The incidental adrenal mass

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



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

Main Right Adrenal Vein

Main left adrenal vein

Phrenic Venous Branch from Adrenal

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”

G

F

R

Medulla

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 Cortex

Hormone Production

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


• Healthy Humans Circulating Catecholamines Norepinehprine 73%

Epinephrine 14%

Dopamine 13%

Adrenal Physiology



Epinephrine 14%

Dopamine 13%

• Phenylethanolamine-N-methyltransferase (PNMT)

From the Medulla

Methylation of Norepinephrine = Epinephrine

Adrenal Physiology



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


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


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%





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





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





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


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



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

Benign Adenoma

Hypo-intense

on T1 MRI

And also

Hypo-intense

on T2 MRI

Adrenal Metastasis Inhomogeneous on

CT

And is

Hyper-intense

on T2 MRI

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

Paraganglion System

Derived from Fetal Chromaffin Bodies

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

Pheochromocytoma


Episodic headache

Tachycardia

Diaphoresis

• Most Commonly Young to middle-age adults

Sustained HTN with superimposed paroxysms

Pheochromocytoma


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

MIBG Adrenal Scintigraphy

“<“ indicates widespread pheochromocytoma

Pheochromocytoma showing tumor cells arranged in nest of cells termed “Zellballen”

Pheochromocytoma

Peri-Operative Management

Is it Necessary?

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


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 (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


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


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°


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


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


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


Result of Adrenalectomy

• 35% Cured of hypertension

• 56% Improved hypertension

fewer or milder medications

• All but 9% have:

cure or improvement


Classic Clinical Findings • Obesity in 90%

80% with Buffalo hump or truncal obesity

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


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%


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


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


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)


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)


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


Diagnosis # 3: Specific Entity? • Measure Plasma ACTH and Cortisol

• Later afternoon Blood Draw


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


CT of Adenoma and Abundant Retroperitoneal Fat Classic for Cortisol-Producing Adenoma

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


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


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


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


Pathophysiology and Clinical • Deficiency of both glucocorticoid and

mineralocorticoid

• Chronic More Subtle:

Fatigue

Weight loss Anorexia Nausea and Vomiting Abdominal pain


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°


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


Suspected Adrenal Insufficiency


Possible

250 µg ACTH (cosyntropin)

Stimulation Test


Possible

8 AM Serum ACTH

Primary Adrenal

Insufficiency

Secondary Adrenal

Insufficiency


Unlikely


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


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


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


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


Typical ACC “Brightly Lights up”

on T2-weighted MRI

Benign Adenoma does not

“light up” on T2

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


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


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 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

CT-guided FNA of Adrenal Gland

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



•Prevention Find Correct Landmarks:

Right: Vena Cava

Renal Vein

Adrenal Vein More Superior

•Avoid Hunting Through Fat!!

•Use LigaSure and or Harmonic Scalpel

Adrenalectomy



•Endocrine Imbalance

•Liver or Spleen Laceration

•Pneumothoax Trocar Placement

Diaphram Injury

Adrenal Gland

Take Home Messages Do the limited work up

Follow the patient

Treat surgical lesions laparoscopically

When you go Be Prepared !

Treat with Respect

Pheochromocytoma

Adrenal Carcinoma

The incidental adrenal mass

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