What are the diagnostic approaches and treatments for Cushing's syndrome versus pheochromocytoma?

Symptoms and Diagnostic Approaches for Cushing's Syndrome versus Pheochromocytoma

The key distinguishing features between Cushing's syndrome and pheochromocytoma are their characteristic symptom patterns, with Cushing's presenting with central obesity, striae, and metabolic abnormalities, while pheochromocytoma typically manifests with paroxysmal hypertension, headaches, palpitations, and sweating.

Clinical Presentation

Cushing's Syndrome

• Physical findings:

  • Central obesity with redistribution of fat (buffalo hump, supraclavicular fat pads)
  • Purple/red abdominal striae
  • Facial plethora and moon facies
  • Muscle weakness and proximal myopathy
  • Hirsutism and menstrual irregularities in women
  • Thin, fragile skin with easy bruising
  • Dorsal fat pad ("buffalo hump")

• Metabolic manifestations:

  • Hypertension (70-90% of patients) 1
  • Glucose intolerance/diabetes mellitus
  • Dyslipidemia
  • Sleep apnea
  • Osteoporosis/pathological fractures
  • Mood disorders (depression, irritability)

Pheochromocytoma

• Classic triad (high diagnostic specificity of 90%): 1

  • Headaches
  • Palpitations
  • Sweating (often described as "cold sweat")

• Blood pressure patterns:

  • Paroxysmal hypertension (episodic spikes)
  • Sustained hypertension in up to 50% of cases 1
  • Orthostatic hypotension in epinephrine-predominant tumors 1
  • Marked blood pressure variability (independent risk factor for cardiovascular morbidity) 1

• Other symptoms:

  • Pallor during attacks
  • Anxiety/panic attacks
  • Piloerection
  • Weight loss (contrasts with weight gain in Cushing's)
  • Tremor
  • Flushing

Diagnostic Approach

Initial Screening Tests

For Cushing's Syndrome:

1. 1-mg overnight dexamethasone suppression test (DST) 1, 2

   • First-line screening test
   • Cutoff of ≤50 nmol/L (≤1.8 μg/dL) to exclude cortisol hypersecretion
   • Failure to suppress cortisol suggests Cushing's syndrome

2. 24-hour urinary free cortisol (UFC) 1

   • Collect at least two samples
   • Elevated levels support diagnosis of Cushing's syndrome

3. Late night salivary cortisol (LNSC) 1

   • Collected at 11 PM-midnight
   • Elevated levels indicate loss of normal diurnal cortisol rhythm

For Pheochromocytoma:

1. Plasma free metanephrines or 24-hour urinary fractionated metanephrines 1, 2

   • Gold standard screening test (sensitivity 96-100%, specificity 89-98%)
   • Levels >2-4 times upper limit of normal strongly suggest pheochromocytoma
   • False positives can occur with obesity, OSA, and certain medications (e.g., tricyclic antidepressants)

2. Clonidine suppression test 1

   • Used to differentiate true positives from false positives
   • Failure to reduce plasma metanephrines by 40% is diagnostic (100% specificity)

Confirmatory Testing

For Cushing's Syndrome:

1. ACTH levels 1

   • To differentiate ACTH-dependent (pituitary or ectopic source) from ACTH-independent (adrenal) causes
   • Low/suppressed ACTH suggests adrenal source
   • Normal/elevated ACTH suggests pituitary or ectopic source

2. High-dose dexamethasone suppression test

   • Helps differentiate pituitary from ectopic ACTH sources

   • 50% suppression suggests pituitary source

3. CRH stimulation test

   • Pituitary tumors typically respond with increased ACTH
   • Ectopic sources typically don't respond

For Pheochromocytoma:

• Biochemical diagnosis should be established before imaging 1
• Imaging should only be pursued after biochemical evidence is obtained

Imaging Studies

For Cushing's Syndrome:

1. MRI of pituitary (for ACTH-dependent cases)
2. CT/MRI of adrenal glands (for ACTH-independent cases)
3. Chest/abdominal CT (for suspected ectopic ACTH source)

For Pheochromocytoma:

1. CT or MRI of abdomen/pelvis 1, 2

   • First-line imaging modality
   • CT with contrast washout studies can help characterize adrenal masses

2. Functional imaging 1

   • Indicated for suspected metastatic disease or high risk for metastases
   • Options include FDG-PET/CT, MIBG scintigraphy

Treatment Approaches

Cushing's Syndrome

1. Surgical management:

   • Transsphenoidal surgery for pituitary adenomas
   • Adrenalectomy for adrenal tumors
   • Resection of ectopic ACTH-producing tumors

2. Medical therapy (when surgery is contraindicated or as bridge to surgery):

   • Ketoconazole or metyrapone (steroidogenesis inhibitors)
   • Mifepristone (glucocorticoid receptor antagonist)
   • Mineralocorticoid receptor antagonists (spironolactone/eplerenone) are most effective for hypertension management 1

3. Radiation therapy (for pituitary tumors when surgery fails)

Pheochromocytoma

1. Preoperative management:

   • Alpha-blockade with phenoxybenzamine 3 or doxazosin (2-3 weeks before surgery)
   • Beta-blockade only after adequate alpha-blockade if tachycardia persists 3
   • Volume expansion and high-salt diet

2. Surgical management:

   • Complete surgical resection (R0) is the mainstay of curative treatment 1
   • Laparoscopic approach for smaller tumors
   • Open surgery for larger tumors or those with concerning features

3. Management of metastatic disease:

   • Radiopharmaceuticals (131I-MIBG)
   • Combination chemotherapy (CVD: cyclophosphamide, vincristine, dacarbazine)
   • Locoregional ablative procedures 1

Important Clinical Pitfalls

1. Diagnostic delays:

   • Average 3-year delay in diagnosing pheochromocytoma 1
   • Missed pheochromocytomas contribute to 55% of deaths in autopsy studies 1

2. Rare but important associations:

   • ACTH-secreting pheochromocytomas can cause Cushing's syndrome 4, 5, 6
   • Always consider genetic syndromes in young patients with either condition

3. Perioperative management:

   • Failure to identify pheochromocytoma before surgery can lead to life-threatening hypertensive crisis
   • Inadequate glucocorticoid coverage for Cushing's patients can lead to adrenal crisis

4. Follow-up requirements:

   • Lifelong surveillance recommended for malignant pheochromocytoma 1
   • Regular monitoring for recurrence in both conditions

5. Medication interactions:

   • Many medications can cause false positive metanephrine results
   • Dexamethasone can worsen hypertension and glucose intolerance in undiagnosed pheochromocytoma 7

By understanding these distinct clinical presentations and following appropriate diagnostic algorithms, clinicians can effectively differentiate between these two important endocrine causes of secondary hypertension and implement appropriate treatment strategies to reduce morbidity and mortality.