A Case Of Cushing’s Syndrome associated with

Pheochromocytoma

Dr. Sanam Shorey

PGY5 Endocrinology Fellow

University of Western Ontario

Outline

1. Case Report

2. Ectopic ACTH Syndrome

3. Case Reports of Cushing’s Syndrome associated with Pheochromocytoma.

4. Patient Follow-Up

History 43 yr old healthy female

PMHX: Depression

Med’ns: Elavil

Nov 18th/02 admitted Markdale Hospital:

One week hx LUQ pain, Fever, N/V

Intermittent palpitations, headaches, diaphoresis past yr

History (Cont’d)

2-3 month preceding hx:• facial fullness• facial hirsutism• alopecia • irregular periods• wt gain noted primarily in the abdomenal • area

Physical Examination

Bp 205mmHg/105mmHg, HR: 100 regular, RR 14 and afebrile

General exam revealed obese lady

Head and neck: moon like facies, acanthosis nigricans, and hirsutism of the upper lip and chin. Her hair was moist and quite thin. The thyroid exam was unremarkable.

Cardiac exam was normal outside of sinus tachycardia.

Respiratory exam revealed bronchial breath sounds in the left lower base.

Physical Examination (Con’td)

The abdomen was protuberant with striae, however they were not violaceous in appearance. There was generalized tenderness in all quadrants with no evidence of hepatosplenomegaly.

Neurological exam was normal except for mild proximal muscle weakness.

The remainder of the examination was normal.

LABS

Normal Electrolytes

Normal Creatinine

Liver enzymes normal

Mild elevation in WBC count (11)

LABS (CONT’D)

AM cortisol 2644 (am170-660 nmol/L)

Cortisol PM 1312 (½ am range)

Urinary 24 hr free cortisol 400 (l50-220 nmol/d)

Plasma DHEA 5.3 (<6.5 umol/L)

Plasma total testosterone 3.2 (1.0-2.5 nmol/L)

Free testosterone 2.3 (1.0-17.5 pmol/L)

Plasma aldosterone 547 (110-860pmol/L standing28-444pmol/L supine)

LABS (CONT’D)

Urinary 24 h VMA 366 (10-35 µmol/d)

Urinary 24 h E: 5078.7 (< 60 nmol/d)

Urinary 24 h NE: 5645 (< 600 nmol/d)

Urinary 24 h M 107.3 (< 5.5 µmol/d)

Urinary 24 hr Dop: 445 (< 2500)

Investigations (Cont’d)

Chest X-ray : LLL Consolidation. CT Abdomen: 11.6 cm AP by 9.9 cm transverse left

suprarenal mass left sided pleural effusion left lower lobe consolidation no enlarged lymph nodes detected.

Treatment

IV fluids for rehydration

IV Cefuroxime and oral Azithromycin

Atenolol 100mg pood for hypertension!!!!

subsequently discharged a few days later on oral Ceftin and Atenolol.

HISTORY (CONT’D)

November 25th ( a few days post discharge) readmitted to Markdale hospital

woke up with a terrible headache

in Hospital had a seizure and was sent to their ICU

her family mentioned she had worsening episodic headaches, diaphoresis and palpitations since being discharged

polyuria and polydipsia as well over this time

PHYSICAL EXAM

BP 210mmhg/110mmhg with a mild orthostatic drop., P: 96, Afebrile

she was confused with decreased LOC but still able to protect her airway

PERLA and there was no evidence of papilledema

no nuchal rigidity was noted

no focal neurological signs were detected

LABS creatinine 730 (120 prior admission)

K: 5.1, Na 137

mild AG acidosis

BG: 26

CK :81800

AST: 3893.

Urine myoglobin was greater than 10,000 with urinalysis showing granular casts.

INVESTIGATIONS(CONT’D)

CT Head Normal

Lumbar puncture Normal

ECG showed Left anterior hemiblock with t-wave inversion.

Echocardiogram: hypokinesis of septum , apex and distal inferior wall of left ventricle EF: 35%.

Management

started on IV labetolol infusion, nitropatch 0.6mg/hr

insulin drip

Dilantin

Subsequently transferred to a tertiary ICU center with progressive renal failure and multi-organ dysfunction for potential need for dialysis

MANAGEMENT

IV nitroprusside, phentolamine and labetolol, as well as oral phenoxybenzamine were initially required for BP.

Therapy with the the catechol-O-methyl transferase inhibitor metyrosine was also instituted early, given the refractory nature of the hypertension and ongoing crisis.

Medications on discharge from the Intensive care unit were phenoxybenzamine, metoprolol, amlodipine, doxazosin, and metyrosine.

FURTHER IMAGING

An MRI was performed as well revealing the 10X12X12cm left adrenal mass which was displacing the left kidney inferiorly.

SURGICAL REMOVAL

After ensuring control of blood pressure , surgery was performed to remove the left adrenal tumor.

In addition due to the size of the tumor the spleen and the left kidney were also removed.

Adrenal Function Pre-Operative Intra-

Op Post-Operative (Immediate)

Post-Operative (approx 2-3 months)

Plasma Epinephrine < 50 Plasma Norepinephrine < 2800

226000 22800 428

Plasma Dopamine < 210

4095 2164 < 150

Urinary 24 h Epinephrine < 60 nmol/d

5078.7 11 < 10

Urinary 24 h Norepinephrine < 600 nmol/d

5645 153 254 (March) 317 (May)

Urinary 24 h Metanephrine < 5.5umol/d

107.3 3.7

Adrenal Function Pre-Operative Intra-

Op Post-Operative (Immediate)

Post-Operative (approx 2-3 months)

Plasma Cortisol am 170-660 nmol/L

2644 456 (Dec 19)

213 179

Cortisol PM ½ am range

1313 227 77

ACTH 0-18 pmol/L

4.4 1.91 3.1 11.4 11.2

Urinary 24 hr free cortisol 50-220 nmol/d

400 242

Plasma total testosterone 1.0-2.5 nmol/L

3.2 1.0

Lab values for adrenal function were taken either immediately preop, intraop as well as postop and showed an immediate decline of catecholamines and cortisol as well as a subtle rise in ACTH

Glucocorticoid therapy which was started during surgery was gradually tapered and discontinued within a few weeks post-operatively.

Pathological Report

The left adrenal gland mass was 11 X 11.5 X 10.5 cm.

Sectioning revealed a variegated tan-brown lesion with extensive necrosis, hemorrhage and cystic degeneration.

Capsule invasion was not identified extensive confluent necrosis was present as

were prominent mitotic figures.

Immunohistochemistry

Immunomarkers within tumor cells were positive for chromogranin and synaptophysin

The sustenacular cells around the tumor groups are positive of S-100 protein.

ACTH markers showed faint granular intracytoplasmic staining.

Incidental finding in kidney revealed a 3mm renal cell carcinoma raising the possibility of a Von-Hippel-Lindau syndrome.

Patient Disposition

Following surgery : blood sugars normalized Liver and renal function tests also

returned to normal. Sent home on labetolol.

Ectopic ACTH Syndromes

Comprises approx 10-20% of cases of Cushing’s Syndrome

Number of tumors that may cause ectopic ACTH production

Clinically divided into two categories

1) Malignant tumors: (eg. small cell ca lung)

2) Indolent cases occurring in pts with underlying neuroendocrine tumors such as bronchial carcinoids.

Malignant tumors

Clinically resemble Addison’s disease more than Cushing’s Syndrome

Duration of symptoms from onset of presentation is short (< 3months)

Wt loss, hyperpigmentation, myopathy, hirsutism and acne are prominent

ACTH levels and cortisol levels very high

Hypokalemic alkalosis and peripheral edema should alert physician to the diagnosis

Indolent Tumors Symptoms and signs are commonly present for 18

months from from onset to clinical presentation.

Typical features of Cushing’s disease

ACTH levels mildly elevated but may be normal with high serum cortisol

Hard to differentiate pituitary dependent Cushing’s disease from the indolent causes of ectopic ACTH production

Ectopic ACTH syndromes Pheochromocytoma

Very few reported cases

General consensus:

Relatively benign lesion where surgical intervention may be curative

Clinical symptoms and signs vary from typical cushingoid appearance to cases of hyperpigmentation, wtloss, profound hirsutism and acne

Majority were female, majority had left adrenal mass, onset of symptoms were rapidly progressing

Laboratory Testing Vary:

Majority of cases:

elevated plasma ACTH average 200’s (0-100pg/mol) Plasma DHEAS 300-400 (60-230ug/dl), plasma testosterone 95-200 (20-54 ng/dl)

All: were hypokalemic elevated cortisol levels, elevated 24 hr urine cortisol lack of adrenal suppression with dexamethasone

Pathology

Adrenocortical hyperplasia

Positive Immunostaining for ACTH

Other cases: Pheochromocytoma with hypercortisolemia

Retrospective study of 6 cases of adrenal cortical and medullary hyperplasia

pts here presented with features of P. alone elevated catecholamines and elevated 24 hr

samples of cortisol

Chen M, Lu G et al. 2002 J huazhong Univ Sci Technol Med Sci 22(4):367-368

Other cases Two reported cases of a mixed adenoma consisting

of adrenomedullary and cortical cells.

presenting with new onset diabetes and hypertension

pt was not cushingoid

Plasma cortisol and 24 hr urine levels elevated, Plasma ACTH normal

Dexamethasone Supression test did not supress cortisol or ACTH

Akai H, Sanoyama K et al. 1993 Nipporn Naibunpi Gakkai Zasshi Aug 20;69(7)659-69

Did our pt have either of these? Against Ectopic ACTH:

Clinically: not hyperpigmented, no wt loss Lab: ACTH normal, normal DHEAS, normal

testosterone, not hypokalemic on presentation

Pathology: adrenocortical hyperplasia absent

Against Adrenal tumor:

absence of real corticol histology supporting this.

Was this simply a hypercortisolemic response from the stress of the pheochromoctyoma?

Current Status: palpitations, headaches, diaphoresis and weakness

have resolved

periods regularized

she gained a few pounds since discharge but the weight is more generalized than before and has less facial fullness

was subsequently switched to diltiazem and is currently on no antihypertensives with a normal blood pressure

Current Status

A MIBG scan done post- operatively was negative.

We are currently following her by clinical exam and by repeating 24 hour collections of catecholamines and cortisol and are requesting a repeat MIBG in a year’s time