Study reference

Study characteristics

Patient characteristics

Intervention (I)

Comparison / control (C)

Follow-up

Outcome measures and effect size

Comments

Khan, 2019

SR of 15 cohort studies, 1 RCT, and 2 cross-sectional studies

Literature search up to June 2018

A: Toniato, 2009

B: Iacobone, 2012

C: Kawate, 2014

D: Petramala, 2017

E: Tsuiki, 2008

Study design:

Systematic review

Setting and country:

A: Italy

B: Italy

C: Japan

D: Italy

E: Japan

Source of funding:

Nil.

Conflicts of interest:

None declared.

Inclusion criteria SR:

Original retrospective, prospective, or cross-sectional studies, analyzing patients with nonfunctioning and/or subclinical cortisol secreting Adrenal Incidentalomas (AIs), reporting at least two components of metabolic syndrome (diabetes, impaired glucose tolerance, fasting hyperinsulinemia, dyslipidemia, HTN, and obesity/central adiposity), and the results of adrenalectomy and/or conservative management on these outcomes included.

Exclusion criteria SR:

Studies without biochemically confirmed subclinical hypercortisolism, studies reporting only preoperative data or insufficient postoperative data, case reports and case series including fewer than 10 operated patients.

5 studies included

Important patient characteristics at baseline:

Study size (n):

A: Intervention 23, control 22

B: Intervention 15, control 20

C: Intervention 15, control 12

D: Intervention 26, control 44

E: Intervention 10, control 12

Age (years):

A: Intervention 63 ± 4.1, control 64 ± 1.8

B: Intervention median 57 (range 36-78), control median 58 (range 39-75)

C: Intervention 55.3 ± 9.4, control 66.3 ± 8.8

D: 61.9 ± 8.4

E: Median 59.7 (range 43-74)

Sex of participants (male):

A: Intervention 12, control 10

B: Intervention 12, control 8

C: Intervention 2, control 6

D: 52

E: 6

Intervention: Surgery: adrenalectomy.

Control: Conservative management.

Duration of follow-up:

A: Mean 7.7 years (range 2-17 years)

B: Intervention mean 54 ± 34 months, control 56 ± 37 months

C: Median 5.3 years

D: Mean 12 months (range 9-15 months)

E: Intervention 7-19 months (average 13 ± 3.8 months), control 15-69 months (average 27 ± 15.2 months)

For how many participants were no complete outcome data available?

Not reported.

Hypertension:

Defined as:

A: Systolic blood pressure >150 and diastolic blood pressure >90

B, C: Systolic blood pressure ≥140, diastolic blood pressure ≥90 or antihypertensive treatment.

E: Systolic blood pressure >140 and/or diastolic blood pressure >90

A: Intervention: Improved 7 (38.9%), normalized 5 (27.8%)

Control: worsened 5 (22.7%)

P=0.046

B: Control: worsened 3/12 (25%)

P=0.002

C: Intervention: improved 6 (67%)

Control: improved 0 (0%), worsened 4 (67%)

D: Baseline: Intervention: 85%

Control: 63.1%

Follow-up: Intervention: 58.82%

Control: 72.5%

P<0.05

E: Intervention: improved 5

Control: worsened 1, developed HTN 1

Diabetes mellitus:

Defined as:

A: Fasting glucose >126 mg/dl or treatment with antidiabetic drugs

B: FPG >126 mg/dl or treatment with antidiabetic drugs

C: FPG ≥126 mg/dl and/or random glucose ≥200 mg/dl and/or HbA1c ≥6.5% and/or treatment with antidiabetic drugs

E: FPG >126 mg/dl or 2h plasma glucose >200 mg/dl

A: Intervention: improved 3 (37.5%), normalized 2 (25%)

Control: worsened 2 (9%)

P=0.619

B: Control: worsened 3/12 (25%)

P=0.032

C: Intervention: improved 3 (60%)

Control: improved 1 (20%), worsened 2 (40%)

D: Baseline: Intervention: 38%

Control: 25%

Follow-up: Intervention 23.5%

Control: 38.5%

Hypercholesterolemia (data retrieved from Toniato, 2009)

A: Intervention: normalized 3 (37.5%)

Control: worsened 3 (13.6%)

P=0.619

Dyslipidemia

Defined as:

A: Triglycerides >150 mg/dl, HDL <40 mg/dl in men, HDL <50 mg/dl in women

B: Triglycerides ≥150 mg/dl, HDL <40 mg/dl in men, HDL <50 mg/dl in women, patients on anti-dyslipidemic treatment

C: Total cholesterol ≥220 mg/dl and/or LDL ≥140 mg/dl and/or HDL <40 mg/dl and/or triglycerides ≥150 mg/dl, treatment with lipid-lowering medication

E: Total cholesterol >220 mg/dl

B: Baseline: Intervention: 10 (50%)

Control: 7 (46.7%)

Follow-up: Control: no change

P=0.47            

C: Baseline: Intervention: 8 (53%)

Control: 10 (83%)

Follow-up: Intervention: 1 improvement (13%)

Control: 1 improvement (10%)2, 2 worsening (20%)

E: Baseline: Intervention: 9 (90%)

Control: 6 (50%)

Follow-up: Intervention: 6 improvement

Control: none worsened, 2 developed

P<0.001

Obesity

Defined as:

A: Overweight: BMI 25-30 kg/m², obese: BMI >30 kg/m²

B: Overweight: BMI 25-29.9 kg/m², obese: ≥30 kg/m²

C: Obesity: BMI ≥25 kg/m²

E: Obesity: BMI ≥25 kg/m²

A: Intervention: BMI normalized 3 (50%)

B: Control: BMI worsened 3/12 (25%)

P=0.19

C: Baseline: Intervention: 5 (33%)

Control 5 (42%)

D: Baseline: Intervention: 53.8%

Control: 33%

Follow-up: Intervention: 24.5%

Control: 42.7%

P<0.05

E: Baseline: Intervention: 3 (30%)

Control: 3 (25%)

Follow-up: Intervention: 0 improvement

Control: none worsened, 2 developed

Metabolic syndrome

Defined as:

D: Defined by ATP III-NCEP criteria

D: Baseline: Intervention 54%

Control 39%

Follow-up: Intervention: 23%

Control: 45%

P<0.05

High triglycerides

D: Baseline: Intervention: 34%

Control: 34%

Follow-up: Intervention: 27%

Control: 38%

Impaired glucose metabolism (data retrieved from Tsuiki, 2008):

E: Baseline: Intervention: 9 (90%)

Control: 6 (50%)

Follow-up: Intervention: 2

Control: 1 worsened, 2 developed

The author concludes that cardiometabolic risk factors should be screened for in patients with subclinical cortisol secreting AIs.

In general, adrenalectomy data indicated improvement in metabolic complications in patients with subclinical cortisol secreting AI. Metabolic complications deteriorated or did not improve in patients who were treated conservatively.

No GRADE performed.

No meta-analysis and sensitivity analysis performed.

Age, gender, and size of the AI might influence cardiovascular outcomes, but subgroup analysis was not possible, as the individual studies did not consistently report these variables.

Bancos, 2016

[individual study characteristics deduced from Bancos, 2016]

SR and meta-analysis of 6 cohort studies

Literature search up to 17 November 2015

A: Rossi, 2000

B: Guerrieri, 2010

C: Giordano, 2010

D: Chiodini, 2010

E: Azaka, 2011

F: Ricciato, 2014

Study design:

2 prospective cohort studies and 4 retrospective cohort studies

Setting and Country:

A: Italy

B: Italy

C: Italy

D: Italy

E: Japan

F: Italy

Source of funding:

No specific grant from any funding agency in the public, commercial or not-for-profit sector was received.

Conflicts of interest:

Authors have no conflicts of interest to declare. IB, WA and MT are members of the European Society of Endocrinology and European Network for the Study of Adrenal Tumors Clinical Guideline Panel.

Inclusion criteria SR:
Original prospective and retrospective, comparative and non-comparative studies, adults with either non-functioning adrenal tumors or adrenal tumors with subclinical cushing, at least five patients undergoing adrenalectomy, outcomes of interest before and after adrenalectomy reported.

Exclusion criteria SR:

Nonoriginal studies and case reports.

6 studies included

Important patient characteristics at baseline:

N patients

A: Intervention: n=5, control: n=7

B: Intervention: n=19, control: n=28

C: Intervention: n=6, control: n=10

D: Intervention: n=25, control: n=16

E: Intervention: n=8, control: n=8

F: Intervention: n=16, control: n=17

Definition of subclinical Cushing’s syndrome:

A: Overnight dexamethasone: 3 µg/dL (2 mg), UFC >2 SD above normal range, ACTH Low, Average daily cortisol.

B: Not defined.

C: Overnight dexamethasone: 1.8 µg/dL (1 mg), UFC >100 µg/24h, ACTH <5 pg/mL, Loss of circadian cortisol rhythm.

D: Overnight dexamethasone: 3 µg/dL (1 mg), UFC >70 µg/24h, ACTH <10 pg/mL.

E: Overnight dexamethasone: 3 µg/dL (1 mg), cortisol cutoff 1 µg/dL, Normal basal cortisol AND one of: low DHEA-S, low ACTH, loss of circadian cortisol rhythm, unilateral uptake on scintigraphy.

F: Overnight dexamethasone: 1.8 µg/dL (1 mg), UFC >137 µg/24h, ACTH <10 pg/mL, Midnight serum cortisol >50 µg/mL.

Groups comparable at baseline: not reported.

Intervention:

Adrenalectomy

Control:

Conservative management

End-point of follow-up:

Most studies reassessed patients 6 months after surgery, with a mean follow-up of 28 (1-109) months (median or mean follow-up was reported in only 11 studies).

For how many participants were no complete outcome data available?

Not reported.

Hypertension improvement

Defined as:

A: Decrease in the dose, number of discontinuation of medications.

B: Before and after SBP and DBP means/SD, P values, and magnitude of change reported.

C: Not defined.

D: Change of HTN grade (European Society Cardology Mean SBP and DBP before and after.

E: Decrease in blood pressure <140/90 mmHg leading to decrease of the dose, number or discontinuation of medications.

F: Before and after blood pressure measurements, reduction or discontinuation of blood pressure meds.

A: Intervention: 4/4

Control: 0/7

RR 14.400 [95% CI 0.968 to 214.193]

B: Intervention: 8/12

Control: 0/20

RR 27.462 [95% CI 1.726 to 436.947]

C: Intervention: 0/6

Control: 0/7

RR 1.143 [95% CI 0.026 to 50.397]

D: Intervention: 8/14

Control: 0/10

RR 12.467 [95% CI 0.802 to 193.845]

E: Intervention: 5/5

Control: 0/4

RR 9.167 [95% CI 0.654 to 128.533]

Diabetes Mellitus improvement

Defined as:

A: Reduction of oral medications or insulin.

B: P values and magnitude of change reported to fasting plasma glucose.

C: Not defined.

D: Fasting plasma glucose considered changed if move from one category to another according to Adult Treatment Panel III criteria Fasting plasma glucose mean before and after.

E: Normoglycemia (glucose <110 mg/dL) on OGTT, HbA1c decreased by >0.3% or discontinuation/decrease of medications.

F: Change in glucose level.

A: Intervention: 3/3

Control: 0/4

RR 8.750 [95% CI 0.615 to 124.534]

C: Intervention: 0/1

Control: 0/2

RR 1.500 [95% CI 0.046 to 49.070]

D: Intervention: 3/7

Control: 0/4

RR 4.375 [95% CI 0.281 to 68.058]

E: Intervention: 4/6

Control: 0/2

RR 3.875 [95% CI 0.289 to 51.407]

Dyslipidemia improvement

Defined as:

A: Not reported.

B: P values and magnitude of change reported for HDL.

C: Not defined.

D: Move from one category to another based on Adult Treatment Panel III criteria LDL means before and after.

E: LDL <140 mg/dL, trigs <150 mg/dL; HDL>40 or discontinuation/decrease of medications.

F: Before and after mean HDL and TG.

C: Intervention: 0/5

Control: 0/3

RR 0.667 [95% CI 0.016 to 27.240]

D: Intervention: 4/12

Control: 1/5

RR 1.667 [95% CI 0.243 to 11.448]

E: Intervention: 1/3

Control: 0/5

RR 4.500 [95% CI 0.238 to 85.117]

Obesity improvement

Defined as:

A: Not reported.

B: Before and after mean BMI/SDs, P values, and magnitude of change reported.

C: Not defined.

D: Improvement = greater than 5% decrease in body weight, body weight before and after mean.

E: Weight decrease by ≥3 kg

F: Before and after mean BMIs.

D: Intervention: 4/12

Control: 1/8

RR 2.667 [95% CI 0.361 to 19.712]

E: Intervention: 2/2

Control: 0/1

RR 3.333 [95% CI 0.287 to 38.752]

Systolic blood pressure:

B: MD -10.000 [95% CI -17.250 to -2.750]

D: MD -22.800 [95% CI -37.780 to -7.820]

F: MD -14.300 [95% CI -36.054 to 7.454]

Diastolic blood pressure:

D: MD -14.900 [95% CI -25.082 to -4.718]

F: MD -4.800 [95% CI -15.431 to 5.831]

Fasting blood glucose:

D: MD -31.600 [95% CI -56.031 to -7.169]

F: MD -12.100 [95% CI -37.944 to 13.744]

Facultative:

The authors conclude that a beneficial effect of adrenalectomy compared to conservative management on cardiovascular risk factors in patients with subclinical Cushing’s syndrome is suggested.

No GRADE performed.

Subgroup analyses were performed for dexamethasone suppression test (DST) cortisol cutoff. The three groups were:

1. Cortisol cutoff ≥3 µg/dL, 83 nmol/L

2. Cortisol cutoff <3 µg/dL, 83 nmol/L

3. Studies that did not report DST cortisol cutoff or did not provide how SCS was defined.

Subgroup analysis was performed for outcomes hypertension (HTN) and diabetes mellitus type 2 (DM2).

Patients in the three subgroups experienced similar rates of HTN and DM2 improvement following adrenalectomy. 

Heterogeneity was low for the outcome measures reported.

Study reference

Study characteristics

Patient characteristics ²

Intervention (I)

Comparison / control (C) ³

Follow-up

Outcome measures and effect size ⁴

Comments

Morelli, 2022

Data from a randomized clinical trial

Setting and country:

Fondazione IRCCS Ca’ Granda, Milan, Italy, IRCCS Istituto Ortopedico Galeazzi, Milan, Italy, and IRCCS “Casa Sollievo della Sofferenza” Hospital, San Giovanni Rotondo, Foggia, Italy.

Source of funding

Funded by the Grant RF 2013-02356606 from the Italian Ministry of Health to IC, VM, AS, and SC.

Conflicts of interest:

IC received consulting fees from Corcept Therapeutics and HRA Pharma. The remaining authors declare they have no conflicts of interest.

Inclusion criteria:

Age between 40 and 75 years, and diagnosis by imaging of unilateral Adrenal Incidentaloma (AI) larger than 1 cm with radiological features at computed tomography consistent with an adrenocortical adenoma (homogeneous and hypodense, Hounsfield units <10 or with proven radiological dimensional stability).

Exclusion criteria:

Hypogonadism, thyrotoxicosis, chronic renal failure and hepatic disease, alcoholism, rheumatologic and hematological disease, and eating disorders, including binge eating disorder, bulimia nervosa, and anorexia nervosa, intake of drugs influencing cortisol and dexamethasone metabolism or cortisol secretion, signs or symptoms specific to hypercortisolism, possible metastatic diseases or radiologic appearance not consistent with an adrenocortical adenoma, biochemical evidence of pheochromocytoma and aldosteronoma, ACTH dependency, and incomplete diagnostic work-up, and patients with AI larger than 5 cm.

N total at baseline:

Intervention: 31

Control: 31

Important prognostic factors²:

Age ± SD:

Intervention: 62.5 ± 10.4

Control: 66.1 ± 9.1

Sex (female):

Intervention: 68

Control: 80

Patients with obesity (%):

Intervention: 8 (26.7)

Control: 8 (32)

Patients with DL (%):

Intervention: 15 (60)

Control: 21 (70)

SBP (mmHg):

Intervention: 139.1 ± 14.0 (100-170)

Control: 139.7 ± 15.3 (110-165)

DBP (mmHg):

Intervention: 82.2 ± 10.1 (70-100)

Control: 77.7 ± 10.2 (60-97)

Patients with HT (%):

Intervention: 16 (64)

Control: 22 (73)

Patients with diabetes (%):

Intervention: 5 (20)

Control: 6 (20)

Patients with IGT/IFG (%):

Intervention: 7 (28)

Control: 9 (30)

Groups were comparable at baseline.

Intervention: adrenalectomy

Control: Conservative approach. Patients with borderline-elevated BP or grade 1 hypertension, with prediabetes, or with overweight were suggested to follow intensive lifestyle behaviour changes. Patients with grade 2-3 hypertension, with not fully controlled diabetes, with obesity, or with dyslipidemia were addressed to cardiologists and/or diabetologists. Patients received personalised treatment.

Length of follow-up:

6 months.

Loss-to-follow-up:

Intervention:

N=6 (19.4%)

Reasons: consent withdrawal (n=4), cancer occurrence (n=1), death for COVID-19 (n=1)

Control:

N=1 (3.2%)

Reasons: adrenalectomy for adenoma enlargement (n=1)

Incomplete outcome data:

No incomplete outcome data.

Patients with obesity:

Intervention: 6 (24.0)

Control: 7 (23.3)

P=1.00

Body weight change (stable/worse/better):

Intervention: 19/2/4 (76/8/16)

Control: 26/1/3 (86.7/3.3/10)

P=0.48

Patients with dyslipidemia:

Intervention: 15 (60)

Control: 20 (66.7)

P=0.41

DL control (stable/worse/better):

Intervention: 23/1/1 (92/4/4)

Control: 23/4/3 (76.7/13.3/10)

P=0.31

SBP (mmHg):

Intervention: 133.2 ± 12.8 (105-160)
Control: 142.9 ± 16.7 (110-170)

P=0.02

DBP (mmHg):

Intervention: 77.1 ± 8.9 (60-90)

Control: 78 ± 10.7 (60-100)

P=0.74

Patients with HT:

Intervention: 14 (56)

Control: 22 (73)

P=0.14

HT grade:

Intervention: 0.6 ± 0.5 (0-2)

Control: 1.1 ± 0.8 (0-2)

P=0.02

BP control (stable/worse/better):

Intervention: 7/1/17 (28/4/68)

Control: 18/8/4 (60/26.7/13.4)

P=0.001

Patients with DM:

Intervention: 5 (20)

Control: 6 (20)

P=1.00

Patients with IGT/IFG:

Intervention: 5 (20)

Control: 10 (33.3)

P=0.37

DM grade:

Intervention: 0.8 ± 1.2 (0-3)

Control: 1.1 ± 1.2 (0-4)

P=0.34

GL control (stable/worse/better):

Intervention: 16/2/7 (64/8/28)

Control: 23/6/1 (76.7/20/3.3)

P=0.03

Association blood pressure control improvement with surgical or conservative approach:

- Surgical approach (yes):

OR 3.0 [95% CI 3.8 to 108.3]

P<0.001

- Hypertension (yes/no):

OR 1.2 [95% CI 0.20 to 6.21]

P=0.90

- Diabetes (yes/no):

OR 2.34 [95% CI 0.33 to 16.52]

P=0.40

Study

First author, year

Appropriate and clearly focused question?¹

Yes/no/unclear

Comprehensive and systematic literature search?²

Yes/no/unclear

Description of included and excluded studies?³

Yes/no/unclear

Description of relevant characteristics of included studies?⁴

Yes/no/unclear

Appropriate adjustment for potential confounders in observational studies?⁵

Yes/no/unclear/notapplicable

Assessment of scientific quality of included studies?⁶

Yes/no/unclear

Enough similarities between studies to make combining them reasonable?⁷

Yes/no/unclear

Potential risk of publication bias taken into account?⁸

Yes/no/unclear

Potential conflicts of interest reported?⁹

Yes/no/unclear

Khan, 2019

Yes

Reason: Inclusion criteria and research question are predefined. PICO and research question only match for part of the studies in the SR.

Yes

Reason: Search period and strategy are described, multiple databases, including Medline, were searched.

No

Reason: Excluded studies are not referenced.

Yes

Reason: Study characteristics of included studies are described.

No

Reason: No multivariate analysis performed.

Yes

Reason: NIH quality assessment tool for observational cohort and cross-sectional studies was used.

No

Reason: Clinical heterogeneity exists between studies. Studies are not pooled.

No

Reason: Publication bias was not assessed.

No

Reason: Sources of support (nil) were reported for the SR but not for every individual study.

Bancos, 2016

Yes

Reason: Inclusion criteria and research question are predefined. PICO and research question only match for part of the studies in the SR.

Yes

Reason: Search period and strategy are described, multiple databases, including Medline, were searched.

No

Reason: Excluded studies are not referenced.

Yes

Reason: Study characteristics of included studies are described. 

No

Reason: No multivariate analysis performed. 

Yes

Reason: Newcastle-Ottawa tool was used to assess the quality of included observational studies. 

Yes

Reason: Low statistical heterogeneity for pooled data. 

No

Reason: Publication bias was not assessed.

No

Reason: Sources of support were reported for the SR but not for every individual study.

Study reference

(first author, publication year)

Was the allocation sequence adequately generated?

Definitely yes

Probably yes

Probably no

Definitely no

Was the allocation adequately concealed?

Definitely yes

Probably yes

Probably no

Definitely no

Blinding: Was knowledge of the allocated

interventions adequately prevented?

Were patients blinded?

Were healthcare providers blinded?

Were data collectors blinded?

Were outcome assessors blinded?

Were data analysts blinded?

Definitely yes

Probably yes

Probably no

Definitely no

Was loss to follow-up (missing outcome data) infrequent?

Definitely yes

Probably yes

Probably no

Definitely no

Are reports of the study free of selective outcome reporting?

Definitely yes

Probably yes

Probably no

Definitely no

Was the study apparently free of other problems that could put it at a risk of bias?

Definitely yes

Probably yes

Probably no

Definitely no

Overall risk of bias

If applicable/necessary, per outcome measure

LOW

Some concerns

HIGH

Morelli, 2022

Definitely yes

Reason: Block randomization was used.

No information

Reason: Not reported.

No information

Reason: Not reported.

Definitely no

Reason: Loss-to-follow-up in intervention group was 19.4% and in control group was 3.2%.

Probably yes

Reason: All outcomes in the methods section are reported in the results. 

Probably no

Reason: Treatments in control group were not standardized, study bias might exist.

HIGH

Due to lack of information about allocation concealment and blinding, high loss-to-follow-up, and other bias that might exist.

Reference

Reason for exclusion

Thompson LH, Ranstam J, Almquist M, Nordenström E, Bergenfelz A. Impact of Adrenalectomy on Morbidity in Patients with Non-Functioning Adrenal Cortical Tumours, Mild Hypercortisolism and Cushing's Syndrome as Assessed by National and Quality Registries. World J Surg. 2021 Oct;45(10):3099-3107. doi: 10.1007/s00268-021-06214-0. Epub 2021 Jun 27. PMID: 34180008; PMCID: PMC8408086.

Does not match with PICO: no comparison with no surgery or follow-up

Sheikh-Ahmad M, Dickstein G, Matter I, Shechner C, Bejar J, Reut M, Sroka G, Laniado M, Saiegh L. Unilateral Adrenalectomy for Primary Bilateral Macronodular Adrenal Hyperplasia: Analysis of 71 Cases. Exp Clin Endocrinol Diabetes. 2020 Dec;128(12):827-834. doi: 10.1055/a-0998-7884. Epub 2019 Oct 21. PMID: 31634962.

Does not match with PICO: SR on unilateral adrenalectomy for primary bilateral macronodular adrenal hyperplasia

Morelli V, Arosio M, Chiodini I. Cardiovascular mortality in patients with subclinical Cushing. Ann Endocrinol (Paris). 2018 Jun;79(3):149-152. doi: 10.1016/j.ando.2018.03.005. Epub 2018 Mar 30. PMID: 29606280.

Wrong publication type: communication

Loh HH, Yee A, Loh HS, Sukor N, Kamaruddin NA. The natural progression and outcomes of adrenal incidentaloma: a systematic review and meta-analysis. Minerva Endocrinol. 2017 Mar;42(1):77-87. doi: 10.23736/S0391-1977.16.02394-4. Epub 2015 Dec 23. PMID: 26698544.

Does not match with PICO: no comparison with surgery

Thomas AZ, Blute ML Sr, Seitz C, Habra MA, Karam JA. Management of the Incidental Adrenal Mass. Eur Urol Focus. 2016 Feb;1(3):223-230. doi: 10.1016/j.euf.2015.12.006. Epub 2016 Feb 3. PMID: 28723391.

Wrong publication type: communication

Guerin C, Taieb D, Treglia G, Brue T, Lacroix A, Sebag F, Castinetti F. Bilateral adrenalectomy in the 21st century: when to use it for hypercortisolism? Endocr Relat Cancer. 2016 Feb;23(2):R131-42. doi: 10.1530/ERC-15-0541. PMID: 26739832.

Does not match with PICO: no comparison of surgery with follow-up

Fassnacht M, Arlt W, Bancos I, Dralle H, Newell-Price J, Sahdev A, Tabarin A, Terzolo M, Tsagarakis S, Dekkers OM. Management of adrenal incidentalomas: European Society of Endocrinology Clinical Practice Guideline in collaboration with the European Network for the Study of Adrenal Tumors. Eur J Endocrinol. 2016 Aug;175(2):G1-G34. doi: 10.1530/EJE-16-0467. PMID: 27390021.

Wrong publication type: guideline

Iacobone M, Citton M, Scarpa M, Viel G, Boscaro M, Nitti D. Systematic review of surgical treatment of subclinical Cushing's syndrome. Br J Surg. 2015 Mar;102(4):318-30. doi: 10.1002/bjs.9742. Epub 2015 Feb 2. PMID: 25640696.

Does not add studies to Bancos (2016)

Shen J, Sun M, Zhou B, Yan J. Nonconformity in the clinical practice guidelines for subclinical Cushing's syndrome: which guidelines are trustworthy? Eur J Endocrinol. 2014 Oct;171(4):421-31. doi: 10.1530/EJE-14-0345. Epub 2014 Jul 1. PMID: 24986532.

Wrong publication type: overview of guidelines

Di Dalmazi G, Berr CM, Fassnacht M, Beuschlein F, Reincke M. Adrenal function after adrenalectomy for subclinical hypercortisolism and Cushing's syndrome: a systematic review of the literature. J Clin Endocrinol Metab. 2014 Aug;99(8):2637-45. doi: 10.1210/jc.2014-1401. Epub 2014 May 30. PMID: 24878052.

Does not match with PICO: no comparison of surgery with follow-up

Ritzel K, Beuschlein F, Mickisch A, Osswald A, Schneider HJ, Schopohl J, Reincke M. Clinical review: Outcome of bilateral adrenalectomy in Cushing's syndrome: a systematic review. J Clin Endocrinol Metab. 2013 Oct;98(10):3939-48. doi: 10.1210/jc.2013-1470. Epub 2013 Aug 16. PMID: 23956347.

Does not match with PICO: SR on outcomes of bilateral adrenalectomy in Cushing’s Syndrome

Perysinakis I, Marakaki C, Avlonitis S, Katseli A, Vassilatou E, Papanastasiou L, Piaditis G, Zografos GN. Laparoscopic adrenalectomy in patients with subclinical Cushing syndrome. Surg Endosc. 2013 Jun;27(6):2145-8. doi: 10.1007/s00464-012-2730-5. Epub 2013 Jan 26. PMID: 23355146.

Does not match with PICO: no comparison with no surgery or follow-up

Chiodini I. Clinical review: Diagnosis and treatment of subclinical hypercortisolism. J Clin Endocrinol Metab. 2011 May;96(5):1223-36. doi: 10.1210/jc.2010-2722. Epub 2011 Mar 2. PMID: 21367932.

Wrong publication type: narrative review

Toniato A, Merante-Boschin I, Opocher G, Pelizzo MR, Schiavi F, Ballotta E. Surgical versus conservative management for subclinical Cushing syndrome in adrenal incidentalomas: a prospective randomized study. Ann Surg. 2009 Mar;249(3):388-91. doi: 10.1097/SLA.0b013e31819a47d2. PMID: 19247023.

Included in the review of Khan (2019)

Tabarin A, Bardet S, Bertherat J, Dupas B, Chabre O, Hamoir E, Laurent F, Tenenbaum F, Cazalda M, Lefebvre H, Valli N, Rohmer V; French Society of Endocrinology Consensus. Exploration and management of adrenal incidentalomas. French Society of Endocrinology Consensus. Ann Endocrinol (Paris). 2008 Dec;69(6):487-500. doi: 10.1016/j.ando.2008.09.003. Epub 2008 Nov 20. PMID: 19022420.

Wrong publication type: consensus document, review