1. ADRENAL INCIDENTALOMA CORTEX DISORDERS ENDOCRINOLOGICAL ASPECTS
Dr. Mohan T Shenoy
DM trainee in Endocrinology
Amrita Institute of Medical Sciences, Kochi
NUCLEAR MEDICINE INTERDEPARTMENTAL – 27/8/2015

2. OUTLINE BACKGROUND CASE HISTORY ADRENAL INCIDENTALOMA – APPROACH
ADRENAL CORTEX DISORDERS
PHYSIOLOGICAL ASPECTS
BIOCHEMICAL ASSAYS / HORMONAL WORKUP
RADIOLOGICAL GADGETS TO DIAGNOSIS
SURGICAL ASPECTS AND MEDICAL TREATMENT

3. RESOURCES/ REFERENCES
Williams textbook of Endocrinology
Campbell textbook of Urology
American Journal of Radiology
Journal of Clinical Endocrinology and Metabolism
European Journal of Endocrinology
Best Practice & Research Clinical Endo & Metab

4. CASE HISTORY August 2015: 55y M working in Gulf referred to AIMS,Kochi
Evaluated outside for fever, cough, vague abdominal region pain ; detected to have raised blood pressur hypertension with uncontrolled sugars
Recently detected diabetes 6 months duration.
Found to have an adrenal mass in CT abdomen.

5. Evaluated at AIMS FBS 92.9 mg/dl Creat: 1.0 mg/dl Hba1c: 7.2 %
Corrected Ca- 8.8
ONDST: S. Cortisol: 2.4 ug/dl
DHEA-S : ug/dl ( )
Metanephrines-Urine: ug/24hrs (<350ug/24hrs)
Nor MN Urine: ug/24hrs (<600 ug/day).
Date
S. Na+
S. K+
28/814
130.5
3.4
28/8/14
132.7
3.0

6. Endocrine Causes of Hypertension
Acromegaly
Hyperparathyroidism
Thyrotoxicosis
Glucorticoid – suppressible hyperaldosteronism
Pheochromocytoma
Cushing's syndrome
Primary hyperaldosteronism (Conn's syndrome)
Congenital adrenal hyperplasia due to 11 Beta hydroxylase or 17 alpha hydroxylase deficiency

7. DD for Hypertension + Hypokalemia
Renovascular disease
Cushing’s syndrome
Primary aldosteronism
Renin secreting tumors

8. Cross Sectional Anatomy
Retroperitoneal organ – Normally : 3 cm × 6 mm
Gerota’s fascia : connect gland to upper pole of kidney

10. ADRENAL ZONES
Cortex derived from embryonic mesoderm, secreting steroid hormone
Medulla derived from neurectoderm, secreting catecholamines

11. NORMAL ADRENAL
ABNORMAL ADRENALS
ATROPHY
HYPERPLASIA

12. Adrenal incidentaloma - Introduction
“Serendipitously discovered adrenal mass lesion > 1 cm by radiologic examinations – CT/MRI in the absence of symptoms or clinical findings suggestive of adrenal disease”
Demonstration : Unilateral/ bilateral enlarged unusual shape (?bulky)
Recent study : report prevalence from high resolution scanner CT abdomen = 4.4%
Two relevant questions Is it malignancy ?
- Is it functioning ?

13. Adrenal disorders Cushing syndrome Hyperaldosteronism CAH
Pheochromocytoma
CAH
Adrenal tumours
Hypoaldosteronism
Pseudohypoaldosteronism
Adrenal insufficiency

14. ADRENAL INCIDENTALOMA
ADRENAL CORTEX
ADRENAL MEDULLA
Adenoma
Pheochromocytoma
Nodular hyperplasia
Ganglioneuroma
Ganglioneuroblastoma
Carcinoma
Hemorrhage
Metastasis
OTHER ADRENAL MASSES
Adrenal Cyst, Myelolipoma, Neurofibroma Hematoma, Hamartoma, Teratoma
Xanthomatosis, Amyloidosis
Granulomatosis (TB, Histo)
METASTASES
Breast, Lung, Colon
Lymphoma, Leukemia
PSEUDOADRENAL MASSES
Arising from KIDNEY, PANCREAS, SPLEEN, LYMPH NODES, SARCOMA, GREAT VESSELS
Technical artefacts

15. PHYSIOLOGY

16. BIOCHEMISTRY

17. BILATERAL ADRENAL MASSES
Studies : 887 and 202 cases (with adrenal incidentaloma)
- bilateral 10-15%
One adrenal mass : non-functioning cortical adenoma
Contralateral adrenal mass : hormone secreting
+++ All patients with bilateral adrenal masses should be screened for adrenocortical hyper/hypo function +++

18. HORMONAL ASSAYS AND CUTOFFS
S. ACTH: Electrochemiluminescence:
To be collected in chilled tube. Transport in ice
Refrigerated centrifugation. Store freezed. susceptible to degradation by peptidases
S. Cortisol: Chemiluminescence :
Plasma Renin Activity:
Plasma Aldosterone concentration:

20. Statistics (The Mayo clinic 1985 – 1990)
Radiology : 61,054 Abd CT : (3.4% = 2,066 cases)
2,066 cases
- 50% metastasis cancer
- 25% other known lesions
- 7.5% symptomatic tumors
% incidental (include nodules < 1cm)
Overall incidental adrenal tumor (> 1cm) = 0.4 %

21. STATISTICS FROM NIH Autopsy : 739 cases (adrenal masses 2 mm-4 cm)
85 percent of the masses were non-functioning.
9 percent secreted sufficient cortisol to produce subclinical Cushing's syndrome
4 percent were pheochromocytomas (<50% of which caused hypertension).
2 percent were aldosteronomas.

22. UNILATERAL ADRENAL MASS
FUNCTIONAL
NON- FUNCTIONAL
Adrenal adenoma
Adrenal carcinoma
Pheochromocytoma
Ganglioneuroma
Myelolipoma
Hyperplasia : “looks like” /”bulky”
Hemorrhage
Metastasis

23. BILATERAL ADRENAL MASS CAUSES
FUNCTIONAL
NON- FUNCTIONAL
ACTH-dependent Cushing’s
Infections : TB, fungus
cortical adenoma
- Conn’s : hyperplastic variety
infiltrative disease of adrenal gl (lymphoma
Micronodular adrenal disease
pheochromocytoma
Replacement: amyloidosis
Myelolipoma
ACTH-independent bilateral macronodular adrenal hyperplasia
Hemorrhage
congenital adrenal hyperplasia
Metastasis

25. CUSHING SYNDROME

26. CORTISOL
EXCESS SECRETION
NORMAL AXIS
LIDDLE’S SIGN

27. TYPES OF CUSHING’s

28. CLASSIFICATION ACTH dependent ACTH independent "Normal” or high ACTH
Normal ACTH pg/ml
Blood collected at ACTH Nadir – around midnight
Values correlate with tumour size when ACTH arise from pituitary
Source of ACTH may be extrapituitary
Low ACTH levels
Usually, adrenal origin of disease
Circadian rhythm lost
Paradoxical response may be seen

29. BIOCHEMICAL TESTS

30. Dexamethasone suppression test
Overnight- 1mg at 11 pm, 8 am cortisol<1.8mcg
LDDST – 0.5mg 6h 48 hours – 8 am <1.8
HDDST – 8, 16 and 32mg – for larger pituitary adenoma and differentiating Ectopic ACTH production – Bronchial carcinoids- cutoff 1.8mcg
8 mg Infusion - Cut off 1.8mcg

31. Varying degrees of sensitivity and specificity
In hyperfunction, high hormone levels -> Circadian fluctuation of hormones are lost ; Even am-pm reversal
Varying degrees of sensitivity and specificity
Vary from lab to lab, batch to batch of reagents
Hence, one method can not be totally relied upon
Usually combination of more than one method used

32. PSEUDO CUSHING STATES

33. URINE FREE CORTISOL
Measures cortisol that is not bound to CBG. Therefore, unlike serum cortisol, which measures both CBG-bound and free hormone, UFC is not affected by conditions and medications that alter CBG.
Useful in pregnant pts, Cyclical Cushing’s, pts on antiepileptics.
Because most of cortisol secreted during any 24-hour period is usually between 4 AM and 4 PM, subtle increases in night time cortisol secretion may not be detected in standard 24-hour urine free cortisol measurements.
It also requires an adequate urine collection that must be verified with a measurement of urinary creatinine.

34. Late-night salivary cortisol
Ask patient to collect a saliva sample on two separate evenings between 2300 and 2400h.
Saliva is collected either by passive drooling into a plastic tube or by placing a cotton pledget (salivette) in the mouth and chewing for 1–2 min.
Normal < 145ng/dl (4nmol/L)
Sensivity: % , specificity %
In US- ELISA/LC-MS/MS.

35. Other essential investigations
1. FBS , PPBS / GTT.
2. FLP
3. Ca Profile ( Fasting Ca, P, ALP,Albumin, Urine calcium creatinine ratio).
4. AST, ALT.
5. SE (Na, K, HCO3)
6. CXR PA
7. X-ray spine and hip/DEXA.
8. RFT.
9. ECG, Echo

36. ENDOGENOUS HYPERCORTISOLISM

37. Diagnostic approach Two measurements
At least two first line tests are done – Salivary, LDDST, urinary cortisol
Urine cortisol x 3 times
Diagnosis confirmed if two tests confirmed
When discordant, repeat the test
When results normal, Cushings unlikely

38. Central-peripheral gradient
LOCALISATION
CRH stimulation
1ug/kg single dose
Positive response
- 100% rise ACTH,
- 50% in S. cortisol over baseline
Central-peripheral gradient
inf petrosal : peripheral <1.4: 1 - ECTOPIC

41. Primary aldosteronism

42. Aldosterone secretion
Inducing factors
Inhibitors
Angiotensin II
Potassium
ACTH
Dopamine
ANP
Heparin
Aldosterone secretion occur only in zona glomerulosa as the enzyme aldosterone synthase is expressed
only in this region

43. Diagnostic and therapeutic approach to primary aldosteronism
Hoorn, E. J. et al. (2010) A case of primary aldosteronism revealed after renal transplantation
Nat. Rev. Nephrol. doi: /nrneph

44. PRA/PAC Time : 0800-1000 hrs Paired plasma aldosterone concentration
Correct hypokalemia if present
Avoid : (6 wks)
Spironolactone, eplerenone
Renin inhibitor
Amiloride

47. Pheochromocytoma 3-10% incidentalomas prove to be pheochromocytomas.
Screening for pheochromocytoma is mandatory in all cases because high rate morbidity and mortality.
It is symptomatic up to 15% of case.
Screening test is measurement of plasma free metanephrines or 24 hr urine metanephrine .
Plasma free metanephrines is 99% sensitive.
Not very specific 85-89%

48. - Is it malignancy ? - Is it functioning ?
Two questions
- Is it malignancy ? Is it functioning ?
IS IT FUNCTIONAL?
Hormonal hypersecretion most likely in mass at least 3 cm in diameter.
Occurs mostly within first 3 years after diagnosis.
6% - 20% of incidentalomas: hormonal abnormality.

49. RADIOLOGICAL ASSESSMENT

50. CT scan Abdomen Density (black is less dense)
Spectrum : Air -black, Bone-white
Hounfield scale is a semiquantitative method of measuring x-ray attenuation
Typical precontrast HU values
adipose tissue = -20 to – 150 HU
kidney = 20 to – 150 HU
If adrenal mass < 10 HU on unenhanced CT (ie, has density of fat) likelihood benign adenoma 100 %

51. DICTUMS on Size and Imaging phenotype
The National Italian Study Groups
- 4 cm cutoff
- sensitivity 93 %
- specificity 76 %
Imaging phenotype does not predict hormone function, it can predict underlying pathology, and surgical resection

52. Evaluate for malignancy
Primary adrenal carcinoma : quite rare
Others : - metastasis (particularly lung)
Evaluate : size and imaging characteristics (imaging phenotype)

53. Fine-needle aspiration biopsy
Cannot distinguish a benign adrenal mass from the rare adrenal carcinoma
Thus; FNA biopsy
- indicated a suspicion of cancer outside the adrenal gland
- staging evaluation for a known cancer
- not useful routine evaluation

54. Imaging phenotype MRI or CT Characteristics of the mass (benign tumor)
3-5 mm. cuts : predict histological type of adrenal tumor
Characteristics of the mass
example ; lipid-rich nature of cortical adenomas
(benign tumor)

55. Contrast-enhanced CT Adenoma : rapid contrast medium washout
Non-adenoma : delayed washout
10 mins after administration of contrast
Adenoma : absolute contrast media washout > 50 % ( 100% sensitivity & specificity)
if compared with carcinomas, metastasis or pheochromocytoma

56. Size The maximum diameter is predictive of malignancy
Important : if the smaller is at the time of diagnosis, the better overall prognosis
Adenocortical carcinomas
- significantly asso. with mass size
- 90% > 4 cm

57. CT scan in AMRITA (Adrenal Protocol)

58. MRI Although CT : primary adrenal imaging
MRI has advantages in certain clinical situations
Several MRI equipments
Conventional spin-echo MRI (Initial)
- T1 and T2 weighted
Distinguish benign adenomas from malignancy and pheochromocytoma

59. Gadolinium-DPTA-enhanced MRI
Adenoma : mild enhancement and rapid washout of contrast
Malignancy : rapid and marked enhancement and a slower washout pattern

61. Chemical shift imaging (CSI) MRI
Lipid sensitive imaging: Works on the principle that hydrogen protons in water, lipid molecules have alignment issues.
Chemical shift technique
1. In-phase : water & lipid are aligned : signal intensity high
2. Out of phase: opposite from each other: signal intensity low
Interpretation: Benign adrenal cortical adenoma : lose signal on out-of-phase images, but appear relatively bright on in-phase images

63. Imaging characteristics

64. Benign adenoma Benign cortical adenoma Round & homogenous density
< 4 cm, unilateral
Low unenhanced CT attenuate values (<10HU)
Isointensity with liver on both T-1 & T-2 (MRI)
Chemical shift : lipid on MRI
Rapid contrast washout (10 min)
Absolute contrast washout >50%

65. Adrenocortical carcinoma
Irregular shape; High unenhanced CT (>20HU)
> 4 cm, unilateral, calcified
Inhomogenous density (central necrosis) Evidence of local invasion or metas.
Hypointensity compared with liver T-1 and high to intermidiate intensity T-2 MRI
High standard uptake value (SUV) on FDG-PET-CT study
Delayed contrast washout (10 min)
Absolute contrast washout < 50 %

66. Metastasis Irregular, inhomogenous Bilateral
High enhanced CT (>20 HU)
Enhancement with contrast
Delayed contrast washout (10 min)
Absolute contrast washout < 50%
Isointensity or slightly less intense than liver T-1 , high to intermediate intensity T-2 MRI (represent water increase)

67. Others Adrenal cysts Adrenal hemorrhage Myelolipoma
Typical adrenal myelolipoma appears as an adrenal mass with fat-containing components. The mass is usually relatively well circumscribed

69. Pheochromocytoma Increase attenuate on nonenhanced CT (>20HU)
Increase mass vascularity
High signal intensity on T-2 MRI
Cystic and hemorrhage
Variable size
Delayed contrast washout (<10 min)
Absolute contrast washout <50 %

70. Pheochromocytoma

71. ALTERNATE IMAGING PET (Positron emission tomography)
- Fluoro-2-deoxy-D-glucose (FDG)
High sensitivity for detect malignancy
However : 16% benign cortical lesions may have FDG-PET uptake
- Metomidate (MTO) PET:
Lack of MTO – specific to non-adrenal cortical origin
(metastasis & pheochromocytoma

72. Management of adrenal incidentaloma

73. Therapeutic goals
IDENTIFY COMPENSATORY ENLARGEMENT a) Enzyme deficiency b) Excess renin c) Excess ACTH
IDENTIFY HORMONE SECRETING TUMORS
- Cortisol, Aldosterone, catecholamines, Androgens ,
IDENTIFY BENIGN and NON-FUNCTIONING LESIONS
- Tumors, Infection, hemorrhage
4 . IDENTIFY PRIMARY ADRENAL CANCERS
5. IDENTIFY CANCER METASTATIC TO ADRENAL TISSUE

74. GUIDELINES IN ADRENAL MASS
PET (Positron emission tomography)/FDG-PET and MTO-PET are not recommended (cost and insufficiency data to support their routine use)

75. 24 hr Urine Metanephrines DST/ UFC PAC/PRA
History & Examination
24 hr Urine Metanephrines
DST/ UFC
PAC/PRA
Imaging - CT
Nonfunctional
Benign
Size < 4 cm
Functional
Malignant
Size > 4 cm
Follow up
Surgery

79. SUMMARY Adrenal incidentalomas should not be ignored.
All patients should be evaluated for functional status and malignant potential .
History and physical examination are important in the initial assessment.

80. BIOCHEMISTRY TO PRECEDE RADIOLOGY
Pheochromocytoma should be excluded by measuring 24-hour urinary fractionated metanephrines and catecholamines.
Subclinical Cushing's syndrome should be ruled out by the 1-mg overnight dexamethasone.
Primary aldosteronism. should be screen in patient is hypertensive by a plasma aldosterone-to-plasma renin activity ratio and plasma potassium concentration

81. Benign cortical adenoma
A homogeneous adrenal mass <4 cm in diameter,
A smooth border,
Attenuation value <10 HU on unenhanced CT, rapid contrast medium washout (eg, >50 percent at 10 minutes)
Adrenal carcinoma or metastases
irregular shape.
inhomogeneous density.
high unenhanced CT attenuation values (>20 HU), delayed contrast medium washout (eg, <50 percent at 10 minutes),
diameter >4 cm, and tumor calcification.

82. Suggest surgery for patients with adrenal masses greater than 4 cm in diameter .
If there is evidence of metastasis and after excluding pheochromocytoma with biochemical testing, suggest performing a diagnostic CT-guided FNA biopsy .

83. Recommend surgery: pheochromocytoma, aldosteronoma.
Suggest surgery for patients with subclinical Cushing's syndrome who are younger and who have disorders potentially attributable to autonomous glucocorticoid secretion.

84. Subclinical Cushing’s syndrome, Best Practice & Research Clinical Endocrinology & Metabolism. 2012
In 5–20% of cases, adrenal incidentaloma are responsible for a subtle cortisol overproduction, commonly defined as “subclinical Cushing’s syndrome” (SCS).
The standard biochemical tests used to screen for overt Cushing’s syndrome are generally ill-suited.
Adrenalectomy or medical management of associated disease has been indicated as therapeutic options due to lack of data demonstrating the superiority of a surgical or non-surgical treatment.

85. Subclinical Cushing's syndrome and unilateral adrenalectomy?
lack of suppression to both an overnight DST) and a two-day high-dose DST.
absence of a prospective randomized study
candidates for unilateral adrenalectomy ??