1. Approach to Adrenal Incidentalomas
Moayad Assiri
Urology R4
KAUH

2. Definition.
Prevalence.
Causes led to it discovery.
DDx.
Diagnostic approach
-Hormonally.
-Imaging.
-? FNA.
Management approach.
F\U.
Summary.
References.

3. (Clinically inapparent adrenal masses).
Definition
(Clinically inapparent adrenal masses).
adrenal tumor not suspected prior to radiological studies led to it discovery.
A disease of modern technology.
J Endocrinal Metab Clin North Am 1997
Except:
-Pt w known non adrenal malignant tumor.
-pt known HTN.

4. Incidence of adrenal masses is 9 - 12% in autopsies.
Incidence of AI is 2- 5 %.
>
Rt > lt .
Bil 2 – 10 %.
NATIONAL INSTITUTES OF HEALTH Management of the Clinically Inapparent Adrenal Mass (Incidentaloma).
Final Statement. July 16, 2002

5. Adrenal Incidentalomas Study - Chi Mei Medical Center
1998 Jan – 2002 Dec
Abdominal CT scan 70,101 in 5 years
127 cases of AI in 256 cases of adrenal tumors
Incidence of AI: 0.18%
Hormonally active: 4%

6. Mayo clinic
61,054 CT scans performed .
Adrenal mass in 2066 pts ( 3.4%).
16.5% were present incidental ( <1 cm ).
Overall, AI 259 pts ( 0.4% )
50% metastatic ca.
25% other known lesions.
7.5% symptomatic tumors.

7. Abecassis et al, Toronto, Canada
Prevalence of Adrenal Incidentalomas on CT Imaging
Study
Year
Number of Scans
Number with Mass
Frequency (%)
Abecassis et al, Toronto, Canada
1985
1,459 19
1.3
Belldegrun et al,
Boston, MA
1986
12,000 88
0.7
Caplan et al,
LaCrosse, WI
1994
1,779 33
1.9
Glazer et al,
St. Louis, MO
1982
2,200 16
Herrera et al,
Rochester, MN
1991
61,054
259
0.4
Prinz et al,
Chicago,IL
1,423 4
0.3
TOTAL(average)
79,915
419
(0.9)
Cheng & Shen
2003
70101
127
0.18

8. Causes led to discover IA
342 cases, men and 206 women
Reasons for CT scan: nonspecific abdominal pain, % known abdominal or thoracic disease, renal problems, musculoskeletal pain
Acta Endocrine (copenh)1989

9. Age-dependent occurrence of adrenal adenomas
Increases with Age
1% in age < 30 y.
3 -7 % in age > 50 y.
Compensatory growth in response to local ischemic damage of arteriosclerotic disease
Higher number of diagnostic procedures performed in aged patients
N Engl J Med, 1990

10. Age-dependent occurrence of adrenal cortical adenomas autopsy studies with total of 57,262 subjects
Endocrine and Metabolism Clinics of North America
2000; 29(1):

11. Clinical characteristics
Per definition ,NO clinical symptoms or signs of adrenal disease should be present at the time of Dx.
More detailed Q and careful PE might reveal evidence of subtle hormonal excess;
-recent w.t gain
-skin atrophy.
-episodic of headaches.

12. Àdrenal incidentaloma
Majority are neither function nor malignant
70-90%.
The malignant tumors may and may not secrete hormonal.
The 3 mains hormone-producing tumors:
Cortisone producing adenoma SCCS 11%.
Pheochromocytoma 7%.
Aldoestrone producing adenoma 2%.

13. ________________________________________
PREVALENCE OF ADRENAL INCIDENTALOMAS
IN DIFFERENT SERIES
_______________________________
Type of Tumor Mantero et al Al-SIE Othorst
_______________________________________________
Nonhypersecretory tumors
Hypersecretory tumors
Cortisol-secreting adenomas
Aldosteronomas
Pheochromocytomas
Adrenal carcinomas
Myelolipomas
Cysts
Ganglioneuromas
Metastases
Unselected patients
Oncological patients
________________________________________
AI-SIE: Adrenal Incidentaloma Study Group of the Italian Society of Endocrinology
Prevalence (%)
Endocrine and Metabolism Clinics
of North America 2000; 29(1):

14. Adrenal cancer Benign Adenoma 50% Cyst 10% Myelolipoma 10%
Pheochromocytoma %
Metastases %
Adrenal Cancer %
The incidental adrenal mass. Am J Med 1996

15. Differential Diagnosis of Adreanl Incidentalomas
Benign nonfunctioning
Adenoma
Adrenolipoma
Amyloidosis
Cyst / Pseudocyst Ganglioneuroma Granuloma
Infection
Hamartoma Hemangioma Leiomyoma
Lipoma Myelolipoma
Malignant nonfunctioning
Angiosarcoma Ganglioneuroblastoma Leiomyosarcoma Malignant schwannoma Metastatic carcinoma Malignant melanoma
Malignant lymphoma
Adrenocortical carcinoma
Endocrine and Metabolism Clinics
of North America 2000; 29(1):

16. - Mistaken vasculature - Liver - Lymph nodes - Pancreatic mass
Differential Diagnosis of Adreanl Incidentalomas
Pseudoadrenal mass
- Mistaken vasculature Liver
- Lymph nodes
- Pancreatic mass
- Spleen
- Renal mass
- Stomach mass
- Technical artifact
Hyperfunctioning mass
- Pheochromocytoma
- Preclinical Cushing’s
syndrome
- Primary aldosteronism
- Nodular hyperplasia
- Congenital adrenal
hyperplasia
- Masculinizing or
feminizing tumor
- Primary malignancy
(Adrenocortical
carcinoma)
Endocrine and Metabolism Clinics
of North America 2000; 29(1):

17. After incidental discovery of an adrenal mass, 2 questions should be addressed
Functional status
hormonally active even in the absence of
a classic clinical presentation
Malignant potential
any chance that the mass is malignant

18. Important consideration
Trying not to miss important pathology.
Trying no to subject the pt to unnecessary procedure or surgery.
Cost effect.

19. 1-Endocrinology investigation significant endocrine activity increase with increase tumor size

20. Subclinical Cushing’s Syndrome
Most frequent hormonal abnormality (5 – 20%)
Autonomous cortisol secretion without stigmata of Cushing’s syndrome
Diagnostic criteria not yet clearly defined
10-20 mg/day
Controlled Primarily By ACTH
Negative and Positive Feedback Between Cortisol and ACTH at Pituitary and Hypothalamic Levels

21. Dx Increased Urinary Free Cortisol (UFC)
Unsuppressed Serum Cortisol Levels After 1-mg Overnight Dexamethasone
Low ACTH Levels
No Clinical Signs Of Cushing Syndrome
Mantero F, Masini AM, Opocher G, Giovagnetti M, Arnaldi G. Horm Res 47:284–289, 1997

22. Dexamethasone Suppression Test
Low-dose: 1mg dexamethasone at 2300, followed by assay of cortisol at 0800 the following day
Cortisol > 3 mcg/dl suggests autonomous secretion
High-dose: 8 mg dexamethasone at 2300 with assay of cortisol at 0800 the next day
Cortisol > 1 mcg/dl indicates autonomous secretion
Reduces false positives
“Intermediate-dose”: 2 – 3 mg dexamethasone at 2300, followed by cortisol at 0800
Cortisol > 3 mcg/dl reportedly suggestive of autonomy
Easier to perform overnight suppression rather than 2-day oral load

23. Association with Metabolic Syndrome?
May contribute to, and worsen, hypertension, obesity , diabetes, dyslipidemia and osteoporosis
1990’s Italian multiinstitutional study collection 1004 patients with adrenal incidentaloma
41% prevalence HTN
10% prevalence DM
28% prevalence obesity

24. Pheochromocytoma Approximately 5-7 % of adrenal incidentalomas.
0.5% among screened hypertensive pt’s
Can be clinically silent and not suggested by history
Mixed recommendations on diagnostic testing

25. Dx
24-h Urinary fractionated catecholamine excretion or free metanephrines.
24 hour urine fractionated metanephrines recommended by some as first diagnostic test
Especially in incidentalomas without radiographic features suggestive of pheochromocytoma
Sensitivity and specificity between 91 – 98%
Increased even further when fractionated catecholamines added

26. Plasma Free Metanephrines
Used when imaging characteristics and other pre-test probability of pheochromocytoma are high, but 24 hr urine normal
Due to high sensitivity (97 – 100%) but low specificity (85 – 89%, ) of test
Negative result quite effective at ruling out

27. Which Is Better?
Catecholamine-Secreting Tumors Histologically Proven In 31 of 340 Patients:
Sensitivity Of Plasma Free Metanephrine 97% Specificity 98%
Sensitivity Of Urinary Total Metanephrine And Catecholamines 90%; Specificity 85%
Sawka et al. JCEM 88(2):

28. Aldosteronism (Conns Sx)
Quite rare cause <1%
Most have already been diagnosed before become large enough to be detected by CT/MRI
Should be evaluated in all hypertensive patients with incidentaloma
Serum potassium not sufficient, but should be included
Common to have normokalemia with aldosterone producting adrenal tumor 7 – 38%.

29. Signs and Symptoms in Primary Hyperaldosteronism
Hypertension
Headache
Weakness And/Or Fatigue
Paresthesias
Muscle Cramps
Polyuria, Polydipsia, Nocturia
Arrhythmias

30. Aldosterone Production
ug/day
Stimulated by the Renin-Angiotensin System  Decreased Perfusion Pressure
Hyperkalemia Stimulates and Hypokalemia Inhibits Aldosterone Secretion
ACTH Acutely May Stimulate Aldosterone Secretion

31. Dx
Plasma aldosterone/plasma renin activity ratio greater than 30 highly suggestive
Especially with plasma aldosterone >15 ng/dl
Confirm with aldosterone suppression test
IV 0.9 NS infusion – 2L over 2 hrs, with supine aldosterone >10 suggestive
Can also do 24 hour urinary aldosterone while patient orally ingests 5000 mg sodium/day x 3 days
Urinary aldosterone >14 mcg/24º
ACE’s and ARB’s can also falsely elevated PRA and should typically be avoided during testing

32. Appropriate screening tests should be performed if the patient has clinical features that are suggestive of increased adrenal function
Diagnosis
Suggestive Clinical Features
Laboratory Tests
Pheochromocytoma
Hypertension, Paroxysmal Symptoms (eg, palpitation, diaphoresis, headache, pallor, tremor)
24-hr urine:
fractionated metanephrines fractionated catecholamines
Blood:
fractionated metanephrines
SC Cushing's syndrome (SCCS)
Central obesity, proximal muscle weakness, thin skin, supraclavicular fat pad, facial plethora
For patients lacking symptoms of CS:
1-mg overnight dexamethasone suppression test

33. Diagnosis
Suggestive Clinical Features
Laboratory Tests
Primary aldosteronism
Hypertension, hypokalemia
Plasma aldosterone concentration
Plasma renin activity
Adrenocortical carcinoma
Mass effect symptoms, symptoms related to excess glucocorticoid, mineralocorticoid, androgen, or estrogen secretion
Serum dehydroepiandrosterone sulfate
Measures of clinically indicated steroid

35. Stepwise diagnostic approach
Step I :
1- 24-h Urinary catecholamine excretion or free metanephrines.
2- Serum cortisol after dexamethasone suppression 1mg at 11 pm PO.
3-HTN , Serum K and – PAC\PRA ratio.

36. Stepwise diagnostic approach
Step II : confirmatory test.
1- MRI . CT scan or 123-I-MIBG scintigraphy or 131 I-MIBG.
2- high-dose dexamethasone 8mg suppression test. If +ve
.CRH test analysis of diurnal cortisol secretion
, and 24-h urine free cortisol.
3- confirm with aldosterone suppression test.
And 24-h urine aldosterone .

37. Stepwise diagnostic approach
Step III. Revaluation
-repeat screening tests after 2 years in patient with a tumor size of > 3 cm.

38. 2- Imaging

39. Imaging Characteristics
Hounsfield Units for Relative Densities of Various Substances
Substance Hounsfield units(H)
-1,000
Air
-50
Fat
Water
+40
Soft tissue (i.e., muscle)
+100 to +400
Calculus
+ 1,000
Bone
Hounsfield units = units of x-ray attenuation used in CT. each pixel is assigned a value on a scale from ,000 to +1,000.
CT Scan
Hounsfield Scale
Measures xray attenuation
Each number represents a shade of grey, with air and bone
Water as zero
Air = -1000
Bone = +1000

40. CT scan Attenuation On CT Scan Is Measured In Hounsfield Units (HU)
Lipid-Rich Masses Are Usually Benign
Lipid-Rich Lesions Have Low Attenuation
Low Attenuation Lesions Have Low HU Values

41. Computed Tomographic Scans
Unenhanced CT:
Adenomas: < 10 HU
Malignancies: > 18 HU
Sensitivity: 73% Specificity: 96%
Delayed Enhanced CT:
Adenomas: < 30 HU
Malignancies: > 30 HU
Sensitivity 95% And Specificity: 100%

42. Adrenocortical carcinoma
Size large, typically > 4 cm
Shape irregular with unclear margins
Texture inhomogenous with mixed densities
compared with liver
Laterality usually solitary and unilateral
CT > 10 HU without contrast and >30-40 HU 30 min
after contrast administration
MRI hyperintense to liver on T2-weighted image
Presence of necrosis, hemorrhage, or calcifications-- common
Growth usually rapid

43. Adrenal cancer CT
Contrast-enhanced CT scan through the abdomen of a 56-year-old man reveals a complex solid and cystic, calcified mass (arrow) in the right suprarenal fossa extending into the adjacent liver. The tumor proved at surgery to be a carcinoma of the adrenal cortex. .

44. Malignant Potential
Imaging phenotype and mass size are two major predictors of malignancy
Additional test that may be preformed to predict malignancy include image-guided needle biopsy and iodocholesterol scintigraphy
Hormonal evaluation is not predictive of malignancy
Approximately 41% of 1,891 published cases of adrenocortical carcinoma, was not hormone-secreting

45. size
The probability that an AI is ACC is increases with increasing size of the lesion.
90% of all ACC is > 6 cm in size.
The prevalence of ACC related to size of tumor
2% in tumors < 4 cm.
6% in tumors 4-6 cm.
25% in tumor > 6 cm.
Resection all tumor > 4 cm
- 8 benign tumors removed for each cancer resected.

46. Imaging Phenotypes of Adrenal Incidentalomas Adrenal cortical adenomas
Size small, typically < 3 cm
Shape round to oval with smooth margins
Texture homogenous and low density compared with liver
Laterality usually solitary and unilateral
CT < 10 HU without contrast and <37 HU 30 min after
contrast administration
MRI isointense to liver on T2-weighted image
Presence of necrosis, hemorrhage, or calcifications-- rare
Growth usually stable size over time or very slow growth

47. Adrenal adenoma hypodense
Abdominal CT showing a 1.5-cm round hypodense left adrenal cortical adenoma (arrow).

48. Pheochromocytoma Size large, typically > 3 cm
Shape round to oval with smooth margins
Texture inhomogenous with cystic texture
Laterality usually solitary and unilateral
CT >10 HU without contrast and >40 HU 30 min after contrast administration, usually vascular, marked enhancement
MRI marked hyperintense compared with liver on T2-weighted image
Presence of necrosis, hemorrhage, or calcifications-- hemorrhage and cystic necrotic areas common
Growth very slow

49. Pheochromocytoma silent
Abdominal CT showing an 8-cm left adrenal mass (arrow) discovered incidentally. Note the vascular and inhomogenous imaging characteristics of this mass. Biochemical evaluation was consistent with a clinically silent pheochromocytoma, which was confirmed at surgery..

50. MRI of the abdomen shows a 4
MRI of the abdomen shows a 4.5-cm right adrenal pheochromocytoma (arrows). Upper panel: T1-weighted image. Lower panel: T2-weighted image shows increased signal intensity typical of a pheochromocytoma.

51. Metastasis Size variable, frequently < 3 cm
Shape round to irregular with unclear margins
Texture inhomogenous
Laterality often bilateral
CT > 10 HU without contrast and >40 HU 30 min after contrast administration, usually vascular, enhancement on tumor rim
MRI hyperintense compared with liver on T2-weighted image
Presence of necrosis, hemorrhage, or calcifications-- hemorrhage and cystic necrotic areas common
Growth usually slow

52. Imaging Characteristics
Adenoma
Adrenocortical
Carcinoma
Pheochromocytoma
Metastasis
Size
< 3 cm diameter
>4 cm diameter
>3 cm diameter
Usually <3 cm
Shape
Round, smooth
Margins
Irregular, no clear margins
Round/oval, clear margins
Oval/irregular, unclear margins
Texture
Homogenous
Heterogenous, mixed densities
Heterogenous, cystic
Lateralize
Solitary, unilateral
Solitary, unilateraly
Bilateral
CT Attenuation
<10 HU
>25 HU
CT Washout at 10 minutes
>50%
<50%
T2 MRI Appearance (compare to liver) = +
+++
Necrosis, Ca, hemorrhage
Rare
Common
Occasional
Growth rate
Slow
Rapid
Variable

53. Nuclear Imaging Radionuclide Scintigraphy
PET – most useful in patients with oncologic history and incidentaloma
100% sensitive determining both metastasis and benign adenomas based on adrenalectomy studies

55. MIBG – used to confirm suspicion of pheochromocytoma, little utility in eval of incidentalomas in general

56. NP-59 – radiolabeled cholesterol derivative, preferentially taken up by adrenal adenomas
Unilateral uptake suggests functional adenomas, and may be useful in screening for subclinical cushing’s syndrome

57. 3- Fine-needle aspiration biopsy
(FNA) cannot distinguish a benign adrenal mass from the rare adrenal carcinoma.
It can distinguish between an adrenal tumor and a metastatic tumor.
FNA may be indicated :
when there is a suspicion of cancer outside the adrenal gland,
or in the patient undergoing a staging evaluation for a known cancer.
? Infection.
NATIONAL INSTITUTES OF HEALTH Management of the Clinically Inapparent Adrenal Mass (Incidentaloma).
Final Statement. July 16, 2002

58. FNA is not useful in the routine evaluation.
Tumors that most commonly metastasize to adrenals are carcinomas of lung, breast, kidney and gastrointestinal tract, melanoma or lymphoma
FNA is not free of S.E .
FNA is not useful in the routine evaluation.
Pheochromocytoma should always be excluded before attempting FNA biopsy of an adrenal mass
NATIONAL INSTITUTES OF HEALTH Management of the Clinically Inapparent Adrenal Mass (Incidentaloma).
Final Statement. July 16, 2002

60. Bilateral masses
Analyses from two large adrenal incidentaloma studies with 887 and 202 patients showed that bilateral masses were found in 10 to 15 percent of cases.
Bilateral adrenal masses can be seen with
metastatic disease,
congenital adrenal hyperplasia,
cortical adenomas, lymphoma,
infection (eg, tuberculosis, fungal),
hemorrhage,
ACTH-dependent Cushing's,
pheochromocytoma,
amyloidosis,
infiltrative disease of the adrenal glands, and
ACTH-independent bilateral macronodular adrenal hyperplasia

61. Adrenalectomy? Individualized approach
The decision to operate on pt should be based on :
Suspicious of the presence of malignancy.
Evidence of function of the tumor.
Pt age .
Pt preference .

62. Adrenalectomy? Recommended for: all patients with mass size > 6 cm,
pheochromocytoma,
aldosteronism,
and Cushing’s syndrome
Aldosteronism and CS can be treated medically, but surgical approach favored
Medical
Spironolactone
Inhibits sodium-postassium exchange in the distal tubule, normalizes serum K and may lower blood pressure.

63. 4 – 6 cm masses
Either surgical approach or close follow-up considered reasonable
*Strongly consider adrenalectomy:
if imaging phenotype suspicious,
increase in size > 1 cm during f/u,
or development of hormonal hyperfunction during f/u.

64. No difference between open and laparoscopic approaches
Considered in SCS, especially in pt’s < 40 or 50 y/o, and those with disorders attributable to hypercortisolism
- Caution for postoperative adrenal insufficiency in SCS patients taken to adrenalectomy.
No difference between open and laparoscopic approaches
Complication rate of ~3%
Special consideration :
-Poor surgical patient – FU.
-Not possible or difficult FU – Sx.
Izaki H et al. Indications for laparoscopic adrenalectomy for non-functional adrenal tumor with hypertension: usefulness of adrenocortical scintigraphy. Int J Urol 2006:13(6):

65. 52 patients underwent adrenalectomy 5 patients had malignancy:
342 pts AI.
52 patients underwent adrenalectomy
5 patients had malignancy:
4 adrenocortical carcinomas and one metastasis
1.2% of 342 had cancer
No malignancy < 5 cm in diameter
287 of 342 had follow-up; 90% at one year
None had extension of tumor or hormonal excess
Herrera et al, Surgery

66. (1) Hormonal screening on patients with an AI > 1 cm,
Conclusions:
(1) Hormonal screening on patients with an AI > 1 cm,
(2) any patient with a hyper-secretory state should undergo adrenalectomy,
(3) advise adrenalectomy on AIs > 4 cm and
(4) comparison CT scans at 3 month intervals for those choosing observation only of their AI < 4 cm
Herrera et al, Surgery

67. National survey on AI
Purpose: To evaluate AI based on imaging size alone
Strict exclusion criteria
1004 enrolled; 584 women and 420 men
All patients underwent CT scan or MRI
Montero, JCEM

68. 85% underwent hormonal evaluation Results:
9.2% had SCS, 1.6% had an aldosteronoma and 4.2% had pheochromocytomas
All these patients underwent adrenalectomy
A total of 380 patients underwent adrenalectomy.
Montero, JCEM

69. Table 4 Histological picture in relation with gender, age, and mass size (CT measurement). Mantero, JCEM

70. (1) An AI > 4 cm is 93% sensitive for detecting all malignancies
Conclusions:
(1) An AI > 4 cm is 93% sensitive for detecting all malignancies
and (2) Pain at presentation may be associated with a malignant outcome
Mantero, JCEM

71. The Mayo Clinic Study
432 Patients With Adrenal Incidentaloma Retrospectively Evaluated
Tumor Diameter Averaged 2.5 cm.
Most Malignant Tumors Measured > 5 cm.
Removing All Tumors > 4 cm Would Have Removed Eight Benign Tumors For Every Carcinoma
Incidentally discovered adrenal tumors: an institutional perspective. Herrera MF; Grant CS; van Heerden JA; Sheedy PF; Ilstrup DM. Surgery 1991 Dec;110(6):

72. Incidentaloma Follow-Up
No single approach is proof yet.
1st Follow up m with another FU at 12 m.
Repeat hormone screening after 12m.
Then annually y

73. IA Mass Risk of progression
Adrenal Hyperfunction:
Unlikely If Lesion < 3 cm
Cortisol Hypersecretion Most Likely Disorder
4% After 1 Year
9.5% Within 3 Years  None Thereafter
Mass Enlargement:
8% After 1 Year
18% After 5 Years
Most Enlargement Occurred Within 3 Years
Barzon et al J Clin Endocrinol Metab 1999

74. Summary Relatively common – prevalence ~ 2 – 5 %.
Increases with age, so expected to increase further in future.
1 in every million adrenal tumors are malignant
Up to 20% are hyperfunction.
All patients with incidentaloma need hormonal eval
-24º urinary metanephrines
-Midnight dexamethasone suppression test
-PAC\PRA ratio in pt’s with underlying HTN or hpokalemia.
No optimal radiologic test to distinguish between benign and malignant tumors

75. Summary FNA of little value.
Sx indicated for hyperfunction masses , size >6cm and possibility of malignancy .
Malignant tumors more likely to be > 4 cm
Nearly all masses <4 cm are benign
No consensus on follow-up

76. References
NATIONAL INSTITUTES OF HEALTH Management of the Clinically Inapparent Adrenal Mass
(Incidentaloma).Final Statement. July 16, 2002
Endocrine and Metabolism Clinics of North America 1997
Endocrine and Metabolism Clinics of North America 2000; 29(1):
AI-SIE: Adrenal Incidentaloma Study Group of the Italian Society of Endocrinology
Barzon et al J Clin Endocrinol Metab 1999
Acta Endocrine (copenh)1989
N Engl J Med, 1990

77. References
Endocrine and Metabolism Clinics of North America 2000; 29(1):
Mantero F, Masini AM, Opocher G, Giovagnetti M, Arnaldi G. Horm Res 47:284–289, 1997
Sawka et al. JCEM 88(2):
Izaki H et al. Indications for laparoscopic adrenalectomy for non-functional adrenal tumor with hypertension: usefulness of adrenocortical scintigraphy Int J Urol 2006:13(6):
Incidentally discovered adrenal tumors: an institutional perspective. Herrera MF; Grant CS; van Heerden JA; Sheedy PF; Ilstrup DM. Surgery 1991 Dec;110(6):