This document provides information on pheochromocytoma, including: 1) It describes the history, epidemiology, clinical features, differential diagnosis, and "10% tumor rule" characteristics. 2) Biochemical testing using urine or plasma tests for metanephrines is described as the primary diagnostic method. Localization uses CT, MRI, or MIBG scans. 3) Extensive pre, intra, and postoperative management is outlined to prevent hemodynamic instability, including alpha-blockade, IV fluids, and monitoring. The goal of treatment is surgical removal which is often curative.

1. Dr G Praveen Chandra

3. HISTORY
 “dusky-colored tumor” from the Greek phaios, or
dusky.
 First published in 1886 by Felix Frankel, who described
a young woman suffering from intermittent attacks of
palpitations, anxiety, vertigo & headache.
 Successful surgical management of
pheochromocytoma was described in 1926 by both
César Roux and Charles Mayo.

4. Epidemiology
 Affects ≈0.2% of hypertensive individuals.
 Males and females are affected equally.
 The peak incidence in sporadic cases lies between the
ages of 40 and 50.
 Familial cases tend to be manifested earlier.

5. Clinical features
 The classic triad of headache, diaphoresis, and
palpitations.
 Hypertension is present in 90% of cases and may be
episodic or sustained { 50 % }.
 Only 0.5% of patients with hypertension and
suggestive features will ultimately prove to have the
disease.

6. Differential Diagnosis
 Hyperthyroidism,
 Hypoglycemia,
 CAD,
 Heart failure,
 Stroke,
 Drug-related effects,
 Panic disorder.

7.  “The 10% tumor”
 10% bilateral
 10% malignant
 10% extra-adrenal
 10% familial
 10% multi focal
 10% occur in children

8. BIOLOGICAL TIME BOMB
 Cardiac decompensation suggestive of acute MI –
precipitated by partial necrosis of the tumor with
sudden release of a bolus of epinephrine & NE into the
blood stream.
 Causes of paroxysms:
 Urination
 Vigorous physical exercise
 Defecation
 Sexual intercourse
 Ingestion of alcohol

9.  In unprepared pts. , lethal paroxysms with inavasive
procedures like
 Angiography
 Labor & delivery
 Diagnostic needle biopsy
 GA
 Surgical procedures.

10. Diagnosis

11. Biochemical Diagnosis
 Detection of elevated levels of catecholamines
and their metabolites in body fluids.
 Measurement of 24-hour urine levels of these
compounds.
 In 2002, measurement of free metanephrines in
plasma was introduced as an alternative screening
tool
 High sensitivity ≈99%
 A one-time blood test.

12.  Tests performed during episodes of acute pain,
critical illness or urgent hospitalization may be
misleading.
 Biochemical testing is ideally performed when
the patient is as free as practically possible of all
confounding factors.

13.  A urine collection may be considered positive if
total metanephrines or any single catecholamine
fraction (epinephrine, norepinephrine or
dopamine) is elevated above its cutoff value.
Clonidine suppression testing:
 Measurement of plasma free normetanephrine
levels after the oral administration of 0.3 mg of
clonidine may help clarify equivocal test results.

15. Localisation
CT:
 Better anatomic definition for operative planning.
 Images the normal contralateral gland.
 But additional extra adrenal pheochromocytomas may
be overlooked.
 Routine scan from the diaphragm to atleast below the
bifurcation of the aorta.

16. MRI:
 Lack of radiation exposure
 Clear definition of surrounding vascular structures.
Disadvantages:
 Relative lack of availability
 Claustrophobia
 Cost
 Anatomic detail

17.  Both CT & MRI provide excellent images of the liver &
periaortic lymph nodes { in metastatic disease }.

18. MIBG scanning:
Scintigraphy with 131I- or 123I-labeled
metaiodobenzylguanidine
 To image or search for bilateral tumors as in
MEN type 2 syndromes.
 To identify multiple tumors.
 Mediastinal, intracardiac tumors & bone metastases.
Unfortunately,
 Thyroid must be blocked by oral iodine consumption
 Repaeted scans required for ≈3 days.
 Location not precise.

19. MIBG
scan

20. PET:
 With the use of novel 18F-labeled catecholamine
analogues – more sensitive.

21. Perioperative Care

22. Preoperative Management
 Perioperative mortality rates in the treatment of
pheochromocytoma from 50% in the 1st half of 20th
century to ≈2% now.

23.  Adverse changes:
 Intraoperative HTN:
 Stimulation of catecholamine release by
 anesthetic induction agents &
 direct manipulation of the tumor.
 Postoperative hypotension.
 Peripheral arterial vasodilation
 Dramatic increase in venous capacitance.
Cardiovascular collapse

24.  As soon as the biochemical diagnosis of
pheochromocytoma has been confirmed, α-adrenergic
blockade is initiated to protect against hemodynamic
lability.
 Phenoxybenzamine:
10 mg twice daily. The dosage can be titrated
upward every 2 to 3 days to a maximum of 40 mg three
times daily to achieve normalization of heart rate and
blood pressure.
 The period of preoperative conditioning lasts at least 2
weeks to allow adequate reversal of α-adrenergic
receptor down-regulation.

25.  Phenoxybenzamine is a nonspecific, noncompetitive
(irreversible), long-acting (half-life of 24 hours) α-
adrenergic antagonist.
 Nasal congestion - indicator of adequate blockade.
 Phenoxybenzamine provides the most complete α-
blockade.
 Its pharmacokinetics permits serum drug levels to
decay in parallel with catecholamine levels
postoperatively
Side effects:
 postural hypotension
 nasal congestion

26.  Alpha 1-selective agents – prazosin & doxazosin.
 Calcium channel blockers.
 β-Blockers may be administered after adequate α-
blockade has been achieved in the subset of patients with
persistent tachycardia.
 3 days preoperatively
 Propranolol - 10 mg thrice daily

27.  Combined alpha & beta blockade - Labetalol
 Cardioselective agents:
 Atenolol
 Metoprolol
 Preoperative volume expansion with isotonic fluids

28. Intraoperative management
 Invasive hemodynamic monitoring.
 Meticulous Fluid management.
 Minimum manipulation of the tumor.
 Anesthetic team must be prepared to administer
supplemental IV α-and β-blockers, as well as
vasopressors, when necessary.

29.  Control of acute HTN:
Sodium nitroprusside
Intermittent small doses of Esmolol.
 Hypotension coincident with tumor excision:
Dopamine
Short bolus administration of
Ephedrine or Phenylephrine

30.  Blood infusion.
 Ventricular arrhythmias
Lidocaine – bolus followed by a constant infusion.

31.  Surgery is curative in greater than 90% of
pheochromocytoma cases.
 Laparoscopic approach.
 Laparoscopic resection is contraindicated when
preoperative imaging demonstrates local invasion.

32. Postoperative management
 Need for vasopressors….
 Monitoring in an ICU for 24 hrs
 24 hr urine collection for matanephrines &
catecholamines after 2 weeks.
 Similar annual screening for atleast 5 yrs.

34. Primary hyperaldosteronism
 Jerome Conn, an endocrinologist at the University
of Michigan, in 1954.
 Characterised by
 Excessive secretion of aldosterone from one or both
adrenal glands.
 Suppression of plasma renin activity { PRA }.

35.  Resistant hypertension
 Hypokalemia in severe or late-stage disease.
 Prevalence….?????
 ≈ 1%
 ≈7%

36.  Mean age at diagnosis ≈ 50
 Mild male predilection.
 Most patients are asymptomatic.
 If significant hypokalemia,
 muscle cramps, weakness, paresthesias

37.  Typically moderate to severe hypertension that is
refractory to medical therapy.
 Require two to four antihypertensive medications.
 Responsiveness to spironolactone may be seen, a
feature that is predictive of a good response to surgical
treatment.
 Coexistent with:
 Hyperparathyroidism
 Prolactinoma

38.  Significantly increased risk for stroke, MI, AF &
LVH.
 Causes of primary hyperaldosteronism:

39. Biochemical Diagnosis &
Localization
 Biochemical screening should be performed in all
patients with
 hypertension and unexplained hypokalemia,
 hypertension sufficiently resistant to medical
therapy to warrant investigation for secondary
hypertension.
 Ratio of plasma aldosterone concentration { PAC }
to plasma renin activity { PRA }.

40.  Cutoff value for the ratio - 30
 Inclusion of an absolute aldosterone concentration of
greater than 15 mg/dL increases the specificity of
initial screening.
 Patients who test positive and are younger than 30
years are genetically screened for glucocorticoid-
remediable aldosteronism
(familial hyperaldosteronism type 1), especially if they
have a family history of early-onset hypertension.

41.  Confirmatory biochemical testing is aimed at
demonstrating inappropriately high (nonsuppressible)
aldosterone levels by creating a state of
hypervolemia/sodium excess.
 This is done with
 IV saline loading (2-3 L of isotonic saline given over a 4-
to 6-hour period, followed by measurement of plasma
aldosterone) or
 oral salt loading (200 mEq=5000 mg sodium daily over a
3-day period, followed by measurement of 24-hour urine
aldosterone excretion).
 High-dose fludrocortisone (0.1 mg every 6 hours)
during oral salt loading to increase the specificity of
suppression testing….??

43.  Initial Localization with
Thin-cut (3 mm)
adrenal computed
tomography .

44. Selective adrenal venous
sampling
 90% technical success rate in experienced hands.
 Applied in all cases in which-
 biochemical diagnosis of primary hyperaldosteronism
has been confirmed &
 thin-cut adrenal CT reveals either no abnormalities or
bilateral abnormalities.
 Simultaneous measurement of cortisol and
aldosterone levels in the peripheral circulation, as well
as the left and right adrenal veins

45.  Greater than a fivefold elevation in cortisol
concentration in a sample relative to peripheral blood
indicates successful cannulation of an adrenal vein
(positive control).
 Lateralization is indicated by an unbalanced ratio of
aldosterone to cortisol in the left and right adrenal
veins, with a fourfold greater ratio on one side than on
the other identifying the culprit gland.

46. Successful , Lt. adrenal
lateralized
Successful ,
Non lateralizing
Failed study

47.  Functional scanning with radiolabeled 131I-6-β-
iodomethylnorcholesterol (NP-59) may be considered
as a third-line localization test for patients without
conclusive lateralizing information on either CT or
adrenal venous sampling.
 The sensitivity of NP-59 scanning is low in small
tumors.

48.  Laparoscopic adrenalectomy is the preferred
procedure for the management of aldosteronoma as
with most other adrenal tumors.
 As soon as 24 hours after successful surgery,
 Reductions in
 blood pressure
 antihypertensive medication requirements
 plasma/urine aldosterone levels
 resolution of hypokalemia (if previously present)

49.  More than 80% of patients can expect either
normalization of blood pressure or a significant
reduction in antihypertensive medication
requirements.
 Stop all antihypertensive medications immediately
after surgery, with the exception of β-blockers, which
must be tapered.
 Medications may be added back temporarily as
needed.

50. Preoperative features with
reduced benefit from
surgical treatment:
• male,
• age older than 45 years,
• family history of hypertension,
• long-standing hypertension &
• no response to spironolactone.

52.  Harvey Cushing, in 1912, described a young woman of
“extraordinary appearance” in whom obesity,
hirsutism, amenorrhea, easy bruising, and extreme
muscle weakness developed.
 The principal differential diagnosis to be considered
when evaluating patients for Cushing's syndrome is
obesity.
 5-fold excess in mortality - hypertension (present in
>70% of cases), hyperglycemia & truncal obesity.

53.  The most common cause of Cushing's syndrome is
pharmacologic glucocorticoid use for the treatment of
inflammatory disorders.
 Endogenous Cushing's syndrome is rare, with 5 to 10
individuals affected per million-
 Cushing's disease (75%) , glucocorticoid excess caused
by an ACTH-hypersecreting pituitary adenoma ,
 ectopic ACTH syndrome (<10%), from either
neuroendocrine tumors or bronchogenic malignancies
in the thorax.
 primary adrenal Cushing's syndrome (15%)

54. Cushing’s
syndrome
Iatrogenic Spontaneous
Corticotropin
dependent
Pituitary
dependent
Cushing’s disease
{ 70% }
ECTOPIC
Cushing’s
syndrome {10% }
Corticotropin
independent
Unilateral cortisol
secreting
adrenocortical
Adenoma { 10% }
Carcinoma
{ < 10% }
Primary adrenal
hyperplasia
{ < 1% }

55. SIGNS & SYMPTOMS %
Obesity 90
Hypertension 80
Menstrual disorders 70
Hirsutism 70
Facial plethora 70
Neuropsychiatric symptoms 60
Impotence 60
Muscular weakness 60
Cutaneous striae 60
Bruising 40
Acne 30
Headache 10

57. Metabolic manifestataions %
Hyperlipidemia 70
Abnormal OGTT 70
Lymphocytopenia, Eosinopenia 50
High HCT & Hb 40
Hypercalciuria 30
Diabetes 15

58. Diagnosis
 Diagnosis of Cushing's syndrome relies on
demonstration of inappropriate cortisol secretion or
loss of physiologic negative feedback.
 Normally, cortisol release follows a predictable
circadian rhythm.
 Inappropriate cortisol secretion can be detected as
either elevated cortisol release over a 24-hour period or
a higher than expected level in the late evening.
 Recent advent of late evening salivary cortisol testing.

59.  More than 90% of circulating cortisol is bound to
plasma proteins.
 Unbound cortisol can be detected in urine and
saliva.

61. Surgical Management-Outcomes
 Primary adrenal Cushing's syndrome –
Adrenalectomy -90% effective
 Cushing's disease - Pituitary microsurgery via a
transnasal transsphenoidal approach - 75% successful
in experienced hands.
 Remission rates may be improved by reoperation or
pituitary irradiation in patients whose basal cortisol
levels do not fall appropriately after initial surgery.
 Laparoscopic bilateral adrenalectomy is considered for
patients in whom pituitary surgery has failed.

62.  Ectopic Corticotrophin syndrome:
 Complete resection of the tumor if localized.
 Medical treatment:
 Ketoconazole { 600 – 1200 mg/day orally }
 Mitotane { 2 – 4 g/day orally }
 Aminoglutethimide + Metyrapone
 Mifepristone

63.  For patients undergoing adrenalectomy for Cushing's
syndrome, perioperative “stress dose” steroids
(hydrocortisone, 100 mg IV every 8 hours for 24
hours).
 Perioperative antibiotics for 24 hours.
 Prophylactic anticoagulation using LMWH or
unfractionated heparin for atleast 2 weeks is to be
started 6-8 hrs postoperatively.

64.  After resection of a solitary adrenal Cushing's
adenoma, steroids can usually be tapered to
physiologic replacement levels over the course of
several weeks.

65. Management of patients who undergo pituitary surgery
for Cushing's disease
 Glucocorticoids are withheld during the immediate
postoperative period to provide a window during
which early remission may be assessed.
 A subnormal morning cortisol level on postoperative
day 1 or 2 is indicative of cure.
 Glucocorticoid supplementation is then resumed, for
at least 6 months, until the HPA axis recovers.
 Significant risk for postoperative adrenal crisis in
patients with Cushing's syndrome of all subtypes.

67. Renal artery stenosis
Small vessel disease
• Vasculitis
• Atheroembolic renal infarction
• Thrombosis & infarction
Traumatic injury
• Renal fracture
• Perirenal fibrosis
• Radiation injury
AV malformation/fistula
Other diseases
• Renal Ca.
• Enlarging renal cyst
• Multiple renal cysts
Renin-secreting tumors

68. Renovascular occlusive disease
 5% of hypertensive people have renovascular
hypertension.
 Among patients with diastolic blood pressure greater
than 115 mm Hg, the prevalence of renovascular
hypertension is 15% to 20%.
 Among children younger than 5 years of age, the
prevalence approximates 75%.

69.  Recognition and correction of large artery renal
occlusive disease can result in impressive improvement
in blood pressure control and preservation of renal
function.
 Causes of renovascular occusive disease:
 Atherosclerosis
 Fibromuscular dysplasia
 Takayasu’s arteritis
 Radiation vasculitis
 Neurofibromatosis
 Thromboembolism

71. Clinical correlates
1. Severe hypertension—diastolic >115 mm Hg
2. Refractory hypertension
3. New onset of sustained hypertension at age <20 yr, female age <50 yr
4. Hypertension and epigastric or flank bruit
5. Moderate progressive or severe hypertension in patients with
manifestations of systemic atherosclerosis and unexplained stable or
progressive renal insufficiency
6. Malignant hypertension or hypertensive crisis
7. Dramatic normalization of blood pressure by angiotensin-converting
enzyme inhibitor
8. Increase in serum creatinine with blood pressure improvement

72. Screening Studies for
Renovascular Occlusive Disease
Renal ultrasound to assess kidney size, alternative diagnoses
(cysts, hydronephrosis)
Renal artery duplex ultrasound
Renal scintigraphy with captopril
Magnetic resonance imaging
Arteriography

73. Therapy
 Medical therapy
 Percutaneous transluminal renal angioplasty
{ PTRA } / Stent.
 SURGERY.

75. Coarctation of the aorta
 One of the most frequently encountered congenital
cardiac lesions.
 A wide range of presentations, from the severely
symptomatic newborn with CHF and depressed
ventricular function to the adult with proximal
hypertension and minimal symptoms.

76.  Significant upper-lower extremity blood pressure gradient and
diminished or absent femoral and pedal pulses.
 In older patients with well-developed intercostal collateral
arteries, a continuous murmur may be auscultated over the
posterior thorax.

78. Bibliography
 TEXTBOOK OF ENDOCRINE SURGERY /
ORLO CLARK, QUAN-YANG DUH, ELECTRON
KEBEBEV, 2nd ed.
 Sabiston Textbook of Surgery, 18th ed.