DR FARHAN ALI MBBS,MCPS,FCPS MEDICAL SPECIALISTCDA HOSPITAL ISLAMABAD PAKISTAN
BACKGROUND1969 (Pearse) described APUD cells (amine precursor uptake and decarboxylation) cells that make polypeptides and biogenic aminesThese cells have dense core secretory granules which store and release hormones in response to external stimuli
Do not have axons/synapsesAre part of the diffuse endocrine system (DES)Endocrine tumors of the gut and pancreas originate from DES cells
IncidenceIncidence 1-2 in 100,000Account for <2% of GI malignanciesNeuroendocrine tumors of the lung, GI tract and mediastinum have a higher incidence in patients >50carcinoid of the appendix have a higher incidence in patients age <30
WHO CLASSIFICATION Well differentiated NET (non-invasive, benign behaving or uncertain malignant potential) Well-differentiated NE carcinomas (low grade malignant and has invasion or muscularis propria or metastasis) Poorly differentiated endocrine carcinomas (high grade, malignant)
GENERAL CLASSIFICATION1- Carcinoid Tumors 25% foregut (lung, thymus, gastric mucosa, duodenum) 40-60% midgut (distal ileum and jejunum) (includes carcinoid syndrome) Hindgut (colon, rectum)2-Endocrine Pancreatic Tumors 60% Functioning (Zollinger Ellison, insulinoma, glucagonomas, VIPomas, etc) Non-functioning (usually large and metastatic at the time of diagnosis
1-Endocrine Pancreatic Tumorsa-INSULINOMASIslet cell tumorsSecrete excess of predominantly insulinUsually present at age 40-50More common in womenClinical symptoms include sweating, tremors, tachycardia, confusion, weakness10% of patients develop metastasisComplete resection cures most patients
b-GASTRINOMASOver secretion of gastrinZollinger-Ellison Syndrome: atypical peptic ulcer disease, gastric hyperacidity and hypersecretion, associated with islet cell pancreatic tumorsAge at diagnosis ~50More common in males (~60%)Metastasis in 60% of patientsComplete resection results in 10 year survival of 90%; less likely if large primary
c-GLUCAGONOMASPresents with mild DM and severe dermatitis (necrolytic migratory erythema), stomatitis, diarrhea~70% are malignantMetastasis in >60% patients
d-VIPOMASOver secretion of VIPCauses watery diarrhea, marked hypokalemia80% are associated with the pancreasMetastasis occurs in ~70% of patientsComplete resection results in 5 year survival of 95%
e-SOMATOSTATINOMASCholelithiasis, DM, diarrhea, weight loss, steatorrheaMetastasis in ~50% patientsComplete resection with 5 year survival of 95% and if has metastasis the 5 year survival decreases to 60%
2-Carcinoid Tumoursarise in the thymus, bronchi and throughout the gastrointestinal tract,most commonly observed in the small bowel.present due to local mass effects, e.g. small bowel obstruction, appendicitis, pain from hepatic metastases, or because of symptoms related to hormone excess.This includes ectopic secretion of ACTH, causing Cushings syndrome , or 5-HT, causing carcinoid syndrome.
CLINICAL FEATURES OF THECARCINOID SYNDROMEFlushingWheezingDiarrhoeaFacial telangiectasiaCardiac involvement (tricuspid regurgitation, pulmonary stenosis, right ventricular endocardial plaques leading to heart failure
Carcinoid syndrome only occurs when the vasoactive hormones reach the systemic circulation. In the case of gastrointestinal carcinoids, this invariably means that the tumour has metastasised to the liver, as hormones secreted by the primary tumour into the portal vein are metabolised by the liver
DIAGNOSTIC PROCEDUREBiopsy Immunohistochemistry Antibodies to chromogranin A Neuron specific enolase Stain for serotonin if suspect carcinoid Stain for gastrin if suspect Zollinger – Ellison
LABORATORY EVALUATIONCarcinoid: 24 hour urinary 5-HIAA raised in carcinoid tumors of the foregut and midgut but not generally raised in tumors of the hindgutGastrinoma: raised basal serum gastrin, high gastric acid secretionInsulinoma: raised fasting insulin/glucose ratio, proinsulin or C-peptide
Glucagonoma: raised serum pancreatic glucagon and enteroglucagonVIPoma: raised fasting vasoactive intestinal peptideSomatostatinoma: elevated fasting somatostatinAll NETs: elevated chromogranin A
RADIOLOGIC DIAGNOSISCTMRIUSSomatostatin Receptor Scintigraphy (SRS) – based on presence of somatostatin receptors in 80-90% of NETPET to evaluate tumor metastasisEndoscopic ultrasound – sensitivity/specificity appx 80% for tumors in pancreas and duodenum and can allow for FNA
Anatomic Imaging: CT Std Arterial Venous DelayedImaging studies property of James Yao, MD. CT: computed tomography.
MRI = magnetic resonance imagingImaging studies property of James Yao, MD.
THERAPYSurgery For localized disease Only way to cure Can include debulking or laser procedures however not applicable to all cases as many pts present with metastatic diseaseMedical therapy: Somatostatin analogs Interferon alpha Diazoxide may reduce insulin secretion in insulinomas Cytotoxic drugs
SOMATOSTATIN ANALOGSUsed since 1980’sHormone blocking agents that are synthetic somatostatin derivatives (ex: octreotide and lanreotide)First line of treatment for neuroendocrine gastroenteropancreatic tumors2nd -3rd line for insulinomas and gastrinomasSide effects: development of gallstones secondary to inhibition of cholecystokinin release, pain at site, hypo or hyperglycemia, rash, alopecia, fluid retention
Interferon AlphaFor mid-gut carcinoidsWork by direct effect on tumor cells by blocking cell cycle in G1/S phase and inhibiting protein/hormone synthesis and inhibition of angiogenic functionCan by used with or without somatostatin analogsSE: flu-like symptoms, fever, anemia, thrombocytopenia, leukopenia
CHEMOTHERAPYCytotoxic treatment is generally a palliative option for metastasizing neuroendocrine carcinomasStreptozotocin, + 5-FU and doxorubicin (response rate >50% in malignant NET)Cisplatin/paraplatin + etoposide (for poorly differentiated NET in fore-gut