Neuroendocrine tumors of the pancreas.

MARCO CASTILLO

DEFINITION:Epithelial neoplasms with neuroendocrine differentiation.Arise from omnipotent endocrine stem cells.Sheet of small round cells with uniform nuclei and cytoplasm.Chromogranin A +; Neuron specific enolase +; Synaptophysin +

Neuroendocrine tumors of the pancreas.

Epidemiology 1 case per 100,000 individuals per year. Represent 2 – 4% of clinical detected pancreatic tumors. Forth to sixth decade of life. GENETICS:

MEN1. 80 – 100% Von Hipple Lindau (VHL). 20% Neurofibromatosis 1 (NF-1). 10% Tuberous sclerosis complex (TSC). 1%

WHO Classification of Pancreatic Endocrine Tumors.

Well-Differentiated Endocrine Tumor

Type 1: Benign Behavior

Confined to the pancreas

<2 cm in diameter

<2 mitoses per high-powered field

<2% Ki-67–positive cells

No vascular or perineural invasion

Well-Differentiated Endocrine Carcinoma Low-grade malignant

Gross local invasion

Metastases

Type 2: Uncertain Behavior

Confined to the pancreas and one

of the following:

>2 cm in diameter

>2 mitoses per high-powered field

>2% Ki-67–positive cells

Vascular or perineural invasion

Poorly Differentiated Carcinoma High-grade malignant

>10 mitoses per high-powered field

TNM Classification for Pancreatic Neuroendocrine Tumors

T: Primary Tumor T0: No evidence of cancer

Tis: Carcinoma in situ

T2: Tumor limited to the pancreas, size >2 cm

T3: Tumor extends beyond the pancreas but does not involve the celiac axis or superior mesenteric artery

T4: Tumor involves celiac axis or superior mesenteric artery (unresectable primary tumor)

N: Regional Lymph Nodes N0: No regional lymph nodes involved

N1: Regional lymph nodes involved

M: Distant Metastases M0: No distant metastases

M1: Distant metastases

Stages 0: Tis N0 M0

IA: T1 N0 M0

IB: T2 N0 M0

IIA: T3 N0 M0

IIB: T1 N1 M0, T2 N1 M0, ……..T3 N1 M0

III: T4, any N, M0

IV: Any T, any N, M1

Types:Insulinomas.Gastrinoma.Glucagonoma.Vasoactive intestinal polypeptide–producing tumor (VIPoma).Somatostatinoma.Growth hormone– releasing factor–producing tumors (GRFomas).

Adrenocorticotropic hormone–producing tumors (ACTHomas).Parathyroid hormone–related protein producing tumors (PTHrpomas).Neurotensinomas.Non Functional:

Pancreatic polypeptide–producing tumor (PPoma).

Ghrelinomas.

Insulinoma. Most common type. Women (2:1) 50 - 60 years old. Benign. Solitary and small. Clinical presentation: Whipple’s triad:

Symptoms of hypoglycemia. Blood glucose < 45 mg/dL. Relief of symptoms with Glucose.

Symptoms of hypoglycemia:◦ Altered mental state.◦ Weakness.◦ Diplopia.◦ Seizures.◦ Coma.◦ Sweating.◦ Palpitations.◦ Anxiety.

Insulinoma. DIAGNOSIS:

Monitored 72 hours fast. Glucose < 50 mg/dL in < 48 hours.

Relief of symptoms with oral glucose.

Elevated insulin > 5 – 10 µU/mL.

Increase proinsulin level > 22 pmol.

Absence of sulfonylureas in plasma or urine.

Elevated C peptide levels.

LOCALIZATION:

CT scan.

Endoscopic ultrasound.

TREATMENT:

Enucleation of the tumor.

Dietary modifications.

Diazoxide or Octreotide.

Insulinoma.

Gastrinoma (Zollinger-Ellison Syndrome). 0.5 to 3 per million population per year Peak age of onset is 50 years Even with metastases: Good prognosis.

Clinical presentation:

Peptic ulcer disease: With diarrhea. Ulcers in unusual locations. Refractory to medication ulcers. Young age ulcer with complications. Disease associated with other endocrinopathies.

Abdominal pain.

Chronic diarrhea.

Heartburn.

Nausea.

Vomiting.

Bleeding.

Esophageal strictures.

Pyloric or duodenal scarring.

Bleeding.

Prominent gastric folds

Gastrinoma (Zollinger-Ellison Syndrome).

LOCATION: CT. Endoscopic ultrasound. Somatostatin Receptor Scintigraphy. Intraoperative palpation and Ultrasound.

DIAGNOSIS: Fasting gastrin level: > 100 pg/mL or >10 times higher

than upper limit. Secretin stimulation test: Gastrin > 200 pg/mL. Calcium infusion provocative testing: Gastrin > 395 pg/dL. Basic acid output level > 15 mEq/L.

TREATMENT: Enucleation.

Glucagonoma Male = Female. Age 50 – 60. Malignant 60 – 70 % Clinical presentation: Diabetes. Necrolytic migratory erythema. Deep vein thrombosis. Depression. Weight loss. Stomatitis.

Glucagonoma

LOCATION: Body and Tail CT, MRI, EUS.

DIAGNOSIS:

Fasting serum glucagon > 1000 pg/dL. Increase glucose. Decrease plasma amino acids. Anemia.

TREATMENT:Correction of metabolic deficits.Subtotal pancreatectomy + Splenectomy.Resection of metastases.Typically not resectable.

Vasointestinal peptide tumor (VIPoma)

Male > Female. Mean age 48. Benign 50%

Clinical presentation: Severe watery diarrhea. Hypokalemia. Achlorhydria. Metabolic acidosis.

Diagnosis:

VIP > 200 pg/mL

Location: Tail

CT or MRI.

Treatment:

Correction of electrolyte imbalance.

Somatostatin.

Partial pancreatectomy or debulkyng of the tumor.

Somatostatinoma. Rare, only 1% of the Neuroendocrine tumors.

Mean age: 50 years.

Men = Women.

Malignant: 60 – 70 %

Clinical presentation:

Hyperglycemia.

Cholelitiasis.

Steatorrhea.

Diarrhea.

Gastric hypochloridia.

Jaundice.

Diagnosis:

Fasting somatostatin > 30 pg/mL

Location: Head.

CT or MRI.

Endoscopic ultrasound.

Somatostatin receptor scintigraphy

Treatment:

Pancreatodudenectomy + Hepatic resection.

Octreotide.

Liver transplantation.

Growth hormone–releasing factor tumor (GRFoma).

Usually large > 6 cm.

Malignant.

30% has metastasis.

50% has also Zollinger-Ellison.

Clinical presentation:

Acromegaly.

Pancreatic mass.

Diagnosis:

Increase GRF by age.

Location: Lung, Pancreas, Jejunum, retroperitoneum.

CT.

Treatment:

Surgical resection.

Debulking prolong survival.

Octreotide for symptoms.

Represents > 75%. Women (2:1) Mean age: 45 Lack of hormonal clinical syndrome. 60 – 80% are metastatic at diagnosis. 60% are malignant. Clinical presentation: Asymptomatic. Abdominal pain. Jaundice.

Diagnosis: Serum: Pancreatic polypeptide, Neurotensin, Neuronspecific enolase, Chromogramin A. CT scan.

Treatment: Surgical resection +/- Partial liver resection.

Non functional neuroendocrine tumor

Clinical pearls: Neuroendocrine tumors.

CT and MRI are highly sensitive for identification of neuroendocrine tumors. Endoscopic ultrasonography is highly sensitive for detection of occult, subcentimeter pancreatic NETs.Somatostatin-receptor-scintigraphy (OctreoScan) offers whole-body imaging and functional information. It’s ability to detect subcentimeter tumors is limited. Chromogranin A is the most common hormone associated with all types of gastroenteropancreatic NETs. CgA or pancreatic polypeptide can be followed as tumor markers if elevated at baseline.

References: Tricia A, Moo-Young and Richard A. Endocrine tumors of the pancreas: clinical picture, diagnosis, and therapy. In: Blumgart's Surgery of the Liver, Biliary Tract, and Pancreas. 5th edition. Chapter 61. Pp 934 – 944.

Ladner D and Norton J. Neuroendocrine Tumors of the Pancreas. In: Shackelford’s Surgery of the Alimentary Tract. 7th edition. Pp 1206 – 1216.

UpToDate:

http://www.uptodate.com/contents/classification-epidemiology-clinical-presentation-localization-and-staging-of-pancreatic-neuroendocrine-tumors-islet-cell-tumors

http://www.uptodate.com/contents/insulinoma?source=see_link

http://www.uptodate.com/contents/zollinger-ellison-syndrome-gastrinoma-clinical-manifestations-and-diagnosis?source=see_link