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Neuroendocrine Tumors

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Page 1: Neuroendocrine Tumors
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GASTROENTEROPANCREATIGASTROENTEROPANCREATIC NEUROENDOCRINE C NEUROENDOCRINE

TUMORSTUMORS

Sima Patel, MD Sima Patel, MD February 29February 29thth 2008 2008

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BACKGROUNDBACKGROUND

Incidence 1-2 in 100,000 (true Incidence 1-2 in 100,000 (true incidence is underestimated due to incidence is underestimated due to vague presentations and misdiagnosis) vague presentations and misdiagnosis)

Account for <2% of GI malignanciesAccount for <2% of GI malignancies Neuroendocrine tumors of the lung, GI Neuroendocrine tumors of the lung, GI

tract and mediastinum have a higher tract and mediastinum have a higher incidence in patients >50 (exception: incidence in patients >50 (exception: carcinoid of the appendix have a higher carcinoid of the appendix have a higher incidence in patients age <30)incidence in patients age <30)

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NEUROENDOCRINE CELLSNEUROENDOCRINE CELLS 1969 (Pearse) described APUD cells (amine 1969 (Pearse) described APUD cells (amine

precursor uptake and decarboxylation) cells precursor uptake and decarboxylation) cells that make polypeptides and biogenic aminesthat make polypeptides and biogenic amines

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

Do not have axons/synapsesDo not have axons/synapses Are part of the diffuse endocrine system Are part of the diffuse endocrine system

(DES)(DES) Endocrine tumors of the gut and pancreas Endocrine tumors of the gut and pancreas

originate from DES cellsoriginate from DES cells

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CLASSIFICATIONCLASSIFICATION

WHO CLASSIFICATION WHO CLASSIFICATION – Well differentiated NET (non-invasive, Well differentiated NET (non-invasive,

benign behaving or uncertain malignant benign behaving or uncertain malignant potential)potential)

– Well-differentiated NE carcinomas (low Well-differentiated NE carcinomas (low grade malignant and has invasion or grade malignant and has invasion or muscularis propria or metastasis)muscularis propria or metastasis)

– Poorly differentiated endocrine Poorly differentiated endocrine carcinomas (high grade, malignant)carcinomas (high grade, malignant)

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CLASSIFICATIONCLASSIFICATION GENERAL CLASSIFICATION of GENERAL CLASSIFICATION of

Neuroendocrine gastroenteropancreatic Neuroendocrine gastroenteropancreatic tumorstumors– Carcinoid tumorsCarcinoid tumors

25% foregut (lung, thymus, gastric mucosa, duodenum)25% foregut (lung, thymus, gastric mucosa, duodenum) 40-60% midgut (distal ileum and jejunum) (includes 40-60% midgut (distal ileum and jejunum) (includes

carcinoid syndrome)carcinoid syndrome) Hindgut (colon, rectum)Hindgut (colon, rectum)

– Endocrine Pancreatic TumorsEndocrine Pancreatic Tumors 60% Functioning (Zollinger Ellison, hyperglycemic, 60% Functioning (Zollinger Ellison, hyperglycemic,

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

time of diagnosistime of diagnosis

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INSULINOMASINSULINOMAS

Islet cell tumorsIslet cell tumors Secrete excess of predominantly insulinSecrete excess of predominantly insulin Usually present at age 40-50Usually present at age 40-50 More common in womenMore common in women Clinical symptoms include sweating, Clinical symptoms include sweating,

tremors, tachycardia, confusion, tremors, tachycardia, confusion, weaknessweakness

10% of patients develop metastasis10% of patients develop metastasis Complete resection cures most patientsComplete resection cures most patients

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GASTRINOMASGASTRINOMAS

Over secretion of gastrinOver secretion of gastrin Zollinger-Ellison Syndrome: atypical peptic Zollinger-Ellison Syndrome: atypical peptic

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

Age at diagnosis ~50Age at diagnosis ~50 More common in males (~60%)More common in males (~60%) Metastasis in 60% of patientsMetastasis in 60% of patients Complete resection results in 10 year Complete resection results in 10 year

survival of 90%; less likely if large primarysurvival of 90%; less likely if large primary

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GLUCAGONOMASGLUCAGONOMAS

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

~70% are malignant~70% are malignant Metastasis in >60% patientsMetastasis in >60% patients

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VIPOMASVIPOMAS

Over secretion of VIPOver secretion of VIP Causes watery diarrhea, marked Causes watery diarrhea, marked

hypokalemiahypokalemia 80% are associated with the pancreas80% are associated with the pancreas Metastasis occurs in ~70% of patients Metastasis occurs in ~70% of patients Complete resection results in 5 year Complete resection results in 5 year

survival of 95%survival of 95%

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SOMATOSTATINOMASSOMATOSTATINOMAS

Cholelithiasis, DM, diarrhea, weight Cholelithiasis, DM, diarrhea, weight loss, steatorrhealoss, steatorrhea

Metastasis in ~50% patientsMetastasis in ~50% patients Complete resection with 5 year Complete resection with 5 year

survival of 95% and if has metastasis survival of 95% and if has metastasis the 5 year survival decreases to the 5 year survival decreases to 60%60%

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CARCINOIDCARCINOID

1.5 per 100,0001.5 per 100,000 Symptoms depend on location and Symptoms depend on location and

size of tumor and presence of size of tumor and presence of metastasismetastasis

Can secrete a number of hormonal, Can secrete a number of hormonal, growth, and other factorsgrowth, and other factors

Symptoms include flushing of the face, Symptoms include flushing of the face, severe diarrhea, and can have severe diarrhea, and can have “asthma” symptoms“asthma” symptoms

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DIAGNOSTIC PROCEDUREDIAGNOSTIC PROCEDURE

Biopsy Biopsy Immunohistochemistry Immunohistochemistry– Antibodies to chromogranin AAntibodies to chromogranin A– Neuron specific endolaseNeuron specific endolase– SynapthophysisSynapthophysis– Stain for serotonin if suspect carcinoidStain for serotonin if suspect carcinoid– Stain for gastrin if suspect Zollinger – Stain for gastrin if suspect Zollinger –

EllisonEllison

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LABORATORY EVALUATIONLABORATORY EVALUATION

Carcinoid: 24 hour urinary 5-HIAA Carcinoid: 24 hour urinary 5-HIAA raised in carcinoid tumors of the raised in carcinoid tumors of the foregut and midgut but not generally foregut and midgut but not generally raised in tumors of the hindgutraised in tumors of the hindgut

Gastrinoma: raised basal serum Gastrinoma: raised basal serum gastrin, high gastric acid secretiongastrin, high gastric acid secretion

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

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LABORATORY EVALUATIONLABORATORY EVALUATION

Glucagonoma: raised serum Glucagonoma: raised serum pancreatic glucagon and pancreatic glucagon and enteroglucagonenteroglucagon

VIPoma: raised fasting vasoactive VIPoma: raised fasting vasoactive intestinal peptideintestinal peptide

Ppoma: elevated fasting pancreatic Ppoma: elevated fasting pancreatic polypeptidepolypeptide

Somatostatinoma: elevated fasting Somatostatinoma: elevated fasting somatostatinsomatostatin

All NETs: elevated chromagranin AAll NETs: elevated chromagranin A

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RADIOLOGIC DIAGNOSISRADIOLOGIC DIAGNOSIS CTCT MRIMRI USUS Somatostatin Receptor Scintigraphy (SRS) – Somatostatin Receptor Scintigraphy (SRS) –

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

PET to evaluate tumor metastasisPET to evaluate tumor metastasis Endoscopic ultrasound – Endoscopic ultrasound –

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

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THERAPYTHERAPY

SurgerySurgery– For localized diseaseFor localized disease– Only way to cureOnly way to cure– Can include debulking or laser proceduresCan include debulking or laser procedures– however not applicable to all cases as many however not applicable to all cases as many

pts present with metastatic diseasepts present with metastatic disease Medical therapy:Medical therapy:

– Somatostatin analogsSomatostatin analogs– Interferon alphaInterferon alpha– Cytotoxic drugsCytotoxic drugs

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Kaltsas, Gregory and Michael Besser. The Guidelines and Medical Management of Advanced Neuroendocrine Tumors. Endocrine Reviews. Kaltsas, Gregory and Michael Besser. The Guidelines and Medical Management of Advanced Neuroendocrine Tumors. Endocrine Reviews. 25(3): 458-511, 200425(3): 458-511, 2004

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SOMATOSTATIN ANALOGSSOMATOSTATIN ANALOGS Used since 1980’sUsed since 1980’s Hormone blocking agents that are synthetic Hormone blocking agents that are synthetic

somatostatin derivatives (ex: octreotide and somatostatin derivatives (ex: octreotide and lanreotide)lanreotide)

First line for neuroendocrine First line for neuroendocrine gastroenteropancreatic tumorsgastroenteropancreatic tumors

22ndnd -3 -3rdrd line for insulinomas and gastrinomas line for insulinomas and gastrinomas Side effects: development of gallstones Side effects: development of gallstones

secondary to inhibition of cholecystokinin secondary to inhibition of cholecystokinin release, pain at site, hypo or hyperglycemia, release, pain at site, hypo or hyperglycemia, rash, alopecia, fluid retentionrash, alopecia, fluid retention

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Interferon AlphaInterferon Alpha

For mid-gut carcinoidsFor mid-gut carcinoids Work by direct effect on tumor cells by Work by direct effect on tumor cells by

blocking cell cycle in G1/S phase and blocking cell cycle in G1/S phase and inhibiting protein/hormone synthesis inhibiting protein/hormone synthesis and inhibition of angiogenic functionand inhibition of angiogenic function

Can by used with or without Can by used with or without somatostatin analogssomatostatin analogs

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

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CHEMOTHERAPYCHEMOTHERAPY

Cytotoxic treatment is generally a Cytotoxic treatment is generally a palliative option for metastasizing palliative option for metastasizing neuroendocrine carcinomasneuroendocrine carcinomas

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

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

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REFERENCESREFERENCES Irvin Modlin et al,. Gastroenteropancreatic Neuroendocrine Tumours. Irvin Modlin et al,. Gastroenteropancreatic Neuroendocrine Tumours.

Lancet Oncology. Volume 9: pages 61-72, 2008.Lancet Oncology. Volume 9: pages 61-72, 2008. Oberg, Kjell. Neuroendocrine Gastroenteropancreatic Tumors: Recent Oberg, Kjell. Neuroendocrine Gastroenteropancreatic Tumors: Recent

Update on Diagnosis and Treatment. US Oncology Review. 1-6, 2006Update on Diagnosis and Treatment. US Oncology Review. 1-6, 2006 JK Ramage et al,. Guidelines for the Management of JK Ramage et al,. Guidelines for the Management of

Gastroenteropancreatic Neuroendocrine (including Carcinoid) Gastroenteropancreatic Neuroendocrine (including Carcinoid) Tumours. Gut. Volume 54: pages 1-16, 2004Tumours. Gut. Volume 54: pages 1-16, 2004

Kaltsas, Gregory and Michael Besser. The Guidelines and Medical Kaltsas, Gregory and Michael Besser. The Guidelines and Medical Management of Advanced Neuroendocrine Tumors. Endocrine Management of Advanced Neuroendocrine Tumors. Endocrine Reviews. 25(3): 458-511, 2004Reviews. 25(3): 458-511, 2004

Kasper, Dennis, and Eugene Braunwald, 16th edition, eds. Harrison’s Kasper, Dennis, and Eugene Braunwald, 16th edition, eds. Harrison’s Principles of Internal Medicine. New York: McGraw-Hill, 2005.Principles of Internal Medicine. New York: McGraw-Hill, 2005.

Tierney Jr, Lawrence, and Stephen McPhee, 45th edition, eds. Current Tierney Jr, Lawrence, and Stephen McPhee, 45th edition, eds. Current Medical Diagnosis and Treatment. New York: McGraw-Hill, 2006.Medical Diagnosis and Treatment. New York: McGraw-Hill, 2006.

Uptodate: Management of Metastatic Gastroenteropancreatic Uptodate: Management of Metastatic Gastroenteropancreatic Neuroendocrine TumorsNeuroendocrine Tumors

Uptodate: Localization of Pancreatic Endocrine Tumors (Islet-Cell Uptodate: Localization of Pancreatic Endocrine Tumors (Islet-Cell tumors)tumors)

Uptodate: Neuroendocrine Carcinoma of Unknown Primary SiteUptodate: Neuroendocrine Carcinoma of Unknown Primary Site


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