Mortality in Patients with Endogenous Cushing’s Syndrome
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Pedram Javanmard, MDª, Daisy Duan, MDª, Eliza B. Geer, MDb, *
KEYWORDS
. Mortality . Cushing’s syndrome . Cushing’s disease . Ectopic Cushing’s
. Adrenal Cushing’s . Subclinical Cushing’s
KEY POINTS
· Cushing’s syndrome, chronic endogenous cortisol hypersecretion, is associated with an overall increased mortality risk.
· The leading causes of mortality in Cushing’s are cardiovascular events, infection, sepsis, and thromboembolism.
· Patients with Cushing’s due to a pituitary tumor or a benign adrenal adenoma seem to have the best survival outcomes; persistent or recurrent disease confers high mortality risk.
· Overall, patients with Cushing’s due to an ectopic adrenocorticotrophic hormone- secreting tumor or adrenocortical carcinoma have the worst survival rate.
· Prompt diagnosis and treatment of Cushing’s and specific monitoring and treatment of comorbidities are paramount to decreasing the burden of mortality.
INTRODUCTION
Endogenous hypercortisolism, known as Cushing’s syndrome (CS), is a chronic endo- crine disorder caused by excessive adrenal cortisol secretion, with an estimated inci- dence of 0.7 to 2.4 cases per million population per year.1-4 The majority (70%) of endogenous CS cases are caused by excess adrenocorticotrophic hormone (ACTH) production from pituitary corticotroph tumors, known as Cushing’s disease (CD). ACTH-independent adrenal cortisol production due to an adrenal tumor or hyperplasia is responsible for 20% of CS cases. The remaining 10% of CS cases are due to ectopic ACTH (or very rarely corticotropin-releasing hormone) production. 1-3
The authors have no relevant disclosures.
a Department of Medicine, Division of Endocrinology, Diabetes, and Bone Disease, Icahn School of Medicine, The Mount Sinai Hospital, 1 Gustave L Levy Place, Box 1055, New York, NY 10029, USA; b Division of Endocrinology, Department of Medicine, Multidisciplinary Pituitary and Skull Base Tumor Center, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, Box 419, New York, NY 10065, USA
* Corresponding author. E-mail address: geere@mskcc.org
CS can occur at any age. It is, however, more frequent during the fourth to sixth de- cades of life and more common in women: 79% of pituitary CS, 81% of adrenocortical adenomas, and 60% to 70% of adrenocortical carcinoma (ACC) cases are female, whereas among patients with ectopic CS (ECS), males have an equal or even higher predominance.5-7
With regard to the overall predictors for mortality in CS, male gender, older age at diagnosis, overall disease activity duration, disease status (persistent or recurrent dis- ease vs remission), persistent hypercortisolism after initial surgery, and hypertension at last follow-up have been associated with higher mortality risk.6,8-10 This article re- views the predictors of mortality in patients with endogenous CS. The majority of avail- able mortality data are on patients with CD, and therefore CD is the focus of the review.
ADRENOCORTICOTROPHIC HORMONE-DEPENDENT CUSHING’S DISEASE
CD, due to an ACTH-secreting pituitary corticotroph adenoma, is the most common form of endogenous CS and accounts for 70% of all cases of CS.3,8,9 In the original series published by Harvey Cushing’s in 1932,11 the median survival in untreated CD was 4.6 years. This finding was validated in a later study12 that reported a 5-year survival rate of 50%. The main causes of mortality in CD are cardiovascular complications including strokes and myocardial infarctions (Table 1).13,14
In the past 2 decades, there have been 12 retrospective nationwide or single-center cohort studies that have reported standardized mortality ratios (SMRs) in CD, with 5 of these studies also reporting mortality data on other causes of CS (Table 2). Most studies have been conducted in Europe, the United States, or New Zealand, and had median follow-up periods from 6 to 20 years since the onset of treatment. The overall SMR for all-cause mortality in CD ranges from 0.98 to 9.30, indicating that mor- tality risk in patients with CD is similar to or higher than that of the general population. The majority of these studies further stratify mortality risk based on disease activity status (ie, remission vs recurrent or persistent disease). In addition, several of these studies identify independent mortality risk factors in patients with CD. A limitation of these studies are the small sample sizes, thus, with even smaller numbers of deaths. As several meta-analyses have pointed out, there is also considerable heterogeneity with respect to the definitions of remission, persistence, and recurrence of disease, the timing of the assessment after initial treatment, methods of treatment, and the duration of follow-up periods (Table 3). Despite these challenges, there is consistent evidence that persistent CD after pituitary surgery confers the highest risk of mortality, although there are conflicting data regarding mortality risk in patients with disease remission after treatment.
Predictors of Mortality and Risk Factors for Increased Mortality in Patients with Cushing’s Disease Overall
Cardiovascular disease results in a 4-fold increase in mortality among patients with persistent CD compared with control populations.9,15,16 More recent studies suggest a more pronounced mortality risk, with a reported SMR of 13.8 for vascular disease. 17 Some mortality risk may also be present in patients with CD who have been in remis- sion for more than 10 years. 18 In addition, given that the cause of mortality in patients with CD is largely attributed to cardiovascular diseases, certain cardiovascular risk factors have been identified as independent predictors of mortality. The presence of diabetes, but not hypertension, was an independent risk factor for mortality (hazard ratio [HR], 2.82; 95% confidence interval [CI], 1.29-6.17) in 1 study18; in other studies,7,9,17 however, the persistence of both diabetes or glucose metabolism
| References | Mortality Rate | Causes of Death |
|---|---|---|
| Clayton et al, 18 2016 | CD: 16% | CD |
| CVª 62.7%; malignancy 17.6%; PE 7.8%; sepsis 3.9%; others or unknown 19.6% | ||
| Ntali et al,24 2013 | CS overall: 9.6%; | CD |
| CD: 9%; AC: 3%; ECS 30% | CV 50%; malignancy 25%; infection/sepsis 21.4%; multiple organ failure 3.6%; perioperative 3.6%; unknown 3.6% | |
| AC | ||
| CV 100% | ||
| ECS Metastatic carcinomatosis 40%; Sepsis 30%; postoperative 20%; unknown 10% | ||
| Yaneva et al,6 2013 | CS overall: 30.3%; | CD |
| CD: 27.5%; ECS: 58.3%; AA: 14.3%; ACC: 89.7%; BAH: 18.2%; unproven: 40% | CV 32%; CVA 15%; infections/sepsis 9%; other neoplasms 7.7%; DM 6.4%; CS 5.1%; thromboembolism 1.3%; ARF 1.3%; hepatic failure 1.3%; others 1.3%; unknown 16.7% ECS CV 43%; infection/sepsis 29%; osteoporosis 14%; unknown 14% | |
| AA Thromboembolism 19%; infections/sepsis 12.5%; CVA 12.5%; other neoplasms 12.5%; unknown 31% | ||
| ACC | ||
| CS 45%; CV 24%; infections/sepsis 21%; CVA 3.4%; unknown 7% BAH | ||
| NR | ||
| Hassan-smith et al,26 2012 | CD: 16.3% | CD |
| CV 61.5%; malignancy 23.1%; infection 7.7%; CD 7.7% | ||
| Bolland et al,7 2011 | CS overall: 14% | CS (including CD, ECS, AA, BAH) |
| CV 19%; carcinoma 22%; CVA 17%; sepsis 17%; PE 17%; suspected adrenal insufficiency 2.8% | ||
| Clayton et al,17 2011 | CD: 22% | CD |
| CV 53.8%; CVA 23.1%; malignancy 15.4%; GI bleed 7.7% | ||
| Dekker et al,21 2007 | CD: 16.2% | CD |
| CV 33.3%; CVA 8.3%; malignancy 8.3%; | ||
| infection 8.3%; persistent disease 8.3%; unknown 16.7%; other 16.7% | ||
| Hammer et al,1º 2004 | CD: 10% | CD |
| NR | ||
| Lindholm et al,8 2001 | CS overall 28.9%; CD 18.2%; AA 10.8%; ACC 100% | CS (including CD, AA, ACC)b Malignancy 40%; CVº 20%; CVA 20%; sepsis |
| 10%; surgical complication 10% | ||
| (continued on next page) |
| Table 1 (continued) | ||
|---|---|---|
| References | Mortality Rate | Causes of Death |
| Swearingen et al,23 1999 | CD: 3.8% | CD CV 33.3%; CVA 33.3%; lymphoma 16.7%; trauma 16.7% |
| Pikkarainen et al,49 1999 | CS overall: 13.5% | CS (including CD, AA) CV 20%; PE 20%; aspiration pneumonia 10%; mitral valve insufficiency and CHF 10%; lung cancer 10%; pancreatitis 10%; intracerebral hemorrhage 10%; morbus Parkinson 10% |
Abbreviations: AA, adrenal adenoma; AC, adrenal Cushing’s; ACC, adrenocortical carcinoma; ARF, acute renal failure; BAH, bilateral adrenal hyperplasia; CD, Cushing’s disease; CHF, congestive heart failure; CS, Cushing’s syndrome; CV, cardiovascular; CVA, cerebrovascular accident; DM, diabetes mellitus; ECS, ectopic Cushing’s syndrome; GI, gastrointestinal; NR, not reported; PE, pulmonary embolism.
a Includes CVA-related deaths and ruptured aortic aneurysms.
b Causes of death were reported for 90 patients with CS who had long-term follow-up data. Only 10 deaths were reported in this cohort.
” CV included ruptured aortic aneurysm and myocardial infarction.
dysfunction and hypertension after treatment were found to increase mortality. More- over, cardiovascular risk in patients with CD who had been in remission for 5 years remained higher when compared with an age- and gender-matched population.15 In a small prospective trial on patients with CS,19 there was significant decrease in glucose impairment, hyperlipidemia, and hypertension only in adrenal but not pituitary Cushing’s 1 year after biochemical remission, a finding that could explain the persis- tent mortality risk some studies have shown in patients with CD despite treatment.
Lambert and colleagues2º examined mortality data from 346 patients with CD over a span of 31 years of follow-up. This study demonstrated that longer exposure to excess glucocorticoids, defined here by a duration of symptoms before diagnosis until remis- sion, was associated with increased risk of death. This observation supports the hy- pothesis that poor outcomes in CD is a consequence of hypercortisolism, as suggested by studies demonstrating that patients with CD have increased mortality compared with patients with nonfunctioning and growth hormone-secreting pituitary adenomas.21,22
Other factors associated with increased mortality found in Lambert and col- leagues20 include older age at diagnosis and preoperative plasma ACTH concentra- tions. Among patients with CD who achieved overall and immediate remission, depression at presentation and male sex also increased the risk of death. Older age at diagnosis has been frequently associated with increased mortality in both CD and CS.6,7,9,17,23,24 Male gender has also been identified in additional studies as a mortality risk factor in both CD and CS.6,10
Mortality in Patients with Persistent or Recurrent Cushing’s Disease
Multiple cohort studies and meta-analyses have consistently demonstrated that pa- tients with CD with persistent or recurrent disease have significantly elevated SMR when compared with the general population. Of note, in all but 1 cohort study,7 a com- bined SMR was calculated for patients with persistent disease and those with recur- rent disease, even if these were distinctly defined groups during data collection. In addition, recurrence rates vary among studies, ranging between 10% and 20% at
| Summary of studies reporting Standardized Mortality Ratio (SMR) in Cushing's syndrome and/or Cushing's diseasea Table 2 | ||||||||||
|---|---|---|---|---|---|---|---|---|---|---|
| References | Study Design | CS vs. CD | Study Participants | Study Period | # of Pts | Median Followup (y) | SMR for All Cause Mortality | SMR for Remission | SMR for Persistent Disease | Indep. Risk Factors of Mortality |
| Clayton et al,18 2016 | Retrospective multi-center cohort | CD | · UK, Denmark, Netherlands, New Zealand tertiary referral centers | 1948-2014c | 320 | 11.8ª | 1.61 | NR | NR | DM; higher number of treatments |
| . Pts cured of hypercortiso- lism for minimum of 10 yb | ||||||||||
| Ntali et al,24 2013 | Retrospective multi-center cohorte | CS (CD, ECS, AA, BAH)f | . 1 tertiary referral centers in Oxford, UKe | 1967-2009 | 209 CS; 182 CD; 16 AC; 11 ECS | CD 12; AC 5; ECS 4.5 | CD 9.3; AC 5.3; ECS 68.5 | CD 8.3; ECS 83.3 | CD 9.9; ECS 66.7 | Older age at diagnosis |
| Yaneva et al,6 2013 | Retrospective | CS (CD, ECS, AA, | . 1 tertiary referral center in | 1965-2010 | 386 CS; 240 CD; | 7.0 | CS 4.05; CD 1.88; ECS 13.33; | CS 1.67 | CS 2.4 | Older age at diagnosis; male; CD pts without initial |
| single-center | ACC, BAH) | Sofia, Bulgaria | 12 ECS; 84 AA; | AA 1.67; ACC 48; | ||||||
| cohort | 11 BAH; 10 etiology unproven | BAH 1.14; unproven 4 | remission after TSS; duration of activity of symptoms | |||||||
| Hassan-Smith et al,26 2012 | Retrospective single-center cohort | CD | . 1 center in the UK . Pts who underwent TSS with 1 surgeon | 1988-2009 | 809 | 10.9h | 3.17 | 2.47 | 4.12ª | NR |
| Bolland et al,7 2011 | Retrospective | CS (CD, ECS, | . 4 endocrinology services in New Zealand' | 1960-2005 | 253 CS; 188 CD; AA 37; BAH 9; | 6.4 | CS 4.1; CD | CD macroadenoma 2.5; CD microadenoma 3.2 | CD macroadenoma 5.7; CD microadenoma 2.4 | CD only - older age at diagnosis; BDX; pituitary irradiation; CD and CS - HTN, DM at final follow-up |
| nationwide | AA, BAH) | macroadenoma | ||||||||
| cohort | occult ECS 10; probable ECS 9 | 3.5; CD microadenoma | ||||||||
| 3.2; AA 7.5; BAH | ||||||||||
| 14; occult ECS 27; | ||||||||||
| probable ECS 3.1 | ||||||||||
| Clayton et al,17 2011 | Retrospective single-center study cohort | CD | · 1 UK center | 1958-2010 | 60 | 15 | 4.8 | 3.3 | 16.0 | HTN; DM; disease persistence |
| Dekker et al,21 2007 | Retrospective single-center cohort | CD | . 1 center in the Netherlands . Patients who underwent TSS for NFMA and CD | 1977-2005 | Total 248; CD 74; NFMA 174 | 10.1 (mean) | 2.39 | 1.8 | 4.38 | Disease persistence |
| Hammer et al,1º 2004 | Retrospective single-center cohort | CD | . 1 tertiary referral center in the US . Pts who underwent TSS with 1 surgeonk | 1975-1998 | 189 | 11.1 | 1.42 | 1.18 | 2.8 | Male; higher tumor stage |
(continued on next page)
| Table 2 | ||||||||||
|---|---|---|---|---|---|---|---|---|---|---|
| (continued) | SMR for All Cause Mortality | Indep. Risk Factors of Mortality | ||||||||
| References | Study Design | CS vs. CD | Study Participants | Study Period | # of Pts | Median Followup (y) | SMR for Remission | SMR for Persistent Disease | ||
| Lindholm et al,8 2001 | Retrospective | CS (CD, | . National Patient Register of | 1985-1995 | 166 CS; 99 | 8.1 | CS 3.68; proven | CD 0.31 | CS 5.06 | Disease persistence |
| national | AA, ACC) | the Danish National Board | CD totall; 48 | CD 1.7; | ||||||
| registry | of Health | adrenal | unproven CD 11.5; | |||||||
| cohort | tumors; 11 | AA 3.48; ACC 11/11 | ||||||||
| ACC; 16 | died-no SMR | |||||||||
| cancer- | ||||||||||
| associated; | ||||||||||
| 3 others | ||||||||||
| Swearingen et al, 23 1999 | Retrospective single-center | CD | · 1 tertiary referral center in the US | 1978-1996 | 161 | 8.0 | 0.98 | NR | NR | Older age at diagnosis |
| cohort | . Pts who underwent TSS with 1 surgeon | |||||||||
| Pikkarainen et al, 49 1999 | Retrospective | CS (CD, AA, | · 1 tertiary referral center in | 1981-1994 | 74 CS; 43 CD; | 7.4 (mean) | CS: 1.68; CD: 2.67; | NR | NR | NR |
| single-center | ECS, ACC, | Finland | ECS 4; unclear | AA 1.35; benign | ||||||
| cohort | BAH) | ACTH dep 1; | pituitary or adrenal | |||||||
| AA 20; ACC 4; | disease 2.02; not | |||||||||
| BAH 2 | reported for ECS | |||||||||
| or ACC | ||||||||||
| Etxabe et al,9 1994 | Retrospective | CD | . National Health Service | 1975-1992 | 49 | 4.7 | 3.8 | NR | NR | Older age at diagnosis; persistent HTN; persistent abnormalities of glucose metabolism |
| national registry | Records in Vizcaya, Spain | |||||||||
| cohort | ||||||||||
Abbreviations: AA, adrenal adenoma; AC, adrenal Cushing’s; ACC, adrenocortical carcinoma; BAH, bilateral adrenal hyperplasia; BDX, bilateral adrenalectomy; HTN, hypertension; indep, independent; NFMA, non-functioning pituitary macroadenoma; NR, not reported; pts, patients; SMR, standardized mortality ratio; TSS, transsphenoidal surgery.
a Studies were included if they are: 1. A cohort study of patients with Cushing’s syndrome and/or Cushing’s disease; and 2. Mortality risk expressed as SMR.
b Patient had continued cure with no relapse until database was frozen or until death.
” Frozen data dates ranged 2009-2014.
d 11.8 years from study entry + 10 years in remission.
e Study also included a second cohort from Athens, Greece but data for this table only included Oxford cohort as SMR was only calculated for this cohort.
f Patients with ACC were excluded.
9 72 patients with clinical follow-up data.
h 10.9 yrs median follow-up for mortality; 4.6 yrs median for clinical follow-up.
i Recurrent and persistent disease were combined.
j Patients with ACC or malignant ECS were excluded.
k Excluded patients who had undergone previous pituitary or adrenal surgery or had Nelson’s syndrome.
73 CD proven; 26 CD unproven.
| Table 3 Definitions of remission/cure and recurrent/persistent disease in mortality studies on Cushing's syndrome | ||
|---|---|---|
| References | Definition of Remission and/or Cure | Definition of Recurrent or Persistent Disease |
| Clayton et al, 18 2016 | Variable depending on the center | NR |
| Ntali et al,24 2013 | · Undetectable 9-h serum cortisol after pituitary surgery, adrenalectomy or removal of an ectopic ACTH-producing tumor . After pituitary radiotherapy, normal 24 h UFC or mean serum cortisol 150-300 nmol/l on a 5-point cortisol day curve or had developed ACTH deficiency and during medical treatment, if the patient had achieved a mean serum cortisol 150-300 nmol/l on a 5-point day curve | Recurrence: clinical and biochemical (elevated 24 h UFC and lack of suppression on overnight or low dose DST) |
| Yaneva et al,6 2013 | Remission - resolution of clinical symptoms after treatment, adrenal insufficiency with need for GC replacement therapy, normalization of UFC Cure- absence of clinical and biochemical hypercortisolism (normal/low UFC or 17-OH and ketosteroids in earlier cases and normal DST at last clinical visit) | NR |
| Hassan-Smith et al,26 2012 | Initial remission: morning post-op cortisol <1.8 ug/dL measured between day 4 and week 6) Cure: initial remission and continued biochemical cure during follow-up | Recurrence: biochemical (raised UFC or failure of cortisol suppression on DST) and clinical after initial remission Persistence: biochemically by post-op cortisol >1.8 ug/dL |
| Bolland et al,7 2011 | Adrenal insufficiency and required GC replacement or normal 24-h UFC or normal overnight 1 mg DST | Recurrence: recurrence of CS following initial biochemical cure |
| Clayton et al, 17 2011 | Clinically - resolution of symptoms and signs Biochemically - normal UFC and low-dose DST, normal mean plasma cortisol day curve for those on metyrapone; achieved within 3 y after treatment | Persistence: failure to achieve remission targets within 3 y despite treatment |
| (continued on next page) | ||
| Table 3 (continued) | ||
|---|---|---|
| References | Definition of Remission and/or Cure | Definition of Recurrent or Persistent Disease |
| Dekker et al,21 2007 | Normal 1 mg DST and 24-h UFC in 2 consecutive samples | Persistence: failure to meet biochemical criteria for remission 3-6 mo after 1st operation; Recurrence: recurrence of hypercortisolism (increased 24-h UFC, abnormal 1 mg DST, and normal or exaggerated response of serum ACTH and cortisol to IV CRH stimulation |
| Hammer et al, 10 2004 | Initial remission: within 1 wk post-op, basal or 1 mg DST plasma cortisol <5 ug/dL; or within 6 mo post-op, low or normal plasma or urinary cortisol, resolution of clinical features, and no additional therapy Long-term remission: at 6 mo post-op, continued clinical remission, plasma cortisol after 1 mg DST cortisol of <5 ug/dL or normal 24-h UFC at last follow-up and had not undergone additional therapy | Recurrence: initial remission followed by recurrent hypercortisolism or additional therapy 6 mo or more post-op |
| Lindholm et al,8 2001 | . Plasma cortisol <18 ug/dL at 30 min after IV 250 ug of corticotropin and/or UFC <18 ug/24 h measured 12-180 d after operation . If the results were ambiguous postop, panhypopituitarism or if UFC <90 ug/24 h at >5 y after first operation | Recurrence: after cure is initially achieved, UFC >90 ug/24 h at any time during follow-up |
| Swearingen et al,23 1999 | Fasting serum cortisol <138 nmol/l and UFC <55 nmol/d at 10-d post-op | Recurrence: based on questionnaire response and results of routine endocrine reevaluation, without independent repeated assay |
| Pikkarainen et al,49 1999 | Normal UFC, disappearance of symptoms, no relapse | NR |
| Etxabe et al,9 1994 | Normalization of UFC and normal DST | NR |
Abbreviations: CRH, corticotropin-releasing hormone; DST, dexamethasone suppression test; GC, glucocorticoid; NR, not reported; UFC, urinary free cortisol.
10 years in patients with a microadenoma and between 12% and 45% in patients with a macroadenoma.25 Aside from individual differences in disease severity and tumor size and characteristics, the variation in reported recurrence rates could reflect differ- ences in treatment outcomes between centers as well as inconsistency in definitions used for establishing recurrent and persistent disease. Given these discrepancies, mortality data for persistent and recurrent CD are presented together.
In the 4 cohort studies 10,17,21,26 that focus on patients with CD only, the SMR for pa- tients with persistent or recurrent disease ranged from 2.8 to 16.0, and was signifi- cantly increased compared with SMR for patients with disease in remission, which ranged from 1.18 to 4.12. Most recently, a meta-analysis of 8 studies that reported mortality rates in CD27 calculated a pooled SMR of 4.6 (95% CI, 2.9-7.3) for patients with persistent or recurrent disease, compared with an SMR of 2.5 (95% CI, 1.4-4.2) for patients with remitted disease, as defined in each study. Given the overwhelming evidence of poor outcomes for patients with persistent or recurrent disease, early diagnosis and aggressive intervention are imperative.
Mortality in Patients with Cushing’s Disease in Remission
In contrast with studies describing mortality in patients with persistent disease, studies that focus on patients with disease remission have yielded conflicting results. Several studies report an SMR (ranging from 1.18 to 1.67) for patients with disease remission similar to that of the general population,6,10,21 but some data suggest treat- ment type may play a role in mortality risk.8,18 A recent study by Clayton and col- leagues18 analyzed census data from multiple tertiary referral centers in the UK, Denmark, the Netherlands, and New Zealand on 320 patients with CD in remission, as defined by each center’s criteria for normalization of hypercortisolism without recurrence for at least 10 years. A strength of this study was its long follow-up (median of 11.8 years from study entry), totaling more than 20 years of survival data. All-cause mortality in patients with disease remission from any treatment for at least 10 years remained increased, with an SMR of 1.61 (95% CI, 1.23-2.12). However, patients who achieved remission after transsphenoidal surgery (TSS) alone had long-term sur- vival comparable to that of the general population (SMR ,0.95; CI, 0.58-1.55). Simi- larly, a previous study by Lindholm and colleagues8 reported that the mortality risk for patients with CD cured by initial TSS was no different from that of the general pop- ulation (SMR, 0.31; 95% CI, 0.01-1.72).
Other studies, however, report a significantly increased SMR (range, 2.47-8.30) in patients with CD who achieve remission versus the general population.7,17,24,26,28 Moreover, in Bolland and colleagues series,7 SMR remained elevated even in patients who were cured after first TSS, although the confidence intervals were wide (the SMR was 2.3 for pituitary macroadenoma with a 95% CI of 0.4-7.5, and 3.1 for pituitary microadenoma with a 95% CI of 1.8-4.9). A more recent meta-analysis by van Haalen and colleagues,27 which extracted data from 8 cohort studies totaling 766 pa- tients, 6-8,17,21,24,26 reported a pooled SMR for patients with disease remission of 2.5 (95% CI, 1.4-4.2), suggesting irreversible effects of long-term excess glucocorticoid exposure. It can be concluded that, although there is some evidence that mortality risk for patients with CD in remissions remain elevated, survival outcomes are still significantly improved compared with patients with CD with persistent or recurrent disease. Moreover, patients with CD cured by TSS alone seem to have the best sur- vival outcomes, possibly no different from that of the general population. The use of consistent definitions of CD remission, persistence, and recurrence between investi- gators would improve the ability to clearly define mortality risk for each of these groups.
The pathophysiology behind the persistently elevated mortality risk despite biochemical remission in CD is not well-characterized. It has been hypothesized that perhaps, due to the difficulty in diagnosis and cure, the prolonged cortisol excess before remission results in irreversible or long-lasting adverse effects that predispose to increased mortality. In support of this hypothesis, Dekkers and colleagues21 re- ported that the SMR for patients with CD was significantly higher than SMR for pa- tients with nonfunctioning pituitary macroadenomas (2.39 vs 1.24), and mortality in CD was increased compared with acromegaly after adjustment for sex and age (HR, 2.4; 95% CI, 1.13-4.91), suggesting that hypercortisolism is responsible for the increased mortality. In addition, a study by Colao and colleagues15 found that athero- sclerosis and cardiovascular risk factors remained elevated in patients who had CD despite being in remission for an average of 5 years. In addition, although whole- body MRI showed that CD remission resulted in favorable changes in body fat distri- bution and decrease in some cardiovascular risk factors, other markers such as adiponectin and C-reactive protein did not change after remission.29 Proinflammatory cytokines also remained increased after CD remission, likely contributing to increased cardiovascular mortality.30 Similarly, Hassan-Smith and colleagues26 showed that although weight loss and improvement in blood pressure were evident with treatment, a significant proportion of patients with CD in remission demonstrated end-organ car- diovascular damage that was likely irreversible, including evidence of left ventricular hypertrophy and myocardial ischemia. Aside from cardiovascular complications, other comorbidities such as bone impairment and neuropsychiatric dysfunction have been shown to persist despite biochemical cure. 31,32
Effect of Treatment Type on Mortality in Cushing’s Disease
Surgical resection, when feasible and performed by an experienced surgeon, remains first-line treatment for CD. As discussed, some data show that patients who were able to achieve remission with pituitary surgery alone had mortality risk similar to that of the general population. However, immediate remission rates with pituitary surgery range from 65% to 90% for microadenomas and are less than 65% for macroadenomas, 25 and pituitary surgery is associated with long-term failure with an average recurrence rate of 32%.4 Perioperative mortality rate range between 0% and 7.1% with a mean of 0.6%.4 In the event of persistent or recurrent disease despite initial pituitary surgery, treatment options include repeat pituitary surgery, pituitary radiotherapy, medical therapy, and bilateral adrenalectomy (BLA). However, there are several drawbacks to these second- and third-line therapies. The disadvantages of pituitary radiotherapy include the delay in effect, potential cerebrovascular complications, and risk for devel- oping hypopituitarism. Limitations of BLA include the development of permanent ad- renal insufficiency and the risk of corticotroph tumor progression and development of Nelson syndrome.
Although several cohort studies report an association between mortality risk and treatment modality, this must be interpreted with caution because these are all retro- spective studies.6,7,17,18 Furthermore, differences in availability and indications for treatment over time and factors contributing to the individual patient’s surgical candi- dacy can confound these findings. Thus, the observed effects of treatment modality on mortality may not accurately reflect the direct effects of the treatment but rather the inherent mortality risks of patients who received these treatments. In a CD cohort followed for a median of 106 months (range, 0-494 months) studied within the larger CS study by Yaneva and colleagues,6 survival outcome at the end of study differed significantly according to the first-line treatment modality received by the patients (P = . 012). Only 29% of patients who received radiotherapy alone were alive at the
end of the study, compared with 58% of patients who received medical therapy alone, 46% treated with BLA alone, and 50% who underwent unilateral adrenalectomy alone or in combination with other treatment. The survival rate for patients who underwent TSS alone or in combination with other therapy was not directly reported, but 79% of these patients were in remission at last follow-up, implying a high survival rate. How- ever, it was not reported why some patients did not have TSS as part of their treatment course and it is possible that these patients may have been poor surgical candidates (ie, more frail or had inoperable tumors) and thus had increased mortality risk even before treatment. In the study by Bolland and colleagues,7 BLA alone and pituitary irradiation alone or in combination with any treatment modality were independently associated with increased mortality (OR, 3.1 and 3.0, respectively), whereas treatment with pituitary surgery had improved mortality (OR, 0.2). In addition, Clayton and col- leagues17 noted that the majority of deaths in the study occurred in patients treated with pituitary radiotherapy alone or in combination with metyrapone, raising the pos- sibility that pituitary radiotherapy itself may be a risk factor for mortality, as it is linked to excess mortality in patients with acromegaly and nonfunctioning pituitary tumors. 33 However, as indicated in the study, patients who received radiotherapy and later died were diagnosed with CD before TSS was routinely offered as first-line treatment. In contrast, Dekkers and colleagues21 reported that radiotherapy in addition to TSS was not associated with increased mortality in CD.
In the disease remission cohort studied by Clayton and colleagues, 18 higher mortal- ity was noted with higher number of treatments. The HR was 1.77 for 2 versus 1 treat- ment, and 2.6 for 3 versus 1 treatment. The median survival time from study entry for 1 treatment was 33 years, for 2 was 27 years, and for 3 treatments was 21 years. This is not a surprising finding, because the more complex cases often require multimodal treatment.
ECTOPIC ADRENOCORTICOTROPHIC HORMONE-DEPENDENT CUSHING’S SYNDROME
ECS was first recognized in 1962 in a case series by Meador and colleagues. 34 Nearly one-half of reported cases are due to small cell lung cancer, which is often associated with rapid tumor progression and disseminated disease.5,35 ECS can also be caused by carcinoid tumors (commonly bronchial or thymic), islet cell tumors, medullary thy- roid carcinomas, and pheochromocytomas, with very rare causes including non-small cell lung cancers and cancers of the prostate, breast, ovary, gallbladder, and colon.5,36,37
Treatment modalities for ECS generally consist of one or a combination of primary tumor resection, medical management/chemotherapy, BLA, and radiotherapy. Series providing survival data are relatively limited given the rarity of this disease. Nonethe- less, almost all published studies indicate significantly increased mortality compared with the general population, with neoplastic progression, infection/sepsis, cardiovas- cular disease, and thromboembolic disease the primary causes of mortality in most cases. 14
Regarding predictors of mortality, age at diagnosis, gender, remission status, and the presence of lymph node metastases have not been shown to be independent predictors of survival.24 However, Isidori and colleagues38 reported that the presence of distant metastases and tumor histology were important predictors of overall survival. Further- more, among patients with ECS, patients with small cell carcinoma overall had the worst prognosis, whereas patients with other tumors, especially bronchial carcinoid tumors, showed relatively prolonged survival. Of note, improved overall survival has been described in patients with an occult ectopic source, particularly with adequate control
of hypercortisolemia, compared with patients who have apparent malignant sources of ACTH, including small cell lung cancer and medullary thyroid carcinoma.37-40
A retrospective review of 43 patients with ECS diagnosed between 1979 and 2009 reported deaths in 27 patients (62.8%) and a median overall survival of 32.2 months, with no significant differences in median overall survival durations between men (32.2 months) and women (32.4 months). Progression of primary malignancies and systemic infections at the time of death were the leading causes of mortality, and 2 pa- tients died from pulmonary embolism.41
Yaneva and colleagues6 described 12 patients with ECS followed for a median of 55 months (range, 1-256 months). The SMR was significant at 13.3 with the most com- mon etiologies of mortality being cardiovascular diseases (43%), infections/sepsis (29%), and osteoporosis-related fracture and its complications (14%).
In a retrospective cohort study of 33 patients with ECS followed for a median of 4 years (range, 0-18 years), Ntali and colleagues24 reported 10 deaths and the highest SMR described in the literature, namely, an overall SMR of 68.5. The main causes of death in this population were progression of the primary malignancy and infection/ sepsis. Sepsis was again highlighted as a leading cause of mortality in a retrospective review of 21 patients with ECS in southern India who were followed for a mean 20.1 months, with 3 of 5 reported deaths (60%) attributed to sepsis and the remainder owing to metastatic disease and postoperative pulmonary embolism. 42
When possible, surgical removal of the ectopic ACTH tumor is the first-line treat- ment. However, when the tumor cannot be located or is unresectable (as seen in wide- spread metastatic disease), and medical therapy is ineffective, BLA is effective in alleviating symptoms and comorbidities owing to excess cortisol production.35 The advantage of BLA is immediate control of hypercortisolism, although lifelong gluco- corticoid and mineralocorticoid replacement is necessary. However, with severe hypercortisolemia, surgical morbidity and mortality is not trivial in the setting of immu- nosuppression, myopathy, metabolic derangements, and hypercoagulability. 42
O’Riordain and colleagues43 reported survival outcomes in 18 patients with ECS who underwent BLA, with 1-, 2-, and 5-year survival rates of 67%, 44%, and 39%, respectively. Among these patients, 73% of deaths were directly related to metastatic malignant disease, with the remaining 27% attributed to cardiovascular and cardio- pulmonary disease. A higher 5-year survival rate of 51% among 35 patients with ECS after BLA was reported in a retrospective chart review conducted from 1996 to 2005.5 Furthermore, complete primary tumor resection, if feasible, was highlighted as the ideal treatment for ECS with no patient deaths reported among 5 patients cured by complete tumor resection in a retrospective review of 38 patients from 1990 to 2011 diagnosed and treated for ECS in a tertiary referral center.35 Additionally, a high mor- tality rate and often inadequate response to medical therapy was illustrated with all 9 patients treated medically, dying at a median of 1.5 months, and 15 of 24 patients (62%) treated with BLA dying with median survival time of 14.5 months.35
In a nationwide retrospective survey of 253 patients with CS between 1960 and 2005 in New Zealand, 10 patients with a localized etiology of ECS had a significant SMR of 27 (95% CI, 8.5-65.20). Notably, the 9 patients classified as ‘probable’ ECS (no tumor source identified) did not show a significant increase in mortality compared with the matched general New Zealand population, however, with an SMR of 3.1 (95% CI, 0.5-10.0) and a P-value of .16.7 This is the only known study with a nonsignificant SMR for patients with ECS, albeit in patients with unconfirmed and ‘probable’ ECS. Given the rarity and tumor heterogeneity among patients with ECS, additional data with larger series will be essential to better characterize mortality risk for these patients.
ADRENOCORTICOTROPHIC HORMONE-INDEPENDENT ADRENAL CUSHING’S SYNDROME
ACTH-independent adrenal Cushing’s accounts for approximately 20% of endoge- nous CS in adults. 44 Unilateral adrenal tumors account for approximately 90% of these cases, 80% of which are benign adenomas with much fewer cases due to ACC; addi- tional adrenal causes that are rare include micronodular/macronodular adrenal hyper- plasia and primary pigmented nodular adrenal disease.44 Patients with adrenal adenomas as compared with carcinomas are younger (39.6 ± 14.4 years vs 51.5 ± 16.6 years) and generally present with smaller tumors (3.3 ± 1.0 cm vs 8.6 ± 4.5 cm).45 Overall, among patients with adrenal CS, a female predominance has been noted.45 The First-line treatment for patients with adrenal CS is surgical resection, either unilateral or BLA, depending on the etiology. Perioperative complica- tions and morbidity have dramatically decreased in recent decades with advance- ments in surgical techniques, including the introduction of minimally invasive laparoscopic adrenalectomy.5,46
Cushing’s Syndrome Due to Adrenal Adenoma
The incidence of CS due to an adrenal adenoma is approximately 0.6 per million per year.8 Numerous studies have been published on this patient population, and overall, mortality seems to be less pronounced as compared with CS of other etiologies. A systematic review and meta-analysis of mortality studies demonstrated that mortality for treated patients with a benign cortisol-producing adrenal adenoma did not differ significantly from the general population with an SMR of 1.90 (95% CI, 0.93-3.91).47 Of note, age at diagnosis, sex, and observation time do not seem to impact mortality in patients with CS due to a benign adrenal adenoma.24,47 Furthermore, biochemical cure rates of up to 100%, after surgical removal of benign adrenal adenomas, with a long-term mortality similar to the general population, has been reported by Iacobone and colleagues. 48
In a retrospective study analyzing 45 years of data, the SMR was not significantly increased among patients with CS due to adrenal adenomas at 1.67 (95% CI, 0.20- 6.02).6 In this group, thromboembolic complications were the most frequent cause of death (19%), followed by infections (12.5%), cerebrovascular diseases (12.5%), and other neoplasms (12.5%). All but 2 of 84 patients with cortisol-secreting adenomas underwent surgery, and the remaining 2 patients died with severe active disease that prevented them from undergoing major surgery.6 Similarly, Pikkarainen and col- leagues49 described a normal SMR of 1.35 (95% CI, 0.16-4.89) among patients with CS due to an adrenal adenoma. The efficacy of adrenalectomy among this patient population was highlighted in a study showing no recurrences among 27 patients with adrenal adenoma causing CS treated with adrenalectomy followed for 5.0 ± 5.5 years, with 1 death (perioperative hypoglycemia presumably due to adrenal insufficiency). 45
In another large series, Ntali and colleagues24 analyzed mortality in 74 patients with adrenal CS, of which 57 of 74 patients (77%) had unilateral adrenal adenomas. Two 2 patients (3%) with adrenal Cushing’s died, neither of whom was in remission, both due to cardiovascular events. Overall, the 10-year probability of survival was 95.5% and the SMR was similar to that of the general population at 5.3 (95% CI, 0.3-26.0) with a P-value of .2. Similarly, a cohort of 54 patients with cortisol-secreting adenomas had an excellent 5-year survival rate (all causes) of 90%.5
Other studies, however, report an increased mortality risk in patients with benign adrenal CS. Among 37 patients with CS due to an adrenal adenoma, 4 (10.8%) died
during a median period of 7.1 years (range, 3.1-13.8 years) yielding an SMR of 3.48 (95% CI, 0.95-8.90).8 Of note, pretreatment 24-hour urinary free cortisol levels did not differ significantly between survivors and nonsurvivors. In this study, excess mor- tality was noted within the first year after the initial admission for hypercortisolism. However, the mortality rate was subsequently not significantly higher than that of the general population.8
Dekkers and colleagues50 reported an increased mortality risk in 132 patients with adrenal CS (excluding ACC, and not differentiating adenoma vs bilateral hyperplasia) compared with the control population (HR, 2.4; 95% CI, 1.6-3.5). Of note, given that data were obtained from population-based registries without access to individual re- cords, the authors comment that some patients with pituitary CD treated with adrenal- ectomy without concomitant pituitary surgery could have been misclassified as adrenal CS, hence skewing their results.
Bolland and colleagues7 also noted an elevated SMR of 7.5 (95% CI, 1.9-20.0) among 37 patients with adrenal adenomas. Notably, however, 2 of the total 3 deaths occurred in untreated patients preoperatively due to pulmonary embolism and sepsis, with only 1 death occurring after treatment, albeit in the immediate postoperative period due to ischemic heart disease. Therefore, although the SMR for adrenal ade- noma was increased in this cohort, untreated patients were included, and there were no deaths outside of the immediate postoperative follow-up period.7 Overall, the mortality risk was most prevalent in the early stages after diagnosis and perioper- atively. These studies highlight the importance of timely treatment, perioperative thromboembolic prophylaxis, optimization of cardiovascular status, and prompt iden- tification and treatment of adrenal insufficiency in patients with adrenal CS.
Cushing’s Syndrome Due to Adrenocortical Carcinoma
The incidence of Cushing’s due to ACC is approximately 0.2 per million per year.8 Complete surgical resection is the only potentially curative treatment for ACC.51 As opposed to benign adrenal pathology, where laparoscopic surgery is preferable, open surgery is often required for patients with ACC, thus increasing risk for potential perioperative complications.52,53 Furthermore, surgical remission is uncommon due to a high prevalence of tumor invasiveness and metastasis and, therefore, adjuvant ther- apy, including mitotane and other cytotoxic agents are often needed.54 Data on mor- tality in patients with ACC are limited, but most cases are associated with a poor prognosis and a high mortality rate.
One cohort of 29 patients with ACC had an SMR of 48.0 (95% CI, 30.75-71.42) with a mean survival from the time of diagnosis of 18 months, the most common causes of death being cardiovascular and infectious/sepsis.6 In total, 24 of 29 patients with ACC underwent adrenalectomy and the remaining 5 (all whom subsequently died) had se- vere active, metastatic disease that precluded them from undergoing surgery.6 All 11 patients in another cohort with ACC died soon after admission (median survival time was 7 months; range, 0.9-46.7 months).8
Another study reported that, among 13 patients with ACC undergoing adrenalec- tomy, 76.9% had recurrences at a mean follow-up of 33 months with the 3- and 5-year survival rates being 41.5% and 31.2%, respectively.45 Porterfield and colleagues5 also described a grim 5-year survival rate (all causes) of 23% among 10 patients with ACC.
Bilateral Adrenal Hyperplasia
Given the rarity of this disease, only a few studies have commented specifically on mortality among patients with ACTH-independent CS due to bilateral adrenal
hyperplasia. In 1 study of 9 patients with bilateral adrenal hyperplasia followed for a mean of 5.7 years, 3 deaths were reported yielding an SMR of 14 (95% CI, 3.7- 40.0).7 In contrast, another study did not identify increased mortality among 11 pa- tients with bilateral adrenal hyperplasia causing CS compared with the general popu- lation, with an SMR of 1.14 (95% CI, 0.21-6.34).6 BLA is the treatment of choice among this population. A systematic review of patients treated with BLA, including 45 patients with CS due to bilateral adrenal hyperplasia, showed a median mortality rate of 0% (95% CI, 0-100), with a total of 4 deaths over the median follow-up time of 36 months (range, 23-294 months).55 More studies are needed to clarify risk factors and etiologies of mortality in this population.
MORTALITY IN SUBCLINICAL OR MILD ADRENAL CUSHING’S SYNDROME
With the increase in use of radiology and advanced imaging technology, adrenal inci- dentalomas are being discovered with increasing frequency. Incidental adrenal masses are found in 4.5% of computed tomography imaging done for an unrelated cause, with an incidence of up to 10% in patients older than 70 years.56,57 Adrenal le- sions are more commonly seen in the elderly population, in women, and in the left ad- renal gland.58,59 Among patients with adrenal incidentalomas, up to 30% may exhibit evidence of autonomous cortisol production.60,61 However, the overwhelming majority of these patients do not demonstrate classical features of CS and, therefore, this diag- nosis has been termed subclinical CS or mild hypercortisolism.62 There is no consensus regarding the biochemical definition of subclinical CS. Most studies define adrenal CS by autonomous cortisol production, with lack of complete serum cortisol suppression after the low dose (1 mg) overnight dexamethasone suppression test (DST); however, serum cortisol cutoffs range from 1.8 to 5 µg/dL, with 1.8 µg/dL being the most sensitive test for defining mild hypercortisolemia, but also yielding a higher false-positive rate.63
The term subclinical may not accurately define this condition, however, given that even low-grade cortisol excess has been linked with morbidities, including hyperten- sion, diabetes, dyslipidemia, cardiovascular events, obesity, metabolic bone disease, and a potentially a higher mortality risk (Table 4).57,62,64-67 Di Dalmazi and col- leagues64 described 198 patients with adrenal incidentalomas who were followed for a mean of 7.5 years. Compared with patients with nonfunctioning adenomas, all- cause mortality (91% vs 57%) and cardiovascular-specific mortality (98% vs 78%) were worse in patients with subclinical CS, defined as cortisol levels of greater than 5 µg/dL after a 1-mg overnight DST. Notably, factors significantly associated with mortality in this study were age and mean concentrations of serum cortisol after DST.
These findings were echoed in a retrospective, longitudinal cohort study by Debono and colleagues57 of 206 patients with benign adrenocortical adenomas. Survival rates decreased with increasing serum cortisol levels after a 1-mg overnight DST: compared with patients with post-DST serum cortisol levels of less than 1.8 ug/dL, the HR of death was 12.0 (95% CI, 1.6-92.6) and 22.0 (95% CI, 2.6-188.3) in patients with serum cortisol values of 1.8 to 5.0 µg/dL, and greater than 5 µg/dL, respectively. In fact, among the 18 patient deaths in this cohort, 94% had post-DST serum cortisol of greater than 1.8 ug/dL, with cardiovascular (50%) and respiratory/infectious (33%) causes being the major causes of death.
Likewise, in a recent retrospective study spanning 13 years, Patrova and col- leagues68 showed increased mortality in patients with adrenal incidentalomas with autonomous cortisol secretion compared with nonfunctioning adrenal incidentalomas. 365 patients with adrenal incidentalomas were classified as having normal post-DST
| References | Study Design | Definitions (Cortisol Level After 1 mg DST) | Study Participants | Study Period | # of Pts | Mean Follow-up (y) | Mortality or Survival Rates (%) | Signif Predictors of Mortality | Causes of Death |
|---|---|---|---|---|---|---|---|---|---|
| Patrova | Retrospective | · Normal | Single center | 2003-2010 | 365 total; NS 204; | 5.2 ± 2.3 | Mortality Rates: | Cortisol levels | · NS: malignancyª |
| et al, 68 | single-center | (<1.8 mcg/dL) | in Sweden | possible | NS 7.8% | post-DST as | 3.9%; CV 2%; | ||
| 2017 | cohort | · Possible | autonomous 128; | Possible | a continuous | pulm 1%; | |||
| autonomous | autonomous 33 | autonomous | variable; age; | unknown 2.5% | |||||
| (1.8-5 mcg/dL) · Autonomous cortisol secretion (>5 mcg/dL) | 11.7% Autonomous 18.2% | tumor size | · Possible autonomous: cancer 3.9%; CV 3.1%; pulm 0.8%; unknown 3.9% | ||||||
| · Autonomous: malignancyª | |||||||||
| 18.2% | |||||||||
| Debono | Retrospective | · Normal | Single center | 2005-2013 | 206 total; | 4.2 ± 2.3 | Mortality Rates: | Cortisol levels | CV 50%; |
| et al,57 | single-center | (<1.8 mcg/dL) | in the UK | · Cortisol <1.8: | Overall 9% | post-DST | respiratory/ | ||
| 2014 | cohort | · Group 1 | n = 95 | · Cortisol | infectious 33%; | ||||
| (1.8-5 mcg/dL) | · Cortisol 1.8-5: | <1.8: 1% | malignancyª 6% | ||||||
| · Group 2 | n = 92 | · Cortisol 1.8-5: | |||||||
| (>5 mcg/dL) | . Cortisol >5: n = 19 | 13% . Cortisol >5: 26%b | |||||||
| Di dalmazi | Retrospective | · NS | Single center | 1995-2010 | 198 total; NS 129; | 7.5 ± 3.2 | Survival Rates: | Age; mean | CV 48%; malignancy |
| et al,64 | single-center | (<1.8 mcg/dL) | in Italy | intermediate 59; | · Intermediate or | concentrations | 43%; hip fracture | ||
| 2014 | cohort | · Intermediate | subclinical CS 10 | subclinical CS 57% | of cortisol | complications | |||
| (1.8-5 mcg/dL) | · NS 91.2% | post DST | 10% | ||||||
| · Subclinical | |||||||||
| CS (>5 mcg/dL) |
Abbreviations: CS, Cushing’s syndrome; CV, cardiovascular; DST, dexamethasone suppression test; NS, non-secreting.
a Excluding adrenocortical carcinoma.
b Mortality HR compared with DST cortisol <1.8 mcg/dL vs 1.8-5 mcg/dL is 12.0 (95% CI 1.6-92.6); DST cortisol <1.8 mcg/dL vs >5 mcg/dL is 22.0 (95% CI 2.6-188.3).
cortisol secretion (<1.8 µg/dL), possible autonomous (1.8-5 µg/dL), and autonomous (>5 µg/dL) cortisol secretion. 37 patients (10.1%) died during the follow-up period (5.2 ± 2.3 years), 7.8% of whom were in the nonsecreting group, 11.7% in the possible autonomous, and 18.2% in the autonomous cortisol secreting group (P = . 019). Inter- estingly, all deaths in the autonomous group were attributed to cancer (excluding ACC), whereas in the possible autonomous group cardiovascular, followed by cancer, and pulmonary etiologies were the leading causes of death, respectively.68 Taken together, patients with subclinical CS may be at risk for increased mortality, and the risk may correlate with the degree of cortisol autonomy.
Unilateral adrenalectomy in patients with subclinical CS has been shown in a num- ber of studies to improve multiple long-term cardiovascular and metabolic outcomes, including blood pressure, fasting blood glucose, obesity, dyslipidemia, and even vertebral fractures.69-72 However, the effect on mortality is less clear. There is currently is no definitive evidence showing a mortality benefit from adrenalectomy among patients with subclinical CS.
With regard to the effect of medical therapy in subclinical CS, there are very few data. Only 1 small study evaluating medical therapy in the setting of mild hypercortis- olism has been reported in the literature to date. DeBono and colleagues73 showed that HOMA-IR (an index of insulin resistance) improved significantly in all 6 patients treated for 4 weeks with the glucocorticoid receptor antagonist mifepristone. Further studies are needed to clarify which patients with subclinical CS may benefit from sur- gery versus medical therapy or even serial monitoring, and how these management modalities affect long-term mortality risk.
SUMMARY
With improved biochemical and imaging diagnostics, surgical techniques, as well as medical and radiation therapies, survival for patients with CS has improved since the data of Plotz in the 1950s and particularly since the time of Harvey Cushing’s when the mean survival period was only 4.7 years. 11,12 Nonetheless, CS is still asso- ciated with several comorbidities as well as increased mortality. Prompt and effective treatment resulting in normalization of cortisol levels improves both comorbidities and mortality, in some series mirroring that of the general population. It is imperative that patients with persistent disease receive prophylaxis and active surveillance for infec- tions and cardiovascular and thromboembolic events to mitigate the burden of these comorbidities. Finally, there is a need for studies with high-quality data involving larger cohorts of all subtypes of CS, thus, better characterizing morbidity and mortality and informing treatment guidelines for patients with CS.
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