Carcinoid Syndrome

A 55-year-old woman presents to the clinic with intermittent facial flushing, diarrhea, and wheezing for the past 6 months. She also reports crampy abdominal pain, nausea, and loose stools occurring 3 to 4 times daily, along with unintentional weight loss of 8 kg over 6 months. On examination, a holosystolic murmur at the left lower sternal border is heard on auscultation. Vital signs show blood pressure 120/80 mmHg, pulse 102/min, respiratory rate 18/min, oxygen saturation 92% on room air, and temperature 99.9°F. 24-hour urinary 5-HIAA is elevated. MRI of the abdomen and pelvis shows a small bowel mass with multiple liver metastases. Diagnosis?

Diagnosis is Carcinoid syndrome due to a metastatic small bowel neuroendocrine tumor.

1. Definition

Carcinoid syndrome is a clinical condition caused by systemic release of serotonin and other vasoactive substances from metastatic neuroendocrine tumors, most commonly after liver metastasis, leading to characteristic features such as flushing, diarrhea, and bronchospasm. It typically presents in the 5th to 7th decade.

2. Etiology

1. Midgut neuroendocrine tumors (most common), especially ileum or small intestine
2. Bronchial neuroendocrine tumors
3. Ovarian neuroendocrine tumors (can cause syndrome without liver metastasis)
4. Rarely pancreatic or other foregut tumors

3. Pathophysiology

1. Neuroendocrine tumors secrete serotonin, histamine, prostaglandins, and tachykinins
2. These substances are released into the portal circulation
3. The liver normally metabolizes them, preventing systemic effects
4. With liver metastasis, hepatic metabolism is bypassed
5. Circulating serotonin causes:
• Increased intestinal motility and secretion leading to diarrhea
• Vasodilation leading to flushing
• Bronchoconstriction leading to wheezing
6. Serotonin is metabolized to 5-HIAA, which is increased in urine
7. Tryptophan depletion leads to niacin deficiency (pellagra)

4. Clinical Features

4.1 Classic Features

1. Flushing (most common, episodic, triggered by stress, alcohol, or certain foods)
2. Watery diarrhea
3. Bronchospasm causing wheezing
4. Crampy abdominal pain

4.2 Cardiac Manifestations (Carcinoid Heart Disease)

1. Right-sided valvular lesions due to fibrotic plaques
2. Tricuspid regurgitation causing holosystolic murmur at LLSB
3. Pulmonic stenosis
4. May progress to right-sided heart failure
5. Left heart usually spared due to inactivation of serotonin in the lungs

4.3 Other Features

1. Weight loss and malnutrition
2. Malabsorption
3. Fatigue
4. Pellagra consisting of dermatitis, diarrhea, and dementia
5. Telangiectasia or persistent flushing
6. Mesenteric fibrosis leading to bowel obstruction or ischemia

5. Diagnosis

5.1 Biochemical Tests

1. 24-hour urinary 5-HIAA is the initial test of choice
2. Avoid serotonin-rich foods such as bananas, pineapples, walnuts, and avocados before testing
3. Chromogranin A is sensitive but nonspecific

5.2 Imaging

1. CT or MRI abdomen and pelvis for tumor localization
2. 68Ga-DOTATATE PET scan for highly sensitive detection
3. Somatostatin receptor scintigraphy as an alternative

5.3 Histology and Immunohistochemistry

1. Chromogranin A
2. Synaptophysin
3. Ki-67 index for tumor grading

5.4 Cardiac Evaluation

1. Echocardiography to assess valvular involvement

6. Management

6.1 First-line

1. Somatostatin analogs such as octreotide or lanreotide

6.2 Symptomatic Treatment

1. Avoid triggers such as alcohol, stress, and certain foods
2. Antidiarrheal agents such as loperamide
3. Correct dehydration and electrolyte imbalance
4. Niacin supplementation

6.3 Refractory Disease

1. Telotristat for persistent diarrhea
2. Peptide receptor radionuclide therapy (PRRT)
3. Targeted therapies such as mTOR inhibitors

6.4 Surgical

1. Tumor resection in localized disease
2. Debulking surgery in metastatic disease

6.5 Liver-directed Therapy

1. Hepatic artery embolization
2. Radioembolization
3. Ablation

7. Key Clinical Insight

Flushing + diarrhea + wheezing + elevated 5-HIAA + liver metastasis = carcinoid syndrome

8. Exam Level Pearls

1. Small bowel neuroendocrine tumor with liver metastasis is classic
2. Right-sided heart lesions are characteristic
3. 5-HIAA is the key diagnostic test
4. Somatostatin analogs are first line for symptom control
5. Niacin deficiency results from tryptophan diversion
6. Left-sided heart involvement suggests bronchial tumor or right-to-left shunt
7. Severe cases may develop carcinoid crisis triggered by surgery or stress