Multiple endocrine neoplasia (MEN) and carcinoid syndrome

1. Multiple Endocrine Neoplasia (MEN)

Overview

• Group of inherited diseases → proliferative lesions (hyperplasia, adenoma, carcinoma) of multiple endocrine organs.
• Compared to sporadic endocrine tumors, MEN tumors:
  • Occur at younger age.
  • Often multifocal.
  • Preceded by hyperplasia.
  • More aggressive.

2. MEN-1 (Wermer Syndrome)

Genetics

• Autosomal dominant.
• Mutation in MEN-1 gene at 11q13.
• MEN-1 = tumor suppressor gene encoding menin protein.
• Menin downregulates AKT-induced tyrosine kinase → suppresses proliferation.
• Loss of menin → uncontrolled proliferation.

Organs involved — “3 P’s”

1. Parathyroid hyperplasia → primary hyperparathyroidism (#1 manifestation).
2. Pituitary adenoma → prolactinoma (#1) or GH-producing adenoma.
3. Pancreatic islet cell tumor:
   • Leading cause of death in MEN-1.
   • Aggressive, metastasizes.
   • Functional tumors:
     • Gastrinoma → Zollinger-Ellison syndrome (multiple recurrent peptic ulcers).
     • Insulinoma → hypoglycemia.

3. MEN-2

Genetics

• All forms share activating mutations of RET proto-oncogene (chromosome 10q11.2).
• Autosomal dominant.

MEN-2A (Sipple Syndrome)

• Parathyroid hyperplasia → primary hyperparathyroidism.
• Bilateral medullary thyroid carcinoma (parafollicular C cells → calcitonin).
• Bilateral pheochromocytoma.

MEN-2B

• Mucosal neuromas (lips, tongue, GI).
• Medullary thyroid carcinoma (more aggressive than 2A).
• Pheochromocytoma.
• Intestinal ganglioneuroma.
• Marfanoid habitus (tall, long limbs).
• NO parathyroid involvement.

4. MEN Comparison Table

Feature	MEN-1	MEN-2A	MEN-2B
Eponym	Wermer	Sipple	—
Gene	MEN-1 (menin, 11q13)	RET	RET
Inheritance	AD	AD	AD
Parathyroid	✅ hyperplasia	✅ hyperplasia	❌
Pituitary	✅ adenoma	❌	❌
Pancreatic islet	✅ (gastrinoma, insulinoma)	❌	❌
Thyroid medullary	❌	✅ bilateral	✅
Pheochromocytoma	❌	✅ bilateral	✅
Mucosal neuromas	❌	❌	✅
Marfanoid habitus	❌	❌	✅

5. Carcinoid Syndrome

Definition

• Carcinoid syndrome = chemicals secreted by carcinoid tumors into the bloodstream cause systemic symptoms.
• Carcinoid tumor = slow-growing neuroendocrine tumor producing hormones.
• Most common location: GI tract (especially small intestine = ileum), then lungs.
• Most carcinoids of GI tract — only symptomatic when they metastasize to liver (liver normally inactivates hormones; mets bypass this filter).
  • Lung carcinoids cause syndrome without liver mets (drain into systemic circulation directly).

Pathophysiology

• Tumors secrete serotonin (5-HT) + kallikrein.
• Serotonin: ↑ peristalsis → less time for fluid absorption → diarrhea.
• Kallikrein → bradykinin → vasodilation → flushing.
• Chronic serotonin/5-HIAA exposure → fibrosis of right-sided heart valves.

Clinical Features

• Episodic flushing (face, neck).
• Diarrhea + abdominal cramping.
• Right-sided heart failure (tricuspid regurgitation + pulmonary stenosis from valvular fibrosis; cyanosis).
• Bronchoconstriction (wheezing, asthma-like).
• Sometimes jaundice (liver mets) + edema.

Diagnosis

• ↑ Urinary 5-HIAA (5-hydroxyindoleacetic acid = serotonin metabolite).
• CT/octreotide scan for tumor localization.

Treatment

• Octreotide (somatostatin analog) — suppresses serotonin release.
• Surgical resection.

💡 High-yield: MEN-1 (Wermer) = MEN1/menin, 3 P’s = Parathyroid hyperplasia + Pituitary adenoma + Pancreatic islet (gastrinoma, insulinoma); pancreatic tumors = #1 cause of death. MEN-2A (Sipple) = RET, parathyroid + medullary thyroid Ca + pheochromocytoma. MEN-2B = RET, mucosal neuromas + medullary thyroid + pheochromocytoma + marfanoid habitus (no parathyroid). All AD. Carcinoid syndrome = neuroendocrine tumor, #1 site ileum; syndrome requires liver mets (GI) or lung primary; secretes serotonin + kallikrein → flushing + diarrhea + right-sided heart failure + bronchoconstriction; diagnose with ↑ urinary 5-HIAA; Tx octreotide.