REVIEWS
Adrenocortical carcinoma: a clinician’s update
Martin Fassnacht, Rossella Libé, 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 3 months 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 phase III 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, 323-335 (2011); published online 8 March 2011; doi:10.1038/nrendo.2010.235
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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.
Introduction
In contrast to benign adrenal tumors, which belong to the most common human neoplasias with a prevalence of>4%,1-4 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 0.7-2.0 cases per million population per year.5-7 The incidence in adults is maximal in those aged around 40-50 years, but the tumor can appear at any age.8 An unusually high incidence of adrenocortical carcinoma has been found in children in southern Brazil-3.4-4.2 versus 0.3 per 1 million chil- dren younger than 15 years worldwide. The elevated incidence is possibly related to a founder germline 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 series11-13 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 adrenocortical carcinoma registry (55% versus 45%; P=0.009; n = 603).14 However, the mechanism behind this observation is unknown.
Pathophysiology and genetic alterations
Progress has been made in understanding the molecu- lar 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 Würzburg, Oberdürrbacher Straße 6, 97080 Würzburg, Germany (M. Fassnacht, M. Kroiss, B. Allolio). Department of Endocrinology, INCa COMETE network, Cochin Hospital, University Paris Descartes, 24 Rue du Faubourg-Saint- Jacques, 75014 Paris, France (R. Libé).
Correspondence to: M. Fassnacht fassnacht_m@medizin. uni-wuerzburg.de
Key points
· Overexpression of insulin-like growth factor 2 and constitutive activation of ß-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 carci- noma,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 dis- ruption 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 altera- tions 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).
Oncogenes
IGF-2
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 adreno- cortical tumors.17 The IGF-2 gene, which is located on chromosome 11p15, encodes a fetal growth factor that is expressed exclusively from the paternally inherited allele
owing to maternal imprinting.18 Genetic or epigenetic defects in the imprinted 11p15 region can increase IGF-2 expression (Table 1), as in patients with Beckwith- Wiedemann syndrome (BWS), with macrosomia, organomegaly and predisposition to the development of multiple tumors, including adrenocortical carcinoma.19 High overexpression of IGF-2 mRNA is observed in the vast majority of adrenocortical carcinomas.20,21 It occurs mostly 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 is mediated via the IGF-1 receptor (Figure 1a,b).22 Analysis of the 11p15 locus is useful in adrenocortical tumors, as 11p15 LOH is significantly more frequent in adreno- cortical carcinoma than in the benign adrenocortical adenoma (78.5% versus 9.5%) and is associated with a higher risk of tumor recurrence.17
ß-catenin
Genetic alterations of the Wnt signaling pathway, which were initially identified in patients with familial adeno- matous polyposis coli (APC), have been found in a variety of cancers;23 occasionally, adrenocortical tumors have been observed in familial APC (Table 1).24 The Wnt signaling pathway is active during normal embryonic develop- ment, and ß-catenin is a key component of this signaling pathway. Constitutive activation of ß-catenin is the most frequent alteration in benign and malignant adreno- cortical tumors.25,26 In a subset of these tumors, somatic mutations of the ß-catenin gene inactivate its phosphory- lation site for glycogen synthase kinase 3ß (GSK3}).25 Wnt signaling correlates with intracellular ß-catenin concen- tration (Figure 1c,d). In a transgenic mouse model, con- stitutive ß-catenin activation induces adrenal hyperplasia and promotes adrenal cancer development.27
Steroidogenic factor 1
SF1 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 in many cases of adult onset, adrenocortical tumors.31-34 In addition, elevated levels of SF1 have been shown to increase proliferation of human adrenocortical cells in vitro and to induce tumorigenesis in mice.35,36 Accordingly, SF1- stimulated adrenocortical cell proliferation was inhibited by SF1 inverse agonists in vitro.37
| Table 1 | Genetic syndromes associated with adrenocortical carcinoma | ||||
|---|---|---|---|---|
| Syndrome | Chromosomal localization | Genes | Signaling pathway | Cause of sporadic adrenocortical carcinoma |
| Beckwith-Wiedemann syndrome | 11p15 | CDKN1C IGF-2 H19 | IGF | 11p15 paternal isodisomy IGF-2 overexpression |
| Familial adenomatous polyposis coli | 5q12-22 | APC | Wnt | APC mutation (rare) ß-catenin (CTNNB1) somatic mutation |
| Li-Fraumeni syndrome | 17p13 | TP53 | p53 | TP53 germline mutations in children TP53 somatic mutations in adults 17p13 loss of heterozygosity |
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a
IGF-1
IGF-2
b
IGF-2
IGF-2
IGF-2
IGF-1R
IGF-1R
IGF-2
IGF-2
IGF-2
IGF-2
IGF-2
IGF-2
IGF-2
Paternal allele
Paternal allele
Maternal allele
Paternal allele
CDKN1C (p57kip2)
IGF-2
H19
CDKN1C (p57kip2)
IGF-2
H19
Paternal isodisomy
c
d
Wnt
Wnt
Wnt
1
W
W
ß-catenin
Axin
ß-catenin
a-catenin
a-catenin
Dsh
P
7
GSK3 B
Dsh
Axin
ß-catenin
P
APC
P L
WTX
ß-catenin
ß-catenin
WTX
GSK3 B
ß-catenin
B-catenin
ß-catenin degradation (proteasome)
APC
P
ß-catenin
ß-catenin
TCF/LEF
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) a, TGF-ß, and vascular endothelial growth factor (VEGF).38-41 Expres- sion of VEGF is higher in adrenocortical carcinoma than
in adrenal adenomas.41,42 However, the high expression of VEGF contrasts with a low vascularization in adreno- cortical carcinoma, which indicates a dissociation of the angiogenic status and the neoangiogenic capabili- ties of these tumors.42 Interestingly, serum VEGF levels were significantly higher in patients with adrenocortical carcinoma than in patients with adrenal adenomas or
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 prognostic relevance.44
Tumor suppressor genes
TP53
Germline mutations in the TP53 gene, located on 17p13 (Table 1), are present in 70% of families with Li-Fraumeni syndrome. This syndrome confers suscep- tibility 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 50-80% of children with apparently sporadic adrenocortical carcinoma.46 In adults, somatic mutations of TP53 are found in 20-35% of cases of sporadic adrenocortical carcinoma47-49 and might be associated with more aggressive and advanced tumors.49 LOH at 17p13 has been reported more fre- quently 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 identi- fied 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 recep- tor 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
Gene profiling of adrenocortical carcinoma
By use of large-scale analyses of gene expression, so- called 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 IGF-2 is the most upregulated gene in adrenocortical carcinoma com- pared with adrenocortical adenoma or healthy adrenal
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 differen- tially expressed between recurring and nonrecurring adrenocortical tumors, thereby demonstrating their diag- nostic usefulness.53 Moreover, independent analyses led to the discrimination of two different types of adreno- cortical carcinoma, with either poor or good prognosis, which indicates that transcriptome analysis could also uncover new prognostic factors.53,54 Furthermore, a meta- analysis 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
Clinical presentation
Most patients with adrenocortical carcinoma (50-60% of cases) seek medical advice because of clinical evidence of 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 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 domi- nating features. Massive hypercortisolism activates mineralocorticoid receptors by overriding the inacti- vating capacity of corticosteroid 11ß-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 syn- drome. 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 hyper- tension 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-2.64-66
Patients with a nonfunctioning adrenocortical carci- noma 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 con- trast, 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
| Table 2 | Diagnostic work-up in patients with suspected or proven adrenocortical carcinoma* | |
|---|---|
| Hormonal work-up | Tests |
| Glucocorticoid excess (minimum 3 out of 4 tests) | Dexamethasone suppression test (1 mg, 2300h) |
| Excretion of free urinary cortisol (24h urine) | |
| Basal cortisol | |
| Basal ACTH (plasma) | |
| Mineralocorticoid excess | Potassium |
| Aldosterone:renin ratio (only in patients with arterial hypertension and/or hypokalemia) | |
| Sex steroids and steroid precursors | DHEAS |
| 17OH-progesterone | |
| Androstenedione | |
| Testosterone | |
| 17ß-estradiol (only in men and postmenopausal women) | |
| Exclusion of a pheochromocytoma | Fractionated metanephrines in 24h urine or free plasma metanephrines |
| Imaging | CT or MRI of abdomen* and CT of thorax Bone scintigraphy (if skeletal metastasis is suspected) FDG-PET (optional) |
*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; Table 2).67-69
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 adreno- cortical 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
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 malig- nant 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.71-77
| Table 3 | ENSAT staging for adrenocortical carcinoma | |
|---|---|
| Stage | ENSAT tumor stage 2008 |
| I | T1, N0, M0 |
| II | T2, N0, M0 |
| III | T1-2, N1, MO T3-4, NO-1, MO |
| IV | T1-4, NO-1, M1 |
T1, tumor size ≤5cm; T2, tumor size >5cm; 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. et al. Cancer 115, 243-250 (2009).
100
80
Disease-specific survival (%)
60
40
20
0
0
1
2
3
4
5
6
7
8
9
10
Time (years)
ENSAT I (n=29)
ENSAT III (n=144)
ENSAT II (n=227)
ENSAT IV (n=166)
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 tech- nology, including chemical shift MRI, the sensitivity for differentiating benign from malignant adrenal lesions has been around 81-89%, with a specificity of 92-99%.75,78
18F-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 standardized uptake value (SUV) ratio >1.45 (Figure 2). In a prospec- tive 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 pheo- chromocytoma or adrenal metastasis. To answer this question, metomidate is emerging as a new radiotracer. Metomidate specifically binds to adrenal 11ß-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
Histopathology
The pathological differential diagnosis of adrenal neo- plasias 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 et al.83 suggested SF1 as a marker to differentiate between tumors of adrenocortical and nonadrenocortical origin. The value of this marker has been confirmed in a large cohort, in which SF1 immuno- histochemistry 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 car- cinoma versus adenoma, different diagnostic scores84,85 have been introduced; the Weiss score86,87 is the most popular and consists of parameters related to tumor struc- ture, 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.90-93 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
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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.
Staging
Tumor staging is a widely used tool to assess prognosis in patients with cancer. For adrenocortical carcinoma, the tumor-node-metastasis (TNM) classification pro- posed by ENSAT is recommended (Table 3).95 This staging system, which represents a modification of the Lee system,9% 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 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 adrenocortical carcinoma registry (Figure 3)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 resec- tion (R0), often followed by a long period of disease- free survival. Furthermore, limited evidence supports the theory that surgery for tumor recurrence may also prolong 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 steroid levels. After the first 2 years of follow-up, intervals may be gradually increased. However, follow-up in patients without evidence of disease is recommended over a minimum of 10 years after surgery.
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 3-4.98 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 ques- tion concerns the optimal surgical approach. In patients
| Table 4 | Radiotherapy for adrenocortical carcinoma | ||
|---|---|---|
| Setting | Indication | Dosage |
| Adjuvant | Strongly recommended after R1 resection in ENSAT stage I-III tumors Recommended after Rx resection in ENSAT stage I-III tumors Individualized decision: R0 resection in high-risk patients* Not recommended: R2 resection* and ENSAT stage IV tumors | >40 Gy (1.8-2.0 Gy per fraction) Limited boost volume (tumor bed) to reach 50-60 Gy |
| Palliative | Bone metastasis with spinal cord compression Thoracic or abdominal metastasis with vena cava obstruction Painful thoracic or abdominal metastasis Symptomatic cerebral metastasis | 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 ≤8cm. * Consider re-surgery by an expert surgeon. Abbreviations: RO, complete resection; R1, microscopic residual tumor; R2, macroscopic residual tumor; Rx, unknown resection status.
ACC amenable to complete resection 1
Complete resection (R0)
Rx/R1 resection
2
Ki67 ≤10% 3 Ki67>10%
Low-intermediate risk
High risk
Consider adjuvant mitotane
4
Adjuvant mitotane Consider additional therapy
5
Adjuvant mitotane plus irradiation of the tumor bed
Follow-up every 3 months Imaging and tumor markers
6
Tumor free
Recurrence
Within 6 months* or not resectable
>12 months plus complete resection feasible
with an infiltrating tumor or suspected lymph nodes (presumable stage III), open adrenalectomy is required. However increasing evidence supports the hypothesis
Box 1 | Recommended medical treatment in advanced adrenocortical carcinoma
Mitotane monotherapy*
· Start with 1.5g daily and increase dose within 4-6 days to 6.0g per day*
· After 3 weeks, adapt dosage according to tolerability and blood level; if mitotane concentration is <7 mg/l, consider adding cytotoxic chemotherapy
· Maximum dose 12g per day, but most patients do not tolerate >8 g daily
· Target a mitotane blood level of 14-20 mg/l. With this regimen, about 50% of patients achieve target levels within 3 months
Etoposide, doxorubicin and cisplatin plus mitotane*§
· Every 28 days:
· 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 14-20 mg/l
Streptozotocin plus mitotane*§
· Induction (day 1-5): 1 g streptozotocin per day
· Afterwards: 2g streptozotocin every 21 days
· Plus oral mitotane aiming at a blood level between 14-20 mg/l
Gemcitabine plus capecitabine!
· 800 mg/m2 gemcitabine on day 1 and 8 (repeated every 3 weeks)
· 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 >3g daily. $These regimens are currently compared in a randomized phase III trial, the results of which are expected in 2011.121 ||Alternative regimen for second or third-line therapy. Results of a phase II trial reported that 13 of 28 patients had stable disease for more than 4 months. 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 incidenta- loma with evidence of tumor growth) is justified on the basis of current data.99,100
Given that complete resection is the single most impor- tant 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 adreno- cortical carcinoma should be limited to centers with >20 adrenalectomies per year and experience in surgery for adrenocortical carcinoma.
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 evi- dence 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
reduced by adjuvant use of the adrenolytic agent mito- tane (median recurrence-free survival 42 months versus 10 and 25 months 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 center- driven 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.68,105-107 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 (Table 4).108-110 In some patients, adjuvant streptozotocin in combination with mitotane might be justified. Guidance for risk stratification is given in Figure 4.
Almost all published case series suffer from a marked selection bias, as was recently demonstrated by an analy- sis from the German adrenocortical carcinoma regis- try.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 adreno- cortical carcinoma is no longer obvious. To address this important issue, the ADIUVO (Efficacy of Adjuvant Mitotane Treatment) study, a randomized trial in low-to- intermediate risk patients (mitotane versus observation only) 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 all tumoral lesions. Radiofrequency ablation is an alterna- tive 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.
Recurrent disease
Reports 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 time between 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 be expected. After surgery for recurrence, adjuvant therapy must be started as soon as possible. In patients with recur- rent 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
recommended first-line treatment regimens are mitotane monotherapy; etoposide, doxorubicin, cisplatin plus mito- tane;122 or streptozotocin plus mitotane120 (Box 1). The treatment is chosen on the basis of the clinical judgment of the speed of tumor progression (Figure 5) 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 3 weeks 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 experi- enced physician (Table 5).123,124 During treatment with mitotane, virtually all patients will experience adrenal insufficiency and gastrointestinal symptoms that both have to be treated actively (Box 1). 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 adreno- cortical carcinoma is not radiotherapy-resistant, 109,126 and palliative radiotherapy has been successfully used to treat symptomatic metastatic lesions (Table 4). Hyper- secretion 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.127-131 New ‘targeted therapies’ have also been tested in patients with adrenocortical carcinoma. However, the results of these studies were rather disappointing. Neither inhibi- tion of EGFR nor targeting of VEGF in adrenocortical carcinoma resulted in a substantial benefit in advanced disease.132-135 By contrast, preliminary results of phase I trials with an orally available IGF-1 receptor inhibitor (OSI-906) are promising. In five of 16 patients, stabi- lization of progressive adrenocortical carcinoma for >12 weeks was achieved, including one patient with a
80% reduction of tumor mass.136 A phase III trial on this drug as second-line or third-line therapy is now recruit- ing 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.
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 (Figure 3). 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
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
3
Mitotane level at 3 weeks
<5 mg/l
4
>7 mg/l
Continue monotherapy
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 chemotherapy
5
Consider radiotherapy or radioablation
markers for prediction of tumor behavior are available. Functionality, age and sex have no major role.66,137-139 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 adreno- cortical 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, down- regulation of microRNA miR-195 and upregulation of miR-483-5p were found to correlate with poor prog- nosis.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
| 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 effects | At every visit (initially every 4 weeks; after 6 months, every 8 weeks) | 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 |
| ACTH | Suspected glucocorticoid deficiency or excess | 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) |
| GOT, GPT, bilirubin, (GGT) | Initially every 4 weeks; after 6 months, every 8 weeks | GGT is invariably elevated without clinical consequences If other liver enzymes increase above threefold of baseline, stop mitotane as risk of liver failure exists |
| TSH, free T3, free T4 | Every 3-4 months | Disturbance of thyroid hormones is frequent Thyroid hormone replacement is recommended in patients with clinical symptoms of hypothyroidism |
| Testosterone | Every 3-4 months | Primary hypogonadism frequently occurs. Replacement should be initiated in patients with symptoms of hypogonadism |
| Renin | Every 6 months | If renin increases add fludrocortisone |
| Cholesterol (HDL, LDL), triglycerides | Every 3-4 months (in adjuvant setting) | If LDL and HDL cholesterol increase, consider treatment with statins |
| Blood count | Every 3-4 months | Check for relevant leucopenia, thrombocytopenia and anemia (rare) |
| *In the first 3 months, mitotane blood levels should be checked every 2-3 weeks. After reaching a plateau, the interval can be extended. Abbreviations: ACTH, adrenocorticotropic hormone; GGT, y-glutamyltransferase; GOT, aspartate aminotransferase; GPT, alanine aminotransferase, HTR3, 5-hydroxytryptamine receptor 3. | ||
study of 45 patients treated with platinum-based chemo- therapy, 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 prog- ress in the care of patients with adrenocortical carci- nomas. Insights into the molecular pathogenesis of adrenocortical carcinoma have led to the first clinical trials using targeted strategies, such as IGF-1R inhibi- tors. The European network ENSAT has established a validated adrenocortical carcinoma staging system95 and has outlined a detailed work-up for patients with sus- pected adrenocortical carcinoma (Table 2). Following a consensus meeting in September 2003,98 the first ever phase III 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.
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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 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.