DR FARHAN ALIMBBS,MCPS,FCPS

MEDICAL SPECIALISTCDA HOSPITAL ISLAMABAD

PAKISTAN

BACKGROUND

1969 (Pearse) described APUD cells (amine precursor uptake and decarboxylation) cells that make polypeptides and biogenic amines

These cells have dense core secretory granules which store and release hormones in response to external stimuli

Do not have axons/synapses

Are part of the diffuse endocrine system (DES)

Endocrine tumors of the gut and pancreas originate from DES cells

IncidenceIncidence 1-2 in 100,000

Account for <2% of GI malignancies

Neuroendocrine tumors of the lung, GI tract and mediastinum have a higher incidence in patients >50

carcinoid 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 CLASSIFICATION

1- Carcinoid Tumors25% foregut (lung, thymus, gastric mucosa,

duodenum)40-60% midgut (distal ileum and jejunum) (includes

carcinoid syndrome)Hindgut (colon, rectum)

2-Endocrine Pancreatic Tumors60% Functioning (Zollinger Ellison, insulinoma,

glucagonomas, VIPomas, etc)Non-functioning (usually large and metastatic at the

time of diagnosis

1-Endocrine Pancreatic Tumors

a-INSULINOMAS

Islet 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-GASTRINOMAS

Over secretion of gastrinZollinger-Ellison Syndrome: atypical peptic

ulcer disease, gastric hyperacidity and hypersecretion, associated with islet cell pancreatic tumors

Age 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-GLUCAGONOMAS

Presents with mild DM and severe dermatitis (necrolytic migratory erythema), stomatitis, diarrhea

~70% are malignantMetastasis in >60% patients

d-VIPOMAS

Over secretion of VIPCauses watery diarrhea, marked hypokalemia80% are associated with the pancreasMetastasis occurs in ~70% of patients Complete resection results in 5 year survival

of 95%

e-SOMATOSTATINOMAS

Cholelithiasis, DM, diarrhea, weight loss, steatorrhea

Metastasis 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 Cushing's syndrome , or 5-HT, causing 'carcinoid syndrome'.

CLINICAL FEATURES OF THE CARCINOID SYNDROMEFlushing Wheezing Diarrhoea Facial telangiectasia Cardiac 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 ANeuron specific enolaseStain for serotonin if suspect carcinoidStain 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 hindgut

Gastrinoma: raised basal serum gastrin, high gastric acid secretion

Insulinoma: raised fasting insulin/glucose ratio, proinsulin or C-peptide

Glucagonoma: raised serum pancreatic glucagon and enteroglucagon

VIPoma: raised fasting vasoactive intestinal peptide

Somatostatinoma: elevated fasting somatostatin

All NETs: elevated chromogranin A

RADIOLOGIC DIAGNOSISCTMRIUSSomatostatin Receptor Scintigraphy (SRS) –

based on presence of somatostatin receptors in 80-90% of NET

PET to evaluate tumor metastasisEndoscopic ultrasound –

sensitivity/specificity appx 80% for tumors in pancreas and duodenum and can allow for FNA

Anatomic Imaging: CT

Std

Venous Delayed

Arterial

Imaging studies property of James Yao, MD. CT: computed tomography.

MRI = magnetic resonance imagingImaging studies property of James Yao, MD.

Imaging studies property of James Yao, MD.

THERAPYSurgery

For localized diseaseOnly way to cureCan include debulking or laser procedureshowever not applicable to all cases as many pts

present with metastatic diseaseMedical therapy:

Somatostatin analogsInterferon alphaDiazoxide may reduce insulin secretion in

insulinomasCytotoxic drugs

SOMATOSTATIN ANALOGSUsed since 1980’sHormone blocking agents that are synthetic

somatostatin derivatives (ex: octreotide and lanreotide)

First line of treatment for neuroendocrine gastroenteropancreatic tumors

2nd -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 Alpha

For mid-gut carcinoids

Work by direct effect on tumor cells by blocking cell cycle in G1/S phase and inhibiting protein/hormone synthesis and inhibition of angiogenic function

Can by used with or without somatostatin analogs

SE: flu-like symptoms, fever, anemia, thrombocytopenia, leukopenia

CHEMOTHERAPY

Cytotoxic treatment is generally a palliative option for metastasizing neuroendocrine carcinomas

Streptozotocin, + 5-FU and doxorubicin (response rate >50% in malignant NET)

Cisplatin/paraplatin + etoposide (for poorly differentiated NET in fore-gut