Cancers & Neoplasias

The three major types of adrenal tumors are adrenal adenomas, adrenal hyperplasias, and adrenocortical carcinomas. Adrenal adenomas included in this chapter are non-functioning (non-hormone secreting), cortisol-producing (Cushing’s syndrome), and aldosterone-producing (including Conn’s adenoma) adenomas. Adrenal hyperplasias, technically referring to increased ACTH-independent cell growth of parts of the adrenal cortex, included are cortisol-producing (macronodular and micronodular) and aldosterone-producing (familial hyperaldosteronism types I, II and III). Both unilateral aldosterone-producing adenomas and bilateral adrenal hyperplasias can give rise to primary aldosteronism. Adrenocortocol carcinomas can arise in patients with hereditay predisposition such as Lynch syndrome, Li-Fraumeni syndrome, Multiple Endocrine Neoplasia type 1, Beckwith-Wiedemann syndrome and Familial Adenomatous Polyposis.

3.1    PREVALENCE AND INCIDENCE

Estimates of the prevalence of adrenal tumors vary greatly according to the screening method and the population examined. Most adrenal tumors are incidentally discovered by imaging procedures, conducted for different purposes, and are therefore termed incidentalomas. Adrenal incidentalomas can cover a range of phenotypes from non-functioning adenomas or functioning (hormone-secreting), associated with primary aldosteronism or autonomous cortisol production to carcinomas.^100-102 The prevalence of adrenal incidentalomas by subtypes is shown in Table 3.1.

Abbreviations: N/A, not applicable.

Detection frequency of adrenal tumors has increased in recent years with increasing use of sensitive imaging methods: computed tomography (CT) scans, magnetic resonance imaging (MRI), and ultrasonography (Table 3.2).¹⁰¹ Adrenal incidentalomas are among the most prevalent tumors in humans, being detected in 0.1% of the normal population by ultrasound, and in 1-4% by abdominal imaging analysis (CT scans, MRI and ultrasound).^109,110 Worldwide studies roughly estimate the same prevalence at autopsy (1.4 to 6%) and in CT scans (0.35 to 6%).^100-102 In a systemic review, adenomas and adrenocortical carcinomas comprised 41% and up to 10% of all incidentalomas, respectively.¹⁰⁹ However, these numbers likely overestimate the presence of adrenocortical cancer, which is a very rare disease.¹¹¹

An estimated 10% of subjects with adrenal incidentalomas secrete excess cortisol in the absence of clinically overt Cushing’s syndrome, defined as subclinical Cushing’s syndrome; and while most cases may undergo extensive screening, an adrenalectomy may be performed in some. However, the incidence of subclinical Cushing’s syndrome is 79 per 100,000 persons, while clinical adrenal Cushing’s syndrome is very rare (~1 person per 100,000).¹¹² As the majority of incidentalomas will never progress to clinical Cushing’s syndrome, some authors suggest that extensive screening and adrenalectomy are unnecessary.¹¹³

Aldosterone-producing adenomas (Conn’s adenoma or aldosternoma) are most commonly small (<2cm) tumors, arising sporadically. It is thought to comprise 33-67% of primary aldosteronism, which itself accounts for up to 10% of all hypertension patients.¹¹⁴ In a study of 71 adrenal glands removed from unilateral primary aldosteronism cases in Italy, 77.5% of patients had a single nodule and 22.5% had multinodular hyperplasia.¹¹⁵

Adrenocortical carcinomas are rare, aggressive malignancies (Table 3.2), with an estimated incidence of 0.5-2.0 per million (300 cases per year) in the US, and 0.7-2.0 million worldwide.^116-118  According to the SEER database (1973 and 2000), the age-adjusted incidence of adrenocortical carcinoma in the US was 0.72 per million, accounting for only a small fraction of all adrenal incidentalomas, and comprising 0.02% – 0.2% of all cancers reported annually in adults.^119-121 Childhood adrenocortical carcinomas have a worldwide incidence of 0.2-0.3 per million and represent 0.2-1.3% of all childhood cancers.^122,123

TEMPORAL INCREASE

A temporal increase in the prevalence of incidentalomas and adrenocortical carcinomas has been observed, probably due to increased use of advanced imaging analysis (CT scan, MRI, ultrasonography), and progression towards use of high-resolution imaging techniques (Table 3.3).¹¹⁹

Source: Kebebew et al. 2006¹¹⁹

In a 2013 report of adrenocortical carcinomas (n=359, 55% female, age 1-91 years, median age 56 years), in the Netherlands Cancer Registry (1993-2010), incidence appeared to be decreasing over time from 1.3 per million in 1993 to 1.0 per million in 2010. However, the authors suggested that individuals with pre-malignant tumors might have undergone early surgery.¹²⁷

AGE

The prevalence of adrenal tumors is reported to increase with age (Table 3.4). Pooled studies of deceased individuals estimate the incidence of adrenal incidentalomas to be <1% for age <30 years and 7-10% for age ³70 years. ^116,128 Overall the prevalence is estimated to be 3% of the population at middle-age and up to 10% in the elderly.^116,128,129 In a worldwide literature review (1952-1992, n=1,330) of adrenocortical carcinomas, 62.3% of patients were >30 years of age. Several large series (>50 patients) suggest a bimodal age distribution for peak of incidence (<5 years and at 40-50 years) (Table 3.5).¹²¹

Source: National Cancer Institute.¹³⁰

Pediatric adrenal carcinomas are rare, with an estimated incidence of 0.3 per million children (<15 years) in the US, with ~25 new cases diagnosed each year, representing 0.2% of childhood tumors.^132,133 The main presenting symptoms are hormonal excess (61%), abdominal pain (13%) and abdominal mass (26%).¹³³  A very significant proportion of adrenocortical carcinoma (50-80%) is associated with TP53 germline mutations and the diagnosis of Li Fraumeni syndrome. Childhood ACC can also occur as part of Beckwith Wiedemann syndrome.¹³⁴

TUMOR LOCATION

While a left- or right-located adrenal lesion is not linked to any particular disease state, bilateral lesions can indicate metastasis, congenital adrenal hyperplasia, bilateral cortical adenomas, or infiltrative disease.¹⁰⁰ In a prospective evaluation in Italy, Bovio and colleagues suggested that the right-side dominance of adrenal tumors in earlier studies may be explained by ultrasonography being less accurate in detecting left-side adrenal masses.¹¹⁶ More recent imaging with CT and MRI scans shows left adrenal gland tumors to be slightly higher than right adrenal tumors (Table 3.6).^108,116

TUMOR SIZE AND STAGE

Despite some overlap, adrenal adenomas are generally smaller (usually £4cm) than adrenal carcinomas (Table 3.7), with 5-25% of adrenal adenomas increasing in size during follow-up.¹⁰¹ Reinhard and colleagues analyzed 498 consecutive autopsies in Germany, and identified 0.3-8 mm nodules in 53.7% of cases, and 3.2-28 mm adenomas in 5% of cases.¹³⁶ In a large study of adrenal incidentalomas, tumor mass size was the most reliable variable to distinguish adenomas and carcinomas.¹³⁵ In a US report of 166 non-functional unilateral benign adrenal incidentalomas identified by CT scan (between 1976 and 1994) in 100% of patients, masses were £3cm, while 89% were £2cm, and 52% were £1cm.¹³⁷ Contrary to these findings in benign incidentalomas, adrenocortical carcinomas are larger in size. In a US study of 392 adrenocortical carcinomas, only 4.2% were £6cm and in another single center study, only 3% of 391 adrenocortical carcinomas were <5cm.^119,138 In a US SEER database study (1988-2000) of 457 adrenocortical carcinomas compared to 47 benign adrenal tumors, the risk of malignancy increased with tumor size: 52% for tumors ³4cm, 80% for those ³6cm, 95% for ³8cm, and 98% for ³10cm.¹³⁹

Abbreviation: SEER, Surveillance, Epidemiology, and End Results; SEM, standard error of mean.

At diagnosis, the majority of adrenocortical carcinomas are already at the advanced stages III and IV (Table 3.8).^{119,133,138,140}

Abbreviations: SEER, Surveillance, Epidemiology, and End Results.

METASTASES

Adrenal masses discovered during abdominal imaging are not generally considered to be adrenal incidentaloma, however, in patients with known malignancies, the risk of an adrenal mass being a metastasis is high (45-73%) and increases with tumor size (43-100% for >3cm tumors). In patients with extra-adrenal malignancies (lung, breast, kidney cancers; melanoma and lymphoma), adrenal metastases were identified in 3-40% at autopsy, and 6-20% of patients in radiological studies.¹⁰¹ Cancer in an unknown primary site can occasionally involve the adrenal glands, but metastatic cancer presenting as a true incidentaloma is rare. A 1998 US retrospective review of 1,639 cancer patients with an occult primary malignancy identified involvement of the adrenal gland (original site or metastasis) in 5.8% of patients, and tumors solely in the adrenal gland in 0.2% of patients.¹⁴¹.

HORMONE EXCESS SYNDROMES

Most adrenal incidentalomas are non-functioning, while ~15% show secretion of cortisol, aldosterone or medullary hormones.¹⁰¹ The most common disorder in incidentalomas (1-29%, average 9%) is the development of autonomous cortisol secretion, which remains subclinical in two-thirds of cases.¹⁰¹ Less than 1 in every 1000 adrenal masses, originally identified as benign, eventually became malignant, and 1.7% developed hyperfunction, usually involving cortisol.¹⁰¹ Although most adrenal adenomas are benign and non-functioning, there is still a concern that subclinical levels of autonomous hormone secretion cause metabolic abnormalities, which represent well known risk factors for example cardiovascular morbidity (e.g. hypertension, diabetes, dyslipidemia)  (Table 3.9).^142,143

A study of adrenal incidentalomas (n=94, 1995-2005, Turkey) identified hypertension in 63%, obesity in 55%, diabetes mellitus in 36%, hypercholesterolemia in 36%, and low HDL cholesterol in 36% of cases, with similar frequencies to those in clinical Cushing’s syndrome.¹⁴⁴ The risk of autonomous hormone secretion is higher with larger (>3cm) lesions.^101,108 A 2011 report by Muscoguri and colleagues identified a direct correlation between mass size and insulin resistance, and in 2010, Kolanska and colleagues reported a higher prevalence (40%) of obesity in a cohort with non-functioning adenomas than in the general population.^{145 146}

A number of worldwide studies indicate a higher prevalence (average 10%; range 6-23%) of subclinical Cushing’s syndrome in adrenal incidentalomas.¹⁴⁷ Sub-clinical Cushing’s syndrome is associated with metabolic syndrome, hypertension, and dyslipidemias, but without overt clinical symptoms or signs of Cushing syndrome (Table 3.9).^100,101,103 Patients with subclinical Cushing’s syndrome showed increased risks of cardiovascular disease and of developing overt Cushing’s disease (12.5% after 1 year).^101,126,148 It was reported to be higher in patients with resistant hypertension (8%, 423 patients, age 1-80 years, Brazil), in young subjects (7.5%, 80 hypertensive patients, age 12-40 years, Romania), and in patients with osteoporosis and vertebral fractures (4.8%), relative to those with secondary hypertension (1%, 4,429 patients at a hypertension referral center, US).^147,149-151 However, not all of the patients in these studies had a proven adrenal mass, but rather biochemical evidence for some degree of autonomous cortisol production. In the hypertensive population, the prevalence of primary hyperaldosteronism is estimated to be up to 10%; (60% of which is caused by aldosterone-producing adenomas).

Abbreviations: N/G, not given; N/A, not available.

Primary aldosteronism is a diverse group of adrenal disorders, usually arising due to either sporadic aldosterone-producing adenoma (Conn adenoma or aldosteronoma) or sporadic uni- or bilateral adrenal hyperplasia, and very rarely as familial form of bilateral adrenal hyperplasia.¹¹⁵ In primary aldosteronism, the adrenal gland produces aldosterone in an autonomous fashion, resulting in secondary hypertension with detrimental effects on the cardiovascular and renal systems.^107,153-155 Even moderate increases in aldosterone are implicated in increased cardiovascular morbidity and mortality.¹⁵⁶ Studies indicate that aldosterone-producing adenomas exist in 3.3-11.2% of the hypertensive population.^153,157 Conn adenomas represent ~30-60% of the primary aldosteronism population.¹⁵⁸ Mulatero and colleagues reported a higher risk for cardiovascular events in aldosterone-producing adenoma patients compared to patients with essential hypertension. During follow-up, aldosterone-producing adenoma patients had more strokes and arrhythmias and a higher percentage developed type-2 diabetes than did patients with essential hypertension.¹⁵⁹

MUTATIONS

Table 3.10 presents data on the prevalence of somatic mutations associated with aldosterone-producing adenomas (Conn’s adenoma). Another cause of primary aldosteronism is bilateral adrenal hyperplasia, which can arise sporadically or in the setting of germline mutations.¹⁶⁰ Table 3.11 summarizes prevalence data of the different types of adrenal hyperplasia and their associated mutations.

In one study TP53 germline mutations were found in 67% of individuals with adrenocortical carcinoma (n=21), of which 80% were children (<18 years).¹⁶¹ In a German report the TP53 mutation was identified in 3.9% of Caucasians with adult-onset adrenocortical carcinoma.¹⁶² In a US series, the prevalence of TP53 mutations was 5.8% in the adult population.¹⁶³ The prevalence of the TP53 germline mutation R337H was reported to be 15-times higher (0.3%) in children in southern Brazil than other areas, with prevalence of 97% in childhood adrenocortical tumors.^118,164,165

Li-Fraumeni syndrome is rare, autosomal dominant cancer disorder often caused by gene mutations that inactivate the tumor suppressor TP53 gene. Li-Fraumeni syndrome patients are at high risk of developing different types of cancers including breast, bone, brain and adrenal cancer (Table 3.12). Another fairly prevalent syndrome in adrenal cancer patients is Lynch syndrome, which is responsible for 3-5% of all adrenal cancers.¹⁶³ Individuals with Beckwith-Wiedemann Syndrome are at a high risk of developing cancers of the liver, kidney and occasionally the adrenal cortex. Described as a complex of myxomas, spotted skin pigmentation and endocrine overactivity, Carney complex, caused by PRKAR1A, is a multiple neoplasia syndrome, mostly associated with micronodular hyperplasia. Two cases of adrenal cancer have also been described.^166-168 Germline mutations in a related gene, PRKACA has been found mutated in patients with adrenal hyperplasia, and somatic mutations are found in 30% of cortisol-producing adenomas.¹⁶⁹

Source: Zennaro et al. 2015¹⁶⁰

3.2    COST BURDEN OF DISEASE

In the treatment of primary aldosteronism, some clinicians advocate oral therapy with mineralcorticoid-receptor antagonists to be more cost-effective than operative resection, while others have determined that surgery is more cost-effective than a pharmacological approach (Table 3.13). Based on 2009 treatment costs, a laparoscopic adrenalectomy in a hospital setting is expected to cost $8,378.63.¹¹⁴ The authors estimated that if adrenalectomy costs rose 2.5-fold to $22,524.59, or the cost of selective venus sampling quadrupled from $2,171 to $9,041, or the surgical failure in improving blood pressure increased six-fold to affect 32% of patients, then the pharmacological option would be the least costly strategy. However, treatment costs vary significantly, even within the United States, and there is no conclusive study suggesting a cost-benefit of strategy, surgery or pharmacotherapy.

Source: Reimel et al. 2010¹¹⁴

3.3    DEMOGRAPHIC DIFFERENCES

In a literature review of 6 worldwide studies (n=71,206), no overall sex differences in incidentalomas were identified at autopsy.¹⁰¹ However, two studies reported a high female-to-male ratio in adrenal masses.^101,174 Both studies hypothesized that the increased incidence in females could be entirely due to the higher rates of abdominal scans in females than males (Table 3.14).^101,103 Barzon and colleagues also reported an increase in prevalence of autopsy incidentalomas with age: 0.2% in young patients and 6.9% in patients of age >70 years.¹⁰¹ In adults with adrenocortical carcinomas, a lower median age-at-diagnosis was reported for females vs. males (30 vs. 39 years). In males, adrenocortical carcinoma tumors were found more often in patients age >30 years (71.7%) than age <30 years (28.4%).¹²¹ In several studies, adrenocortical carcinoma (n=1891) is more common in females than males with a ratio of 1.5:1.^121,138

No significant differences were identified in the incidence of adrenocortical carcinoma between races.¹³⁰

3.4    LIFE EXPECTANCY AND MORTALITY

Autonomous cortisol production bears an increased mortality in patients with adrenal incidentalomas. In one study analysing 206 patients, 18 patients had died and of these 17 had cortisol level >1.8 mg/dL.¹⁷⁸ No statistics on mortality were available for nodular hyperplasias or adrenal familial hyperplasias. However, Li and Yang reported that in a retrospective review of 23 cases of bilateral adrenal macronodular hyperplasias (and the associated Cushing’s syndrome) in China, 20 showed elevated cortisol levels (associated with high morbidity and mortality).¹⁷⁹ Zenarro and colleagues stated that familial hyperaldosteronism-I (in France) was associated with hypertension from an early age (family history of hypertension <50 years, history of hypertension <20 years, hypertension that is difficult to control), resulting in high morbidity and mortality at an early age.¹⁶⁰

Adrenocortical carcinoma is a malignancy with a poor prognosis with median 5-year survival rates (range 25-54%).^176,180 Data from a number of studies suggests that tumor size does not appear to correlate with metastatic disease or survival.^108,180,181 In a 2008 review by Bilimoria and colleagues of 3,982 adrenocortical carcinoma cases diagnosed between 1985 and 2005 in the US, survival was significantly diminished with increasing age (>55 years), high-grade tumors (HR, 2.26), incomplete surgery (HR, 2.06), nodal metastases (HR, 1.56), distant metastasis (HR, 2.20), or in patients who had undergone surgery with resection of a contiguous organ (HR, 1.23).¹⁰⁸ Microscopically complete resection was associated with lower recurrence rates in a 2013 study.¹⁸² Several studies also showed that disease stage correlated with poor outcomes.^{122,138,176,183} Table 3.15 presents the relationship between disease stage and median survival.

In a US study of 3,982 adrenocortical carcinomas, 26.5% of patients had nodal metastasis and 21.6% had distant metastasis. The 5-year survival for patients who had undergone resection was 38.6% (median 31.9 months).¹⁰⁸ The risk of death was higher in older patients (>55 years), high-grade tumors (HR, 2.3), involved margins (HR, 2.1), nodal (HR, 1.6) or distant metastasis (HR, 2.2), or surgery with resection of a contiguous organ (HR, 1.2).¹⁰⁸ Distant metastasis was mostly found in liver, lung and bone in 10.9%, 9.0% and 3.1% of cases, respectively.¹⁰⁸ The adjusted HR for death increased with age: 1.0, 1.1, 1.5 and 2.3 for age 18-35 years, 36-55 years, 56-75 years, and >75 years respectively; and the 5-year observed survival rate decreased with age 14.6%, 42.1%, 35.8%, and 23.7% respectively.¹⁰⁸  In a Netherlands study of adrenocortical carcinoma patients, the survival time decreased with advanced disease stage (Table 3.16). The relative-survival decreased with increasing age-at-diagnosis (5-year survival: 44% 0-44 years, 36% 45-59 years, 23% 60-74 years, and 37% >75 years).¹⁰⁸

Source: Bilimoria et al. 2008¹⁰⁸

In pediatric adrenal tumors, complete tumor excision was associated with significantly better outcome. Outcome for ACC was better at earlier disease stages (Table 3.17).¹³³

3.5    KEY TRENDS AND HEALTH OUTCOMES

Surgery is the mainstay of treatment for carcinomas and most hormone producing adrenal adenomas. Laparoscopic adrenalectomy (first described in 1992) is preferred over open adrenalectomy for small-to-medium size (<8cm), benign, functioning and non-functioning adrenal tumors.¹⁸⁴ Tumors with a presurgical suspicion for adrenocortical carcinomas are best approached with an open adrenalectomy, following oncological principles. In two US studies comparing the two surgeries, the recurrence rate was 86% in 156 adrenocortical carcinoma patients who had undergone open adrenalectomy and 100% in 6 patients who had undergone laparoscopic adrenalectomy, although 2 other studies suggested there was no significant difference between the two surgeries at Stages 1 and 2.¹²² Contraindications for laparoscopic adrenalectomy include large benign tumors (>8 cm) and adrenocortical carcinomas. Robot-assisted adrenalectomy (introduced early 2000s) is becoming increasingly popular as it can overcome technical limitations of laparoscopic adrenalectomy, and is shown to consistently reduce blood loss during and after surgery. In a 2011 report from Italy of cortical adenomas (n=19), aldosteronomas (n=2), hyperplasias (n=2), adrenal carcinoma (n=1), others (n=18); robot-assisted adrenolectomies led to minimal blood loss (median 27ml) and short operative times (118±46 mins). Differences in surgery time between right and left side (125 min vs. 110 min) and blood loss (86 ml vs. 35 ml) were not statistically significant.¹⁸⁵ In a 2014 retrospective study (n=76, 2000-2010) of US medical charts by Brandao and colleagues, a significantly lower surgery-related blood loss was reported for robot-assisted adrenolectomies than for laparoscopic adrenalectomy (median 50ml vs. 100ml) performed by the same surgeon, but the authors identified no significant differences in the length of hospital stay.¹⁸⁶

A 2008 study by Brunaud and colleagues, reported operating times were determined by the surgeon’s experience; the longer operation times with robot-assisted adrenalectomies compared with laparoscopic adrenalectomy did not apply after a surgeon’s learning curve of 20 cases. The mean operating time in laparoscopic adrenalectomies was higher in obese patients (body mass index >30 kg/m²) than those with a lower BMI (90 vs. 78 min respectively), and for patients with tumor size >5.5cm, than those with smaller tumors (100 vs. 80 min, respectively).  These difference did not apply to robot-assisted adrenalectomies.¹⁸⁷

In a 4-study review of robot-assisted adrenalectomies, the morbidity rate was 0-20% and the mortality rate was 0%; in a single study for laparoscopic adrenalectomy, the reported mortality rate was 0%. ¹⁸⁵ From a review of 100 laparoscopic adrenalectomies from 19 publications, the most commonly reported complications of surgery were bleeding (40%) and injury to peritoneal and retroperitoneal organs (4.2%), with an overall mortality rate of 0.2% 30 days post surgery (0.8-1.2% deaths in 4 centers, and zero deaths in 15 centers).^184,188 Bilateral surgery can lead to higher blood loss, higher mortality (4/7 deaths) and lower success rates of disease management (50-100%) than unilateral adrenalectomies, which can achieve endocrinolgical cure.¹⁸⁸

Non-functioning adrenal incidentalomas

Conservative management is recommended over surgery in cases of stable non-functioning adrenal incidentalomas that lack autonomous hormone production. A quality-of-life survey of non-functioning adrenal incidentaloma patients (released from surveillance after 24 months of stable disease) found that although the follow-up program was well tolerated, 30% of cases showed signs of depression, possibly related to the significant hypertension and metabolic co-morbidities, as outlined earlier in Table 3.9.¹⁵²

Conn’s syndrome

Complication rates for aldosterone-producing adenomas are reported to be 7%.^184,188 Post-surgery studies of laparoscopic adrenalectomies for Conn’s syndrome showed 95-100% success in achieving normokalaemia, with hypertension cured or significantly improved in 88-100% of surgeries.¹⁸⁸ Persistant hypertension was reported in 0-12% of patients post-adrenalectomy.¹⁸⁴ A worldwide review of 13 studies with respect to outcome of laparoscopic adrenalectomies is shown in Table 3.18.

Source: Gumbs and Gagner. 2006¹⁸⁴

Subclinical Cushing’s syndrome

Subclinical Cushing’s syndrome is detected at low rates in the course of surveillance of non-functioning adrenal adenomas. In a retrospective study of conservatively managed non-functioning adrenal incidentalomas, Morelli and colleagues reported that 8.2% of patients progressed to subclinical Cushing’s syndrome during 5 years of follow-up.¹⁸⁹ Giordano and colleagues reported this to be the case in just 5.1% of patients.¹⁰²

In 2014 Morelli and colleagues reported that at diagnosis, patients with subclinical Cushing’s syndrome had higher rates of diabetes mellitus and cardiovascular incidents than patients without subclinical Cushing’s syndrome. After a 5-year follow-up, subclinical Cushing’s syndrome correlated with worsening metabolic symptoms and cardiovascular incidents.¹⁸⁹ These studies contradicted data from Giordano and colleagues, who reported finding no differences in hypertension and metabolic diseases between non-functioning adrenal incidentalomas and subclinical Cushing’s syndrome.¹⁰²

While some studies recommend simply monitoring subclinical Cushing’s syndrome, others suggest the higher prevalence of cardiovascular disorders warrants surgery in both subclinical Cushing’s and non-functioning tumors, especially in patients exhibiting hypertension, obesity, and diabetes.¹⁴⁴ A study of 45 subclinical Cushing’s syndrome cases, by Toniato and colleagues, reported that surgery relieved hypercortisolism and co-morbidities (Table 3.19); while conservative management only led to a worsening of certain conditions (diabetes mellitus, hypertension, hyperlipidemia).¹⁹⁰ The improvement in comorbidities post surgery from another study, a systemic review by lacobone and colleagues, are also shown in Table 3.19.¹⁹¹ However, subclinical Cushing’s syndrome poses a particular challenge as there is no consensus, whether it needs to be treated or whether treatment of co-morbidities is favorable.

 Adrenal hyperplasia

Macronodular adrenal hyperplasia can present with or without hormone excess; patients with hypercortisolism can present with subclinical Cushing syndrome or clinical Cushing syndrome. Unilateral adrenalectomy addressing the larger adrenal gland is often the treatment of choice and often normalizes the clinical symptoms.¹⁷⁹ Familial macronodular adrenal hyperplasias with a predisposition to cortisol production is caused by ARMC5 mutations in a significant number of patients. Adrenocortical hyperplasias can also lead to primary aldosteronism, particulalrly in the setting of KCNJ5 germline mutations. However, sporadic hyperplasia of the zona glomerulosa is rarely evident on imaging, but can be observed microscopically. If untreated, adrenal hyperplasias with primary aldosteronism results in the early onset of hypertension and cerebral hemorrhage.¹⁹² Untreated familial hyperaldosteronism also results in left ventricular hypertrophy.^192,193

Surgery for sporadic unilateral hyperplasia causing primary aldosteornism usually reduces hypertension and improves cardiovascular outcomes, similar to aldosterone-producing adenomas. Bilateral disease requires pharmacological management.^155,192

Adrenocortical carcinoma

More adrenocortical carcinomas are detected as a result of increased adrenal hormone production rather than as an incidental finding on a CT scan (Table 3.20).¹²²

Source: Else et al. 2014¹²²

The mainstay of a curative approach for ACC is complete oncological surgery, with consideration of an open surgical approach.

The adrenolytic medication, Mitotane, is used as standard care in advanced adrenocortical carcinomas. The first-line therapy for metastatic cancer includes Mitotane with etoposide, doxorubicin and cisplatin.¹¹⁸ Mitotane has been shown to improve 5-year survival rates in several studies (Table 3.21).^122,180

Radiation therapy improves local control, but has not been shown to significantly improve survival times.¹⁹⁴ Furthermore, it is recommended that radiation not be used when TP53 mutations are present.¹²²

A study by Fassnacht and colleagues, argued for specialized centers with multidisciplinary teams for treatment and follow-up of adrenocortical carcinoma patients.^122,195 Adrenocortical carcinoma patients appear to have better outcomes when patients are treated at specialized centers.¹⁹⁵