Neuroendocrine Tumors

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Neuroendocrine Tumors

  1. 1. GASTROENTEROPANCREAGASTROENTEROPANCREA TIC NEUROENDOCRINETIC NEUROENDOCRINE TUMORSTUMORS Sima Patel, MDSima Patel, MD February 29February 29thth 20082008
  2. 2. BACKGROUNDBACKGROUND  Incidence 1-2 in 100,000 (true incidenceIncidence 1-2 in 100,000 (true incidence is underestimated due to vagueis underestimated due to vague presentations and misdiagnosis)presentations and misdiagnosis)  Account for <2% of GI malignanciesAccount for <2% of GI malignancies  Neuroendocrine tumors of the lung, GINeuroendocrine tumors of the lung, GI tract and mediastinum have a highertract and mediastinum have a higher incidence in patients >50 (exception:incidence in patients >50 (exception: carcinoid of the appendix have a highercarcinoid of the appendix have a higher incidence in patients age <30)incidence in patients age <30)
  3. 3. NEUROENDOCRINE CELLSNEUROENDOCRINE CELLS  1969 (Pearse) described APUD cells (amine1969 (Pearse) described APUD cells (amine precursor uptake and decarboxylation) cells thatprecursor uptake and decarboxylation) cells that make polypeptides and biogenic aminesmake polypeptides and biogenic amines  These cells have dense core secretory granulesThese cells have dense core secretory granules which store and release hormones in responsewhich store and release hormones in response to external stimulito external stimuli  Do not have axons/synapsesDo not have axons/synapses  Are part of the diffuse endocrine system (DES)Are part of the diffuse endocrine system (DES)  Endocrine tumors of the gut and pancreasEndocrine tumors of the gut and pancreas originate from DES cellsoriginate from DES cells
  4. 4. CLASSIFICATIONCLASSIFICATION  WHO CLASSIFICATIONWHO CLASSIFICATION – Well differentiated NET (non-invasive, benignWell differentiated NET (non-invasive, benign behaving or uncertain malignant potential)behaving or uncertain malignant potential) – Well-differentiated NE carcinomas (low gradeWell-differentiated NE carcinomas (low grade malignant and has invasion or muscularismalignant and has invasion or muscularis propria or metastasis)propria or metastasis) – Poorly differentiated endocrine carcinomasPoorly differentiated endocrine carcinomas (high grade, malignant)(high grade, malignant)
  5. 5. CLASSIFICATIONCLASSIFICATION  GENERAL CLASSIFICATION ofGENERAL CLASSIFICATION of Neuroendocrine gastroenteropancreatic tumorsNeuroendocrine gastroenteropancreatic tumors – 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 carcinoid40-60% midgut (distal ileum and jejunum) (includes carcinoid syndrome)syndrome)  Hindgut (colon, rectum)Hindgut (colon, rectum) – Endocrine Pancreatic TumorsEndocrine Pancreatic Tumors  60% Functioning (Zollinger Ellison, hyperglycemic, verner-60% Functioning (Zollinger Ellison, hyperglycemic, verner- morrison, glucagonomas, VIPomas, etc)morrison, glucagonomas, VIPomas, etc)  Non-functioning (usually large and metastatic at the time ofNon-functioning (usually large and metastatic at the time of diagnosisdiagnosis
  6. 6. 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, weaknesstremors, tachycardia, confusion, weakness  10% of patients develop metastasis10% of patients develop metastasis  Complete resection cures most patientsComplete resection cures most patients
  7. 7. GASTRINOMASGASTRINOMAS  Over secretion of gastrinOver secretion of gastrin  Zollinger-Ellison Syndrome: atypical peptic ulcerZollinger-Ellison Syndrome: atypical peptic ulcer disease, gastric hyperacidity and hypersecretion,disease, gastric hyperacidity and hypersecretion, associated with islet cell pancreatic tumorsassociated with islet cell pancreatic 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 survival ofComplete resection results in 10 year survival of 90%; less likely if large primary90%; less likely if large primary
  8. 8. GLUCAGONOMASGLUCAGONOMAS  Presents with mild DM and severePresents with mild DM and severe dermatitis (necrolytic migratory erythema),dermatitis (necrolytic migratory erythema), stomatitis, diarrheastomatitis, diarrhea  ~70% are malignant~70% are malignant  Metastasis in >60% patientsMetastasis in >60% patients
  9. 9. VIPOMASVIPOMAS  Over secretion of VIPOver secretion of VIP  Causes watery diarrhea, markedCauses watery diarrhea, marked hypokalemiahypokalemia  80% are associated with the pancreas80% are associated with the pancreas  Metastasis occurs in ~70% of patientsMetastasis occurs in ~70% of patients  Complete resection results in 5 yearComplete resection results in 5 year survival of 95%survival of 95%
  10. 10. SOMATOSTATINOMASSOMATOSTATINOMAS  Cholelithiasis, DM, diarrhea, weight loss,Cholelithiasis, DM, diarrhea, weight loss, steatorrheasteatorrhea  Metastasis in ~50% patientsMetastasis in ~50% patients  Complete resection with 5 year survival ofComplete resection with 5 year survival of 95% and if has metastasis the 5 year95% and if has metastasis the 5 year survival decreases to 60%survival decreases to 60%
  11. 11. CARCINOIDCARCINOID  1.5 per 100,0001.5 per 100,000  Symptoms depend on location and size ofSymptoms depend on location and size of tumor and presence of metastasistumor and presence of metastasis  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 “asthma”severe diarrhea, and can have “asthma” symptomssymptoms
  12. 12. DIAGNOSTIC PROCEDUREDIAGNOSTIC PROCEDURE  BiopsyBiopsy  ImmunohistochemistryImmunohistochemistry – 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 – EllisonStain for gastrin if suspect Zollinger – Ellison
  13. 13. LABORATORY EVALUATIONLABORATORY EVALUATION  Carcinoid: 24 hour urinary 5-HIAA raisedCarcinoid: 24 hour urinary 5-HIAA raised in carcinoid tumors of the foregut andin carcinoid tumors of the foregut and midgut but not generally raised in tumorsmidgut but not generally raised in tumors of the hindgutof the hindgut  Gastrinoma: raised basal serum gastrin,Gastrinoma: raised basal serum gastrin, high gastric acid secretionhigh gastric acid secretion  Insulinoma: raised fasting insulin/glucoseInsulinoma: raised fasting insulin/glucose ratio, proinsulin or C-peptideratio, proinsulin or C-peptide
  14. 14. LABORATORY EVALUATIONLABORATORY EVALUATION  Glucagonoma: raised serum pancreaticGlucagonoma: raised serum pancreatic glucagon and enteroglucagonglucagon and enteroglucagon  VIPoma: raised fasting vasoactiveVIPoma: raised fasting vasoactive intestinal peptideintestinal peptide  Ppoma: elevated fasting pancreaticPpoma: elevated fasting pancreatic polypeptidepolypeptide  Somatostatinoma: elevated fastingSomatostatinoma: elevated fasting somatostatinsomatostatin  All NETs: elevated chromagranin AAll NETs: elevated chromagranin A
  15. 15. RADIOLOGIC DIAGNOSISRADIOLOGIC DIAGNOSIS  CTCT  MRIMRI  USUS  Somatostatin Receptor Scintigraphy (SRS) –Somatostatin Receptor Scintigraphy (SRS) – based on presence of somatostatin receptors inbased on presence of somatostatin receptors in 80-90% of NET80-90% of NET  PET to evaluate tumor metastasisPET to evaluate tumor metastasis  Endoscopic ultrasound – sensitivity/specificityEndoscopic ultrasound – sensitivity/specificity appx 80% for tumors in pancreas and duodenumappx 80% for tumors in pancreas and duodenum and can allow for FNAand can allow for FNA
  16. 16. 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 ptshowever not applicable to all cases as many pts present with metastatic diseasepresent with metastatic disease  Medical therapy:Medical therapy: – Somatostatin analogsSomatostatin analogs – Interferon alphaInterferon alpha – Cytotoxic drugsCytotoxic drugs
  17. 17. Kaltsas, Gregory and Michael Besser. The Guidelines and Medical Management of Advanced Neuroendocrine Tumors. Endocrine Reviews. 25(3): 458-511,Kaltsas, Gregory and Michael Besser. The Guidelines and Medical Management of Advanced Neuroendocrine Tumors. Endocrine Reviews. 25(3): 458-511, 20042004
  18. 18. SOMATOSTATIN ANALOGSSOMATOSTATIN ANALOGS  Used since 1980’sUsed since 1980’s  Hormone blocking agents that are syntheticHormone blocking agents that are synthetic somatostatin derivatives (ex: octreotide andsomatostatin derivatives (ex: octreotide and lanreotide)lanreotide)  First line for neuroendocrineFirst line for neuroendocrine gastroenteropancreatic tumorsgastroenteropancreatic tumors  22ndnd -3-3rdrd line for insulinomas and gastrinomasline for insulinomas and gastrinomas  Side effects: development of gallstonesSide effects: development of gallstones secondary to inhibition of cholecystokininsecondary 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
  19. 19. Interferon AlphaInterferon Alpha  For mid-gut carcinoidsFor mid-gut carcinoids  Work by direct effect on tumor cells byWork by direct effect on tumor cells by blocking cell cycle in G1/S phase andblocking cell cycle in G1/S phase and inhibiting protein/hormone synthesis andinhibiting protein/hormone synthesis and inhibition of angiogenic functioninhibition of angiogenic function  Can by used with or without somatostatinCan by used with or without somatostatin analogsanalogs  SE: flu-like symptoms, fever, anemia,SE: flu-like symptoms, fever, anemia, thrombocytopenia, leukopeniathrombocytopenia, leukopenia
  20. 20. CHEMOTHERAPYCHEMOTHERAPY  Cytotoxic treatment is generally aCytotoxic treatment is generally a palliative option for metastasizingpalliative option for metastasizing neuroendocrine carcinomasneuroendocrine carcinomas  Streptozotocin, + 5-FU and doxorubicinStreptozotocin, + 5-FU and doxorubicin (response rate >50% in malignant NET)(response rate >50% in malignant NET)  Cisplatium/paraplatin + etoposide (forCisplatium/paraplatin + etoposide (for poorly differentiated NET in fore-gutpoorly differentiated NET in fore-gut
  21. 21. REFERENCESREFERENCES  Irvin Modlin et al,. Gastroenteropancreatic Neuroendocrine Tumours. LancetIrvin Modlin et al,. Gastroenteropancreatic Neuroendocrine Tumours. Lancet Oncology. Volume 9: pages 61-72, 2008.Oncology. Volume 9: pages 61-72, 2008.  Oberg, Kjell. Neuroendocrine Gastroenteropancreatic Tumors: RecentOberg, 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 ofJK Ramage et al,. Guidelines for the Management of Gastroenteropancreatic Neuroendocrine (including Carcinoid) Tumours.Gastroenteropancreatic Neuroendocrine (including Carcinoid) Tumours. Gut. Volume 54: pages 1-16, 2004Gut. Volume 54: pages 1-16, 2004  Kaltsas, Gregory and Michael Besser. The Guidelines and MedicalKaltsas, Gregory and Michael Besser. The Guidelines and Medical Management of Advanced Neuroendocrine Tumors. Endocrine Reviews.Management of Advanced Neuroendocrine Tumors. Endocrine Reviews. 25(3): 458-511, 200425(3): 458-511, 2004  Kasper, Dennis, and Eugene Braunwald, 16th edition, eds. Harrison’sKasper, 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. CurrentTierney 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 GastroenteropancreaticUptodate: Management of Metastatic Gastroenteropancreatic Neuroendocrine TumorsNeuroendocrine Tumors  Uptodate: Localization of Pancreatic Endocrine Tumors (Islet-Cell tumors)Uptodate: Localization of Pancreatic Endocrine Tumors (Islet-Cell tumors)  Uptodate: Neuroendocrine Carcinoma of Unknown Primary SiteUptodate: Neuroendocrine Carcinoma of Unknown Primary Site

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