Version May 2024
INTRODUCTION — Unilateral tumors or masses of the adrenal gland are common. They are categorized as either functional (hormone-secreting) or silent and as either benign or malignant.
●The majority of adrenocortical tumors are benign, nonfunctioning adenomas that are discovered incidentally on abdominal imaging studies (adrenal incidentalomas). (See "Evaluation and management of the adrenal incidentaloma".)
●Others are benign, hormone-secreting adenomas that cause Cushing's syndrome, primary aldosteronism, or, much less commonly, virilization.
●Adrenocortical carcinomas (ACCs) are rare, often aggressive tumors that may be functional and cause Cushing's syndrome and/or virilization, or nonfunctional and present as an abdominal mass or an incidental finding.
●Pheochromocytomas are catecholamine-secreting tumors that arise from chromaffin cells of the adrenal medulla. They may be benign or malignant. These are discussed separately. (See "Treatment of pheochromocytoma in adults".)
The clinical presentation and evaluation of adrenocortical adenomas and staging of carcinomas will be reviewed here. Evaluation of adrenal incidentalomas and treatment of adrenocortical adenomas and carcinomas are discussed separately. The rarer bilateral micronodular and macronodular adrenal disorders that cause Cushing's syndrome are also reviewed separately. (See "Evaluation and management of the adrenal incidentaloma" and "Treatment of adrenocortical carcinoma" and "Cushing's syndrome due to primary bilateral macronodular adrenal hyperplasia" and "Cushing syndrome due to primary pigmented nodular adrenocortical disease".)
ADRENOCORTICAL ADENOMAS — Adrenocortical adenomas are benign neoplasms of adrenocortical cells that can secrete steroids independently from corticotropin (ACTH) or the renin-angiotensin system. They can produce syndromes of hypercortisolism and hyperaldosteronism and rarely produce virilization or feminization. Many are discovered incidentally on abdominal imaging studies (adrenal incidentalomas), while others present with symptoms of hormonal excess.
Incidentalomas — Adrenal tumors are most often discovered as an incidental finding, in over 4 percent of high-resolution abdominal imaging studies. Although most incidentalomas are nonfunctional, as many as 15 percent are functional, causing low levels of autonomous cortisol secretion (previously called subclinical Cushing's syndrome) [1,2]. In one series of 1004 adrenal incidentalomas, 85 percent were nonfunctional, 9.2 percent were found to secrete low levels of cortisol, 4.2 percent were pheochromocytomas, and 1.6 percent were aldosteronomas [3].
Adenomas secreting low levels of cortisol and pheochromocytoma are sufficiently common that all patients with an adrenal incidentaloma should be screened for these disorders. In addition, hypertensive patients should be screened for primary aldosteronism, even if the serum potassium concentration is normal. The approach to the adrenal incidentaloma is reviewed in detail separately. (See "Evaluation and management of the adrenal incidentaloma" and "Epidemiology and clinical manifestations of Cushing syndrome" and "Clinical presentation and diagnosis of pheochromocytoma" and "Pathophysiology and clinical features of primary aldosteronism".)
Pathogenesis — It is thought that the majority of adrenal tumors are of monoclonal origin. Most adrenocortical carcinomas (ACCs) are sporadic, but some occur as a component of hereditary cancer syndromes. (See 'Hereditary cancer syndromes' below.)
Aberrant receptors — Cortisol hypersecretion is the most frequent hormonal abnormality detected in patients with functioning unilateral adrenal adenomas. It had been assumed that the mechanism for this was non-ACTH-dependent autonomous cortisol secretion from the adenoma. However, it is now known that in a proportion of cases, particularly those with modest secretion [4], cortisol can be regulated by the aberrant expression and activation of G-protein coupled receptors (GPCRs) distinct from the melanocortin 2 (MC2)-ACTH receptor in the adrenocortical tissues. (See "Evaluation and management of the adrenal incidentaloma".)
The role of aberrant hormone receptors in adrenal adenomas, and more frequently in bilateral macronodular adrenal hyperplasia (BMAH), is reviewed in detail separately. (See "Causes and pathophysiology of Cushing syndrome", section on 'Primary adrenocortical hyperfunction' and "Cushing's syndrome due to primary bilateral macronodular adrenal hyperplasia".)
Reports of small numbers of cases indicate that one or more aberrant receptors may also be implicated in the renin-independent aldosterone-secreting adenomas and bilateral idiopathic hyperaldosteronism (IHA), including ACTH, gastric inhibitory polypeptide (GIP), 5-hydroxytryptamine receptor 4 (5-HT4), luteinizing hormone (LH), gonadotropin-releasing hormone (GnRH), vasopressin, or thyroid-stimulating hormone (TSH) [5-8].
Beta-catenin mutations (CTNNB1) — Constitutive activation of beta-catenin in the Wnt signaling pathway has been identified as a frequent alteration in benign and malignant adrenocortical tumors [9,10]. The increased occurrence of adrenal tumors in patients with mutations of adenomatous polyposis coli (APC) suggested that the Wnt/beta-catenin pathway could be involved in adrenal tumorigenesis [11]. This pathway is essential for embryonic development of the adrenal [12], and its ectopic constitutive activation is associated with cancer development in a number of tissues [13,14].
Activating mutations of exon 3 of the CTNNB1 gene (beta-catenin) are frequent in adrenocortical adenomas [15-21]. In one series of 39 adrenocortical tumors, an activating somatic mutation of the CTNNB1 gene was identified in 7 of 26 adrenocortical adenomas (27 percent) and in 4 of 13 ACCs (31 percent); most were point mutations altering the Ser45 of exon 3 [15]. In a second report, genetic alterations of exon 3 of beta-catenin were found in 5 of 33 adenomas (15 percent) but none in 4 ACCs or 13 BMAH [16].
In a larger study of 100 surgically removed adrenal adenomas (excluding aldosteronomas), 36 percent had CTNNB1 mutations, mostly in larger and nonsecreting adenomas, suggesting that the Wnt/beta-catenin pathway activation is associated with the development of less differentiated tumors [17]. Somatic CTNNB1 mutations may explain only approximately 50 percent of beta-catenin accumulation observed in adrenocortical tumors, indicating that other components of the Wnt pathway may be involved.
Mutations in adrenal Cushing's syndrome — Somatic mutations of protein kinase A (PKA) catalytic subunit (PRKACA) were identified in 22 of 59 adenomas (37 percent) from patients with overt Cushing's syndrome but not in adenomas secreting less cortisol [22]. This was confirmed in a second report; 35 percent of cases with overt Cushing's syndrome had the same mutation compared with only 11 percent of those with subclinical cortisol secretion [18]. In additional reports, the same mutation was found in over 50 percent of patients with Cushing's syndrome due to adrenal adenomas [10,19,21,23]. The most frequent hotspot p.Leu206Arg mutation is located in the active cleft of the catalytic subunit, inactivating the site where the regulatory subunit RII-beta usually binds, thus causing a constitutive PKA activation. Examination of a larger number of samples collected in several European centers identified additional somatic mutations of PRKACA with similar functional consequences; patients with PRKACA mutations had higher levels of cortisol after dexamethasone test and smaller adenomas than nonmutated ones [21,24]. The infrequent presence of PRKACA mutation in low cortisol-secreting adenomas may explain why they rarely progress to overt Cushing's syndrome with time.
Somatic activating mutations of the Gs alpha subunit (GNAS) similar to those found in endocrine tumors of patients with McCune-Albright syndrome have been identified in 5 to 17 percent of cortisol-secreting adrenal adenomas [18,21,23]. Adenomas with PRKACA or GNAS mutations appear to be significantly smaller and secrete more cortisol than adenomas without these mutations, and individuals with these tumors presented at significantly younger ages [18,23].
Mutations in aldosterone-producing adenomas — The most frequent causes of primary aldosteronism include bilateral IHA (60 to 70 percent) and unilateral aldosterone-producing adenoma (APA, 30 to 40 percent). (See "Diagnosis of primary aldosteronism".)
This classical distinction between APA and IHA was challenged by the observation of adrenal cortex remodeling, with increased nodulation, reduced vascularization, and functional zona glomerulosa hyperplasia in the adrenal cortex adjacent to APAs [25,26].
Somatic mutations in KCNJ5 have been identified in patients with primary aldosteronism due to APAs. These mutations are more common in women than men; APAs with KCNJ5 mutations are larger than those without mutations. Somatic mutations in other important genes implicated in regulation of aldosterone synthesis (ATP1A1, ATP2B3, CACNA1D, CTNNB1, CLCN2 chloride channel ARMC5) have also been identified [27]. These mutations are reviewed in greater detail separately. (See "Pathophysiology and clinical features of primary aldosteronism", section on 'Mutations in aldosterone-producing adenomas'.)
Germline mutations in KCNJ5 or other ion channel genes have been identified in rare families with familial hyperaldosteronism type III but not in patients with APA or IHA. (See "Familial hyperaldosteronism", section on 'Mutations in KCNJ5 gene'.)
Clinical features
Cushing's syndrome — Approximately 10 percent of cases of overt Cushing's syndrome are due to adrenal adenomas. Both the degree of hypercortisolemia and many of the clinical manifestations of Cushing's syndrome tend to be less severe in patients >50 years of age [28]; this may be related to the fact that younger patients with overt Cushing's syndrome are more likely to harbor PRKACA mutations [18,19,22-24]. As noted above, low levels of ACTH-independent cortisol secretion (mild hypercortisolism without clinical manifestations of Cushing's syndrome) is common in patients with adrenal incidentalomas. However, glucose intolerance and hypertension are common in these patients [29], and patients may be at increased risk of cardiovascular morbidity [30,31]. The causes, clinical features, and diagnosis of Cushing's syndrome are reviewed in detail separately. (See "Causes and pathophysiology of Cushing syndrome" and "Epidemiology and clinical manifestations of Cushing syndrome" and "Establishing the diagnosis of Cushing syndrome".)
Primary aldosteronism — Aldosteronomas are rare causes of adrenal incidentaloma because most have been diagnosed by the time they reach a size detectable by computed tomography (CT) or magnetic resonance imaging (MRI). However, using more carefully selected control groups to establish normal cutoffs and 48-hour low-dose dexamethasone tests and saline loading test under dexamethasone in 151 patients with adrenal incidentalomas, the prevalence of aldosterone excess was 24 percent, with combined excess of cortisol and aldosterone in 12 percent [32,33]. Renin-independent, incompletely suppressible (primary) hypersecretion of aldosterone is an increasingly recognized but still underdiagnosed cause of hypertension [34]; it is estimated to be responsible for 5 to 13 percent of hypertension in humans and can reach 20 percent in those with resistant hypertension and up to 35 percent of patients with sleep apnea. The classic presenting signs of primary aldosteronism were previously hypertension and hypokalemia, but potassium levels are frequently normal in modern-day series of aldosteronomas; screening for primary aldosteronism should be conducted in all patients with adrenal incidentaloma and hypertension. (See "Pathophysiology and clinical features of primary aldosteronism" and "Diagnosis of primary aldosteronism", section on 'Variable presentation'.)
Androgen and estrogen-secreting tumors — Androgen-secreting adrenal tumors are usually malignant, but benign tumors have also been described in women. In a report of 21 women with androgen-secreting tumors, malignant tumors (n = 10) were larger at presentation than benign tumors (n = 11; 14 versus 9 cm, respectively). In addition, serum testosterone levels were 2.6-fold higher in the women with malignant tumors [35]. Benign cortisol-secreting adenomas can also produce small amounts of androgens, but the serum androgen levels are usually not elevated [36].
Estrogen-secreting tumors are rare and are usually malignant [37,38]. In males, it can present as feminization with gynecomastia, decreased libido, testicular atrophy; in women, it can present with breast tenderness and dysfunctional uterine bleeding.
Imaging — The maximum diameter of the adrenal mass is predictive of malignancy. Most adrenal adenomas are less than 4 cm in diameter. In contrast, most ACCs are greater than 4 cm in diameter when discovered. (See "Evaluation and management of the adrenal incidentaloma", section on 'Size'.)
The "imaging phenotype" of an adrenal tumor refers to the characteristics of the mass on CT or MRI. The lipid-rich nature of cortical adenomas is helpful in distinguishing this benign tumor from ACC. Evaluation of lipid content, through assessment of mass density, may be even more informative than the size of the mass in capturing either primary or secondary adrenal malignancies. (See "Evaluation and management of the adrenal incidentaloma", section on 'Imaging phenotype'.)
●As an example, CT attenuation of a benign adenoma, as expressed in Hounsfield units (HU), is usually <10 on an unenhanced scan (ie, has the density of fat), which suggests that the likelihood that it is a benign adenoma is nearly 100 percent.
●In contrast, ACCs are usually of larger size, have higher attenuation values, and may also display features such as inhomogeneity, irregular borders, calcifications, invasion of surrounding structures or lymph node enlargement. Precontrast HU >20 and <50 percent contrast washout at 10 minutes is more suspicious for malignancy [39]. (See "Evaluation and management of the adrenal incidentaloma", section on 'Imaging phenotype'.)
●Although CT remains the primary adrenal imaging procedure, MRI has advantages in certain clinical situations to characterize local invasion from adrenal carcinoma. (See "Evaluation and management of the adrenal incidentaloma", section on 'MRI'.)
●The use of fluorodeoxyglucose (FDG)-positron emission tomography (PET) scanning is emerging as a useful tool to distinguish ACC from benign adenomas with elevated HU or delayed contrast washout values [40]. (See 'Radiographic studies' below.)
●Metomidate (MTO) is an inhibitor of 11-beta-hydroxylase (CYP11B1) and aldosterone synthetase (CYP11B2), with high affinity for these enzymes. C-MTO PET can distinguish tumors of adrenocortical origin from noncortical lesions but cannot distinguish benign from malignant adrenocortical lesions [41,42]. Wider availability and combination of FDG and MTO PET studies may well be useful to distinguish primary and isolated metastatic adrenal lesions from benign adrenocortical lesions.
ADRENOCORTICAL CARCINOMA
Epidemiology — Adrenocortical carcinomas (ACCs) are rare; the incidence is approximately one to two per million population per year [43-45]. However, the incidence is approximately 10-fold higher in children in southern Brazil, where a number of environmental and genetic risk factors have been identified [46,47].
Although ACC can develop at any age, there is a bimodal age distribution, with disease peaks before the age of five and in the fourth to fifth decade of life [43]. In general, the level of aggressiveness and pace of disease progression are more rapid in adults than in children.
Women develop ACCs more often than men (female-to-male ratio 1.5 to 2.5:1) [48-50]. In the southern Brazil population, girls are also more commonly affected than boys (1.6:1) [51]. Studies using human adrenal cancer cell line suggest proliferative effects of estrogen, but it is unclear whether this may explain the higher occurrence of ACC in women [52].
Pathogenesis
Hereditary cancer syndromes — Although most cases of ACC appear to be sporadic, some have been described as a component of several hereditary cancer syndromes [53,54]:
●Li-Fraumeni syndrome (also known as the Sarcoma, Breast, Leukemia, and Adrenal gland [SBLA] cancer syndrome) is inherited as an autosomal dominant disorder and is associated with inactivating mutations of the TP53 tumor suppressor gene on chromosome 17p. (See "Li-Fraumeni syndrome".)
●Beckwith-Wiedemann syndrome (Wilms' tumor, neuroblastoma, hepatoblastoma, and ACC), associated with abnormalities in 11p15. (See "Congenital cytogenetic abnormalities" and "Rhabdomyosarcoma in childhood and adolescence: Epidemiology, pathology, and molecular pathogenesis".)
●Multiple endocrine neoplasia type 1 (MEN1; parathyroid, pituitary, and pancreatic neuroendocrine tumors and adrenal adenomas, as well as carcinomas), associated with inactivating mutations of the MEN1 gene on chromosome 11q. Unilateral or bilateral adrenal tumors can be found in 20 to 40 percent of patients with MEN1; the majority are benign tumors, usually nonfunctional, but they can present with excess production of aldosterone or cortisol. (See "Multiple endocrine neoplasia type 1: Genetics".)
Sporadic ACC — Although the molecular mechanisms underlying tumorigenesis in many of the hereditary syndromes described above are well characterized, the molecular pathogenesis of sporadic adrenocortical carcinomas (ACCs) is less well understood [55]. A multistep tumor progression model, similar to that described for colorectal cancer, has been proposed [53,56,57]. (See "Molecular genetics of colorectal cancer".)
TP53 gene, located on chromosome 17p13, is the most frequently mutated gene in human cancers. A role for the TP53 tumor suppressor gene in sporadic ACCs is suggested by the frequent finding of loss of heterozygosity (LOH) at the 17p13 locus in sporadic ACCs [58,59]. Although loss of heterozygosity at 17p13 is common, only approximately one-third of these tumors have a mutation of TP53 [60-67]. This suggests that another as yet unidentified suppressor gene is present in this locus [67].
In contrast, a distinct germline TP53 mutation (R337H) has been identified in a high percentage of children with adrenocortical tumors from southern Brazil [60,61] and North America [68,69], which may at least partly explain the higher frequency of ACC in this population. Amplification of the steroidogenic factor 1 (SF-1) gene in tumors also has been reported in this population [70].
In a study that used next-generation sequencing to determine the contribution of germline predisposing gene mutations in 1051 children and adolescents with cancer, mutations that were deemed to be pathogenic or probably pathogenic were identified in 90 patients (8.5 percent). The 39 patients with adrenocortical cancers carried the highest prevalence of mutations (69 percent), which were mostly in the TP53 gene [71]. Importantly, family history did not predict the presence of an underlying predisposition syndrome in most patients.
Another chromosomal locus that is strongly implicated in the pathogenesis of ACC is 11p, the area of abnormality in Beckwith-Wiedemann syndrome [72] and the site of the insulin-like growth factor-2 (IGF-2) gene. LOH at the 11p15 locus and overexpression of IGF-2 have been associated with the malignant phenotype in sporadic ACCs [58,73,74]. However, other growth-related tumor suppressor genes at this locus may also be involved [59].
Activating somatic mutation of the CTNNB1 gene has also been identified in ACCs (see 'Beta-catenin mutations (CTNNB1)' above). Wnt/beta-catenin pathway activation was an independent predictor of less favorable disease-free and overall survival in patients with resected primary adrenal carcinoma [75].
Using exome sequencing, nucleotide polymorphisms arrays, and confirmation in 123 ACCs, mutations in ZNRF3, encoding a cell-surface E3 ubiquitin ligase, were identified in 21 percent [76]. ZNRF3 is thought to be a potential tumor suppressor gene related to the beta-catenin pathway. Other known mutations associated with ACC were also observed (CTNNB1, TP53, CDKN2A [cyclin-dependent kinase inhibitor 2A], RB1 [retinoblastoma 1], and MEN1 [multiple endocrine neoplasias]). Two distinct groups of ACCs, those with poor or good outcome, could be identified by their genetic features. A comprehensive Cancer Genome Atlas (TCGA) group characterization of ACC identified additional driver genes, including PRKAR1A, RPL22, TERF2, CCNE1, and NF1. Whole-genome doubling was associated with an aggressive clinical course increased telomerase reverse transcriptase (TERT) [77].
There is an emerging interest in detecting such mutations in circulating cell-free tumor DNA for the follow-up of patients with ACC [78].
Clinical presentation — Approximately 60 percent of ACCs are sufficiently secretory to present clinical syndrome of hormone excess [43,45,49,79-81]. Adults with hormone-secreting ACCs usually present with Cushing's syndrome alone (45 percent), or a mixed Cushing's and virilization syndrome, with overproduction of both glucocorticoids and androgens (25 percent) [43,82]. Fewer than 10 percent present with virilization alone, but the presence of virilization in a patient with an adrenal neoplasm suggests an ACC rather than an adenoma.
The clinical symptoms associated with glucocorticoid excess, such as weight gain, weakness, and insomnia, usually develop very rapidly (over three to six months). Patients who have coexisting hypersecretion of adrenal androgens may not experience the typical catabolic effects of glucocorticoid excess (muscle and skin atrophy).
Feminization and hyperaldosteronism occur in fewer than 10 percent of cases [43].
Most patients with nonfunctioning tumors (or more precisely with modest production of steroids) present with clinical manifestations related to tumor growth (ie, abdominal or flank pain) or with an incidentally found adrenal mass detected on radiographic imaging performed for a different reason; constitutional symptoms (weight loss, anorexia) are frequent in this clinical context (see "Evaluation and management of the adrenal incidentaloma"). Uncommonly, a varicocele or fever and leucocytosis from tumor necrosis or production of chemokines may occur [83].
The impact of clinical characteristics on outcome of ACC is controversial. In initial cohort studies, nonfunctioning ACCs were more common in older adults and tended to progress more rapidly than functioning tumors [84,85]. However, in a second study, patients with functioning ACC and cortisol hypersecretion (versus androgen secretion) had shorter survival (hazard ratio [HR] 3.9) [86]. Overt Cushing's syndrome represents an important cause of morbidity when patients are treated surgically or with chemotherapy, due to the increased risk of infections and metabolic or vascular complications.
Children usually present with virilization (84 percent), while isolated glucocorticoid excess (Cushing's syndrome) is much less common (6 percent) [51,87].
Diagnostic evaluation — A careful history and physical examination should be performed to exclude signs and symptoms of pheochromocytoma, hyperaldosteronism, hyperandrogenism, and Cushing's syndrome.
Hormonal evaluation — The evaluation in apparently asymptomatic patients has been debated. Even in asymptomatic patients, the European Network for the Study of Adrenal Tumors (ENSAT) recommends performing the following tests to determine the secretory activity of the tumor: fasting blood glucose, serum potassium, cortisol, corticotropin (ACTH), 24-hour urinary free cortisol, fasting serum cortisol at 8 AM following a 1 mg dose of dexamethasone at bedtime, adrenal androgens (dehydroepiandrosterone sulfate [DHEAS], androstenedione, testosterone, 17-hydroxyprogesterone), and serum estradiol in men and postmenopausal women [88].
Adrenal carcinomas are typically inefficient steroid producers, but they secrete excessive amounts of adrenal steroid precursors due to decreased expression of several steroidogenic enzymes (which also results in diminished cortisol production). Even in patients with adrenal carcinomas who presumably did not produce excess steroids, more sensitive methods such as gas chromatography/mass spectrometry identify increased urinary metabolites of several steroids and precursors of androgens (pregnanediol, pregnanetriol, androsterone, etiocholanolone) or glucocorticoids (17-hydroxyprogesterone, tetrahydro-11-deoxycortisol, cortisol, 6-hydroxycortisol, tetrahydrocortisol, and alpha-cortol); this is different from cortisol-secreting adenomas, which produce cortisol, but little androgens [89]. Low serum aldosterone concentrations, but normal or high serum or urinary concentrations of aldosterone precursors (ie, deoxycorticosterone, 18-hydroxydeoxycorticosterone, corticosterone, and 18-hydroxycorticosterone, tetrahydro-11-deoxycorticosterone [THDOC], and 5 alpha-THDOC) are found in most adrenal carcinomas but not in adrenal adenomas [89,90].
The ENSAT also recommends that plasma metanephrines or urinary metanephrines and catecholamines be obtained in all patients to exclude pheochromocytoma and that plasma aldosterone and renin be obtained in patients with hypertension and/or hypokalemia (see "Establishing the cause of Cushing syndrome" and "Adrenal hyperandrogenism" and "Pathophysiology and clinical features of primary aldosteronism" and "Evaluation and management of the adrenal incidentaloma"). Hormonal evaluation may help in establishing the adrenal origin of the tumor and provide tumor markers that can be useful during follow-up to estimate the presence of residual tumor or tumor recurrence after surgery.
Radiographic studies — As noted above, computed tomography (CT) scanning can usually distinguish adenomas from ACCs. Magnetic resonance imaging (MRI) is complementary to CT, in that local invasion and involvement of the vena cava are more readily identifiable. These and other radiographic imaging studies that are useful in the evaluation of adrenal masses are discussed elsewhere. (See "Evaluation and management of the adrenal incidentaloma", section on 'Evaluation for malignancy'.)
Positron emission tomography (PET) scanning with fluorodeoxyglucose (FDG) is of value for identifying unilateral adrenal tumors with a higher index of suspicion for malignancy [40,90-94]. In a report of 26 patients with nonsecreting adrenal masses (13 benign, 13 malignant [6 ACC, 1 sarcoma, 6 metastases]), FDG uptake was observed in all of the malignant and none of the benign lesions [91]. However, others have shown that a minority of benign cortical adenomas accumulate FDG, although to a lesser extent [40,95].
Integrated or "fused" PET-CT imaging improves the performance of PET because adrenal adenomas can be better differentiated from nonadenomas using a combination of CT attenuation measurements plus the intensity of FDG uptake, as described by the standardized uptake value (SUV) for the adrenal lesion [96-98]. In the largest series, 150 patients with a total of 175 adrenal masses underwent PET-CT; the final diagnosis was based on histology in six cases, prolonged imaging follow-up in 118, and morphologic imaging criteria in 51 [96]. Using PET alone (with an SUV cutoff of 3.1), the sensitivity, specificity, positive predictive value, and negative predictive values for malignant lesions versus adenomas were 99, 92, 89, and 99 percent, respectively. The corresponding values for PET-CT were 100, 98, 97, and 100 percent, respectively. PET-CT correctly classified all masses less than 1.5 cm in diameter.
Alternative PET scan tracers are under study (eg, 11C-metomidate [MTO]) that might further improve specificity [41,99,100].
The most common sites of distant spread for ACC are the liver, lungs, lymph nodes, and bone [43,86]. For this reason, CT imaging of the chest and liver, as well as bone scan, are typically included in the staging workup if an ACC is suspected based upon the imaging evaluation or clinical presentation. It is not yet clear that PET and/or PET-CT are sufficiently accurate to replace all of these other radiographic studies as a single staging method in patients with suspected ACC [92]. While PET is more sensitive than CT or radiographic bone scans for distant metastases in a variety of clinical settings, small lesions may be missed [90].
On the other hand, FDG-PET-CT is complementary to regular CT in the follow-up of patients with adrenal carcinoma, and it is increasingly utilized in the regular follow-up evaluations; however, its precise role (first-line test, second-line after positive/dubious conventional imaging) and timing remain to be better defined [88].
Fine-needle aspiration biopsy — Cytology from a specimen obtained by fine-needle aspiration (FNA) cannot distinguish a benign adrenal mass from adrenal carcinoma. It can, however, distinguish between an adrenal tumor and a metastatic tumor.
Thus, FNA is sometimes performed when there is a suspicion of cancer outside the adrenal gland or in the patient undergoing a staging evaluation for a known cancer [101,102]. Pheochromocytoma should always be excluded by biochemical testing before attempting FNA biopsy of an adrenal mass. (See "Clinical presentation and diagnosis of pheochromocytoma", section on 'Approach to initial evaluation'.)
Even when diagnostic material is available, the distinction between benign and malignant adrenocortical tumors may be difficult and should only be made by a pathologist experienced in using the microscopic Weiss criteria [103,104]. The only definitive diagnostic criterion for a malignant adrenocortical tumor is distant metastasis or the presence of local invasion. In the absence of these findings, the Weiss histopathologic system is the most commonly used method for assessing the likelihood of malignant behavior because of its simplicity and reliability [103,105]. The five criteria used in the updated Weiss system include: >6 mitoses/50 high-power fields, ≤25 percent clear tumor cells in cytoplasm, abnormal mitoses, necrosis, and capsular invasion [105]. Each criterion is scored 0 when absent, or 2 for the first two criteria and 1 for the last three when present; the threshold for malignancy is a total score ≥3.
Other immunohistochemical criteria utilized include Ki-67 proliferation index, but cutoff values between benign and malignant lesions vary from 1.5 to 10 percent [106]. Overexpression of TP53, IGF-2, and cyclin E are found in ACC but are not sufficiently discriminatory [106]. Several markers (such as alpha-inhibin, Melan A, SF-1) can confirm the primary adrenal origin [88,107].
Staging — A variety of staging systems have been used for adrenocortical cancer [72,80,81,108-111]. The variability in disease classification used in individual studies complicates the comparison of reported results.
Adults — The eighth tumor, node, metastases (TNM) staging system from the combined American Joint Committee on Cancer (AJCC)/Union for International Cancer Control (UICC) was revised in 2017 for implementation in January 2018 (table 1) [112]. The TNM classification definitions were the same as those initially proposed by the UICC/World Health Organization (WHO) in 2004 [109], which were in turn based upon the Sullivan modification of the original McFarlane staging system [72].
In the eighth edition of the TNM staging system, stage IV disease now, in contrast to the previous 2004 AJCC/UICC classification (table 2), is limited to patients with distant metastases, and those with local invasion or invasion of adjacent organs (T3 or T4) but without distant metastases are classified as having stage III disease. These changes are consistent with the modifications initially proposed by the ENSAT group [113] and confirmed by others (table 2) [114].
The significantly better survival of patients with stage III ACC without distant disease as compared with those with distant metastases (stage IV) was shown in the series from the German Adrenocortical Cancer Registry described above (HR for death 0.44, 95% CI 0.25-0.78) [113].
Based on the eighth edition of the TNM staging system and by the ENSAT classification, the five-year, disease-specific survival rates in 416 adult cases reported to the German ACC registry were [113]:
●Stage I – Confined to the adrenal gland without local invasion or distant metastases; greatest tumor dimension ≤5 cm (T1N0M0): 82 percent
●Stage II – Same as stage I but with tumor size >5 cm without risk factors (T2N0M0): 61 percent
●Stage III – Tumor of any size with at least one of the following factors: tumor infiltration in surrounding tissues (T3), tumor invasion into tumor thrombus in the vena cava or renal vein (T4), positive lymph nodes (N1) but no distant metastases: 50 percent
●Stage IV – Distant metastases: 13 percent
Most contemporary treatment studies use the modification for stage groupings proposed by ENSAT over the 2004 UICC/AJCC classification (table 2).
A modification has been proposed for the ENSAT staging system that incorporates histologic grade of differentiation (table 3). (See "Treatment of adrenocortical carcinoma", section on 'Stage and margin status'.)
Children — The staging systems described above were developed primarily for adults [81,115,116]. A slightly different system has been used for children, which identifies only three prognostically distinct groups [46,51]:
●Completely resected small tumors (200 g or smaller) – Excellent prognosis (five-year, event-free survival 91 percent in one series of 228 children [51])
●Completely resected large tumors (over 200 g) – Intermediate prognosis (five-year, event-free survival 52 percent in the same series [51])
●Residual or distant metastatic disease – Poor prognosis
Although ACC has historically been considered to have a poor prognosis, newer data suggest that survival may be improving. (See "Treatment of adrenocortical carcinoma", section on 'Prognosis'.)
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Adrenal cancer" and "Society guideline links: Adrenal incidentaloma".)
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Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)
●Basics topic (see "Patient education: Adrenal cancer (The Basics)")
SUMMARY — Unilateral tumors or masses of the adrenal gland are common. They are categorized as either functional (hormone-secreting) or silent, and as either benign or malignant.
●The majority of adrenocortical tumors are benign, nonfunctioning adenomas that are discovered incidentally on abdominal imaging studies (adrenal incidentalomas). (See "Evaluation and management of the adrenal incidentaloma".)
●Others are benign, hormone-secreting adenomas that cause Cushing's syndrome, primary aldosteronism or, much less commonly, virilization or feminization. Pheochromocytomas are adrenomedullary, not adrenocortical tumors. (See 'Adrenocortical adenomas' above.)
●Adrenocortical carcinomas (ACCs) are rare, frequently aggressive tumors, which may be functional and cause Cushing's syndrome and/or virilization, or nonfunctional and present as an abdominal mass or an incidental finding. (See 'Adrenocortical carcinoma' above.)
●Most adrenal adenomas are less than 4 cm in diameter. In contrast, most ACCs are greater than 4 cm in diameter when discovered. The lipid-rich nature of cortical adenomas is helpful in distinguishing this benign tumor from carcinoma on computed tomography (CT) scanning. (See 'Imaging' above.)
●At initial presentation, approximately 50 percent of adult patients with ACC have relatively advanced disease stage. (See 'Staging' above.)
DISCLOSURE — The views expressed in this topic are those of the author(s) and do not reflect the official views or policy of the United States Government or its components.
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