Endocrine System Pancreatic Neoplasms & MEN Syndromes

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Endocrine SystemPancreatic Neoplasms MEN
Syndromes

• Adriana Acurio, M.D.
• Department of Pathology

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Endocrine Pancreas Histology

• The endocrine pancreas is composed of cell
  aggregates, the islets of Langerhans, scattered
  throughout the exocrine tissue.
• The islets of Langerhans are composed of
• b-cells (75)? insulin, stimulate glycogen
  synthesis
• a-cells (20)? glucagon, stimulate glycogenolysis
• d-cells (5) ? somatostatin, suppress insulin and
  glucagon release
• Pancreatic polypeptide cells ? stimulate chief
  cell in gastric glands and inhibits bile and
  bicarbonate secretion
• D1 cells ? Vasoactive intestinal polypeptide
  (VIP), induces glycogenolysis /hyperglycemia and
  GI fluid secretion
• Enterochromaffin cells ? serotonin

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Islets of Langerhans
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Pancreatic Endocrine Neoplasms

• Represent 2 of all pancreatic neoplasms,
  majority of pancreatic neoplasms occur in the
  exocrine pancreas
• Occur mostly in adults
• Exhibit variable biologic behavior (benign or
  malignant). Malignant forms a defined by presence
  of metastases, vascular invasion, and local
  infiltration
• May produce hormones or be non-functional. Type
  of hormone produced has prognotic implications
• 90 of insulinomas are benign (most common)
• Up to 90 of other functioning and nonfunctioning
  tumors are malignant

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Insulinomas (Hyperinsulinism)

• Most common pancreatic endocrine neoplasm,
  originating from b-cells
• Clinical features (80 of cases)
• Hypoglycemic episodes cause confusion, stupor,
  and loss of consciousness, often induced by
  fasting or strenuous excercise
• Relieved by feeding or parenteral glucose
• Lab findings
• Blood glucose levels below 50 mg/dL
• Increased insulin and C-peptide levels
• Whipples triad Hypoglycemia, CNS symptoms and
  reversal by glucose administration

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Morphology of Insulinomas

• The majority are benign, may be single or
  multiple
• Often lt2 cm, encapsulated nodules
• Histologically,
• Have the appearance of enlarged islets, without
  disruption of normal architechture and no
  evidence of anaplasia (even in malignant cases)
• Amyloid deposition in extracellular is often seen

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Insulinomas Clinical Management

• Surgical removal of the tumor is usually followed
  by prompt reversal of the hypoglycemia
• Differential diagnosis should include abnormal
  insulin sensitivity, liver disease, ectopic
  production of insulin (fibromas and
  fibrosarcomas) and exogenous insulin (excess
  therapeutic or surreptitious)

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GastrinomaZollinger-Ellison Syndrome

• Tumor characterized by hypersecretion of gastrin
• Specific cell of origin is undetermined, tumors
  arise form endocrine cells in the gut or
  pancreatic islet cells
• The can arise anywhere within the Gastrinoma
  Triangle
• Patients present with multiple peptic ulcers
  which are resistant to treatment and can extend
  into jejunum

• The gastrinoma triangle Formed from cystic and
  common bile ducts superiorly, the junction of the
  second and third portion of the duodenum
  inferiorly and the junction of the neck and body
  of the pancreas medially

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Zollinger-Ellison Syndrome

• Hypergastrinemia (gastrinoma)
• Hypersecretion of gastric acid
• Severe peptic ulceration
• Diarrhea is present in over half of patients
• Treatment is focused on control of gastric acid
  secretion by H,K-ATPase inhibitors surgical
  resection of neoplasm

Multiple peptic ulcers
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GastrinomaZollinger-Ellison Syndrome

• The majority of these tumors are malignant and
  present with metastatic disease, usually to liver
  leading to hepatic failure in lt10 years
• One fourth of these tumors are multifocal and
  arise in association with MEN-1 syndrome
  (parathyroid adenomas/hyperplasia, pancreatic
  tumors, pituitary adenomas)

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a-Cell Tumors (Glucagonomas)

• Rare tumor
• Increased serum levels of glucagon results in
• Mild diabetes mellitus (hyperglycemia)
• Necrolytic migratory erythema
• Anemia
• Most frequently seen in peri- and postmenopausal
  women
• 60 of tumors are malignant, common metastasis to
  liver

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VIPomas

• Very rare tumors, that secrete vasoactive
  intestinal peptide (VIPoma)
• Presents with
• Watery diarrhea
• Hypokalemia
• Achlorhydria (low or absent gastric acid
  production)
• Syndrome also known as WDHA, Verner-Morrison or
  pancreatic cholera
• Surgery is usually curative, however, 1/3 of
  patients present with metastatic disease

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MEN Syndromes

• Multiple Endocrine Syndromes are autosomal
  dominant conditions characterized by hyperplasia,
  adenomas, and carcinomas of multiple endocrine
  organs
• In comparison to sporadic conditions, MENs
• Occur at a younger age
• Multiple endocrine organs are affected,
  synchronously or metachronously
• Within one organ, tumors appear multifocally
• Tumors are often preceded by hyperplasia
• Have aggressive biologic behavior

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Multiple Endocrine Neoplasm, Type 1Wermer
Syndrome

• Rare inherited disorder seen in 1/50K
• It affects the parathyroid, pituitary and
  pancreas (3Ps)
• Parathyroid The majority of the patients present
  with primary parathyroidism caused by hyperplasia
  and/or adenomas
• Pancreas Endocrine pancreatic tumors are the
  major cause of morbidity and mortality in
  patients with MEN-1. Multiple tumors are common
  with dominant lesions showing aggressive behavior
  and metastasis. Gastrinomas (Zollinger-Ellison
  syndrome) and insulinomas are most common
• Pituitary Prolactin and GH adenomas are most
  common

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Multiple Endocrine Neoplasm, Type 1Wermer
Syndrome

• In addition to the 3Ps patients also develop
  carcinoid tumors, thyroid and adrenocortical
  adenomas, and lipomas
• It results from germline mutations in MEN1 tumor
  suppressor gene. Its product, menin, regulates
  gene expression of a variety of cell cycle
  proteins
• Patients usually die as a result of the malignant
  behavior of one or more of the endocrine

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Multiple Endocrine Neoplasia, Type 2

• Composed of three well recognized syndromes
• MEN2A or Sipple Syndrome
• Familial Medullary Thyroid Cancer
• MEN2B

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MEN 2ASipple Syndrome

• Medullary carcinomas of the thyroid are
  multifocal and can show aggressive clinical
  behavior
• It is caused by germline mutations in the RET
  proto-oncogene, encodes a receptor tyrosine
  kinase that signals growth and differentiation.
  Gain of function mutations of RET cause
  constitute activation are present in MEN2A and 2B
• Loss-of-function mutations in RET result in
  Hirschsprung disease

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Familial Medullary Thyroid Cancer

• Variant of MEN-2A which predisposes to
  development of medullary thyroid cancer alone
• Familial medullary thyroid cancers develop at an
  older age compared to classic MEN-2 syndrome and
  follow a more indolent course

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MEN 2B

• MTC are very aggressive in these patients and
  leading cause of death
• RET gene point mutation leads to constitutive
  activation and signanling. Presence of mutation
  (in family members) warrants prophylactiv
  thyroidectomy

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MEN, 2B