# Clinical Cases: Adrenal Medulla and Pheochromocytoma

## Case 1: Pheochromocytoma Presenting with Paroxysmal Hypertension

### Patient Demographics
- **Age:** 42 years
- **Sex:** Male
- **Occupation:** Construction foreman

### Chief Complaint
"I get these terrible episodes with headaches, sweating, and my heart racing."

### History of Present Illness
A 42-year-old man presents with a 6-month history of episodic symptoms occurring 2-3 times per week. During episodes, he experiences severe pounding headaches, profuse sweating, palpitations, and an overwhelming sense of anxiety or "impending doom." Episodes last 15-30 minutes and resolve spontaneously. He becomes pale rather than flushed during attacks. Between episodes, he feels generally well. His blood pressure at home ranges from 120-135/80 during asymptomatic periods but spikes to 200-220/110-120 during episodes. He notes that episodes can be triggered by bending over, lifting heavy objects at work, or straining during bowel movements. He has lost 10 pounds over 6 months despite normal appetite.

### Physical Examination (Between Episodes)
- **Vital Signs:** BP 142/88 mmHg (seated), 118/76 mmHg (standing - orthostatic drop), HR 78 bpm
- **General:** Appears anxious but well-nourished
- **Skin:** No hyperpigmentation, mild diaphoresis
- **HEENT:** Fundoscopic exam shows mild hypertensive changes
- **Cardiovascular:** Regular rhythm, no murmurs, normal heart sounds
- **Abdomen:** Soft, no palpable masses
- **Neurologic:** Normal

### Workup
- **Biochemical Testing:**
  - Plasma free metanephrines:
    - Metanephrine: 1.8 nmol/L (elevated, normal <0.5)
    - Normetanephrine: 4.2 nmol/L (markedly elevated, normal <0.9)
  - 24-hour urine fractionated metanephrines:
    - Metanephrine: 890 μg/24hr (elevated, normal <400)
    - Normetanephrine: 1,650 μg/24hr (elevated, normal <900)
  - 24-hour urine catecholamines:
    - Epinephrine: 45 μg/24hr (elevated)
    - Norepinephrine: 520 μg/24hr (elevated)
  - Chromogranin A: 380 ng/mL (elevated, normal <100)
- **Imaging:**
  - CT adrenal glands: 4.5 cm right adrenal mass, heterogeneous enhancement, 35 HU (not lipid-rich)
  - MRI: T2 hyperintense ("light bulb sign"), heterogeneous enhancement
  - I-123 MIBG scan: Intense uptake in right adrenal mass, no extra-adrenal uptake
- **Genetic Testing:** No pathogenic variant identified (sporadic case)
- **Additional Studies:**
  - Glucose: 142 mg/dL (elevated)
  - Calcium: Normal (rules out MEN2-associated hyperparathyroidism)

### Diagnosis
**Pheochromocytoma** (catecholamine-secreting adrenal tumor)

### Treatment
**PREOPERATIVE PREPARATION (Critical - 10-14 days before surgery):**
1. **Alpha-blockade FIRST:**
   - Phenoxybenzamine 10 mg BID, titrate up every 2-3 days
   - Target: BP <130/80 sitting, systolic >90 standing (adequate blockade without excessive orthostasis)
2. **Liberal salt and fluid intake:** To expand intravascular volume (counters chronic vasoconstriction-induced volume depletion)
3. **Beta-blockade ONLY AFTER adequate alpha-blockade:**
   - Propranolol 20 mg TID or metoprolol (for reflex tachycardia)
   - **NEVER start beta-blocker before alpha-blocker** (risk of unopposed alpha-mediated hypertensive crisis)
4. **Monitor for orthostatic symptoms** (indicates adequate alpha-blockade)
5. **Avoid triggers:** Certain medications (metoclopramide, opioids), abdominal palpation

**SURGICAL:**
1. Laparoscopic right adrenalectomy
2. Intraoperative arterial line monitoring
3. IV phentolamine and nitroprusside available for hypertensive surges during tumor manipulation
4. Expect hypotension after tumor removal (prepare volume and vasopressor support)

**POST-OPERATIVE:**
1. Monitor blood pressure (hypertension should resolve)
2. Monitor glucose (often normalizes)
3. Repeat plasma metanephrines at 2-4 weeks (confirm biochemical cure)
4. Annual biochemical surveillance (lifetime - recurrence possible)
5. Genetic counseling and testing (recommended for all patients)

### Clinical Pearl
Pheochromocytoma classically presents with the triad of episodic headache, sweating, and palpitations, often with paroxysmal hypertension. Plasma free metanephrines have >96% sensitivity, making a negative result essentially rule out the diagnosis. The "rule of 10s" has been updated: 30-40% of cases are now known to be hereditary (not 10%), mandating genetic testing for all patients. The principle of "alpha before beta" is critical in preoperative preparation - beta-blockade alone eliminates beta-2 vasodilation, leaving alpha-1 vasoconstriction unopposed, which can precipitate life-threatening hypertensive crisis. Phenoxybenzamine provides irreversible, long-acting alpha-blockade ideal for preoperative preparation. Surgical cure is possible in >90% of patients with benign tumors.

### Clinical Image
![Pheochromocytoma Histology](case_01_image.jpg)

*High-power microscopic image of pheochromocytoma showing characteristic nests of chromaffin cells (Zellballen pattern) with granular cytoplasm containing catecholamine-rich secretory granules.*

**Image Source:** Wikimedia Commons - "Pheochromocytoma histology"
**License:** CC BY-SA 3.0
**URL:** https://commons.wikimedia.org/wiki/File:Pheochromocytoma_-_very_high_mag_-_cropped.jpg

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## Case 2: Hereditary Pheochromocytoma - Von Hippel-Lindau Syndrome

### Patient Demographics
- **Age:** 28 years
- **Sex:** Female
- **Occupation:** Graduate student

### Chief Complaint
"I was told I might have a tumor because of my genetic condition."

### History of Present Illness
A 28-year-old woman with known Von Hippel-Lindau (VHL) syndrome presents for routine annual screening. Her VHL diagnosis was made at age 18 after genetic testing prompted by her father's history of renal cell carcinoma and cerebellar hemangioblastoma. She has been followed with annual surveillance. Previous screenings revealed a small retinal hemangioblastoma treated with laser photocoagulation at age 22. She reports recent intermittent headaches over the past 2 months, occasional palpitations, and episodes of sweating, particularly during exercise. She attributed these symptoms to stress from her dissertation work. No weight loss or tremor.

### Physical Examination
- **Vital Signs:** BP 155/95 mmHg (elevated for age), HR 92 bpm
- **General:** Healthy-appearing young woman
- **HEENT:** Fundoscopic exam shows prior laser scars, no active lesions
- **Cardiovascular:** Regular tachycardia, no murmurs
- **Abdomen:** Soft, no palpable masses
- **Neurologic:** Normal cerebellar function

### Workup
- **Biochemical Screening:**
  - Plasma free metanephrines:
    - Metanephrine: 0.3 nmol/L (normal)
    - Normetanephrine: 2.8 nmol/L (elevated - characteristic of VHL-associated pheochromocytoma)
  - Plasma epinephrine: Normal
  - Plasma norepinephrine: Elevated
- **Imaging:**
  - CT abdomen: Bilateral adrenal masses - 2.2 cm right, 1.5 cm left
  - MRI: Both masses T2 hyperintense
  - 68Ga-DOTATATE PET/CT: Avid uptake in both adrenal masses, no metastatic disease
  - MRI brain/spine: No new hemangioblastomas
  - Renal protocol CT: No renal masses
- **Genetic Confirmation:** VHL gene mutation (previously confirmed)

### Diagnosis
**Bilateral pheochromocytoma** in the setting of **Von Hippel-Lindau syndrome**

### Treatment
**SURGICAL APPROACH (Cortical-sparing to preserve adrenal function):**
1. Preoperative alpha-blockade followed by beta-blockade (standard protocol)
2. Bilateral cortical-sparing adrenalectomy (partial adrenalectomy)
   - Preserves zona fasciculata to maintain cortisol production
   - Reduces risk of lifelong adrenal insufficiency
   - Accepted approach for bilateral hereditary pheochromocytomas
3. If complete bilateral adrenalectomy required: Lifelong glucocorticoid and mineralocorticoid replacement

**VHL SYNDROME SURVEILLANCE (Lifelong):**
1. Annual plasma free metanephrines (pheochromocytoma recurrence)
2. Annual ophthalmologic examination (retinal hemangioblastoma)
3. Annual MRI brain and spine (CNS hemangioblastoma)
4. Annual abdominal imaging (renal cell carcinoma, pancreatic lesions)
5. Annual audiometry (endolymphatic sac tumor)

**FAMILY IMPLICATIONS:**
1. Cascade genetic testing for first-degree relatives
2. At-risk relatives: Begin surveillance at age 5-10 years
3. Genetic counseling regarding inheritance (autosomal dominant, 50% transmission risk)

### Clinical Pearl
VHL syndrome is caused by mutations in the VHL tumor suppressor gene and includes pheochromocytoma (20% penetrance), CNS and retinal hemangioblastomas, clear cell renal cell carcinoma, and pancreatic neuroendocrine tumors. VHL-associated pheochromocytomas characteristically secrete predominantly norepinephrine (not epinephrine) because of lower PNMT expression. They are frequently bilateral (50-80%) and virtually always benign. The recognition that 30-40% of all pheochromocytomas are hereditary has made genetic testing standard of care for all patients. Identifying germline mutations enables surveillance for associated tumors and cascade testing of family members. Cortical-sparing surgery aims to preserve adrenal function in bilateral cases, though recurrence risk necessitates continued surveillance.

### Clinical Image
![Pheochromocytoma Histology](case_01_image.jpg)

*Histologic appearance of pheochromocytoma showing chromaffin cells arranged in characteristic nests (Zellballen pattern), typical of both sporadic and syndromic tumors.*

**Image Source:** Wikimedia Commons - "Pheochromocytoma histology"
**License:** CC BY-SA 3.0
**URL:** https://commons.wikimedia.org/wiki/File:Pheochromocytoma_-_very_high_mag_-_cropped.jpg

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