The Incidental Adrenal Mass
Jay T Bishoff, MD, FACS Director, Intermountain Urological Institute
Clinical Professor Surgery University of Utah School of Medicine
Salt Lake City, Utah
Adrenal Gland
Focus --Test Questions • Anatomy
• Physiology
• Disease Processes
For each disease: Pathophysiology
Diagnosis
Management
• Surgical Treatment
Adrenal Gland
Focus --Test Questions • Anatomy
• Physiology
• Disease Processes
For each disease: Pathophysiology
Diagnosis
Management
• Surgical Treatment
Adrenal Gland
Outline Continued Diseases
• Incidental Adrenal Mass
• Pheochromocytoma
• Primary Hyperaldosteronism
• Cushing’s Syndrome
• Adrenal Insufficiency
• Carcinoma
Adrenal cortical carcinoma
Metastatic cancer
Adrenal Anatomy
Size Length 3 - 5 cm
Width 2.5 - 3 cm
Depth 0.4 - 0.6 cm
Weight 3 - 5 gm
Fetal Adrenal Cortex Involutes after birth,
Ratio of Adrenal to Kidney Weight is:
• Neonate 1:3
• Adult 1:30
Adrenal Anatomy
Location Retroperitoneal
Triangular
Fragile
Thin, Wispy
Own sub-compartment of Gerota’s fascia
At anterior / superior / medial aspect of kidney, separated by a fusion of Gerota’s fascia
Adrenal Anatomy
Arterial Supply • 7 cc/gram minute
• Superior –
Inferior phrenic artery
• Middle -- Aorta
• Inferior -- Renal artery
• Can Have Gonadal Branches
60% fetal dissection
• Usually not visualized 3%
must know origins
for hemostasis
Campbell’s 8th Edition, Chapter 1, John Kabalin, MD
Adrenal Anatomy
Arterial Supply • 7 cc/gram minute
• Superior –
Main Inferior phrenic artery
• Middle -- Aorta
• Inferior -- Renal artery
Campbell’s 8th Edition, Chapter 1, John Kabalin, MD
Adrenal Anatomy
Venous Drainage • Single Main Adrenal Vein
Most important surgical structure
• Right from IVC Gland is often under IVC
Always short
• Left from Renal Vein Variable length
• Left Significant Phrenic Branch
Adrenal Anatomy
Nerve Supply • Medulla - Sympathetic Branches
T/10 – L/1
Release of Medullary Hormones:
Epinephrine
Norepinephrine
• Cortex - No Known innervation
Adrenal Anatomy
Lymphatic Drainage • Lateral Aortic Nodes
Renal artery to diaphragm
• Adrenal Carcinoma
Extensive Dissection required for lymphadenectomy
Adrenal Physiology
Adrenal Cortex • Developed from Mesoderm
• Three zones “GFR”
• Secretes Steroids – Glomerulosa (outer)
Aldosterone
– Fasciculata (middle)
Cortisol
– Reticularis (inner)
Sex steroids
G
F
R
Medulla
Adrenal Physiology
Adrenal Cortex - Aldosterone • Activates Na-K Pump in Nephron:
Retention of Na (water follows Na)
Kidney – Intestine – Salivary gland
Depletion of potassium
• Stimulants of Aldosterone Secretion: Primary Angiotensin II
Secondary – ACTH
Decreased Serum Na
Elevated Serum K
Renin-Angiotensin-Aldosterone System
Angiotensinogen
Angiotensin I
Angiotensin II
Renin
(Kidney Juxtaglomerular)
Converting
Enzyme
(lung)
Vasoconstriction
Stimulation of Thirst
Secretion of ADH
Adrenal Gland
Aldosterone
Na K
Na K
Decreased
Circulating
Blood
Volume
(liver)
Adrenal Physiology
Adrenal Cortex - Glucocorticoids • Multitude of Metabolic Functions:
Salt retention
Skeletal and cardiac contractions
Protein catabolism
Inhibit bone formation
Inhibits collagen synthesis
Increases vascular contractility
Anti-inflammation
Anti-immune activity
Maintains normal GFR
Adrenal Physiology
Adrenal Cortex - Cortisol • Multitude of Metabolic Functions
• Corticotropin-Releasing Hormone (CRH) Released from hypothalamus
Stimulates pituitary corticotropin (ACTH) release
Stimulates adrenal cortisol release
• Normal ACTH and Cortisol = diurnal variation
High AM, Low PM
• Both ACTH and Cortisol inhibit CRH release by feedback
Adrenal Physiology
Testosterone and Estrogen • Regulatory Functions
• Sex Steroid Secretion by Adrenal Gland Stimulated by ACTH
Not gonadotropins
• Sex Steroid Secretion by Adrenal Gland
Minor physiologic importance,
Significant only in disease states
Adrenal Physiology
Adrenal Medulla • Distinct from Cortex Embryologically
Derived from neuroectoderm
• Stored in Secretory Cells • Secretes Cathecolamines Sympathetic
Stimulation • Preganglionic Neurons Trigger Release • Can be released with out sympathetic
stimulation Pheochormocytoma
Adrenal Physiology
Adrenal Medulla - Catecholamines
• Large Chromaffin Cells Precursors: Dietary Tyrosine and Phenylalanine
Site of Production: Adrenal, CNS, Adrenergic Nerve Terminals
Adrenal Physiology
Adrenal Medulla - Catecholamines
• Healthy Humans Circulating Catecholamines Norepinehprine 73%
Epinephrine 14%
Dopamine 13%
Adrenal Physiology
Adrenal Medulla - Catecholamines
• Healthy Humans Circulating Catecholamines Norepinehprine 73%
Epinephrine 14%
Dopamine 13%
• Phenylethanolamine-N-methyltransferase (PNMT)
From the Medulla
Methylation of Norepinephrine = Epinephrine
Adrenal Physiology
Adrenal Medulla - Catecholamines
• Healthy Humans Circulating Catecholamines Norepinehprine 73%
Epinephrine 14%
Dopamine 13%
• Phenylethanolamine-N-methyltransferase (PNMT)
From the Medulla
Methylation of Norepinephrine = Epinephrine
Excess Norepi and Epi source is -- Adrenal Pathology
Adrenal Physiology
Adrenal Medulla –
Epinephrine / Norepinephrine • Catecholamine Secretion Neural Meditated
• Half Life 20 seconds Metabolism: Catechol-O-methyltransferase
Monoamine oxidase
Products: Primary Urine vanillylmandelic acid (VMA)
Metanephrine
Normetanephrine
Incidentaloma
Definition • Mass > 1cm
• Discovered on examination for non-adrenal purpose
• Absence of signs or symptoms of adrenal disorder
Incidentaloma
Incidence • Autopsy Studies 87,065 patients 1,2
Overall frequency of adenomas 6% (Range 1-32%)
1 Endocr Met Cl North Am 2000:29:159-185
2 Endocr Rev 1995:16:460-484
3 J Endocrin Invest 2006:29:298-302
Incidentaloma
Incidence • New Physical Examination: Vitals, CT, Physical Exam
• Abdominal CT Incidence 4% 3
• Probability Increases with age
Age 20-29 = 0.2%
Age >70 = 7%
1 Endocr Met Cl North Am 2000:29:159-185
2 Endocr Rev 1995:16:460-484
3 J Endocrin Invest 2006:29:298-302
Incidentaloma
Incidence • New Physical Examination: Vitals, CT, Physical Exam
• Abdominal CT Incidence 4% 3
• Probability Increases with age
Age 20-29 = 0.2%
Age >70 = 7%
• 85% of these are non-functional and benign
• Huge cost of evaluation unless streamlined
• Balance of costs and benefits 1 Endocr Met Cl North Am 2000:29:159-185
2 Endocr Rev 1995:16:460-484
3 J Endocrin Invest 2006:29:298-302
Incidentaloma
Questions to be Asked • Is the Mass Functional?
Physical Signs or Symptoms
Biochemical Evidence
Pheo screen
Potassium Glucocorticoid Screen
• Is the Mass Malignant? History of another malignancy? Imaging suggestive of malignancy?
Incidentaloma
Nature of Mass N=2005
• Non-functioning Adenoma 82%
• Functioning Adenoma Cushing’s Syndrome 5%
Pheochromocytoma 5%
Aldosteronoma 1%
• Malignancy Adrenal Metastasis 3%
Adrenal Cortical Ca. 4%
Young WF, Endocrinol Clin N America 2000
Incidentaloma
Nature of Mass • Medical History and Size
Key Characteristics
• Adrenal Metastasis 6% - No history of cancer
50% - Positive history of cancer
• Adrenal Cortical Carcinoma 2% For all masses
65% For masses > 6 cm
Incidentaloma
• Other (Rarer) Possibilities • Myelolipoma / Lipoma
CT similar to that of renal angiomyelolipoma (fat)
• Adrenal Cyst / Hematoma Benign cysts can be followed
True cyst or pseudo-cyst
• Ganglioneuroma
• Neuroblastoma
Incidentaloma
Findings • No Overt Symptoms
• Endocrine Activity Cushing’s 5 %
Pheochromocytoma 2 %
Aldosteronoma < 1 %
• Presence of Known Primary Cancer, Adrenal mass is metastasis in 50% - 70 %
Incidentaloma
Sub-Clinical Cushing’s Syndrome • Total 24° Cortisol Production
Often normal
Subtle changes occur - loss of diurnal variation
• Prognosis Variable Normalization
Persistence
Progression to clinical Cushing’s
• Indication for adrenalectomy
May be subtle physical effects
NEJM, 356:6 2007
Incidentaloma
Sub-Clinical Cushing’s Syndrome • Autonomous cortisol secretion
• With out typical signs symptoms of hypercortisolism
• 5% - 20 % of Incidentalomas have SCCS
• Spectrum: Slight attenuation of diurnal cortisol rhythm
Complete atrophy of contralateral gland
Young, EF, Clin North Am, 2000;29:159-185
Ohashi A et al Jendocr J, 2001: 677-683
Young WF et al, J of Medicine, 2007:601-610
MitchellI et al, Surgery, 2007: 900-905
Reincke M, Endocrin Metab Clin North AM, 200, Mar:43-56
Incidentaloma
Sub-Clinical Cushing’s Syndrome
Clinical Manifestations recent or rapid onset:
HTN 80%
Obesity 50%
Diabetes mellitus 40%
Osteoporosis/Osteopenia 25%
Irregular Menses 20%
Young, EF, Clin North Am, 2000;29:159-185
Ohashi A et al Jendocr J, 2001: 677-683
Young WF et al, J of Medicine, 2007:601-610
MitchellI et al, Surgery, 2007: 900-905
NEJM, 356:6 2007
Incidentaloma
Sub-Clinical Cushing’s Syndrome • Best Test
1) 3 mg dexamethasone suppression
serum cortisol suppressed to less 3 mg/dl (80 nmol/L) excludes significant cortisol secretion
2) 8 mg dexamethasone suppression 68% not suppressed
2) Cortisol >5ug/dl
• Glucocorticoid autonomy 91% specific
Young, EF, Clin North Am, 2000;29:159-185
Ohashi A et al Jendocr J, 2001: 677-683
Young WF et al, J of Medicine, 2007:601-610
MitchellI et al, Surgery, 2007: 900-905
NEJM, 356:6 2007
Incidentaloma
Sub-Clinical Cushing’s Syndrome • Surgical Candidates:
• Symptoms: Obesity, HTN, DM, ostopenia
• < 50 yo
• Suppressed plasma ACTH
• Most will progress to overt Cushing's 1-5 years
Young, EF, Clin North Am, 2000;29:159-185
Ohashi A et al Jendocr J, 2001: 677-683
Young WF et al, J of Medicine, 2007:601-610
MitchellI et al, Surgery, 2007: 900-905
NEJM, 356:6 2007
Incidentaloma
Diagnosis • History and Physical Exam
Signs of Hormonal Syndromes
Search for Occult Malignancy
- CXR
- Stool for occult blood
- Mammogram (in women)
Limited Endocrine Evaluation
Pheo -- Potassium -- Cortisol
Incidentaloma
Diagnosis: Limited Endocrine Evaluation • Extent Remains Controversial
• Most Limited Evaluation
- Serum K if hypertensive
R/O Aldosteronoma
Unlikely if not hypertensive
- Plasma Free Metanephrines (normetanephrine and metanephrine)
Most sensitive test (99% sensitive/ 89% specific)
Most important “sub-clinical” entity Pheochromocytoma
- 24 hour Urine Cortisol
Annals of Internal Med,138:5, 2003
Incidentaloma
Diagnosis: Limited Endocrine Evaluation • Extent Remains Controversial
• Consider also obtaining …
- Serum K in all (Aldosteronoma)
- Plasma DHEA (ACC)
- 24° urine cortisol
- low dose dexamethasone suppression test
(Cushing’s Syndrome; last is more sensitive for “subclinical”)
Incidentaloma
Diagnosis: Endocrine Evaluation
• Indications - Complete Endocrine Evaluation - Findings on Examination and H & P
Suggestive of an excess of specific hormone
- Positive Findings on limited evaluation
- Then do workup for that hormone
Incidentaloma
Hypertension -- Adrenal Gland • 15% of Adult Population is Hypertensive
• 1% is Adrenal in Origin 0.5% primary hyperaldosteronism
0.2% pheochromocytoma
0.2% Cushing's Syndrome
• Evaluation is the Same
Incidentaloma
Diagnosis: Imaging • Most Incidentalomas Non-functional
If not a metastasis
non-functioning adenoma
adrenal cortical carcinoma
• Uncertain Progression of Non-functional Adenoma Complicates Issue
• Several reports of conversion to autonomous production
• Follow annually x 4 years
Euro J Endocrin 2002:146:61-66
Euro J Endocrin 2002:147:489-494
Incidentaloma
Diagnosis: Imaging • Uncertain Progression of Non-functional Adenoma
Complicates Issue
o 5-25% increase in size
o 20% develop hormonal overproduction
• Follow annually x 4 years
Euro J Endocrin 2002:146:61-66
Euro J Endocrin 2002:147:489-494
Annals of Internal Med,138:5, 2003
Incidentaloma
Diagnosis: Imaging • Most Series Report No Progression of Small
Adenomas to Cancer Kloos 1997: 3 cancers in patients initial 3 - 5 cm masses that
did not follow-up
Linos 1997: 3 cancers measuring 2.6 - 2.9 cm
Zaluaka, 1998: 311 Incidental Masses 22 Carcinoma (7%)
Tumor Size 3.2 cm – 20 cm
Incidentaloma
Diagnosis: MRI Carcinoma and Pheochromocytomas
– Hyperintense on T2 images
– (i.e., they “light up” as go from T1 to T2) – Intensity adrenal gland on T2 relative to liver
< 0.8 suggests cortical adenoma
Chemical-shift MRI – Signal from cortical adenomas drops out in
opposed phase
Incidentaloma
Diagnosis: CT Adenoma Sharp Margins
Smooth and Homogenous
Lipid-rich Most
have density < 10 HU non-contrast images higher values for cancer and pheochro.
Density Reduces at least 60%
Initial contrast density at scan delayed 15 min
Incidentaloma
Diagnosis: Nuclear Scintigraphy NP-59 (131I-6b-iodomethyl-norcholesterol)
Taken up by adrenal cortex (inc. adenoma)
Not space occupying lesion (cancer, pheochromocytoma)
Contralateral gland may suppress in Cushing’s
MIBG
Taken up preferentially by pheochromocytoma
Incidentaloma
Diagnosis: Imaging Criteria
Size Criteria 90% adrenal cortical carcinomas > 6 cm
Few Adenomas this large
CT underestimates actual size by 20%
Some recommend Exploration >5 cm
There is no cut-off with perfect accuracy
Incidentaloma
Diagnosis: Imaging Criteria
Study Indicating Adenoma Sens Spec
* CT density < 10 HU 71% 98% † CT washout > 60% 100% 100% * MRI T2 intensity < 0.8 compared to liver 80% 80% * Loss of signal on
chemical shift MRI 95% 100%
* All evaluating for fat content
† Not yet widely accepted
Incidentaloma
Management Recommendations • Hormonally Active Mass
Should be removed
• Hormonally Inactive Mass
If imaging suggests cancer, remove If > 5 cm at any age = remove
If < 3 cm, observe
Incidentaloma
Management Recommendations Observation • Consensus Recommendation
CT at 6 months,
Annual endocrine evaluation for 4 years
Growth/ development of endocrine function, remove
• Emerging Recommendation
If mass stable on scans at 3 and 12 months
No function
Routine follow-up not required
Pheochromocytoma
Incidence and Presentation • Hypertension in 90% of cases
Paroxysmal, Sustained, or both
May have Orthostatic Hypotension
plasma volume
• 30% at Autopsy (death often due to cardiovascular disease)
• Can Arise anywhere in Paraganglion System
Pheochromocytoma
Pathophysiology • Excessive Secretion of Catecholamines
Norepinephrine
Epinephrine
To lesser extent, Dopamine
• Levels that May be Measured Diagnostically 21 Different tests
Breakdown products of the primary catecholamines
VMA
Metanephrines
Pheochromocytoma
Clinical Findings • Classic Triad:
Episodic headache
Tachycardia
Diaphoresis
• Most Commonly Young to middle-age adults
Sustained HTN with superimposed paroxysms
Pheochromocytoma
Clinical Findings • Classic Triad:
Episodic headache 49% Tachycardia 46% Diaphoresis 49% Palpitations 46% Hypertension 60%
• Most Commonly Young to middle-age adults Sustained HTN with superimposed paroxysms
• Pheochromocytoma Etiology of Hypertension in Only 0.2% 10% with Pheo are normotensive Presentation during pregnancy
Pheochromocytoma
Clinical Findings Unexpected Cardiovascular Response Anesthesia
Catecholamine-induced Cardiomyopathy
Necrosis Inflammation Fibrosis
~80% mortality for surgery if untreated
Pheochromocytoma
Clinical Findings Unexpected Cardiovascular Response Anesthesia
Catecholamine-induced cardiomyopathy
Necrosis Inflammation Fibrosis
~80% mortality for surgery if untreated
Other Findings: Flushing Tremor
Pallor Anxiety
Pain Nausea / vomiting
Psychosis Sweating
Small Tumors Less Binding of Catehcholamines
Large Tumors More Binding
Pheochromocytoma
Rule of 10s Bilateral in 10%
Familial (non-sporadic) in 10%
Pediatric in 10%
Malignant in 10%
Normotensive in 10%
Extra-adrenal in 10%
Multiple in 10%
* Childhood Presentation Breaks Rules
25% are bilateral, multiple, or extra-adrenal
Pheochromocytoma
Associated Syndromes • von Hippel-Lindau Disease
• Von Recklinghausen’s Neurofibromatosis
• Multiple Endocrine Neoplasia
Suspect Syndrome
Evaluate for other components
Evaluate family members
Pheochromocytoma
MEN Syndromes
MEN I “Wermer’s”
MEN IIA “Sipple’s”
MENIIB
Parathyroid
Adenoma/Carcinoma
Pituitary
Hyperplasia/Adenoma
Pancreatic Islet Cell
Hyperplasia
Pheochromocytoma
MEN Syndromes
MEN I “Wermer’s”
MEN IIA “Sipple’s”
MENIIB
Parathyroid
Adenoma/Carcinoma
Medullary Thyroid
Carcinoma
Medullary Thyroid
Carcinoma
Pituitary
Hyperplasia/Adenoma
Pheochromocytoma Pheochromocytoma
Pancreatic Islet Cell
Hyperplasia
Parathyroid
Hyperplasia/Adenoma
Mucosal and GI Neuroma
Marfanoid Features
Pheochromocytoma
Diagnosis: First Level • Plasma Free Metanephrines
Most Sensitive Test
• 90% of Patients Have Elevated: - 24° Urinary Catacholamies 2 x normal
Next most sensitive test
- 24° Urinary Metanephrines Total metanephrines and vanillyl mandellic acid (VMA) Most specific tests
• 7% Have normal metanephrines
European J Endocrinology, 2004;150:681-686
Pheochromocytoma
Management • Surgical excision is mainstay
• Evaluate for extra-adrenal, multiple, and bilateral sites
• Primarily radiographic
• Extent of disease staged pre-operatively
• Unless metastatic disease apparent, cannot tell if will be malignant
Pheochromocytoma
Radiographic Localization Imaging Sensitivity Specificity
CT 98% 70%
MRI * 100% 67%
MIBG † 86 - 100% 85 - 99%
* Hyperintense on T2
† Scintigraphy with 123 or 131I-Meta-iodobenzylguanidine
lights up even if not apparent on MRI
Pheochromocytoma
Peri-Operative Management • Pharmaceuticals
+ Calcium-channel blocker
with alpha- followed by beta- blocker as needed
Orthostatic hypotension
• Liberalize Water and Salt Intake
• IV Hydration Pre-operative
• Invasive Monitoring Intra-operative
• Careful Post-operative Observation
Pheochromocytoma
Peri-Operative Management • Pharmaceuticals
- Phenoxbenzamine
- Selective Alpha blockers: Doxazosin, terazosin, prazosin
+ Calcium-channel blocker
- beta- blocker as needed for arythmia
- Goal orthostatic hypotension
• Liberalize Water and Salt Intake
• IV Hydration Pre-operative
• Invasive Monitoring Intra-operative
Pheochromocytoma
Pre-Operative Medical Management Mayo 98% phenoxybenzamine N=50
Cleveland 65% alpha blocker N=37
Max Systolic
BP
IV Fluid
Crystalloid
IV colloid Patient needing
Phenylephrine
Mayo 187mmHg 2977 cc
Cleveland 209 mmHg 5000 cc
P value P<0.11 P<0.10
Weingarten TN et al. Urology 2010, Aug 76:508
Pheochromocytoma
Pre-Operative Medical Management Mayo 98% phenoxybenzamine N=50
Cleveland 65% alpha blocker N=37
Max Systolic
BP
IV Fluid
Crystalloid
IV colloid Patient needing
Phenylephrine
Mayo 187mmHg 2977 cc 0 cc 56%
Cleveland 209 mmHg 5000 cc 1000 cc 27%
P value P<0.11 P<0.10 P<0.001 P=0.009
Weingarten TN et al. Urology 2010, Aug 76:508
Pheochromocytoma
Pre-Operative Preparation Required •Mortality up to 80% on untreated patients
•Consultation:
Endocrinologist
Cardiologist
Anesthesiologist
•Goals
Normalize blood pressure
Expand plasma volume
Prevent cardiac arrhythmias
Prevent intra-op hypertension
Minimize post-op hypotension
Pheochromocytoma
Pre-operative Preparation
• Stepwise Plan: Pharmaceuticals
• Consider starting with long acting calcium-channel blocker
Verapamil SR (120 - 240 mg/d)
Nifedipine XL (30 - 90 mg/d)
Addresses both hypertension and arrhythmias
Few adverse effects
MAY be adequate monotherapy
Pheochromocytoma
Pre-operative Preparation • Stepwise Plan: Pharmaceuticals
• Alpha blocker Alpha-1 blocker prazosin (4 - 10 mg/d) good for HTN
refractory to Ca-blocker, but not for monotherapy
Classic initial therapy is non-selective, long acting phenoxybenzamine
start 5 mg bid, 10 mg qod prn to 100 mg bid
beware post-operative hypotension
Pheochromocytoma
Pre-operative Preparation • If refractory arrhythmias (inc. sinus tachycardia), add
beta blocker
Use only after alpha-blockade (exacerbate HTN if unopposed)
Propranolol (20 - 40 mg tid)
Usually not necessary
• Rarely alpha-methyl para tyrosine -- severe cases
Significant adverse effects
Pheochromocytoma
Intra-operative Management • Pre Op Anesthesia Consultation • Low Threshold to Cancel Case If Not Prepared • Certain popular agents avoided
Halothane, propofol, MSO4, pancuronium • To control intra-operative hypertension
Phentolamine, nitroprusside, esmolol • To control post-excision hypotension
Norepinephrine • ~ 5% of have negative studies, so warn anesthesiologist
Pheochromocytoma
Post-Operative Management • Hypotension
Most commonly hypovolemia
• Hypertension Catecholamine levels elevated for several days Essential HTN
Residual unresected tissue
• Hypoglycemia Insulin , use 5% dextrose in IVF
Pheochromocytoma
Surgical Principles
• Ligate Adrenal Vein First Prevent intra-operative catecholamine surge
Some reports suggest fewer catecholamine surges and less cardiovascular instability with laparoscopy
• “Dissect the patient away from the tumor”
Pheochromocytoma
Surgical Outcome • Excision not always lead long term cure
even in patients with a benign tumor
• Benign recurrence 5%
• Malignant recurrence 10%
• Hypertension may persist
related to age / family history
• 80% 20-year cause-specific survival
• Long-term follow-up required
Primary Hyperaldosteronism
Primary Hyperaldosteronism (Conn’s Syndrome)
• 1955 Clinical Syndrome: Hypertension
Hypokalemia
Hy[ernatremia
Alkalosis
Periodic Paralysis
• Primary Hyperaldosteronism (Conn’s Syndrome) • 1955 Clinical Syndrome:
Hypertension
Hypokalemia
Hypernatremia
Alkalosis
Periodic Paralysis
• Today Hypokalemia
Hypertnesion
Depressed Renin
High urine and plasma aldosterone
Primary Hyperaldosteronism
Clinical Features • Refractory Hypertension
• Hypokalemia
• Profound Hypokalemic Response to Diuretics
• Often Asymptomatic
• May Manifest:
muscle weakness, tetany, headache, polydipsia
• Low-Salt Diet Limits Potassium Wasting
less Na available for K exchange
which improves symptoms
Primary Hyperaldosteronism
Primary Hyperaldosteronism (Conn’s Syndrome)
• Cause of Hypertension in ~ 0.5%
• Most Commonly
Caucasian, 30 - 60 years of age
• Pathology
70% aldosteronoma
30% bilateral adrenal hyperplasia
Bilateral adrenal hyperplasia mostly in men
Primary Hyperaldosteronism
Pathophysiology • Primary Hyperaldosteronism
Autonomous (without stimulation) secretion of aldosterone from adrenal gland
Results in salt retention, hypertension, and potassium wasting
May have autonomous overproduction of cortisol
• Secondary Hyperaldosteronism Renovascular HTN -
Aldosterone is 2° to Renin
Primary Hyperaldosteronism
Diagnosis: First Level • Serum K < 3.0 mEq / dl
• Plasma Renin Activity Suppressed (PRA) < 2 ng / ml
25% of essential hypertensives have depressed PRA
But normokalemic
• Plasma Aldosterone > 15 ng / dl
• Aldosterone:PRA > 20:1
• Confirmation High Sodium Diet 3 Days (>200 mEq/Day)
24 hr Urine Aldosterone
Urine aldosterone > 14 mcg / 24°
Urine K > 30 mEq / 24°
Primary Hyperaldosteronism
Diagnosis: Adrenal Vein Sampling • Recommended:
Aldo/Renin Ratio > 20
Serum aldo > 15
• If age > 40 or bilateral imagining findings needs sampling
• If age < 40 years old • Localize with CT or MRI
• If 1 cm or greater
• No sampling needed remove
American Association of Clinical Endocribnilogists
Endocrine Practice Vol 15: Supp 1 July August 2009
Primary Hyperaldosteronism
Diagnosis: Adrenal Vein Sampling • 12 patients
Positive CT findings
Positive Screening tests
• 11 patients Vein sampling 73% positive from CT defined side
18% positive from opposite side
9% positive from both sides!
Schwab et al, J Endourology, 2008
Espiner et al, J Clin Endocri Metab 2003
Magill et al, J Clin Endocri Metab 2001
McAlister et al, Can J Surg, 1998
Primary Hyperaldosteronism
Management •Bilateral Adrenal Hyperplasia
Medical therapy
Spironolactone (aldosterone antagonist)
Normalizes serum K
Painful gynecomastia
HCTZ normalizes blood pressure
•Unilateral Adrenal Adenoma Adrenalectomy following control of HTN and
hypokalemia (amiloride, triamterene, spironolactone) Partial Adrenalectomy
Primary Hyperaldosteronism
Result of Adrenalectomy
• 35% Cured of hypertension
• 56% Improved hypertension
fewer or milder medications
• All but 9% have:
cure or improvement
Primary Hyperaldosteronism
Classic Clinical Findings • Obesity in 90%
80% with Buffalo hump or truncal obesity
Cushing’s Syndrome
Cushing’s Syndrome
Cushing’s Syndrome - Glucocorticoid Excess • Clinical Picture of Hypercorticolism • 1 per 100,000 - 500,000 • ACTH-Dependent Causes (82%)
Cushing’s Disease = Pituitary hypersecretion of ACTH - 70% Ectopic ACTH - 12%
• ACTH-Independent Causes (18%) Adrenal adenoma - 8% Adrenal carcinoma - 6% Bilateral adrenal hyperplasia - 4%
Pathophysiology
• ACTH-Dependent = Primary Excessive ACTH secretion
From pituitary (Cushing’s disease)
Ectopic ACTH secretion ACTH causes increased cortisol
• ACTH-Independent = Primary excessive cortisol secretion
Adrenal adenoma
Carcinoma, or bilateral hyperplasia
Excess cortisol causes Inhibition of ACTH secretion
Cushing’s Syndrome
Clinical Findings • Obesity in 90%
Muscle Weakness 80% Hirsutism 70%
Hypertension 80% Amenorrhea 70%
Diabetes Mellitus 80% Moon Facies 60%
Striae, thin skin 70% Easy Bruising 50%
• Cushing’s rare cause of HTN in ~ 0.2%
Cushing’s Syndrome
Diagnosis: Is this Pseudo-Cushing’s?
• Rule out Exogenous Sources Glucocorticoids
Topical creams, lotions
Review of oral medications
• Non-Endocrine Causes of Hypercorticolism
Major depression
Alcoholism
Cushing’s Syndrome
Diagnosis: A 3 Step Process # 1 - Establish Hypercorticolism
# 2 - Distinguish Between
ACTH-independent vs ACTH-dependent
# 3 - Determine Specific Etiology
ACTH-Dependent
Cushing’s disease pituitary ACTH
Ectopic ACTH secretion
ACTH-Independent Adrenal adenoma
Carcinoma
Bilateral hyperplasia
Cushing’s Syndrome
Diagnosis # 1: Hypercorticolism?
• 24° Urine Free Cortisol > 100 mg / 24 is diagnostic
• If Equivocal: low-dose dexamethasone test – 1 mg at 11 PM, obtain plasma cortisol at 8 AM
– Normal suppresses plasma cortisol to < 5 ng / ml
– No suppression = Cushing’s Syndrome
• Newest Test: Late night salivary cortisol
– Measure at 2300 h
– Cushings cortisol (24.0 +/- 4.5 nmol/L)
– Normal subjects cortisol (1.2 +/- 0.1 nmol/L)
Cushing’s Syndrome
Diagnosis # 2: Relation to ACTH?
• Measure late afternoon ACTH
> 50 pg/ml =ACTH-dependent Cushing’s
(Cushing’s Disease or Ectopic ACTH)
< 5 pg/ml =ACTH-independent Cushing’s
(Primary Adrenal Cushing’s Syndrome)
Cushing’s Syndrome
Diagnosis # 3: Specific Entity? • ACTH-Dependent Cushing’s
High-dose Dexamethasone Test - 8 mg orally at 11 PM
- Plasma Cortisol at 8 AM < 50% reduction = Ectopic ACTH
> 50% reduction = Pituitary tumor
Adenomas and carcinomas fail to suppress cortisol secretion
Pituitary (Cushings Disease) has relative resistance to feedback
Cushing’s Syndrome
Diagnosis # 3: Specific Entity? • Measure Plasma ACTH and Cortisol
• Later afternoon Blood Draw
Cushing’s Syndrome
SUMMARY
Etiology Plasma Cortisol Plasma ACTH
ACTH Independent Adrenal Cushings fails to suppress
> 50 ug/dl < 5 pg/ml
ACTH Dependent Pituitary
Cushings Disease, Ectopic ACTH or
CRH syndrome f
> 50 ug/dl > 5 pg/ml
Diagnosis # 3: Specific Entity?
• ACTH-independent Cushing’s
Imaging (CT) distinguishes:
Adenoma
Cancer
Bilateral hyperplasia
Cushing’s Syndrome
Management: Adenoma/Cancer • Unilateral Adrenalectomy
• May require pre-operative reduction of cortisol secretion, if markedly elevated (see Ectopic ACTH secretion)
• Excessive Cortisol: Suppresses the other
- intra-operative steroid support
- post-operative steroid taper may be needed
- while the contralateral gland recovers function
Cushing’s Syndrome
Management: Bilateral Adrenal Hyperplasia • Bilateral Adrenalectomy
• 10 - 20% get Nelson’s syndrome
ACTH hyper-secretion by chromophobe adenoma Headache
Deep pigmentation
Visual disturbances
• Lifelong follow-up Sella tursica radiographically
ACTH level
Cushing’s Syndrome
Management • Ectopic ACTH Secretion Resection of tumor if possible
Medical therapy with metyrapone, ketoconozole,
or aminoglutethimide
• Pituitary Tumor Trans-sphenoidal hypophysectomy
For failure
Bilateral adrenalectomy or XRT
Cushing’s Syndrome
Adrenal Insufficiency
Adrenal Insufficiency • 1 per 4,500 - 6,250 hospitalized pts • Third - fifth decade of life • Primary
Autoimmune adrenalitis Infection (TB, HIV most common) Adrenal hemorrhage
• Secondary Metastatic disease Surgical removal, Pituitary disease, Exogenous steroid use
Pathophysiology and Clinical • Deficiency of both glucocorticoid and
mineralocorticoid
• Acute Fever Severe Hypotension Nausea / vomiting Lethargy
Post-operative “crash” without apparent surgical complication
Adrenal Insufficiency
Pathophysiology and Clinical • Deficiency of both glucocorticoid and
mineralocorticoid
• Chronic More Subtle:
Fatigue
Weight loss Anorexia Nausea and Vomiting Abdominal pain
Adrenal Insufficiency
Diagnosis
• Clinical scenario, especially post-operative
• Labs: Hyponatremia, hyperkalemia, azotemia, hypoglycemia
Eosinophilia in 15 - 20%
Rapid IV access
ACTH stimulation -
measure plasma cortisol at 0, 30, 60 minutes
ACTH / CRH levels for 1° vs 2°
Adrenal Insufficiency
Management • Adrenal Crisis
IV access, blood for Chem, ACTH, cortisol
(but don’t wait for result)
2 - 3 liters D5 NS quickly
4 mg dexamethasone IV
(IV cortisol will interfere with dx later)
• Subsequent
Confirm diagnosis
Determine and treat cause
Begin flurocortisone therapy
Adrenal Insufficiency
Suspected Adrenal Insufficiency
Adrenal Insufficiency
Possible
250 µg ACTH (cosyntropin)
Stimulation Test
Adrenal Insufficiency
Possible
8 AM Serum ACTH
Primary Adrenal
Insufficiency
Secondary Adrenal
Insufficiency
Adrenal Insufficiency
Unlikely
Adrenal Insufficiency
Unlikely
8 AM Serum or Salivary Cortisol
Serum Coritsol < 15 µg/dL Serum Cortisol > 15 µg/dL
Post Cortisol < 18 µg/dL Post Cortisol > 18 µg/dL
Increased ACTH Decreased or Normal
Based upon chart 39-7 Townsend: Sabiston Textbook of Surgery, 18th ed
Adrenal Cortical Carcinoma
Adrenal Cortical Carcinoma • Rare: 1 per 1.7 million people
• Accounts for 0.02% of cancers, and 0.2% of cancer deaths
• Weiss Criteria for diagnosis High mitotic rate and nuclear grade Atypical mitosis Eosinophilic cytoplasm Diffuse architecture Necrosis Microscopic invasion
Clinical Findings • Constitutional
Weight loss, malaise, fever, etc
• Endocrine (80% functional) Clinical findings of Cushing’s
Sex steroid excess
Oligomenorrhea
Virilization / Feminization
• Can Present as Incidentaloma
Adrenal Cortical Carcinoma
Diagnosis: Endocrine Evaluation • 80% are Functional
• Often Secrete Multiple Hormones
Glucocorticoids 72%
Androgens 43%
Precursors 22%
Estradiol 8%
Aldosterone 4%
• Cushing’s Accompanied by Virilization / feminization is most common
Adrenal Cortical Carcinoma
Diagnosis: Endocrine Evaluation
• Endocrine Fxn Useful in Diagnosis
Finding of multiple hormones suggestive of carcinoma
Carcinoma more often secretes sex steroids (Plasma DHEA, 24° urine 17-ketosteroids) than does adenoma
• Endocrine fxn useful as marker
• Endocrine fxn is not prognostic except for isolated testosterone secretion
Adrenal Cortical Carcinoma
Diagnosis: Radiography • Cross-sectional imaging localization and staging
CT or MRI
Over 90% are > 6 cm
but in one study 16% < 5 cm
Irregular, inhomogeneous
• Distinction from Adenoma CT ± washout curve
MRI
Adrenal Cortical Carcinoma
Adrenal Cortical Carcinoma showing bizarre
shaped, multilobulated, hyperchromatic nuclei,
many mitotic figures
Staging • Common Sites of Metastases
Lung
Liver
Lymph nodes
• Staging Studies
CXR
CBC, complete serum chemistry
CT and venogram versus MRI
Adrenal Cortical Carcinoma
Management • Surgery is mainstay
• 5-year survival clinically localized disease 35% • 5-year survival for pathologically confined disease 50%
• Frequently Invading Into Adjacent Structures • Radical en-bloc adrenalectomy with regional
lymphadenectomy and total or subtotal excision of adjacent organs (kidney, spleen, liver, colon, pancreas)
• May require cavotomy, bypass, etc
Adrenal Cortical Carcinoma
Management • Metastatic or Recurrent Disease
Mitotane (o,p’-DDD, a cogener of DDT)
Hormonal response in 75%
Response of tumor mass in 35%
No improvement in survival
(6.5 months median survival)
Severe toxicity
Trials of adjunctive use of mitotane
Adrenal Cortical Carcinoma
Adrenal Metastasis
Adrenal Metastasis • More common than adrenal cortical carcinoma
• 40 - 50% of metastases from:
Melanoma Breast
Lung Kidney
• 8 - 38% of patients with extra-adrenal malignancy will have adrenal metastases at autopsy
• With Known Primary Cancer
adrenal mass is metastasis in 32 – 73 (~50) %
Adrenal Metastasis
Diagnosis • In setting of widespread metastases (most common),
diagnosis obvious
• If no other metastases, do work-up as for adrenal incidentaloma (see below), even with known primary cancer
• Findings suggestive of metastases
No endocrine abnormalities
Irregular / inhomogeneous on CT, bright on T2 images of MRI, cold spot on NP-59 scintigraphy
Diagnosis
• Adrenal metastasis is the best indication for FNA of adrenal gland
• FNA cannot reliably distinguish
adrenal adenoma vs
adrenal cortical carcinoma
• Must rule out pheochromocytoma biochemically before attempting FNA
Adrenal Metastasis
Management • Solitary Metastasis : May be benefit to
adrenalectomy
• Decision in concert with oncologist
• Avoid direct gland manipulation Hemorrhage Tumor Spillage
• Take generous peri-adrenal tissue, but resection into other organs should not be necessary
Adrenal Metastasis
Adrenalectomy
Principles of Adrenalectomy
• Division Adrenal Vein
Most important step = pheochromocytoma
• “Dissect Patient Away From Gland”
• Traction on Adjacent Tissues
• For Open Surgery:
Divide superior and lateral attachments
Allow gland to retracted into operative field
Adrenalectomy
Cortical Carcinoma • Still a Laparoscopic Case • Consider open surgery
• large tumors • High suspicion for invasion • Be prepared for adjacent organ removal
Spleen Kidney Vena Cava Portion of Liver
• This is the model for invasive cancers!
Adrenalectomy
Complications Adrenalectomy
•Bleeding: Most Common
•Prevention Find Correct Landmarks:
Left: Renal Vein
Upper Pole Kidney
Adrenal Vein More Medial
Adrenal Lateral To Splenic Artery
Adrenalectomy
Complications Adrenalectomy
•Bleeding: Most Common
•Prevention Find Correct Landmarks:
Right: Vena Cava
Renal Vein
Adrenal Vein More Superior
•Avoid Hunting Through Fat!!
•Use LigaSure and or Harmonic Scalpel
Adrenalectomy
Complications Adrenalectomy
•Bleeding: Most Common
•Endocrine Imbalance
•Liver or Spleen Laceration
•Pneumothoax Trocar Placement
Diaphram Injury