Multiple Endocrine Neoplasias

Snapshot

• A 38-year-old women presents to the emergency department with 1 day of severe flank pain. She also notes that she has had intermittent watery diarrhea for the past few weeks. On physical exam the patient has mild abdominal tenderness to palpation, particularly in the epigastric region and upper left quadrant, as well as costovertebral angle (CVA) tenderness. Lab studies show hypercalcemia and an ultrasound shows the presence of a kidney stone. (Multiple endocrine neoplasia [MEN] type I)

Introduction

• Overview
  • cancer syndrome with severate associated endocrine neoplasias
  • 3 MEN types 
    • MEN I
    • MEN IIA
    • MEN IIB
• Genetics
  • All MEN syndromes haveautosomal dominant inheritance
    • MEN1 gene located on chromosome 11 
    • RET gene located on chromosome 10
• Epidemiology
  • prevalence
    • MEN I: 1 in 50,000
    • MEN II: 1 in 30,000
• Prognosis
• dependent on MEN type and which neoplasias occur in individual patient

Classification

• MEN I (Wermer syndrome)
  • MEN1 gene mutation
  • clinical definition: presence of 2 of the 3 P’s  
    • parathyroid tumors
      • increased PTH causes hypercalcemia
        • results in kidney stones
    • pituitary tumors (prolactin or GH)
    • pancreatic islet cell/endocrine tumors 
      • Zollinger-Ellison syndrome
        • causes gastric ulcers
      • insulinomas
      • VIPomas
        • part of watery diarrhea, hypokalemia, achlorhydria (WDHA) syndrome
      • glucagonomas
• MEN II
  • divided into MEN IIA and IIB
  • common features
    • medullary thyroid carcinoma
    • pheochromocytoma 
    • associated with RET proto-oncogene mutation  
      • gain of function mutation
  • MEN IIA (Sipple syndrome) 
    • medullary thyroid carcinoma
      • secretes calcitonin
    • pheochromocytoma
    • parathyroid tumors
  • MEN IIB
    • medullary thyroid carcinoma
    • pheochromocytoma
    • oral/intestinal ganglioneuromatosis
• associated with marfanoid habitus

Presentation

• Symptoms
  • dependent on which type of MEN syndrome
  • MEN I
    • flank pain
      • secondary to kidney stones
    • abdominal pain and dark stools
      • secondary to gastric ulcers
    • watery diarrhea
  • MEN II
    • neck pain, dysphagia, and hoarseness
      • secondary to thyroid mass
    • episodic headaches, palpitations, tremulousness, and anxiety
      • secondary to pheochromocytoma
• Physical exam
  • MEN I
    • costovertebral angle (CVA) tenderness
    • abdominal tenderness
  • MEN II
    • hypertension
    • tachycardia
    • neck mass or palpable thyroid nodule
• cervical lymphadenopathy

Imaging

• Ultrasound of neck
  • indications
    • patient with dysphagia or hoarseness
  • findings
    • thyroid nodule 
      • follow up with thyroid scintigraphy (radioactive iodine uptake scan)
• Magnetic resonance imaging (MRI) or computed tomography (CT) scan of abdomen
  • indications
    • patient with symptoms consistent with pheochromocytoma
  • findings
• adrenal gland mass

Studies

• TSH levels
  • to evaluate thyroid function
    • decreased TSH more concerning for malignancy
• Serum calcitonin
  • tumor marker for medullary thyroid cancer
• Free serum metanephrine level
  • elevated in pheochromocytoma
  • follow up with 24-hour urin collection
    • increased urine metanephrines
    • elevated vanillyl mandelic acid (due to breakdown of norepinephrine and epinephrine)
• Serum PTH and calcium levels
  • elevated in parathyroid tumor
• Serum glucose
  • elevated in glucagonoma
  • decreased in insulinoma
• Serum glucagon
  • elevated in glucagonoma
• Serum insulin and C-peptide
  • elevated in insulinoma
• Serum gastrin
• increased in gastrinoma

Treatment

• Medical
  • proton pump inhibitor
    • indications
      • Zollinger-Ellison syndrome
    • modalities
      • omeprazole
      • lansoprazole
• Surgical
  • thyroidectomy
    • indications
      • medullary thyroid cancer
        • MEN IIA or IIB
    • follow with thyroid hormone supplementation
  • parathyroidectomy
    • indications
      • parathyroid tumor
        • MEN I
  • duodenal-pancreatic surgery
    • indications
      • Zollinger-Ellison syndrome refractory to medical management
      • pancreatic neuroendocrine tumors
  • adrenalectomy
    • indications
      • pheochromocytoma
    • preoperative medications to prevent hypertensive crisis
      • must start with alpha blockade
      • follow with beta blockade
    • modalities
      • complete bilateral adrenalectomy is recommended to reduce risk of recurrence