) and virilization without or with concomitant Cushing syn-drome. Estrogen-secreting adrenocortical carcinoma inmen leads to feminization, with gynecomastia of recentonset, loss of libido and testicular atrophy. However, of 195 men with adrenocortical carcinoma in the Germanadrenocortical carcinoma registry only 14 showed clinicalevidence of feminization (7%). 14 Aldosterone-producingadrenocortical carcinoma is rare and manifests as hyper-tension with profound hypokalemia. 63 Tumor-inducedhypoglycemia has been repeatedly described in patientswith adrenocortical carcinoma and is most probably

the result of increased glucose utilization induced by paracrine release of IGF-2. 64–66

Patients with a nonfunctioning adrenocortical carci-noma usually show symptoms of abdominal discomfort(nausea, vomiting, abdominal fullness) or back paincaused by the local mass effect of the rapidly growingneoplasia. Few cases initially present as retroperitonealhemorrhage from spontaneous tumor rupture. By con-trast, non specific 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

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discovered incidentally. In a series from the Germanadreno cortical carcinoma registry, 17.7% of 581 patientswere found to have an adrenal incidentaloma. 14

D iagnostic proceduresA comprehensive diagnostic work-up in patients withsuspected or proven adrenocortical carcinoma has beenrecommended by the European Network for the Study of Adrenal Tumors (ENSAT; Table 2). 67–69

Laboratory work-upA thorough initial hormonal work-up is needed, asdemon stration of autonomous steroid hormone excessestablishes the adrenocortical origin of the tumor andexcludes relevant other differential diagnosis, for example,pheochromocytoma or lymphoma. In fact, the hormoneprofile is often already highly suggestive of an adreno-cortical carcinoma before surgery, for example, owing toevidence of co-secretion of glucocorticoids, sex steroidsand steroid precursors. Importantly, the pre operativesteroid hormone pattern can serve as a fingerprint of thetumor 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 carcinomaundergo 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 mis diagnosisand unexpected intraoperative complications.

ImagingImaging plays a key part in the differential diagnosis of anadrenal mass, with CT and MRI being equally effective.Typically, adrenocortical carcinomas are inhomogeneoustumors with evidence of necrosis or hemorrhage andirregular margins. At the time of diagnosis, the mediantumor size is >10 cm, with size a valuable parameter toindicate malignancy. 70

Thin collimation CT Thin collimation CT offers high spatial resolution anddetection of invasion into the surrounding structures.Measurement of Hounsfield units (HU) in unenhancedCT has been helpful to differentiate benign from malig-nant adrenal lesions. By use of a threshold value of 10 HU, sensitivity and specificity for characterizing anadrenal mass as a benign adenoma in unenhanced CT are71% and 98%, respectively.70 In adrenal masses with anunenhanced HU value of >10, delayed post contrast CTtypically shows an enhancement washout of <50% and adelayed attenuation of >35 HU in malignant lesions. 71–77

Table 2 | Diagnostic work-up in patients with suspected or proven adrenocortical carcinoma*

Hormonal work-up Tests

Glucocorticoid excess (minimum 3 outo 4 tests)

Dexamethasone suppression test (1 mg, 2300 h)Excretion o ree urinary cortisol (24 h urine)Basal cortisolBasal ACTH (plasma)

Mineralocorticoid excess PotassiumAldosterone:renin ratio (only in patients with ar terial hypertension and/or hypokalemia)

Sex steroids and steroid precursors DHEAS17OH-progesteroneAndrostenedioneTestosterone17 β-estradiol (only in men and postmenopausal women)

Exclusion o a pheochromocytoma Fractionated metanephrines in 24 h urine or ree plasma metanephrines

Imaging CT or MRI o abdomen ‡ and CT o thoraxBone scintigraphy (i skeletal metastasis is suspected)FDG-PET (optional)

*Recommendation o the adrenocortical carcinoma working group o the European Network or the Study o Adrenal Tumors (ENSAT). 69 ‡Modern imaging is able toidenti y most adenomas correctly. However, measurement o Houns ield units (HU), be ore contrast media and calculation o washout 10 min or 15 min a tercontrast media or MRI with chemical shi t analysis is needed to provide optimal diagnostic yield. Abbreviations: ACTH, adrenocorticotropic hormone; DHEAS,dehydroepiandrosterone sul ate; FDG, luorodeoxyglucose.

Figure 2 | Imaging studies per ormed in a patient withadrenocortical carcinoma. a | Computerized tomographythat shows a tumor o 17 × 14 × 18 cm, indicated by acircle. b | 18 F- luorodeoxyglucose-PET, in which the tumor isindicated by an arrow, demonstrated a high tracer uptakewith SUVmax o 10.2 and an SUV adrenal:liver ratio o 2.4.A ter surgery, adrenocortical carcinoma was con irmed byhistopathology with a Weiss score o 5. Abbreviation: SUV,standardized uptake value.

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Multiplanar MRIMultiplanar MRI is well-suited to separate adrenal massesfrom surrounding structures, such as liver or spleen, and

extremely useful to guide the surgical approach to thetumor. Adrenocortical carcinomas typically produce thesame signal intensity as liver on T1-weighted images andshow an increase in intensity in T2-weighted sequences.A clear enhancement after administration of gadoliniumis followed by a slow wash-out. By use of modern tech-nology, including chemical shift MRI, the sensi tivity fordifferentiating benign from malignant adrenal lesions hasbeen around 81–89%, with a specificity of 92–99%.75,78

18 F‑fluorodeoxyglucose PET A major diagnostic advance represents 18F-fluorodeoxy-glucose (18F-FDG) PET, as virtually all patients with

adrenocortical carcinomas demonstrate high uptake of 18F-FDG, with an adrenal to liver maximum standardizeduptake value (SUV) ratio >1.45 (Figure 2). In a prospec-tive study of 77 operated patients, the sensitivity andspecificity to distinguish adenomas from adreno corticalcarcinomas were 100% and 88%, respectively.79 Thus, inindeterminate cases, 18F-FDG-PET is highly useful todefine the malignant potential of an adrenal mass.

However, not CT, MRI, nor FDG-PET can reliably differentiate an adrenocortical carcinoma from a pheo-chromocytoma or adrenal metastasis. To answer thisquestion, metomidate is emerging as a new radio tracer.Metomidate specifically binds to adrenal 11β-hydroxylaseand aldosterone synthase; therefore, uptake indicates theadrenocortical origin of a lesion. 80 Metomidate can be givenas 11C-metomidate for PET 81,82 or as 123I-iodometomidatefor single photon emission CT (SPECT) imaging. 80

HistopathologyThe pathological differential diagnosis of adrenal neo-plasias is still largely based on morphological features thatrequire an experienced pathologist who is also familiarwith rare tumor subtypes, such as pediatric or oncocyticadrenal tumors. Several markers have been introducedto establish the adrenocortical origin of an adrenal mass.Already in 1995, Sasano et al.83 suggested SF1 as a markerto differentiate between tumors of adreno cortical andnonadrenocortical origin. The value of this marker hasbeen confirmed in a large cohort, in which SF1 immuno-histochemistry was positive in >95% of all adreno corticaltumors but none of the nonsteroidogenic tumors. 34 Inaddition, SF1 provides prognostic information that isindependent of tumor stage. 34 For the diagnosis of car-cinoma versus adenoma, different diagnostic scores 84,85 have been introduced; the Weiss score 86,87 is the mostpopular and consists of para meters related to tumor struc-ture, cytology and evidence of tumor invasion. Importantinformation is provided by immuno histochemistry withthe Ki67 index, which can help differentiate carcinomasfrom adenomas. In addition, our experience with Ki67staining in over 320 cases, together with smaller previousstudies, indicates that a high Ki67 index is associated withshortened disease-free and overall survival. 88,89 Of furtherimportance is the careful definition of the resection status:R0 (complete resection), R1 (microscopic residual tumor)or R2 (macroscopic residual tumor), which is a majorpredictor of prognosis. Similarly, violation of the tumor

capsule is associated with early recurrence and needs tobe 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 beenreported. On the other hand, in some small series, highdiagnostic sensitivity, specificity and positive predictive values have been demonstrated. 90–93 However, ‘real world’data from one study indicates limited diagnostic yield andrelevant adverse effects.94 From our experience, therefore,only two indications for biopsy of an adrenal mass (after

Table 3 | ENSAT staging or adrenocortical carcinoma

Stage ENSAT tumor stage 2008

I T1, N0, M0

II T2, N0, M0

III T1–2, N1, M0T3–4, N0–1, M0

IV T1–4, N0–1, M1

T1, tumor size ≤5 cm; T2, tumor size >5 cm; T3, tumor in iltration insurrounding tissue; T4, tumor invasion in adjacent organs or venous tumorthrombus in vena cava or renal vein. N0, no positive lymph nodes; N1,positive lymph node(s); M0, no distant metastases; M1, presence o distantmetastasis. Abbreviations: ENSAT, European Network or the Study o AdrenalTumors; M, metastasis; N, lymph node; T, tumor. Permission obtained romJohn Wiley and Sons © Fassnacht, M. et al. Cancer 115 , 243–250 (2009).

100 –

80 –

60 –

40 –

20 –

0 –

0 1 2 3Time (years)

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

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

D i s e a s e - s

p e c

i c s u r v

i v a

l ( % )

4 5 6 7 8 9 10

Figure 3 | Disease-speci ic survival according to tumorstage data rom the European Network or the Study o Adrenal Tumors (ENSAT), which includes ollow-up data

rom 566 patients derived rom the German adrenocorticalcarcinoma registry in July 2010. Adapted with permission

rom John Wiley and Sons © Fassnacht, M. et al. Cancer 115 , 243–250 (2009).

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exclusion of a pheochromocytoma) seem reasonable:first, to establish the diagnosis in an already metastasizedadrenal tumor in which surgery is not intended; second,to exclude or demonstrate metastatic disease in a patientwith a history of an extra-adrenal malignancy, providedthe result may affect treatment.

StagingTumor staging is a widely used tool to assess prognosisin patients with cancer. For adrenocortical carcinoma,the tumor–node–metastasis (TNM) classification pro-posed by ENSAT is recommended (Table 3). 95 Thisstaging 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, respec-tively. Stage III tumors are characterized by infiltrationin surrounding tissue, positive regional lymph nodes ora tumor thrombus in the vena cava and/or renal vein,whereas stage IV is def ined by the presence of distantmetastasis. The high prognostic potential of the ENSATstaging system has been established in the large cohortof the German adreno cortical carcinoma registry (Figure 3)95 and has been confirmed in the independentSEER cohort,97 which demonstrates its superiority to thestaging system published by the Union InternationaleContre Le Cancer (UICC). To detect metastatic diseaseearly, careful staging investigations, including chest CT,are required before surgery, as removal of the primary tumor is often of questionable value in metastaticadreno cortical carcinoma (stage IV).

Follow-up investigationsEven in patients with seemingly localized adreno corticalcarcinoma, recurrence after surgery is frequent. Early detection is important, as local recurrence or limitedmetastatic disease may be amenable to complete resec-tion (R0), often followed by a long period of disease-free survival. Furthermore, limited evidence supportsthe theory that surgery for tumor recurrence may alsoprolong overall survival. Thus, for detection of recur-rence, imaging (CT of the chest and CT and/or MRI of the abdomen) should be performed every 3 months,together with monitoring of initially elevated steroidlevels. After the first 2 years of follow-up, intervals may be gradually increased. How ever, follow-up in patientswithout evidence of disease is recommend ed over aminimum of 10 years after surgery.

TherapyUntil now, no single randomized trial in adrenocorticalcarcinoma has been published. The levels of evidence fortreatment recommendations are, therefore, at best level 2,but mostly level 3–4.98 Thus, all patients should be enrolledin clinical trials, which are increasingly available.

Tumors amenable to radical resectionComplete surgical resection is the treatment of choicein adrenocortical carcinoma, as it is virtually the only option to achieve cure. For localized tumors, a key ques-tion concerns the optimal surgical approach. In patients

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

Table 4 | Radiotherapy or adrenocortical carcinoma

Setting Indication Dosage

Adjuvant Strongly recommended a ter R1 resectionin ENSAT stage I–III tumorsRecommended a ter Rx resection in ENSATstage I–III tumorsIndividualized decision: R0 resection inhigh-risk patients*

Not recommended: R2 resection‡

and ENSATstage IV tumors

>40 Gy (1.8–2.0 Gy perraction)

Limited boost volume(tumor bed) to reach50–60 Gy

Palliative Bone metastasis with spinal cord compressionThoracic or abdominal metastasis withvena cava obstructionPain ul thoracic or abdominal metastasisSymptomatic cerebral metastasis

30 Gy in 10 ractionsAlternatively, shor t-term

ractionations (up to singletreatment with 8 Gy)

*Arguments or radiotherapy: microscopic tumor invasion o blood vessels and Ki67 score ≥10%. Argumentagainst radiotherapy: tumor size ≤8 cm. ‡Consider re-surgery by an exper t surgeon. Abbreviations: R0, completeresection; R1, microscopic residual tumor; R2, macroscopic residual tumor; Rx, unknown resection status.

ACC amenable to complete resection

Complete resection (R0)

Ki67 ≤10% Ki67 >10%

Rx/R1 resection

Low–intermediate risk High risk

Tumor free Recurrence

>12 months pluscomplete resection feasible

Consider adjuvantmitotane

Adjuvant mitotaneConsider additional therapy

Follow-up every 3 monthsImaging and tumor markers

Adjuvant mitotane plusirradiation of the tumor bed

Within 6 months*or not resectable

1

2

3

4 5

6

Figure 4 | Treatment o adrenocortical carcinoma amenable to complete resection.(1) Adrenocortical carcinomas amenable to complete resection include all patientswith stage I and II tumors, most patients with stage III tumors and selectedpatients 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 seeFigure 5. (3) I Ki67 staining is not available, a high proli erative index (>5 mitosesper 50 high-power ields) may be used or risk strati ication. Patients with stage IVor recurrence are judged high-risk patients independent o Ki67 index. (4) The

ollowing actors are suggestive o a low risk o recurrence: tumor size <8 cm, no

microscopic evidence o invasion o blood vessels or tumor capsule. I all theseactors are ul illed, observational ollow-up may be justi ied. (5) Parametersavoring additional radiotherapy o the tumor bed: microscopic tumor invasion o

blood vessels and capsule and a Ki67 index ≥20%. A tumor thrombus in the venacava avors additional streptozotocin therapy. (6) A ter 2 years, the time intervalsare gradually extended. *For treatment o advanced adrenocortical carcinoma notamenable to radical surgery see Figure 5. Abbreviations: ACC, adrenocorticalcarcinoma; R1, microscopic residual tumor; Rx, unknown resection status.Adapted with permission rom John Wiley and Sons © Fassnacht, M. & Allolio, B.Clin. Endocrinol. (Oxf.) 73 , 561–565 (2010).

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that stage I and II adrenocortical carcinomas can beremoved as safe by laparoscopic adrenalectomy as by open surgery, 99,100 although this notion remains a matterof debate.101,102 Nevertheless, a laparoscopic approach foradrenal tumors judged preoperatively as only potentially malignant (for example, endocrine inactive incidenta-loma with evidence of tumor growth) is justified on thebasis of current data. 99,100

Given that complete resection is the single most impor-tant therapeutic measure, surgery for adreno corticalcarcinoma should be performed by a specialized surgeonwho 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 adreno-cortical carcinoma should be limited to centers with >20adrenalectomies per year and experience in surgery foradrenocortical carcinoma.

Adjuvant treatmentMost published data indicate a high rate of recurrenceeven after complete resection, which clearly suggestsa need for adjuvant treatment concepts. The best evi-dence for a role of adjuvant treatment derives from alarge retrospective study by Terzolo and colleagues. 104 In this multicenter study with two independent controlgroups, the risk of recurrence and death was significantly

reduced by adjuvant use of the adrenolytic agent mito-tane (median re currence-free survival 42 months versus10 and 25 months in the two control groups; P < 0.01).Although this study was not a randomized trial, the factthat the decision for or against mitotane was center-driven rather than patient-driven reduced the selectionbias in this study comparison with prior reports. 67 Mostbut not all centers, therefore, now recommend adjuvantmitotane after complete resection. 68,105–107 In patientswith incomplete resection (R1) or uncertain resectionstatus (Rx), adjuvant radiotherapy should be offered inaddition to mitotane as an approach to reduce the highrisk of local recurrence (Table 4). 108–110 In some patients,adjuvant streptozotocin in combination with mitotanemight be justified. Guidance for risk stratification is givenin Figure 4.

Almost all published case series suffer from a markedselection bias, as was recently demonstrated by an analy-sis from the German adrenocortical carcinoma regis-try. 111 This study demonstrated that patients who remainfree of disease after surgery rarely contact a specializedcenter. Hence, patients with high risk of recurrence areclearly overrepresented in most reports. Thus, the overallprognosis of early-stage adrenocortical carcinoma mightbe substantially better than previously reported, and theneed for adjuvant therapy in all patients with adreno-cortical carcinoma is no longer obvious. To address thisimportant issue, the ADIUVO (Efficacy of AdjuvantMitotane Treatment) study, a randomized trial in low-to-intermediate risk patients (mitotane versus observationonly) has been initiated and is currently recruiting. 112

Surgery is also recommended in patients with meta-static disease, but only if radical resection seems fea-sible. In some patients, a second surgery (for example,for resection of lung metastases) is needed to remove alltumoral lesions. Radiofrequency ablation is an alterna-tive for selected metastases <5 cm. 113,114 However, evenafter removal of all tumor manifestations, these patientswith stage IV tumors suffer from systemic disease andrequire postoperative medical treatment.

Recurrent diseaseReports on treatment of recurrent adrenocortical carci-noma are scarce. 115–118 Although most reports favor a surgi-cal approach, surgery should only be performed if the timebetween a first operation and recurrence is 6–12 months,and complete resection is achievable, 119 as only then can

a clinically relevant period of disease-free survival beexpected. After surgery for recurrence, adjuvant therapy must be started as soon as possible. In patients with recur-rent disease despite adjuvant mitotane therapy, additionof another drug, such as streptozotocin, 120 or radiotherapy for local recurrence should be considered.

Advanced diseaseIn advanced disease, debulking surgery is only of benefitin patients with severe hormone excess that cannot becontrolled otherwise. Instead, medical therapy shouldbe initiated as soon as the diagnosis is established. Untilthe results of the FIRM-ACT trial 121 become available, the

Box 1 | Recommended medical treatment in advanced adrenocortical carcinoma

Mitotane monotherapy* ■ Start with 1.5 g daily and increase dose within 4–6 days to 6.0 g per day ‡

■ A ter 3 weeks, adapt dosage according to tolerability and blood level;i mitotane 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 o 14–20 mg/l. With this regimen, about 50%o patients achieve target levels within 3 months

Etoposide, doxorubicin and cisplatin plus mitotane* §

■ Every 28 days:

■ Day 1: 40 mg/m 2 doxorubicin

■ Day 2: 100 mg/m 2 etoposide

■ Day 3 and 4: 100 mg/m 2 etoposide plus 40 mg/m 2 cisplatin

■ Plus oral mitotane aiming at a blood level between 14–20 mg/l

Streptozotocin plus mitotane* §

■ Induction (day 1–5): 1 g streptozotocin per day

■ A terwards: 2 g streptozotocin every 21 days

■ Plus oral mitotane aiming at a blood level between 14–20 mg/l

Gemcitabine plus capecitabine ||

■ 800 mg/m 2 gemcitabine on day 1 and 8 (repeated every 3 weeks)

■ 1,500 mg capecitabine orally per day in a continuous ashion

*Available data suggest a response rate or mitotane o 26%, 119 or etoposide, doxorubicin,cisplatin and mitotane o 49% 117 and or streptozotocin and mitotane o 36%. 118 However, CIsoverlap, thus not allowing a direct comparison. ‡In patients su ering rom impaired healthstatus, a slower increase o dosage is recommended. During right-sided radiotherapy, we donot recommend to administer >3 g daily. §These regimens are currently compared in arandomized phase III trial, the results o which are expected in 2011. 121 ||Alternative regimen

or second or third-line therapy. Results o a phase II trial reported that 13 o 28 patients hadstable disease or more than 4 months. 121

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http://slidepdf.com/reader/full/ad-re-no-cortical-carcinoma 9/13



study of 45 patients treated with platinum-based chemo-therapy, the expression of the DNA repair gene ERCC1was correlated with overall survival after treatment; ina multivariate analysis, the hazard ratio for death was2.2 (P = 0.038) for high ERCC1expression. 144 Althoughthis result was not confirmed in a French cohort of 44patients, 145 this study represents the first attempt towardsindividualized medicine for adrenocortical carcinoma.

C onclusionsWithin the past decade, collaborative internationalefforts have paved the way for unprecedented prog-ress in the care of patients with adrenocortical carci-nomas. Insights into the molecular pathogenesis of adrenocortical carcinoma have led to the first clinicaltrials using targeted strategies, such as IGF-1R inhibi-tors. The European network ENSAT has established a validated adrenocortical carcinoma staging system 95 andhas outlined a detailed work-up for patients with sus-

pected adrenocortical carcinoma (Table 2). Following aconsensus meeting in September 2003, 98 the first everphase III trial in adrenocortical carcinoma was initiated

and will, in 2011, hopefully lead to a first-line treatmentin advanced adrenocortical carcinoma that fulfills thestandards of high-level, evidence-based medicine. Moreimportantly, this trial has established an internationalstructure instrumental for further clinical trials, suchas ADIUVO and OSI-906. Based on these internationalefforts, we expect that within the coming decade thecombination of basic science, translational researchand clinical trials will substantially improve the clinicaloutcome of patients with this rare disease.

Review criteria

Original articles and reviews in English were identi iedusing a PubMed search strategy covering the time periodup until August 2010. The ollowing search terms wereused in varying combinations: “adrenal”, “adrenocortical”,“cancer”, “carcinoma”, “tumor”, “pathophysiology”,“diagnosis”, “imaging”, “treatment”, “surgery”,

“radiotherapy”, “mitotane”, “cytotoxic” and “prognosis”.In addition, the re erence list o selected papers served orthe identi ication o additional publications.

1. Abecassis, M., McLoughlin, M. J., Langer, B. &Kudlow, J. E. Serendipitous adrenal masses:prevalence, signi icance, and management. Am.

J. Surg. 149 , 783–788 (1985).2. Grumbach, M. M. et al. Management o the

clinically inapparent adrenal mass(“incidentaloma”). Ann. Intern. Med. 138 ,424–429 (2003).

3. Bovio, S. et al. Prevalence o adrenalincidentaloma in a contemporary computerized

tomography series. J. Endocrinol. Invest. 29 ,298–302 (2006).

4. Song, J. H., Chaudhry, F. S. & Mayo-Smith, W. W.The incidental adrenal mass on CT: prevalenceo adrenal disease in 1,049 consecutiveadrenal masses in patients with no knownmalignancy. AJR Am. J. Roentgenol. 190 ,1163–1168 (2008).

5. Cutler, S. J., Young, J. L. & Connelly, R. R. (Eds)Third national cancer survey: incidenca data (U. S.

Dept o Health, Education, and Wel are, PublicHealth Service, National Institutes o Health,National Cancer Institute, Bethesda, 1975).

6. Kebebew, E., Rei , E., Duh, Q. Y., Clark, O. H. &McMillan, A. Extent o disease at presentationand outcome or adrenocortical carcinoma: havewe made progress? World J. Surg. 30 , 872–878(2006).

7. Golden, S. H., Robinson, K. A., Saldanha, I.,Anton, B. & Ladenson, P. W. Clinical review:

Table 5 | Recommended monitoring during mitotane treatment

Parameter Interval Comment

Mitotane blood level Every 4–6 weeks* Target level in blood: 14–20 mg/l

Adverse e ects At every visit (initiallyevery 4 weeks; a ter6 months, every 8 weeks)

Gastrointestinal adverse e ects: use antiemetics ( or example,metoclopramide or HTR 3 blocker) and/or loperamideCentral nervous system adverse e ects (ataxia, con usion, speech orvisual problems): interrupt therapy or reduce dosage

ACTH Suspected glucocorticoidde ciency or excess Glucocorticoid status is di cult to determineTarget: ACTH in the normal range (< 12 pmol/l) or slightly aboveDue to an increased glucor ticoid clearance, high-dose glucocorticoidreplacement is needed (most patients require at least 50 mghydrocortisone per day)

GOT, GPT, bilirubin, (GGT) Initially every 4 weeks;a ter 6 months, every8 weeks

GGT is invariably elevated without clinical consequencesI other liver enzymes increase above three old o baseline, stop mitotaneas risk o liver ailure exists

TSH, ree T3, ree T4 Every 3–4 months Disturbance o thyroid hormones is requentThyroid hormone replacement is recommended in patients with clinicalsymptoms o hypothyroidism

Testosterone Every 3–4 months Primary hypogonadism requently occurs. Replacement should be initiatedin patients with symptoms o hypogonadism

Renin Every 6 months I renin increases add fudrocortisone

Cholesterol (HDL, LDL),triglycerides Every 3–4 months (inadjuvant setting) I LDL and HDL cholesterol increase, consider treatment with statins

Blood count Every 3–4 months Check or relevant leucopenia, thrombocytopenia and anemia (rare)

*In the irst 3 months, mitotane blood levels should be checked every 2–3 weeks. A ter reaching a plateau, the interval can be extended. Abbreviations:ACTH, adrenocorticotropic hor mone; GGT, γ-glutamyltrans erase; GOT, aspartate aminotrans erase; GPT, alanine aminotrans erase, HTR 3, 5-hydroxytryptaminereceptor 3.

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Prevalence and incidence o endocrine andmetabolic disorders in the United States:a comprehensive review. J. Clin. Endocrinol.Metab. 94 , 1853–1878 (2009).

8. Koschker, A. C., Fassnacht, M., Hahner, S.,Weismann, D. & Allolio, B. Adrenocor ticalcarcinoma—improving patient care byestablishing new structures. Exp. Clin. Endocrinol.Diabetes 114 , 45–51 (2006).

9. Ribeiro, R. C. et al. An inherited p53 mutation

that contributes in a tissue-speci ic manner topediatric adrenal cortical carcinoma. Proc. Natl Acad. Sci. USA 98 , 9330–9335 (2001).

10. Pinto, E. M. et al. Founder e ect or the highlyprevalent R337H mutation o tumor suppressorp53 in Brazilian patients with adrenocorticaltumors. Arq. Bras. Endocrinol. Metabol. 48 ,647–650 (2004).

11. Hutter, A. M. Jr & Kayhoe, D. E. Adrenal corticalcarcinoma. Clinical eatures o 138 patients.

Am. J. Med. 41 , 572–580 (1966).12. Bilimoria, K. Y. et al. Adrenocortical carcinoma in

the United States: treatment utilization andprognostic actors. Cancer 113 , 3130–3136(2008).

13. Wooten, M. D. & King, D. K. Adrenal corticalcarcinoma. Epidemiology and treatment with

mitotane and a review o the literature. Cancer 72 , 3145–3155 (1993).14. Universität Würzburg Offizielle Homepage des

Deutsche Nebennierenkarzinom‑Registers [online], http://www.nebennierenkarzinom.de/ (2010).

15. Sidhu, S. et al. Comparative genomic hybridizationanalysis o adrenocortical tumors. J. Clin.Endocrinol. Metab. 87 , 3467–3474 (2002).

16. Kjellman, M. et al. Genotyping o adrenocorticaltumors: very requent deletions o the MEN1locus in 11q13 and o a 1-centimorgan region in2p16. J. Clin. Endocrinol. Metab. 84 , 730–735(1999).

17. Gicquel, C. et al. Molecular markers and long-term recurrences in a large cohort o patientswith sporadic adrenocortical tumors. Cancer

Res. 61 , 6762–6767 (2001).18. DeChiara, T. M., Rober tson, E. J. &E stratiadis, A. Parental imprinting o the mouseinsulin-like growth actor II gene. Cell 64 ,849–859 (1991).

19. Wiedemann, H. R. et al. The proteus syndrome.Partial gigantism o the hands and/or eet, nevi,hemihypertrophy, subcutaneous tumors,macrocephaly or other skull anomalies andpossible accelerated growth and viscerala ections.Eur. J. Pediatr. 140 , 5–12 (1983).

20. Boulle, N., Logié, A., Gicquel, C., Perin, L. & LeBouc, Y. Increased levels o insulin-like growth

actor II (IGF-II) and IGF-binding protein-2 areassociated with malignancy in sporadicadrenocortical tumors. J. Clin. Endocrinol.Metab. 83 , 1713–1720 (1998).

21. Gicquel, C. et al. Structural and unctionalabnormalities at 11p15 are associated withthe malignant phenotype in sporadicadrenocortical tumors: study on a serieso 82 tumors. J. Clin. Endocrinol. Metab. 82 ,2559–2565 (1997).

22. Logié, A. et al. Autocrine role o IGF-II inproli eration o human adrenocortical carcinomaNCI H295R cell line. J. Mol. Endocrinol. 23 ,23–32 (1999).

23. Kikuchi, A. Tumor ormation by geneticmutations in the components o the Wntsignaling pathway. Cancer Sci. 94 , 225–229(2003).

24. Naylor, E. W. & Gardner, E. J. Adrenal adenomasin a patient with Gardner’s syndrome. Clin.Genet. 20 , 67–73 (1981).

25. Tissier, F. et al. Mutations o beta-catenin inadrenocortical tumors: activation o the Wntsignaling pathway is a requent event in bothbenign and malignant adrenocortical tumors.Cancer Res. 65 , 7622–7627 (2005).

26. Tadjine, M., Lampron, A., Ouadi, L. & Bourdeau, I.Frequent mutations o beta-catenin gene insporadic secreting adrenocortical adenomas.Clin. Endocrinol. (Oxf.) 68 , 264–270 (2008).

27. Berthon, A. et al. Constitutive beta-catenin

activation induces adrenal hyperplasia andpromotes adrenal cancer development. Hum.Mol. Genet. 19 , 1561–1576 (2010).

28. Luo, X., Ikeda, Y. & Parker, K. L. A cell-speci icnuclear receptor is essential or adrenal andgonadal development and sexual di erentiation.Cell 77 , 481–490 (1994).

29. Hammer, G. D., Parker, K. L. & Schimmer, B. P.Minireview: transcriptional regulation o adrenocortical development. Endocrinology 146 , 1018–1024 (2005).

30. Schimmer, B. P. & White, P. C. Minireview:steroidogenic actor 1: its roles indi erentiation, development, and disease. Mol.Endocrinol. 24 , 1322–1337 (2010).

31. Figueiredo, B. C. et al. Ampli ication o thesteroidogenic actor 1 gene in childhood

adrenocortical tumors. J. Clin. Endocrinol.Metab. 90 , 615–619 (2005).32. Pianovski, M. A. et al. Mortality rate o

adrenocortical tumors in children under15 years o age in Curitiba, Brazil. Pediatr. BloodCancer 47 , 56–60 (2006).

33. Almeida, M. Q. et al. Steroidogenic actor 1overexpression and gene ampli ication are more

requent in adrenocortical tumors rom childrenthan rom adults. J. Clin. Endocrinol. Metab. 95 ,1458–1462 (2010).

34. Sbiera, S. et al. High diagnostic and prognosticvalue o steroidogenic actor-1 expression inadrenal tumors. J. Clin. Endocrinol. Metab. 95 ,E161–E171 (2010).

35. Doghman, M. et al. Increased steroidogenicactor-1 dosage triggers adrenocortical cell

proli eration and cancer. Mol. Endocrinol. 21 ,2968–2987 (2007).36. Lichtenauer, U. D. et al. Pre-B-cell transcription

actor 1 and steroidogenic actor 1synergistically regulate adrenocortical growthand steroidogenesis. Endocrinology 148 ,693–704 (2007).

37. Doghman, M. et al. Inhibition o adrenocorticalcarcinoma cell proli eration by steroidogenic

actor-1 inverse agonists. J. Clin. Endocrinol.Metab. 94 , 2178–2183 (2009).

38. Hotta, M. & Baird, A. Di erential e ects o trans orming growth actor type beta on the growthand unction o adrenocortical cells in vitro . Proc.Natl Acad. Sci. USA 83 , 7795–7799 (1986).

39. Feige, J. J. et al. Trans orming growth actorbeta 1: an autocrine regulator o adrenocortical

steroidogenesis. Endocr. Res. 17 , 267–279(1991).40. Feige, J. J., Vilgrain, I., Brand, C., Bailly, S. &

Souchelnitskiy, S. Fine tuning o adrenocorticalunctions by locally produced growth actors.

J. Endocrinol. 158 , 7–19 (1998).41. de Fraipont, F. et al. Gene expression pro iling o

human adrenocortical tumors usingcomplementary deoxyribonucleic Acidmicroarrays identi ies several candidate genesas markers o malignancy. J. Clin. Endocrinol.Metab. 90 , 1819–1829 (2005).

42. Bernini, G. P. et al. Angiogenesis in humannormal and pathologic adrenal cortex. J. Clin.Endocrinol. Metab. 87 , 4961–4965 (2002).

43. Kolomecki, K., Stepien, H., Bartos, M. &Kuzdak, K. Use ulness o VEGF, MMP-2, MMP-3

and TIMP-2 serum level evaluation in patientswith adrenal tumours. Endocr. Regul. 35 , 9–16(2001).

44. Adam, P. et al. Epidermal growth actor receptorin adrenocortical tumors: analysis o genesequence, protein expression and correlationwith clinical outcome. Mod. Pathol. 23 ,1596–1604 (2010).

45. Hisada, M., Garber, J. E., Fung, C. Y.,Fraumeni, J. F. Jr & Li, F. P. Multiple primary

cancers in amilies with Li-Fraumeni syndrome. J. Natl Cancer Inst. 90 , 606–611 (1998).46. Wagner, J. et al. High requency o germline p53

mutations in childhood adrenocortical cancer. J. Natl Cancer Inst. 86 , 1707–1710 (1994).

47. Ohgaki, H., Kleihues, P. & Heitz, P. U. p53mutations in sporadic adrenocortical tumors. Int.

J. Cancer 54 , 408–410 (1993).48. Reincke, M. et al. p53 mutations in human

adrenocortical neoplasms:immunohistochemical and molecular studies.

J. Clin. Endocrinol. Metab. 78 , 790–794 (1994).49. Libè, R. et al. Somatic TP53 mutations are

relatively rare among adrenocortical cancerswith the requent 17p13 loss o heterozygosity.Clin. Cancer Res. 13 , 844–850 (2007).

50. Soon, P. S., McDonald, K. L., Robinson, B. G. &

Sidhu, S. B. Molecular markers and thepathogenesis o adrenocortical cancer.Oncologist 13 , 548–561 (2008).

51. Beuschlein, F., Fassnacht, M., Klink, A., Allolio, B.& Reincke, M. ACTH-receptor expression,regulation and role in adrenocortial tumor

ormation. Eur. J. Endocrinol. 144 , 199–206(2001).

52. Giordano, T. J. et al. Distinct transcriptionalpro iles o adrenocortical tumors uncovered byDNA microarray analysis. Am. J. Pathol. 162 ,521–531 (2003).

53. de Reyniès, A. et al. Gene expression pro ilingreveals a new classi ication o adrenocorticaltumors and identi ies molecular predictors o malignancy and survival. J. Clin. Oncol. 27 ,1108–1115 (2009).

54. Giordano, T. J. et al. Molecular classi ication andprognostication o adrenocortical tumors bytranscriptome pro iling. Clin. Cancer Res. 15 ,668–676 (2009).

55. Szabó, P. M. et al. Meta-analysis o adrenocortical tumour genomics data: novelpathogenic pathways revealed. Oncogene 29 ,3163–3172 (2010).

56. Icard, P. et al. Adrenocortical carcinomas:surgical trends and results o a 253-patientseries rom the French Association o EndocrineSurgeons study group. World J. Surg. 25 ,891–897 (2001).

57. Crucitti , F., Bellantone, R., Ferrante, A.,Boscherini, M. & Crucitti, P. The Italian Registr y

or Adrenal Cortical Carcinoma: analysis o amultiinstitutional series o 129 patients. The

ACC Italian Registry Study Group. Surgery 119 ,161–170 (1996).58. Kendrick, M. L. et al. Adrenocortical carcinoma:

surgical progress or status quo? Arch. Surg. 136 , 543–549 (2001).

59. Schulick, R. D. & Brennan, M. F. Adrenocorticalcarcinoma. World J. Urol. 17 , 26–34 (1999).

60. Dackiw, A. P., Lee, J. E., Gagel, R. F. &Evans, D. B. Adrenal cortical carcinoma. World J.Surg. 25 , 914–926 (2001).

61. Abiven, G. et al. Clinical and biological eaturesin the prognosis o adrenocortical cancer: pooroutcome o cortisol-secreting tumors in a serieso 202 consecutive patients. J. Clin. Endocrinol.Metab. 91 , 2650–2655 (2006).

62. Stewar t, P. M., Walker, B. R., Holder, G.,O’Halloran, D. & Shackleton, C. H. 11 beta-

REVIEWS


http://www.nebennierenkarzinom.de/

http://www.nebennierenkarzinom.de/



Hydroxysteroid dehydrogenase activity inCushing’s syndrome: explaining themineralocorticoid excess state o the ectopicadrenocorticotropin syndrome. J. Clin. Endocrinol.Metab. 80 , 3617–3620 (1995).

63. Seccia, T. M., Fassina, A., Nussdor er, G. G.,Pessina, A. C. & Rossi, G. P. Aldosterone-producing adrenocortical carcinoma: an unusualcause o Conn’s syndrome with an ominousclinical course. Endocr. Relat. Cancer 12 ,

149–159 (2005).64. Hyodo, T., Megyesi, K., Kahn, C. R., McLean, J. P.& Friesen, H. G. Adrenocortical carcinoma andhypoglycemia: evidence or production o nonsuppressible insulin-like activity by thetumor. J. Clin. Endocrinol. Metab. 44 , 1175–1184(1977).

65. Wajchenberg, B. et al. Adrenocortical carcinoma:clinical and laboratory observations. Cancer 88 ,711–736 (2000).

66. Luton, J. P. et al. Clinical eatures o adrenocortical carcinoma, prognostic actors,and the e ect o mitotane therapy. N. Engl. J.Med. 322 , 1195–1201 (1990).

67. Allolio, B. & Fassnacht, M. Clinical review:Adrenocortical carcinoma: clinical update. J. Clin.Endocrinol. Metab. 91 , 2027–2037 (2006).

68. Libè, R., Fratticci, A. & Bertherat, J.Adrenocortical cancer: pathophysiology andclinical management. Endocr. Relat. Cancer 14 ,13–28 (2007).

69. European Network or the Study o AdrenalTumours Adrenocortical carcinomas [online],http://www.ensat.org/acc.htm (2010).

70. Fassnacht, M. & Allolio, B. Clinical managemento adrenocortical carcinoma. Best Pract. Res.Clin. Endocrinol. Metab. 23 , 273–289 (2009).

71. Boland, G. W. et al. Characterization o adrenalmasses using unenhanced CT: an analysis o the CT literature. AJR Am. J. Roentgenol. 171 ,201–204 (1998).

72. Hamrahian, A. H. et al. Clinical utility o noncontrast computed tomography attenuationvalue (houns ield units) to di erentiate adrenal

adenomas/hyperplasias rom nonadenomas:Cleveland Clinic experience. J. Clin. Endocrinol.Metab. 90 , 871–877 (2005).

73. Caoili, E. M. et al. Adrenal masses:characterization with combined unenhanced anddelayed enhanced CT. Radiology 222 , 629–633(2002).

74. Ilias, I., Sahdev, A., Reznek, R. H., Grossman, A. B.& Pacak, K. The optimal imaging o adrenaltumours: a comparison o di erent methods.Endocr. Relat. Cancer 14 , 587–599 (2007).

75. Heinz-Peer, G., Memarsadeghi, M. & Niederle, B.Imaging o adrenal masses. Curr. Opin. Urol. 17 ,32–38 (2007).

76. Szolar, D. H. et al. Adrenocortical carcinomas andadrenal pheochromocytomas: mass andenhancement loss evaluation at delayed contrast-

enhanced CT. Radiology 234 , 479–485 (2005).77. Park, B. K., Kim, C. K., Kim, B. & Lee, J. H.Comparison o delayed enhanced CT andchemical shi t MR or evaluating hyperattenuatingincidental adrenal masses. Radiology 243 ,760–765 (2007).

78. Hönigschnabl, S. et al. How accurate is MRimaging in characterisation o adrenal masses:update o a long-term study. Eur. J. Radiol. 41 ,113–122 (2002).

79. Groussin, L. et al. 18F-Fluorodeoxyglucosepositron emission tomography or the diagnosiso adrenocortical tumors: a prospective study in77 operated patients. J. Clin. Endocrinol. Metab. 94 , 1713–1722 (2009).

80. Hahner, S. et al. [123 I]Iodometomidate ormolecular imaging o adrenocortical cytochrome

P450 amily 11B enzymes. J. Clin. Endocrinol.Metab. 93 , 2358–2365 (2008).

81. Khan, T. S. et al. 11C-metomidate PET imaging o adrenocortical cancer. Eur. J. Nucl. Med. Mol.Imaging 30 , 403–410 (2003).

82. Hennings, J. et al. [11C]metomidate positronemission tomography o adrenocortical tumorsin correlation with histopathological indings.

J. Clin. Endocrinol. Metab. 91 , 1410–1414(2006).

83. Sasano, H. et al. Transcription actor adrenal 4binding protein as a marker o adrenocorticalmalignancy. Hum. Pathol. 26 , 1154–1156(1995).

84. Hough, A. J., Holli ield, J. W., Page, D. L. &Hartmann, W. H. Prognostic actors in adrenalcortical tumors. A mathematical analysis o clinical and morphologic data. Am. J. Clin. Pathol. 72 , 390–399 (1979).

85. van Slooten, H., Schaberg, A., Smeenk, D. &Moolenaar, A. J. Morphologic characteristics o benign and malignant adrenocortical tumors.Cancer 55 , 766–773 (1985).

86. Weiss, L. M., Medeiros, L. J. & Vickery, A. L. Jr.Pathologic eatures o prognostic signi icance inadrenocortical carcinoma. Am. J. Surg. Pathol. 13 ,202–206 (1989).

87. Weiss, L. M. Comparative histologic study o 43metastasizing and nonmetastasizingadrenocortical tumors. Am. J. Surg. Pathol. 8,163–169 (1984).

88. Morimoto, R. et al. Immunohistochemistry o aproli eration marker Ki67/MIB1 in adrenocorticalcarcinomas: Ki67/MIB1 labeling index is apredictor or recurrence o adrenocorticalcarcinomas. Endocr. J. 55 , 49–55 (2008).

89. Terzolo, M. et al. Immunohistochemicalassessment o Ki-67 in the di erential diagnosiso adrenocortical tumors. Urology 57 , 176–182(2001).

90. Fassina, A. S., Borsato, S. & Fedeli, U. Fineneedle aspiration cytology (FNAC) o adrenalmasses. Cytopathology 11 , 302–311 (2000).

91. Saeger, W. et al. High diagnostic accuracy o

adrenal core biopsy: results o the German andAustrian adrenal network multicenter trial in 220consecutive patients. Hum. Pathol. 34 , 180–186(2003).

92. Lumachi, F. et al. Fine-needle aspiration cytologyo adrenal masses in noncancer patients:clinicoradiologic and histologic correlations in

unctioning and non unctioning tumors. Cancer 93 , 323–329 (2001).

93. Lumachi, F. et al. Role and cost-e ectiveness o adrenal imaging and image-guided FNA cytologyin the management o incidentally discoveredadrenal tumours. Anticancer Res. 25 ,4559–4562 (2005).

94. Quayle, F. J. et al. Needle biopsy o incidentallydiscovered adrenal masses is rarely in ormativeand potentially hazardous. Surgery 142 ,

497–502 (2007).95. Fassnacht, M. et al. Limited prognostic value o the 2004 International Union Against Cancerstaging classi ication or adrenocorticalcarcinoma: proposal or a revised TNMclassi ication. Cancer 115 , 243–250 (2009).

96. Lee, J. E. et al. Surgical management, DNAcontent, and patient survival in adrenal corticalcarcinoma. Surgery 118 , 1090–1098 (1995).

97. Lughezzani, G. et al. The European Network orthe Study o Adrenal Tumors staging system isprognostically superior to the international unionagainst cancer-staging system: a NorthAmerican validation. Eur. J. Cancer 46 , 713–719(2010).

98. Schteingart, D. E. et al. Management o patientswith adrenal cancer: recommendations o an

international consensus con erence. Endocr.Relat. Cancer 12 , 667–680 (2005).

99. Porpiglia, F. et al. Retrospective evaluation o theoutcome o open versus laparoscopicadrenalectomy or stage I and II adrenocorticalcancer. Eur. Urol. 57 , 873–878 (2010).

100. Brix, D. et al. Laparoscopic versus openadrenalectomy or adrenocortical carcinoma:surgical and oncologic outcome in 152 patients.Eur. Urol. 58 , 609–615 (2010).

101. Miller, B. S. et al. Laparoscopic resection isinappropriate in patients with known orsuspected adrenocortical carcinoma. World J.Surg. 34 , 1380–1385 (2010).

102. Leboulleux, S. et al. Adrenocortical carcinoma: isthe surgical approach a risk actor o peritonealcarcinomatosis? Eur. J. Endocrinol. 162 ,1147–1153 (2010).

103. Murphy, M. M. et al. Trends in adrenalectomy: arecent national review. Surg. Endosc. 24 ,2518–2526 (2010).

104. Terzolo, M. et al. Adjuvant mitotane treatment oradrenocortical carcinoma. N. Engl. J. Med. 356 ,2372–2380 (2007).

105. Huang, H. & Fojo, T. Adjuvant mitotane oradrenocortical cancer—a recurring controversy.

J. Clin. Endocrinol. Metab. 93 , 3730–3732 (2008).

106. Terzolo, M., Fassnacht, M., Ciccone, G., Allolio, B.& Berruti, A. Adjuvant mitotane oradrenocortical cancer--working throughuncertainty. J. Clin. Endocrinol. Metab. 94 ,1879–1880 (2009).

107. Berruti, A. et al. Adjuvant therapy in patients withadrenocortical carcinoma: a position o aninternational panel. J. Clin. Oncol. 28 ,e401–e402 (2010).

108. Fassnacht, M. et al. E icacy o adjuvantradiotherapy o the tumor bed on localrecurrence o adrenocortical carcinoma. J. Clin.Endocrinol. Metab. 91 , 4501–4504 (2006).

109. Polat, B. et al. Radiotherapy in adrenocorticalcarcinoma. Cancer 115 , 2816–2823 (2009).

110. Sabolch, A. et al. Adjuvant and de initiveradiotherapy or adrenocortical carcinoma. Int. J.

Radiat. Oncol. Biol. Phys. doi:10.1016/ j.ijrobp.2010.04.030.111. Fassnacht, M. et al. Improved survival in patients

with stage II adrenocortical carcinoma ollowedup prospectively by specialized centers. J. Clin.Endocrinol. Metab. 95 , 4925–4932 (2010).

112. US National Institutes o Health Clinicaltrials.gov [online], http://clinicaltrials.gov/ct2/show/NCT00777244 (2010).

113. Bauditz, J., Quinkler, M. & Wermke, W.Radio requency thermal ablation o hepaticmetastases o adrenocortical cancer—a casereport and review o the literature. Exp. Clin.Endocrinol. Diabetes 117 , 316–319 (2009).

114. Wood, B. J., Abraham, J., Hvizda, J. L.,Alexander, H. R. & Fojo, T. Radio requency ablationo adrenal tumors and adrenocortical carcinoma

metastases. Cancer 97 , 554–560 (2003).115. Jensen, J. C., Pass, H. I., Sindelar, W. F. &Norton, J. A. Recurrent or metastatic disease inselect patients with adrenocortical carcinoma.Aggressive resection vs chemotherapy. Arch.Surg. 126 , 457–461 (1991).

116. Pommier, R. F. & Brennan, M. F. An eleven-yearexperience with adrenocortical carcinoma.Surgery 112 , 963–970 (1992).

117. Bellantone, R. et al. Role o reoperation inrecurrence o adrenal cortical carcinoma:results rom 188 cases collected in the ItalianNational Registry or Adrenal Cortical Carcinoma.Surgery 122 , 1212–1218 (1997).

118. Schulick, R. D. & Brennan, M. F. Long-termsurvival a ter complete resection and repeatresection in patients with adrenocortical

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http://www.ensat.org/acc.htm

http://clinicaltrials.gov/ct2/show/NCT00777244




http://www.ensat.org/acc.htm


http://slidepdf.com/reader/full/ad-re-no-cortical-carcinoma 13/13

carcinoma. Ann. Surg. Oncol. 6, 719–726(1999).

119. Erdogan, I. et al. Impact o surgery on clinicaloutcome in patients with recurrence o adrenocortical carcinoma. Endocrine Abstracts(10 th European Congress of Endocrinology) , 20 ,P194 (2009).

120. Khan, T. S. et al. Streptozocin and o,p’DDD in thetreatment o adrenocortical cancer patients:long-term survival in its adjuvant use. Ann. Oncol.

11 , 1281–1287 (2000).121. First International Randomized Trial in locallyadvanced and Metastatic Adrenocortical CancerTreatment (FIRM-ACT) [online],http://www. irm-act.org/ (2010).

122. Berruti, A. et al. Etoposide, doxorubicin andcisplatin plus mitotane in the treatment o advanced adrenocortical carcinoma: a largeprospective phase II trial. Endocr. Relat. Cancer 12 , 657–666 (2005).

123. Hahner, S. & Fassnacht, M. Mitotane oradrenocortical carcinoma treatment. Curr. Opin.Investig. Drugs 6, 386–394 (2005).

124. Da ara, F. et al. Prospective evaluation o mitotane toxicity in adrenocortical cancerpatients treated adjuvantly. Endocr. Relat. Cancer 15 , 1043–1053 (2008).

125. Sperone, P. et al. Gemcitabine plus metronomic5- luorouracil or capecitabine as a second-/third-line chemotherapy in advanced adrenocorticalcarcinoma: a multicenter phase II study. Endocr.Relat. Cancer 17 , 445–453 (2010).

126. Hermsen, I. G., Groenen, Y. E., Dercksen, M. W.,Theuws, J. & Haak, H. R. Response to radiationtherapy in adrenocortical carcinoma. J.Endocrinol. Invest. doi:10.3275/6904.

127. Miller, J. W. & Crapo, L. The medical treatment o Cushing’s syndrome. Endocr. Rev. 14 , 443–458(1993).

128. Schulte, H. M., Benker, G., Reinwein, D.,Sippell, W. G. & Allolio, B. In usion o low doseetomidate: correction o hypercortisolemia inpatients with Cushing’s syndrome and dose-response relationship in normal subjects. J. Clin.

Endocrinol. Metab. 70 , 1426–1430 (1990).

129. Fassnacht, M. et al. New mechanisms o adrenostatic compounds in a humanadrenocortical cancer cell line. Eur. J. Clin. Invest. 30 (Suppl. 3), 76–82 (2000).

130. Johanssen, S. & Allolio, B. Mi epristone (RU 486)in Cushing’s syndrome. Eur. J. Endocrinol. 157 ,561–569 (2007).

131. Castinetti, F. et al. Merits and pit alls o mi epristone in Cushing’s syndrome. Eur. J.Endocrinol. 160 , 1003–1010 (2009).

132. Quinkler, M. et al. Treatment o advancedadrenocortical carcinoma with erlotinib plusgemcitabine. J. Clin. Endocrinol. Metab. 93 ,2057–2062 (2008).

133. Wortmann, S. et al. Bevacizumab pluscapecitabine as a salvage therapy in advancedadrenocortical carcinoma. Eur. J. Endocrinol. 162 ,349–356 (2010).

134. Fassnacht, M., Kreissl, M. C., Weismann, D. &Allolio, B. New targets and therapeuticapproaches or endocrine malignancies.Pharmacol. Ther. 123 , 117–141 (2009).

135. Berruti, A. et al. Emerging drugs or adrenocorticalcarcinoma. Expert Opin. Emerg. Drugs 13 ,497–509 (2008).

136. Carden, C. P. et al. Phase I study o intermittentdosing o OSI-906, a dual tyrosine kinase

inhibitor o insulin-like growth actor-1 receptor(IGF-1R) and insulin receptor (IR) in patients withadvanced 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 corticalcarcinoma. Cancer 64 , 765–769 (1989).

138. Vassilopoulou-Sell in, R. & Schultz, P. N.Adrenocortical carcinoma. Clinical outcome atthe end o the 20th century. Cancer 92 ,1113–1121 (2001).

139. Stojadinovic, A. et al. Adrenocortical carcinoma:clinical, morphologic, and molecularcharacterization. J. Clin. Oncol. 20 , 941–950(2002).

140. Assié, G. et al. Prognostic parameters o metastatic adrenocortical carcinoma. J. Clin.

Endocrinol. Metab. 92 , 148–154 (2007).

141. Volante, M. et al. Matrix metalloproteinasetype 2 expression in malignant adrenocorticaltumors: Diagnostic and prognostic signi icancein a series o 50 adrenocortical carcinomas.Mod. Pathol. 19 , 1563–1569 (2006).

142. Fenske, W. et al. Glucose transporter GLUT1expression is an stage-independent predictor o clinical outcome in adrenocortical carcinoma.Endocr. Relat. Cancer 16 , 919–928 (2009).

143. Soon, P. S. et al. Microarray gene expression

and immunohistochemistry analyses o adrenocortical tumors identi y IGF2 and Ki-67as use ul in di erentiating carcinomas romadenomas. Endocr. Relat. Cancer 16 , 573–583(2009).

144. Ronchi, C. L. et al. Expression o excision repaircross complementing group 1 and prognosis inadrenocortical carcinoma patients treated withplatinum-based chemotherapy. Endocr. Relat.Cancer 16 , 907–918 (2009).

145. Malandrino, P. et al. Prognostic markers o survival a ter combined mitotane- and platinum-based chemotherapy in metastaticadrenocortical carcinoma (ACC). Endocr. Relat.Cancer 17 , 797–807 (2010).

AcknowledgmentsWork described in this Review was supported bygrants o the Deutsche Krebshil e (grant #107111 toM. Fassnacht), the German Ministry o ResearchBMBF (grant #01KG0501 to M. Fassnacht andB. Allolio) and the German Research Foundation DFG(grant #FA466/3-1 to M. Fassnacht).C. P. Vega, University o Cali ornia, Irvine, CA, is theauthor o and is solely responsible or the content o the learning objectives, questions and answers o theMedscape, LLC-accredited continuing medicaleducation activity associated with this ar ticle.

Author contributionsAll authors researched the data or the article,provided a substantial contribution to discussionso the content, wrote the review and reviewed and

edited the manuscript be ore submission.

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