Morbidity & Mortality - SUNY Downstate Medical Center · Adrenal Gland • The adrenal cortex and...

Morbidity & Mortality

Mark H. Tseng MDSUNY Downstate Medical Center

Lutheran Medical CenterDecember 16, 2005

Case presentation

• Pt is a xx year old Asian woman who present to the ED with cc of epigastricpain and tenderness for the past 2 days. Pt denies any previous history of abdominal pain, nausea/vomiting, nor radiation to back. Pt denies any weight loss, headaches, palpitations, and diaphoresis. Surgery was consult after CT scan was performed.

Case presentation

• PMH: none• PSH: none• Shx: denies etoh, smoking, ivdu• Fhx: none• Allergy: nkda

Case presentation

Vital Signs• T: 98.6• BP: 110/70• HR: 80• RR:18

Case presentation

Physical Exam• A x O x 3, calm, age appropriate,

average wt for height• Abdomen: soft, right flank

tenderness, negative murphy’s sign, no mass appreciated, normal bowel sounds

Case presentation

LabWbc 4.2 H/H 12/36 Plt 209Na 141 K 4.0 Glucose 95LFT within normal limitsCortisol 13.3 (nl)VMA 3.3 (nl <6)metanephrine 199 (nl 95 to 475)

Case presentation

Lab:Wbc: 4.2 H/H: 12/36 Plt: 209Na: 141K: 4.0 Glucose: 95LFT: within normal limits

Lab:Cortisol: 13.3 (nl)VMA: 3.3 (nl <6)metanephrine: 199 (nl 95 to 475)

Case presentation

• CXR: unremarkable

• Sono: large mass in RUQ

Case presentation

• CT scan: 6.4 x 7.5 right cystic adrenal mass

Case presentation

• MRI: well defined right suprarenal hyperdensity with thin wall. Compression of IVC. Non invasive

Case presentation

• Pt was taken to OR• Right adrenalectomy was performed

via a right flank incision• Fluid fill cyst was identified and

resected• Pt tolerated the procedure well

Case presentation

• POD #1 start on clears• POD #2 pain management• POD #3 discharge planning• POD #4 discharged home

Case presentation

• Pathology: benign endothelial vascular cyst of the adrenal gland

Adrenal IncidentalomaMark H. Tseng MD

SUNY Downstate Medical CenterLutheran Medical Center

December 16, 2005

Overview

• Embryology• Anatomy and Physiology• Epidemiology• Incidentaloma• Conclusion• References

Adrenal Gland

• The adrenal cortex and medulla are anatomically and functionally distinct endocrine units that are contained in a single capsule

1563 – Eustachius describes the anatomy of the adrenal gland1855 – Addison correlates clinical features of adrenal disease with pathology found in autopsies1886 – Frankel describes pheochromocytoma1912 – Cushing presents clinical features of hypercortisolism1955 – Conn describes hyperaldosteronism

Embryology

• Cortex is mesodermal in origin– Week 4 to 6 – begin development from

coelomic mesoderm adjacent to urogenitalridge

– Week 8 – differentiates into thin outer definitive cortex and thick inner fetal cortex

– Fetal cortex produces fetal steroids during gestation then involutes at birth

– Definitive cortex develops into functional adrenal cortex

• Zona glomerlulosa and fasiculata present at birth• Zona reticularis develops during the first year of life

Embryology• Medulla derived from

neural crest cells– Develops with

sympathetic nervous system

– Week 5 – neural crest cells migrate to para-aortic and para-vertebral regions and along adrenal vein toward medial aspect of fetal cortex

– Extra-adrenal chromaffincells which persist form the organ of Zuckerkandllocated to the left of the aortic bifurcation near the origin of IMA

Anatomy

• Bilateral retroperitoneal organs on superomedialaspect of the upper pole of each kidney

• Approximately 4 grams each, L>R

• Right adrenal lies close to IVC and beneath diaphragm and liver

• Left adrenal located between kidney and aorta near tail of pancreas and splenic artery

Anatomy• Blood supplied by inferior

phrenic artery superiorly, aorta medially, and renal artery inferiorly

– Right adrenal supplied by superior and inferior adrenals, drains to IVC via right adrenal vein

– Left adrenal supplied by middle and inferior adrenals, drains into left renal vein or directly to IVC

– Lymphatic drainage to para-aortic and paracaval lymph nodes

• Important when operating for malignant adrenal lesions

Anatomy

• The location of the adrenal gland deep in the retroperitonium has in the past made them relatively inaccessible

• Understanding the anatomical relationships and appreciate their relationship to the arterial supply and venous drainage are important and have significant surgical ramifications

Histology

• Three distinct zones– Zona glomerulosa

• Small cells with intermediate number of lipid inclusions

– Zona fasiculata• Large foamy cells

secondary to lipid inclusions

• 75% of cortex– Zona reticularis

• Compact cytoplasm and few lipid inclusions

Physiology

• Composed of two distinct organs– Adrenal cortex and adrenal medulla

• Three major biosynthetic pathways produce *glucocorticoids, mineralocorticoids, and adrenal androgens– Zona glomerulosa synthesizes

mineralocorticoids– Zona fasiculata synthesizes glucocorticoids *– Zona reticularis synthesizes adrenal

androgens

* Absolutely required for life

Epidemiology

Figures Vary From O.4-6% Of CT Scans

6.5-8.7% Of Autopsy Series

Incidence Increases With Age; 7% After 70

Seen More Commonly In Women

NATIONAL INSTITUTES OF HEALTHManagement of the Clinically Inapparent Adrenal Mass (Incidentaloma). Final Statement. July 16, 2002

Adrenal Incidentaloma• The evaluation and decision

paradigm for an incidentalomahinges on three issues:

IS IT MALIGNANT? IS IT METASTATIC?IS IT FUNCTIONAL?

Major Causes

Benign Adenoma 50%Cyst 10%Myelolipoma 10%Pheochromocytoma 10%Metastases 6-30%Adrenal Cancer 0.01%

The incidental adrenal mass. Am J Med 1996

Is It Malignant?

• An important and unresolved issue in the management if incidentalomasis the determination of what size of adrenal tumor has malignant potential and requires surgical resection.

Is It Malignant?

Useful in determining malignant potential:

• Size of the mass

• Radiological Findings

The Mayo Clinic Study

• 342 Patients With Adrenal IncidentalomaRetrospectively 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):1014-21

Mass

• Masses > 6 cm Usually Are Treated Surgically

• Masses < 4 cm Are Generally Monitored

• Masses Between 4 And 6 cm:Criteria Other Than Size Should Be Considered In Making The Decision To Monitor Or Proceed To Surgery

• Experienced investigators now recommend excision of all tumors >4 cmNational Institutes Of HealthManagement Of The Clinically Inapparent Adrenal Mass (Incidentaloma) 2002

Computed Tomographic Scans• Attenuation On CT Scan Is

Measured In Hounsfield Units (HU)

• >20 HU—likely malignant

• Lipid-Rich Masses Are Usually Benign

• Lipid-Rich Lesions Have Low Attenuation

• Low Attenuation Lesions Have Low HU (<20)

Computed Tomographic Scans

• Unenhanced CT:Adenomas: < 10 HUMalignancies: > 20 HU Sensitivity: 73% Specificity: 96%

• Delayed Enhanced CT:Adenomas: < 30 HU Malignancies: > 30 HU Sensitivity 95% And Specificity: 100%

MRI

• Equally Effective As CT

• Adenomas Are Iso-Intense With The Liver On T2-weighted Images

• Carcinomas Have A Hyper-Intense Signal Compared With The Liver

Fine-Needle Aspiration Biopsy

CANNOT Distinguish A Benign Adrenal Mass From Adrenal

Carcinoma

Other Tests…

• Iodinated Cholesterol Derivative (NP-59):

Show Uptake In Functioning Lesions

• I-131 MetaiodobenzylGuanidine (MIBG):

Evaluating Pheochromocytoma

• Positron Emission Tomography (PET):

Is It Metastatic?

• The adrenal gland, although relatively small, has the highest blood flow of any endocine organ on a gram per flow basis.

• It is therefore not surprising that metastatic diseases, particularly from lung, esophageal, and breast cancer, occurs in the adrenal gland.

• Majority has history of malignant diseases and metastases to multiple additional sites.

Is It Metastatic?

• Patients with bilateral adrenal metastases are at some risk for adrenal insufficiency.

• Patients with isolated adrenal metastases pose a diagnostic dilemma.

• Tissue diagnosis may affect subsequent care or an adrenalectomy might be indicated.

• FNA is controversial• The only situation where FNA appears indicated

is when metastatic disease is not only likely, but its detection would alter patient management.

IS IT HYPERSECRETORY?

Cortisol

Catecholamines

Mineralcorticoids

Androgens

15 (1.6%)Aldosterone-Producing Adenoma

42 (4.2%)Pheochromocytoma

92 (9.2%)Sub-Clinical Cushings Syndrome (SCC)

854 (85%)Non-Secretory

1004Patients

Journal of Clinical Endocrinology & Metabolism 85 (2) 637-644, 2000

Non-Secretory

• All evaluations begin with a detailed history and physical examination.

• If there are signs and symptoms suggesting a functional adrenal neoplasm, in addition to routine screening evaluation, specific hormone studies are indicated

• Most patients are asymptomatic, CT findings can be pathognomonic

• Hormone screening studies are therefore not required.

Ross NS. Hormonal evaluation of the patient with an incidentally discovered adreanl mass. NEJM 1990:323:1401-1405





1004Patients


Subclinical Hypercortisolism

• Cushing’s syndrome is important to consider in all patients with adrenal tumors

• Some patients has obvious signs and symptoms and are not difficult to diagnose

• However, some patients presents with subtle stigmata of Cushing’s syndrome or “subclinical”and require additional testing.

• Approximately 15% of patients with incidentalomas have subclinical features.

Cushings• Clinical presentations

include hypertension, edema, proximal muscle weakness, diabetes, tuncalobesity, hirsutism

• Caused by exogenous steroids or excess endogenous cortisolsecretion– Most commonly

iatrogenic– Cushing Disease is the

most common pathologic form of endogenous hypercortisolism


Defined By Any Two Of The Following:Defined By Any Two Of The Following:

Increased Urinary Free Cortisol (UFC) Unsuppressed Serum Cortisol Levels

After 1-mg Overnight DexamethasoneLow ACTH Levels No Clinical Signs Of Cushing Syndrome

Mantero F, Masini AM, Opocher G, Giovagnetti M, Arnaldi G. Horm Res47:284–289, 1997


• It is important to rule out subclinicalCushing’s syndrome for two reasons:

• 1) if one elects not to peform an adrenalectomy, then the endocrinopathywill continue and deleterious effects will occur

• 2) if one does perform an adrenalectomy, the contralateral adrenal will be suppressed and if perioperativeglucocorticoids are not administered, the patient will be at risk for Addisonian crisis

Hypercortisolism24 Hour Urinary Free Cortisol

Positive: More Than 3-4 Times The Upper Limit Of Normal Range

Mildly Elevated Levels Can Be Seen In Anxiety, Depression, Alcoholism

When the 24 hr UFC Is Not Conclusive……..

Dexamethasone Suppression Test

1 mg Dexamethasone At 11 pm Measure Cortisol At 8 am

Normal: Cortisol < 5 ug/dl

Specificity Is Reduced In Acute Or Chronic Illness

Subclinical cushings syndrome?

Increased Incidence Of:HTNObesity DMIGT Increased CV Risk Bone Disease





1004Patients


PheochromocytomaRareArise From Neuroectodermally Derived Chromaffin CellsSecretion of Norepinephrine—Most Common19-76% Of Pheochromocytomas Not Diagnosed Until After Death80% Of Patients With Unsuspected PheochromocytomasWho Underwent Surgery Or Anesthesia DiedNot Possible To Determine Which Will Present With CrisisNot Possible To Determine The Malignant

Potential Of Pheochromocytoma

Hypertension In Pheochromocytoma

• Paroxysmal in 48%--episodically secreted

• Persistent in 29%--continually secreted

• Normal in 13%

Clinical Presentation

• Attacks of Headaches (80%) • Palpitations (64%)• Diaphoresis (57%)

Symptomatic Triad Of Headache, Sweating, And Tachycardia In A Hypertensive Patient

Sensitivity 90.9% And Specificity 93.8%

How To Screen…• Because the risk of complications associated with an

occult pheochromocytoma is significant, all incidentalomashould be screened for pheochromocytoma

• Urine Collection Of Catecholamines and Metabolites

• Plasma Collection Of Catecholamines And Metabolites

• Collections are analyzed for metanephrines, vanillylmandelic acid (VMA), and fractional catecholamines.

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 MetanephrineAnd Catecholamines 90%; Specificity 85%

Sawka et al. JCEM 88(2): 553-558. 2003.

Pheochromocytoma

Plasma-Free Metanephrines Are Recommended As The Test Of Choice For Excluding Or

Confirming The Diagnosis Of Pheochromocytoma


Pre-operative Treatment

• Because of chronic hypersecretion of catecholamines, pt with pheochromocytomas are often severely volume contracted and severely hemodynamically unstable after general anesthesia

• selective Alpha 1 adrenergic receptor blocker• Phenoxybenamine-increase dosage until pt experience

orthostatic hypotension • Given 1-4 weeks before surgery• Beta blocker- for breakthrough tachycardia• Alpha blocker before beta blocker• Fear of unapposed alpha recepter would induced malignant

hypertension

Cleveland Clinic study

• 63 pts with pheochromocytoma can undergo successful surgical treatment without preoperative preparation with alpha adrenergic blockade





1004Patients


Aldosterone Producing Adenoma

• Rare• Most Common Cause of

Hyperaldosteronism• Twice as Common in Women• Mean Age 30-50 Years Old• Conn in 1955—First Curative Treatment of

APA by Unilateral Adrenalectomy• Mostly Unilateral• Mostly < 2 cm in size

Hypertension HeadacheWeakness/ FatigueParesthesiasMuscle CrampsPolyuria/ PolydipsiaArrhythmias

HypokalemiaNo Other Cause For Hypertension Or HypokalemiaMetabolic AlkalosisHyperaldosteronismHyporeninemia

Signs, Symptoms, and Laboratory Datain Primary Hyperaldosteronism

Aldosterone-Producing Adenoma

Serum Potassium And Aldosterone /Plasma Renin Activity Ratio Should Be Determined To Evaluate For Primary Aldosteronism

Less Affected by Physiological or Pharmacological Variables


Aldosterone/PRA Ratio• Normals < 20

• Primary Aldosteronism > 30

• > 90% Sensitivity And Specificity

Adenoma (APA) vs Hyperplasia (IHA)

• Very Important to Distinguish APA from IHA (occurs in 25% of pts with primary aldosteronism, bilateral adrenal hyperplasia)

Adenoma (APA) vs Hyperplasia (IHA)

• Very High aldosterone/Plasma ReninActivity Adenoma – Surgical resection of unilateral

adenoma is curative• Increased 18-OH-Corticosterone

Adenoma if >100 mg/dl and hyperplasia if <50 ng/dl– Treatment is with spironolactone

Solid Or With Cystic Degeneration

>6 Cm <6 Cm

EvaluateBiochemicallyAnd Operate

EvaluateBiochemically

BiochemicallyActive

Operate

BiochemicallyInactive

Repeat Scan In3, 6, 18, and 36Months

Larger

EvaluateBiochemicallyAnd Operate

Unchanged

Observe

Pure Cyst

Remove Fluid

Clear Bloody

Observe EvaluateBiochemicallyAnd FollowAs For SolidTumor

Decision Matrix of the Incidental Adrenal Mass on CT or MRI Scan

If the Decision is to Observe?

• Will The Mass Become Malignant?

• Will The Mass Become Hypersecretory?

National Institutes Of Health: Management Of The Clinically InapparentAdrenal Mass (Incidentaloma). Final Statement. July 16, 2002

Incidental Adrenal MassRisk of Progression

Adrenal Hyperfunction: Unlikely If Lesion < 3 cmCortisol Hypersecretion Most Likely Disorder 4% After 1 Year9.5% Within 3 YearsThe Risk Of Tumor Hyperfunction Appears To Plateau After 3 Years

Mass Enlargement:8% After 1 Year18% After 5 YearsMost Enlargement Occurred Within 3 Years

Take Home Points…

Incidental Adrenal MassGood history and physical examSize and HU units Important>4 cm Surgical Removal after workupExclude Hypersecretion:24 Urine Free CortisolPlasma Free MetanephrinesPotassium and Aldo/Renin

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