Adrenocortical carcinoma: current state of the art, ongoing controversies, and future directions in diagnosis and treatment
Omair A. Shariq and Travis J. Mckenzie İD
Abstract: Adrenocortical carcinoma (ACC) is a rare, aggressive malignancy with an annual incidence of ~1 case per million population. Differentiating between ACC and benign adrenocortical tumors can be challenging in patients who present with an incidentally discovered adrenal mass, due to the limited specificity of standard diagnostic imaging. Recently, urine steroid metabolite profiling has been prospectively validated as a novel diagnostic tool for the detection of malignancy with improved accuracy over current modalities. Surgery represents the only curative treatment for ACC, although local recurrence and metastases are common, even after a margin-negative resection is performed. Unlike other intra-abdominal cancers, the role of minimally invasive surgery and lymphadenectomy in ACC is controversial. Adjuvant therapy with the adrenolytic drug mitotane is used to reduce the risk of recurrence after surgery, although evidence supporting its efficacy is limited; it is also currently unclear whether all patients or a subset with the highest risk of recurrence should receive this treatment. Large-scale pan-genomic studies have yielded insights into the pathogenesis of ACC and have defined distinct molecular signatures associated with clinical outcomes that may be used to improve prognostication. For patients with advanced ACC, palliative combination chemotherapy with mitotane is the current standard of care; however, this is associated with poor response rates (RR). Knowledge from molecular profiling studies has been used to guide the development of novel targeted therapies; however, these have shown limited efficacy in early phase trials. As a result, there is an urgent unmet need for more effective therapies for patients with this devastating disease.
Keywords: adrenocortical carcinoma; adrenalectomy; mitotane; adrenal incidentaloma; diagnosis; treatment
Received: 22 December 2020; revised manuscript accepted: 23 June 2021.
Introduction
Adrenocortical carcinoma (ACC) is a rare endo- crine malignancy that arises from the cortex of the adrenal gland and has an estimated world- wide incidence of ~1 case per million population per year.1-3 Despite its rarity, ACC generally portends a poor prognosis as the majority of patients develop locally recurrent or metastatic disease, despite undergoing seemingly curative surgical resection.4 A number of questions and controversies exist regarding aspects of diagno- sis, medical treatment, and the surgical manage- ment of ACC. The rarity of this disease, and short duration of survival, has resulted in a
paucity of prospective clinical trials. Therefore, current treatment recommendations are largely driven by consensus opinion based on retrospec- tive data.5,6 While our understanding of the molecular mechanisms that underpin ACC development has greatly improved as a result of large-scale pan-genomic studies,7,8 the transla- tion of this knowledge into effective clinical ther- apies for patients with advanced disease has been limited to date. In this review, we provide an overview of the current state of the art in the diagnosis and treatment of ACC, highlighting ongoing controversies and recent advances, as well as their potential effect on clinical practice.
Ther Adv Chronic Dis 2021, Vol. 12: 1-21
DOI: 10.1177/ 20406223211033103
@ The Author(s), 2021. Article reuse guidelines: sagepub.com/journals- permissions
Correspondence to: Travis J. Mckenzie Department of Surgery, Mayo Clinic, 200 First Street S.W., Rochester, MN 55905, USA mckenzie.travis@mayo. edu
Omair A. Shariq Department of Surgery, Mayo Clinic, Rochester, MN, USA
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Epidemiology
ACC is a rare malignancy that meets the criteria for ‘orphan’ disease designation in the European Union and in the United States (<50 cases per 100,000 population and <64 cases per 10,000 population, respectively).9 Analysis of the National Cancer Institute’s Surveillance, Epidemiology and End Results (SEER) database indicates an annual incidence of ACC of 0.72-1.02 per million in the United States.1,2 This is in accordance with a pop- ulation-based study from the Netherlands, which reported an incidence of 1 case per million.3 In contrast, the incidence of ACC is 10-fold higher in Southern Brazilian children, which is partly attrib- utable to the high frequency of a specific founder tumor protein 53 (TP53) germline mutation in this population.10 Although ACC can occur at any age, some studies have described a bimodal age distri- bution with an initial peak in incidence during childhood, followed by another in the fourth to fifth decade of life.11,12 Others have depicted only a sin- gle peak with a median age at diagnosis of 55- 56 years.1-3 Despite this, the observation that ACCs account for 1.3% of all pediatric cancers13 versus ~0.02% of malignant tumors in adults, 14,15 suggests a relatively higher incidence in childhood. Regardless of age, ACC shows a slight female pre- dilection (ratio of affected females to males: 1.5- 2.5:1).11,16 Epidemiological risk factors for ACC are not well understood, although recent studies have identified an increased incidence in male ciga- rette smokers.17-19 In females, estrogen exposure has been implicated as a risk factor due to an increased incidence of ACC in users of the oral contraceptive pill,19 and the anti-proliferative effects of estrogen inhibition on ACC cells in vitro.20
Pathogenesis
Initial insights into the genes and signaling path- ways involved in ACC tumorigenesis came from studies of familial diseases associated with ACC development, for which the causative germline alterations are well-defined. These include: Li-Fraumeni syndrome (caused by inactivating TP53 mutations);21 Beckwith-Wiedemann syn- drome [caused by genetic and epigenetic abnor- malities of chromosome 11 (11p15.5)];22 multiple endocrine neoplasia (MEN) type 1 (caused by inactivating MEN1 mutations);23 and Lynch syn- drome [caused by inactivating mutations in the mismatch repair genes MutL homolog 1 (MLH1), MutS homolog 2 (MSH2), MutS homolog 6 (MSH6), and PSM1 homolog 1, mismatched repair
system component (PMS2)].24 However, the vast majority of ACCs are sporadic; it is increasingly understood that they may be driven by a myriad of genetic and epigenetic aberrations. These include somatic DNA mutations, chromosomal aneuploidy, altered DNA methylation, and dys- regulated microRNA (miRNA) expression.25
Much of our current understanding of the land- scape of molecular alterations in ACC is derived from two tour de force studies: one from the European Network for the Study of Adrenal Tumors (ENS@T)7 and another from The Cancer Genome Atlas Study on ACC group (ACC-TCGA).8 Both consortia utilized a range of multi-omics techniques, including DNA exome sequencing, mRNA expression profiling, miRNA profiling, DNA methylation analysis, and single nucleotide polymorphism (SNP) arrays that ena- bled in-depth pan-molecular characterization of a large number of primary ACCs for the first time. Although a detailed discussion of these findings is beyond the scope of this review and has been pro- vided recently by others,25-27 both studies showed that ACCs harbor somatic driver mutations that most frequently affect genes involved in Wnt/ß- catenin signaling [Zinc and ring finger 3 (ZNRF3), Catenin Beta 1 (CTNNB1)]; cell cycle regulation [TP53, cyclin dependent kinase inhibitor 2A (CDKN2A), retinoblastoma protein 1 (RB1), cyclin- dependent kinase (CDK)]; and chromatin remod- eling [MEN1, death domain associated protein (DAXX)].7,8 They also confirmed findings from earlier single platform studies28,29 which showed that overexpression of the insulin-like growth fac- tor-2 (IGF2) occurs in 80-90% of ACCs, largely due to loss of heterozygosity at the IGF2 locus at chromosome 11p15 (i.e. loss of the imprinted maternal allele and duplication of the paternal allele).7,8 Importantly, these studies have enabled the classification of ACC into molecular subtypes with distinct biological signatures associated with good and poor prognosis, and have identified potentially druggable targets.
Clinical features
ACC generally presents in three forms: ~ 40-60% of patients present with symptoms and signs of hor- mone excess, ~30% present with nonspecific symp- toms (e.g. abdominal pain and fullness due to tumor growth or constitutional symptoms of malig- nancy), and 20-30% are asymptomatic and diag- nosed incidentally on cross-sectional imaging performed for other indications.30 The most
common syndrome of hormone excess in patients with functional ACC is Cushing’s syndrome, which occurs in ~45% of patients and may cause central weight gain, plethora, proximal muscle atrophy, diabetes mellitus, and easy bruising. A mixed clini- cal picture of Cushing’s and virilization due to con- comitant cortisol and androgen hypersecretion may also be seen in 20-30% of patients.31,32 The latter phenotype is strongly suggestive of malignancy and is not seen in patients with benign adrenal adenomas.30 While autonomous aldosterone secre- tion is rare in ACC, hypokalemia and hypertension may still occur secondary to glucocorticoid-induced mineralocorticoid receptor activation in patients with hypercortisolism.3º Feminization in males due to excess estrogen production occurs in 1-5% of patients.33 The effect of functional status on sur- vival outcomes in patients with ACC is controver- sial. Although some series have shown hormone secretion to be an independent risk factor for poorer overall survival (OS) and recurrence-free survival (RFS),34-37 these findings have not been consist- ently confirmed by others.38,39 A meta-analysis by Vanbrabant et al.40 demonstrated an increased risk of mortality [relative risk (RR) 1.71] and recur- rence (RR 1.43) in cortisol-secreting, but not androgen-secreting, ACC. However, it is unclear whether these findings are due to the deleterious effects of cortisol hypersecretion rather than true underlying differences in tumor biology and aggressiveness.
Diagnostic evaluation
Clinical workup of suspected ACC is centered around hormonal evaluation and cross-sectional imaging, with a final diagnosis confirmed by his- topathological examination. The combined rarity of this malignancy and the lack of disease-specific symptoms can make ruling out a diagnosis of ACC challenging in a patient with an incidentally discovered adrenal mass, (an adrenal ‘inciden- taloma’) particularly when imaging and biochem- istry are inconclusive.
Biochemistry
Biochemical evidence of hormone excess is found in 60-70% of patients with ACC.41,42 Hormonal evaluation is useful in the workup of ACC for sev- eral reasons: (1) the presence of steroid hormone excess establishes the adrenocortical origin of the tumor and obviates the need for unnecessary inves- tigations such as biopsies; (2) the specific pattern of
hormones excess (e.g. co-secretion of cortisol and androgens) may further raise suspicion for malig- nancy; (3) the measurement of hormone levels may serve as a useful biomarker for recurrence during follow-up after surgery; (4) the need for postopera- tive hydrocortisone replacement in patients with cortisol-producing ACCs can be determined; and (5) the potential for intraoperative hypertensive cri- ses due to undiagnosed pheochromocytoma is avoided.5,30 Specific biochemical tests, as recom- mended in current ENS@T/European Society of Endocrinology (ESE) guidelines,5 are shown in Table 1.
Imaging
Computed tomography. Imaging forms the corner- stone of evaluation in patients with suspected ACC; the most commonly used first-line modality is typi- cally an abdominal computed tomography (CT) scan.43 CT features suggestive of an ACC rather than a benign adrenal mass include the presence of irregular borders, areas of necrosis, hemorrhage, and/or calcification [Figure 1(a)]. Invasion into sur- rounding structures, such as the inferior vena cava, may also be seen [Figure 1(b)].44 The risk of malig- nancy in an adrenal mass increases with size, with ACCs typically presenting with a median diameter of 10cm.31 The risk of ACC by size has been reported as 2%, 6%, and 25% for adrenal lesions of <4cm, 4-6cm, and >6 cm, respectively, leading to the recommendation in some consensus guidelines that adrenalectomy should be considered for lesions >4cm.45,46 Calculation of tissue density as an approximation of intracellular lipid content on unenhanced CT, by measuring Hounsfield units (HU), is also used to distinguish between ACC and benign adrenocortical adenomas. Lipid-rich ade- nomas typically exhibit low attenuation on unen- hanced CT and a HU threshold of ≤10 is suggested as being indicative of a benign lesion in current ENS@T/ESE and European Society for Medical Oncology (ESMO) guidelines.33,47 In contrast, a HU of >10 is suggested as being indicative of malignancy. However, the distinction between benign and malignant adrenocortical tumors based on imaging is not always clear-cut, and the chal- lenges surrounding this are discussed in detail elsewhere.33,48
Positron emission tomography-computed tomog- raphy. The utility of [18F]-fluorodeoxyglucose- positron emission tomography (FDG-PET)/CT in the evaluation of ACC is not well defined. In
| Category of hormonal excess | Recommended test(s) |
|---|---|
| Glucocorticoid excess | 1 mg dexamethasone suppression test |
| Basal ACTH (plasma)a | |
| Sex steroids and steroid precursorsb | DHEA-S |
| 17-hydroxyprogesterone | |
| Androstenedione | |
| Testosterone (only in women) | |
| 17-beta-estradiol (only in men and postmenopausal women) | |
| 11-deoxycortisol | |
| Mineralocorticoid excess | Serum potassium |
| Aldosterone/renin ratio (only in patients with arterial hypertension and/or hypokalemia) | |
| Catecholamine excess (for exclusion of pheochromocytoma) | Free plasma-metanephrines or 24-h urinary fractionated metanephrines |
Table adapted from Fassnacht et al.5
aCan be omitted if hypercortisolism is excluded.
bThe most suitable set of precursors and sex hormones has not yet been established and local testing availability may dictate what tests are available.
ACTH, adrenocorticotropic hormone; DHEA-S, dehydroepiandrosterone sulfate.
(a)
(b)
patients with a history of extra-adrenal malig- nancy, this modality may be useful in distinguish- ing between benign lesions and metastases originating from cancers that have a propensity for spreading to the adrenals (e.g., liver, lung, lymph nodes, and bone).49 However, in patients
without known or suspected extra-adrenal malig- nancy and indeterminate CT findings, the role of FDG-PET/CT is less clear. In a study of 87 patients without known cancer, who underwent workup for adrenal lesions with indeterminate findings on washout CT, Guerin et al.50
demonstrated that an FDG adrenal lesion/liver standardized uptake value (SUV) ratio of >1.5 detected malignant adrenal lesions with reason- able sensitivity and specificity (86.7% and 86.1%, respectively). In contrast, in a study of 106 ACC patients, FDG-PET/CT only provided additional information beyond contrast-enhanced CT in a minority (5%) of patients.51 Other studies evalu- ating FDG-PET/CT for the assessment of adre- nal masses are limited by the inclusion of small numbers of ACC patients and suboptimal report- ing of test accuracy;48 therefore, there is a lack of consensus regarding whether FDG-PET/CT regarding should be recommended for routine use in all patients with suspected ACC.5 Further- more, limitations of this modality include cost, additional radiation exposure, and the potential for false-positive findings, particularly in func- tional adenomas and nonmetastatic pheochromo- cytomas, which may exhibit FDG-avidity.49
Metomidate (MTO) is a potent inhibitor of the adrenal enzymes CYP11B1 (11ß-hydroxylase) and CYP11B2 (aldosterone synthase). Given its selectivity for these adrenal-specific targets, MTO labelled with [11C] for PET imaging or [123I] for single-photon emission computerized tomography (SPECT)/CT has been developed as an alternative tracer for functional adrenal imaging.52 Evidence to date suggests that while MTO may be useful in distinguishing between cortical and noncortical adrenal lesions, its ability to differentiate benign from malignant adrenal tumors is limited.52 Despite this, a subset of patients with metastatic ACC have been shown to demonstrate [123]] MTO uptake, which has provided the rationale for trials of radionuclide-based systematic therapy in this subgroup (discussed below).53,54
Urine steroid metabolomics
Limitations in the diagnostic accuracy of the imag- ing tests described above are reflected in the low prevalence of malignancy (<10%) in contempo- rary series of patients undergoing adrenalectomy for non-functioning incidentalomas.55,56 Therefore, patients are commonly subjected to multiple radio- logical studies and unnecessary surgical resection of adrenal masses that are ultimately revealed to be benign. A technology that has recently come to the forefront as a means of improving current stand- ard-of-care workup for ACC is urine steroid metab- olomics, which utilizes mass spectrometry-based urinary steroid metabolite profiling in combination
with machine-learning-based data analysis.42 The rationale for this approach is based on the finding that ACCs are relatively inefficient steroid produc- ers, due to the dysregulated expression of steroido- genic enzymes.57 This results in the excessive secretion of a range of steroid hormone precursors, instead of the normal end products of steroid hor- mone biosynthesis. These precursors, while not routinely measured in blood tests, can be detected using gas or liquid chromatography/mass spec- trometry analysis of 24-hour urine samples. Proof- of-concept for this approach was first demonstrated by Arlt et al.,41 who retrospectively compared 45 patients with ACC to 102 patients with benign adrenal adenomas, showing that the former had significantly greater urinary excretion of androgen precursor metabolites, metabolites of active andro- gens, deoxycorticosterone, and glucocorticoid pre- cursors. Using a machine-learning-based algorithm, a malignant steroid ‘fingerprint’ was generated, which predicted ACC with 90% sensitivity and 90% specificity.41
The recently published Evaluation of Urine Steroid Metabolomics in the Differential Diagnosis of Adrenocortical Tumours (EURINE-ACT) study prospectively validated the panel proposed by Arlt et al.41 in an international cohort of 2017 patients, 98 of whom had ACC.58 In this study, three tests (tumor diameter, imaging characteristics, and urine steroid metabolomics) were assessed for diagnostic accuracy, either separately or in combi- nation. The combination of all three tests demon- strated the highest positive predictive value (76.5%) for diagnosing ACC in patients with the following results: tumor size >4cm, CT attenua- tion >20 HU, and a high-risk urine steroid metab- olomics profile. The negative predictive value of this triple testing strategy was high, (99.7%) high- lighting its potential value in ruling out ACC and preventing a subset of patients from undergoing unnecessary investigations and surgery. The same group has also shown, in a preliminary study, that urine steroid metabolomics can be used as for the detection of ACC recurrence after surgery; how- ever, prospective validation and comparison against the reference standard for recurrence detection (imaging) is awaited.59
Despite the clear benefits of a non-invasive assay such as urine steroid metabolomics, the wide- spread implementation of this technology into routine clinical practice is currently limited by both the cost and availability of mass spectrome-
(a)
METRIC 1 2 3 4 5 6 7 8 9 1
(b)
2
METRIC 1 2 3 4 5 6 78 9 1
try equipment as well as the need for inter-labora- tory cross-validation of assay results.
Pathology
While the clinical, biochemical, and radiological tests outlined above may raise suspicion for ACC, the final diagnosis is made on histological examina- tion, which should be performed by an experienced endocrine pathologist. Macroscopically, ACCs tend to be large lobulated masses [Figure 2(a)], with heterogenous areas of hemorrhage and necro- sis within a fibrous capsule. Their cut surface ranges from brown to orange to yellow depending upon intracellular lipid content [Figure 2(b)]. The only definitive criteria for malignancy are the presence of distant metastasis and/or loco-regional invasion; in
the absence of these features, the diagnosis may be made using various histological multiparameter scoring systems. In practice, the system first pro- posed by Weiss in 198460 is most widely used. The Weiss score is based on nine microscopic criteria, each of which is weighted equally and given a score of 1 if present (Table 2).60 A total score of ≥3 is consistent with ACC, while a score of 0-2 indicates an adrenocortical adenoma. Some borderline lesions scoring 2, however, are still be considered suspicious and may be deemed as having ‘uncertain malignant potential’.61 The reliability of the Weiss system has been challenged in these borderline cases and, in recent years, additional scoring sys- tems have been developed. These are either simpli- fied versions of the existing Weiss score62 and/or incorporate immunohistochemical staining for reticulin63 or Ki-67.64 Each of these demonstrates similarly high performance, with sensitivities of ~100% and specificities of 90-99% for diagnosing ACC.65 Nonetheless, the very existence of several competing scoring systems highlights the chal- lenges and complexities faced in the pathological assessment of ACC and the fact that no individual system is ideal. In an effort to standardize the reporting process, the International Collaboration on Cancer Reporting (ICCR) have proposed a minimum reporting standard of 23 items that should be included in ACC pathology reports, based on the consensus of an international panel of expert adrenal pathologists.66
It should be noted that the Weiss score overdiag- noses malignancy in the oncocytic subtype of adrenocortical tumors. This is because oncocytic tumors inherently possess at least three features of the Weiss criteria (high nuclear polymorphism, <25% clear cells, and diffuse architecture), whether they are benign or malignant.61 For this variant, a modified scoring system (the Lin- Weiss-Bisceglia system)68 should be utilized. In contrast, the Weiss score underestimates the risk of malignancy in the even rarer myxoid variant of adrenal tumors. Although no specific scoring sys- tem exists for this subtype, the Helsinki score (which incorporates Ki-67) has been shown to outperform the Weiss score in this context.65
Is there a role for preoperative adrenal biopsy?
Transcutaneous adrenal biopsy is not generally indicated in patients with ACC because the limited amount of tissue obtained from this procedure makes the differentiation between benign and
| Criteria | Score awardeda | |
|---|---|---|
| 0 | 1 | |
| Nuclear grade | I/II | III/IV |
| Mitosis | ≤5 per 50 HPF | >5 per 50 HPF |
| Atypical mitoses | Absent | Present |
| Clear cell component | ≤25% of tumor | >25% of tumor |
| Diffuse architecture | ≤1/3 of tumor | >1/3 of tumor |
| Confluent necrosis | Absent | Present |
| Venous invasion | Absent | Present |
| Sinusoidal invasion | Absent | Present |
| Capsular invasion | Absent | Present |
aA total score of >3 is suggestive of ACC. Nuclear grading is based on the Fuhrman nuclear grading system used in renal cell carcinoma.67 HPF, high power fields.
malignant adrenal masses difficult.69 Furthermore, complications may occur in 11% of patients, including hemorrhage, pneumothorax, pancreati- tis, and the small risk of needle-track seeding due to violation of the tumor capsule.70 Despite this, biopsy may be indicated in patients with metastatic ACC who are not surgical candidates and in whom a tissue diagnosis would help inform oncological management. Biopsy may also be useful in situa- tions where the exclusion of suspected metastasis in patients with a known extra-adrenal primary malignancy would guide the choice of therapy (e.g. surgery for limited disease versus chemotherapy for metastatic disease).5 Prior to biopsy being per- formed, biochemical exclusion of pheochromocy- toma is necessary to avoid the possibility of potentially life-threatening catecholamine surge.5
Staging and prognosis
Staging systems
Accurate staging of ACC plays a key role in treat- ment planning and prognostication. Although sev- eral staging systems have been described, the one proposed by the ENS@T group in 2009 is most widely used.71 The ENS@T staging system is a modification of the original 2004 American Joint Committee on Cancer (AJCC)/Union for International Cancer Control (UICC) tumor,
node, metastasis (TNM) classification (Table 3), which was criticized for its inability to discriminate between the survival outcomes of patients with stage II and III disease.71 Furthermore, it was real- ized that patients with tumor invasion into sur- rounding adipose tissue and positive lymph nodes, or those with invasion into adjacent organs fared significantly better than those with distant metas- tases, despite all of these patients being classified as stage IV disease according to the 2004 AJCC/ UICC system.71,72 Instead, the ENS@T system defines stage I and stage II ACC as tumors con- fined to the adrenal gland, that measure ≤5 cm and >5 cm, respectively; stage III denotes tumors that extend into surrounding adipose tissue or adjacent organs or involve locoregional lymph nodes; stage IV only includes tumors with estab- lished distant metastases.71 The changes proposed by ENS@T were recently incorporated into the 2017 (8th edition) AJCC/UICC staging manual for ACC,73 such that both staging systems are now virtually identical (Table 3). Other groups have attempted to further refine the discriminatory abil- ity of the ENS@T staging system with the inclu- sion of additional clinicopathological factors such as age,74,75 Ki-67,75,76 lymphovascular invasion,77 resection margin status,75 number of tumor- involved organs,75 and the presence of symptoms at diagnosis.75 Of these factors, Ki-67 appears to be the single most powerful predictor of disease
| Stage | UICC/AJCC 2004 | ENSAT 2009 and UICC/AJCC 2017 |
|---|---|---|
| I | T1, N0, M0 | T1, N0, M0 |
| II | T2, N0, M0 | T2, N0, M0 |
| III | T3, N0, M0 | T3-T4, N0, M0 |
| T1-T2, N1, M0 | T1-T4, N1, M0 | |
| IV | T3, N1, M0 T4, N0-N1, M0 Any M1 | Any M1 |
Tumors are classified as follows: T1, ≤5 cm; T2, >5 cm tumor; T3, tumor infiltration into surrounding tissue; T4, tumor invasion into adjacent organs; N0, no positive lymph nodes; N1, positive lymph node(s); M0, no distant metastases; M1, presence of distant metastasis.
AJCC, American Joint Committee on Cancer; ENS@T, European Network for the Study of Adrenal Tumors; UICC, Union for International Cancer Control.
recurrence following resection, with the longest RFS seen in patients with a Ki-67 index of <10%.78
Prognosis
Although the overall prognosis of ACC is poor, survival can be heterogenous depending on the extent of disease. The majority of patients with ACC present with advanced disease (34% with stage III disease and 26% with stage IV disease) with the most common sites of metastatic spread being the liver, lungs, lymph nodes, and bone.5,30 Typically quoted 5-year survival rates (in European and North American cohorts) are 66- 82% for stage I, 58-64% for stage II, 24-50% for stage III, and 0-17% for stage IV disease.3,71,72,79 A more recent Finnish series reported favorable 5-year survival rates of 100%, 93%, and 63% for stage I, II, and III disease, respectively.32 This may reflect the increasing utilization of surgery and adjuvant therapy (discussed below) com- pared with historic studies. Despite this, 5-year survival remained dismal (11%) for patients with stage IV disease. 32
Targeted molecular classification as a future tool for individualized prognostication and management
As discussed above, in addition to providing insights into the pathogenesis of ACC, large-scale multi-omics studies from the ENS@T7 and TCGA-ACC8 groups have defined distinct sub- groups of patients with clinically significant differ- ences in survival based on genomic, epigenomic,
and transcriptomic signatures. However, the requirement for prospective collection of fresh- frozen tissue and the costly and resource-intensive nature of pan-genomic bioinformatics analysis pre- cludes its use in routine clinical practice.80 As a method of overcoming these limitations, two recent studies have described how targeted molec- ular profiling (i.e. analysis of only a limited number of the most predictive biomarkers) could recapitu- late the prognostic classification provided by the more comprehensive ENS@T and TCGA-ACC studies at a fraction of the required time and cost (Figure 3).81,82 Furthermore, in one of these studies,81 targeted analysis was feasible using only formalin-fixed paraffin-embedded (FFPE) tissue, which is readily available in most clinical settings. Importantly, the combination of targeted molecu- lar data with clinicopathological parameters in both studies was superior in predicting RFS com- pared to either component alone. In the future, increased utilization of targeted molecular analysis raises the possibility of individualized prognostica- tion and precision medicine in patients with ACC, as has been implemented for other cancers.83
Treatment
Complete surgical resection with negative mar- gins (R0) is currently the only curative treatment for ACC and applies to patients with resectable stage I-III disease. Adjuvant therapies are used to decrease recurrence rates, which are reported to range from 40-70% even after RO resection, depending on stage.4,84,85 For patients with unre- sectable stage III or metastatic (stage IV) disease,
FIRM-ACT: EDP + mitotane established as 1st line therapy for advanced ACC Fassnacht et al N Engl J Med 201214
Ki-67 established as major prognostic factor for ACC recurrence Beuschlein et al J Clin Endocrinol Metab 201577
Demonstration of feasibility of targeted molecular profiling using FFPE samples for prognostication Lippert et al J Clin Endocrinol Metab 201880
Molecular subtypes of ACC first identified using microarray analysis Giordano et al Clin Cancer Res 200928 de Reyniès et al J Clin Oncol 200929
Multi-omic characterisation of ACC by TCGA-ACC group Zheng et al Cancer Cell 20168
Validation of targeted molecular profiling for prognostication Assié et al JAMA Oncol 201981
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First study to show that adjuvant mitotane improves PFS after RO resection in a large number of patients Terzolo et al N Engl J Med 2007127
ENS@T staging system proposed Fassnacht et al Cancer 200970
Multi-omic characterisation of ACC by ENSA@T group Assié et al Nat Genet 20197
ADIUVO
ADIUVO-2
Pathogenesis Prognosis Treatment
First study to suggest that regional lymphadenectomy may improve PFS and OS in localized ACC Reibetanz et al Ann Surg 2012105
GALACCTIC trial: limited efficacy of IGF-1R inhibition in advanced ACC Fassnacht et al Lancet Oncol 2015149
JAVELIN trial: limited efficacy of PDL-1 immunotherapy in advanced ACC Le Tourneau et al J Immunother Cancer 2018161
EURINE-ACT study: prospective validation of urine steroid metabolomics for ACC diagnosis Bancos et al Lancet Diabetes Endocrinol 202058
Diagnosis
First study to show that adjuvant radiotherapy may improve both PFS and OS in localized ACC Gharzai et al J Clin Endocrinol Metab 2019140
ACC, adrenocortical carcinoma; ADIUVO, Efficacy of Adjuvant Mitotane Treatment; EDP, etoposide, doxorubicin, and cisplatin; ENS@T, European Network for the Study of Adrenal Tumors; EURINE-ACT, Evaluation of Urine Steroid Metabolomics in the Differential Diagnosis of Adrenocortical Tumours; FFPE, formalin-fixed paraffin-embedded; FIRM-ACT, First International Randomized Trial in Locally Advanced and Metastatic ACC Treatment; GALACCTIC, A Study of OSI-906 in Patients with Locally Advanced or Metastatic Adrenocortical Carcinoma; JAVELIN, Avelumab in Metastatic or Locally Advanced Solid Tumors; OS, overall survival; PFS, progression-free survival; TCGA-ACC, The Cancer Genome Atlas ACC Study.
the goals of treatment are palliative rather than curative. An additional treatment challenge involves counteracting the deleterious effects of excess hormone secretion, which is associated with increased morbidity and impaired quality of life. For these reasons, and the fact that most patients present with advanced disease, it is strongly recommended that patients with ACC are managed by multidisciplinary teams at insti- tutions with experience and expertise in treating this rare malignancy.86 An overview of current emerging treatment options for patients with localized and advanced disease are provided below. The management of hormone excess in ACC is beyond the scope of this review, and has been extensively covered by Else et al.30
Surgery
Because the only chance for cure in patients with ACC is afforded by complete resection, surgery may necessitate en bloc removal of not only the tumor, but also any adjacent involved organs, such as the ipsilateral kidney, pancreas, and/or
diaphragm, as well as the periadrenal retroperito- neal fat, in order to achieve an R0 resection.6 In the absence of direct invasion, however, there is no convincing evidence that routine en bloc resec- tion of extra-adrenal organs is associated with superior oncological outcomes when negative margins can otherwise be achieved.87,88 Regardless of operative extent, it is crucial that surgery is per- formed meticulously to avoid intraoperative tumor rupture and spillage, which are associated with high recurrence rates and extremely poor survival. Extension of tumor thrombus into the inferior vena cava (T4 disease) is not a contrain- dication to surgery and may require cross-clamp- ing of the retro-hepatic inferior vena cava and/or cardiopulmonary bypass.89 However, this tech- nique requires careful patient selection as long- term survival outcomes remain suboptimal in this subgroup.90
The nuances and challenges of ACC surgery underscore the strong recommendations in cur- rent guidelines for these procedures to be per- formed at specialized centers by experienced
adrenal surgeons.5,6 Indeed, a volume-outcome effect in adrenalectomy has been repeatedly described, with fewer complications reported when procedures are performed by expert sur- geons at higher volume centers.91 Whether this translates into improved oncological outcomes in ACC has not consistently been shown, however, with some studies suggesting longer time to recur- rence92 and better overall survival93 when surgery is performed at high- versus low-volume centers, while others have failed to demonstrate any sur- vival advantage.94 Furthermore, the specific num- ber of ACC surgeries that defines a ‘high-volume’ surgeon or center is unclear and varies widely in the literature from 4 to 20 cases per year.6,92,95
Choice of surgical approach. Despite the benefits afforded by minimally-invasive adrenalectomy in terms of reduced blood loss, improved cosmesis, and shorter recovery time, its role in ACC surgery remains controversial.96-100 This is due to the con- cerns that achieving a curative margin-negative resection may be more challenging laparoscopi- cally, particularly in cases where an infiltrative tumour obliterates dissection planes and precludes good exposure.6 A thin tumour capsule (e.g. in cortisol-secreting ACCs) may also be more likely to rupture secondary to manipulation with laparo- scopic instruments. In accordance with this, some reports have shown higher rates of ACC recur- rence (including in port sites) and poorer disease- free survival with a laparoscopic approach.101,102 However, the literature is not unequivocal on this topic and, as additional experience has accumu- lated, comparable oncological outcomes with lap- aroscopic and open adrenalectomy for ACC have also been reported, particularly for smaller tumors without evidence of local invasion.103,104 The lack of consensus regarding the role of laparoscopy is reflected in differences between guidelines from the American Association of Endocrine Surgeons (AAES)/American Association of Clinical Endo- crinologists (AACE) which recommend open resection for all cases of ACC (regardless of size) 105 versus newer ENS@T/ESE guidelines that suggest that laparoscopic resection is a reasonable option for localized tumors <6 cm in diameter.6
The role of lymphadenectomy. Locoregional lymphadenectomy for therapeutic purposes is standard practice for many intra-abdominal malig- nancies; however, its role in ACC is poorly defined. The first study that attempted to address this topic retrospectively analyzed 283 patients from the
German ACC Registry with stage I-III disease, 17% of whom underwent lymph node dissection (defined as the removal of ≥5 lymph nodes) dur- ing curative-intent adrenalectomy.106 On multi- variable analysis, lymph node dissection was independently associated with a 35% lower risk of tumor recurrence and a 46% lower risk of disease- related death.106 A subsequent retrospective US multi-center study evaluated 120 non-metastatic ACC patients, 27% of whom underwent lymph- adenectomy (defined as a documented attempt to dissect regional lymph nodes in the operative note).107 The authors found that lymphadenec- tomy was associated with a significantly higher 5-year OS rate of 76% compared to 59% in the group that had no lymph nodes excised.107 How- ever, multiple studies using the SEER registry and National Cancer Database (NCDB) have shown contradictory results, with either no effect,108 worse survival,109-112 or a marginal improvement in survival,113 in patients who underwent lymph- adenectomy. Reasons for these discrepancies include the fact that the inclusion criteria in these studies differ widely by stage, presence of metasta- ses, multivisceral resection, and margin status. In addition, the lack of granularity intrinsic to datas- ets such as SEER and NCDB make it impossible to determine whether lymphadenectomy was per- formed intentionally, and which specific lymph node basins were removed. Collectively, these studies highlight the need for a prospective trial in which the a priori objective is to determine whether lymphadenectomy confers a survival benefit in ACC patients. A recent study that described radio- logical patterns of regional nodal recurrences in 56 ACC patients suggested that the definition of lymphadenectomy that is used in a future prospec- tive trial should include removal of periadrenal, renal hilar, ipsilateral para-aortic, or paracaval nodes. 114
Surgery for locally recurrent or metastatic dis- ease. Approximately 20-60% of reported recur- rences in ACC patients are locoregional.115 In these cases, reoperation may be indicated if an R0 resection is achievable. This is supported by data from a number of retrospective studies, which have shown improvements in symptoms and a median survival of >5 years in selected patients who undergo reoperation versus medical manage- ment alone.115-119 Studies have also demonstrated the safety and efficacy of pulmonary120 and hepatic metastatectomy,121 with reported 5-year OS rates of~25-50%. Overall, patients who derive
the greatest benefit from reoperation appear to be those with a disease-free interval from initial resection to recurrence of >9-12 months.117,122,123 The decision to offer reoperation should weigh up the potential survival benefits against the risks of morbidity (12-55%), mortality 0-4%), and the high likelihood of further recurrence (~80%).6
The role of metastasectomy in patients who have synchronous metastases at presentation is less clear, with studies showing that these patients have a poorer overall prognosis compared to those who develop metachronous metastases. 124,125 Studies describing operative intervention in this group are lacking due to the paucity of cases and short duration of survival. A combined series of 27 patients from Mayo Clinic and the MD Anderson Cancer Center showed that those who underwent an R0 resection had significantly bet- ter median OS of 28.6 months versus 13.0 months when only an R2 resection was acheived.126 A similar benefit was also reported in another US multi-center study of 26 patients with Stage IV disease (median survival of 19.0months for R0 resection versus 5.5 months for R1/R2 resec- tion).125 Overall, these findings indicate that patients with metastatic ACC constitute a heter- ogenous group with distinct differences in tumor biology, prognosis, and degree of benefit derived from surgery.
Adjuvant therapy
Although surgical resection is technically feasible in most patients with stage I-III ACC, the major- ity of patients still succumb to disease, presuma- bly due to occult micrometastases that are present at the time of initial presentation. As a result, adjuvant therapies may be used in an attempt to reduce rates of disease recurrence in patients who have a seemingly curative index operation.
Mitotane
Mitotane is a derivative of the insecticide dichlo- rodiphenyltrichloroethane (DDT) and exerts adrenolytic activity through mechanisms that are incompletely understood. One of these mecha- nisms includes endoplastic reticulum stress acti- vation, which impairs steroidogenesis and induces apoptosis of ACC cells.127 Impetus for the use of mitotane in the adjuvant setting arose from a 2007 retrospective study by Terzolo et al.,128 which analyzed 177 stage I-III ACC patients who
were followed up for up to 10 years at referral centers in Italy and Germany (Figure 3). Adjuvant mitotane use was associated with significantly longer median recurrence-free survival of 42 months versus 10 and 25 months in the Italian and German control groups, respectively. Median OS was also better in the mitotane group at 110 months versus 52 and 67 months in the Italian and German cohorts, respectively.128 A subse- quent description of this cohort, after almost 10 additional years of follow-up, showed a sustained survival benefit in the mitotane group.129 A more recent study from this group of authors, in an independent sample of 152 patients, showed that adjuvant mitotane prolonged recurrence-free sur- vival without improving overall survival, although better OS was seen in a subgroup of patients deemed to be at high risk of recurrence (elevated Ki-67 and stage III disease).130
In contrast, studies from US centers have shown conflicting results regarding the benefits of adju- vant mitotane on survival outcomes.131-133 The University of Michigan group observed that while adjuvant mitotane significantly improved RFS, no effect on OS was seen.131 In a study from MD Anderson, patients who underwent index surgery at that institution had a recurrence rate of 50% after a median follow-up of 7.3 years, 132 which the authors noted was similar to the 49% 5-year RFS rate reported for patients who received adjuvant mitotane in the 2007 Italian/German study by Terzolo et al.128 Because 90% of the MD Anderson cohort did not receive adjuvant mito- tane, the authors attributed the comparable recurrence rates in their study to the quality and completeness of surgery performed at their insti- tution, rather than to the use of adjuvant therapy. Similarly, in a 13-institution study from the US ACC group, no significant association between mitotane use and RFS or OS was seen on multi- variable analysis.133 It is important to note that all of the aforementioned studies are retrospective in nature and are fraught with selection bias and heterogeneity with regards to patient characteris- tics and treatment regiments. While recognizing that the evidence base is weak, current European guidelines recommended adjuvant mitotane for patients who are at high risk of recurrence (e.g. stage III disease, R1 resection, or Ki-67 > 10%).5,47 Whether or not adjuvant mitotane is beneficial in patients at low or moderate risk of recurrence (e.g. stage I-II disease, RO resection, and Ki-67<10%) is unclear, and it is anticipated that
the recently-completed Efficacy of Adjuvant Mitotane Treatment (ADIUVO) randomized controlled trial (RCT) will answer this question (Figure 3). Furthermore, the ongoing ADIUVO-2 RCT (due to complete in 2025) will determine whether the combination of cisplatin and etopo- side with adjuvant mitotane is more effective than adjuvant mitotane alone in prolonging RFS and OS in patients with high-risk ACC (Figure 3).
Radiotherapy
Adjuvant radiotherapy is infrequently used in the management of ACC, with only 6 and 14% of patients reported as receiving this treatment modality in two separate NCDB studies covering the periods 1985-2005134 and 2004-2013,135 respectively. Reluctance to refer patients for radi- otherapy likely reflects the widely held viewpoint that ACCs are radioresistant tumors, which is based on data from small pre-2000 series which failed to show any improvement in recurrence or overall survival with adjuvant radiation.136-138 However, the results of recent studies that utilize modern radiotherapy techniques have challenged this notion.139-141 For example, in a case-control study from the German ACC group, in which 14 patients with non-metastatic ACC who received adjuvant radiotherapy were matched to 14 patients that did not, local recurrence was observed in 14% of patients in the radiation group versus 79% of patients in the control group.139 However, no significant differences were seen in terms of disease-free survival and OS. Findings consistent with these were reported by the University of Michigan group, in a case-control study of 20 patients who received adjuvant radio- therapy versus 20 matched controls who did not.140 In this study, 5% of the patients who received radiation experienced a recurrence versus 60% of patients in the control group. Again, no significant differences in RFS or OS were found. The authors speculated that the lack of a detect- able survival benefit was due to the study being underpowered and have recently published a larger series of 78 patients, half of whom received adjuvant radiation.141 Interestingly, in addition to improved local recurrence rates, this study reported significantly better RFS and OS in the radiation group. It should be noted that there are no prospective data evaluating the benefit of adju- vant radiation, and the findings of retrospective studies should be carefully interpreted in light of the potential for referral and selection bias.
Despite this, emerging evidence suggests that adjuvant radiotherapy in the contemporary era is probably more effective than previously thought.
Systemic therapy
The dearth of effective systemic therapies poses a significant challenge in the treatment of patients with metastatic ACC. For years, mitotane has remained the only drug approved by the United States Food and Drug Administration (FDA) and the European Medicines Agency (EMA) for the treatment of unresectable ACC.142 For selected patients with low tumour burden and/or slower growth kinetics, mitotane monotherapy has been used, albeit with disappointing objective RR of 20- 25%.143,144 Otherwise, standard of care palliative treatment is with etoposide, doxorubicin, and cispl- atin, in combination with mitotane (EDP-M). Evidence in support of this regimen came from the FIRM-ACT (First International Randomized Trial in Locally Advanced and Metastatic ACC Treatment) study (Figure 3).145 In this phase III RCT, the authors compared EDP-M (n=151 patients) with another commonly used regimen at the time, streptozosin plus mitotane (SZ-M; n=153), demonstrating superior efficacy in the EDP-M arm (23% RR) compared with the SZ-M arm (9% RR).145 Progression-free survival (PFS) in the EDP-M arm was also significantly longer at 5 months versus 2 months in the SZ-M arm, and there was a suggestion of better OS in the former group (14.8 months for EDP-M versus 12 months for SZ-M), although this did not reach statistical significance, possibly due to the cross-over design of the trial. While this study was important in estab- lishing the superiority of EDP-M for ACC patients with metastatic disease, it also highlighted that, despite gold-standard treatment, prognosis in this group of patients remains dismal.
For patients who experience disease progression despite EDP-M, there is limited evidence regard- ing the efficacy of non-first line chemotherapies. The two most commonly studied second-line agents include SZ-M and gemcitabine plus capecitabine, with or without mitotane. 146,147 However, RRs with these regimens have been disappointing (<10%). A recent study investi- gated temozolomide as a second- or third-line treatment for metastatic ACC showing a RR of 20%, although this was short-lived and did not influence median OS, which remained poor at 7.2months. 148
Newer treatments: targeted therapies, immunotherapy, and radiopharmaceuticals Given the limited effectiveness of current treat- ments, the search for novel therapeutic strategies for advanced ACC is a current research priority. Findings from the comprehensive ENS@T7 and TCGA-ACC8 molecular profiling studies have pro- vided an exhaustive road map of potential drugga- ble targets. Unfortunately, however, this knowledge has not yet resulted in a treatment that demonstrates efficacy above what is currently used in the clinic. For example, the observation that IGF2 is overex- pressed in the majority of ACCs and that inhibition of IGF2/IGF1R was effective in reducing tumor growth in pre-clinical models149 led to the evalua- tion of lisitinib (a small molecule inhibitor of both IGF1R and the insulin receptor) in a phase III RCT, the GALACCTIC (A Study of OSI-906 in Patients with Locally Advanced or Metastatic Adrenocortical Carcinoma) trial (Figure 3).150 Disappointingly, no differences in OS or RFS were seen compared to placebo. In addition, only 15.6% of patients in the lisitinib arm achieving disease con- trol, with a median PFS survival of <2months. Other targeted therapies that have been, or are cur- rently undergoing, evaluation in phase I/II trials include epidermal growth factor receptor (EGFR) inhibitors,151 vascular endothelial growth factor receptor (VEGFR) inhibitors,152 fibroblast growth factor receptor (FGFR) inhibitors, 153 multityrosine kinase inhibitors (TKIs),154,155 and sterol-O-acetyl- transferase (SOAT1) inhibitors.156 Unfortunately, these compounds have shown limited efficacy, with temporary disease stabilization observed in best- case scenarios. Small molecule inhibitors that have been tested pre-clinically but have not yet been eval- uated in early-phase trials include inhibitors of the Wnt/ßcatenin signalling,157 cyclin-dependent kinases,158 Notch signalling,81 and mitogen-acti- vated protein kinase (MAPK)/ERK signalling.159 Preclinical data supporting the rationale for their use in ACC have been reviewed recently by Altieri et al.160
Immunotherapy has emerged as a standard pillar of treatment across a broad spectrum of solid tumors,161 which was spurred enthusiasm for investigating this class of treatment in ACC. To date, four phase I/II clinical trials of immune checkpoint inhibitors in ACC have been pub- lished.162-165 The largest of these, the Avelumib in Metastatic or Locally Advanced Solid Tumors (JAVELIN) trial, was a phase Ib study that evalu- ated the efficacy of avelumab [a programmed
death-ligand 1 (PD-L1) antagonist] in 50 patients with metastatic ACC who had failed to respond to platinum-based chemotherapy (Figure 3).162 Disappointingly, the overall RR was only 6% with a median PFS survival of 2.6months. Potential explanations for the modest results seen in immu- notherapy trials in ACC include an immunosup- pressive action of locally secreted glucocorticoids, and deregulated Wnt/ß-catenin signaling, leading to impaired immune cell infiltration. 166
As described above, a subset (~30%) of patients with metastatic ACC demonstrate significant uptake of MTO in both the primary tumor and dis- tant metastases.53 By replacing [123]] with [13]]], MTO has been adapted for targeted radionuclide therapy.167 In a preliminary study of 11 patients with advanced ACC who demonstrated [123]] MTO avidity on diagnostic scans, a partial response to 1-3 cycles of [13]]] IMTO was achieved in 1 patient, with stable disease achieved in 5 patients. 167 Based on the observation that some ACCs may express somatostatin receptor (SSTRs),168 peptide receptor radionuclide therapy (PRRT) using the radiolabeled somatostatin analogues [9ºLu]- and [177Y]-DOTATOC was recently reported in a pre- liminary study of 19 patients by Grisanti et al.169 In this study, 2 patients were selected for PPRT based on the finding of strong uptake of [68Ga]- DOTATOC on PET/CT, indicating high somatostatin receptor expression. Both patients experienced disease stabilization that lasted 4months and 12months, respectively.169 As a result, radiopharmaceutical therapy may represent a potential salvage treatment option for a small sub- set of cases of metastatic ACC, although this requires validation in a larger number of patients.
Conclusions and future perspectives
ACC is a rare and devastating malignancy that entails a poor prognosis in the majority of cases. The past 20years have seen the publication of a number of important studies that have provided insights into the pathogenesis of ACC and its diag- nosis and treatment (Figure 3). In patients with adrenal incidentalomas, the diagnosis of ACC may be challenging due to the limited diagnostic accu- racy of cross-sectional imaging. Implementation of urine steroid metabolomics into routine workup could improve detection rates and spare patients with benign masses from undergoing unnecessary surgery, although the cost-effectiveness of this tech- nology remains to be demonstrated. Large-scale
pan-genomic analyses have greatly improved our understanding of the pathogenesis of ACC and have paved the way for targeted molecular profiling in the clinic with the possibility of individualized prognostication to guide therapy in the future. Surgery remains the only curative treatment for ACC, although questions remain about the optimal surgical approach, the benefits and definition of regional lymphadenectomy, and the effects of sur- geon volume on oncological outcomes. Despite seemingly curative resection, most patients experi- ence disease recurrence and a better understanding of the factors that influence prognosis and response to adjuvant mitotane treatment are required. Results from ADIUVO and ADIUVO-2 will provide valu- able insights into this topic. The role of postopera- tive radiation needs to be better defined in prospective studies, as emerging evidence suggests a survival benefit in selected patients. There is a clini- cally unmet need for improved treatments for advanced ACC, as current standard of care is asso- ciated with suboptimal survival. Trials of molecu- larly targeted therapy and immunotherapy have been disappointing to date, suggesting that combi- nation therapies that are guided by molecular bio- markers may be more successful than a blanket ‘one-size-fits-all’ approach. Given the rarity of ACC, the success of future research efforts is con- tingent upon continued international collaborations between teams that recognize the urgent need to widen treatment options and improve outcomes for patients with this orphan disease.
Funding
The authors received no financial support for the research, authorship, and/or publication of this article.
Conflict of interest statement
The authors declare that there is no conflict of interest.
Financial disclosures None
ORCID İD Travis J. Mckenzie İD https://orcid.org/0000-0001- 9140-6548
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