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Small Bowel CarcinoidSmall Bowel Carcinoid
Ana M. Grau, MD, FACSAna M. Grau, MD, FACSAssociate ProfessorAssociate Professor
Division of Surgical Oncology and Division of Surgical Oncology and Endocrine SurgeryEndocrine Surgery
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Small Bowel CarcinoidSmall Bowel Carcinoid
Introduction, History, EpidemiologyMacroscopic and Microscopic AppearanceClinical Presentation and DiagnosisTreatment of PrimaryTreatment of Advanced/MetastaticF/U and Prognosis
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Introduction/HistoryIntroduction/HistoryCarcinoids are neuroendocrine neoplasms that most Carcinoids are neuroendocrine neoplasms that most frequently occur in the GI tractfrequently occur in the GI tract
Originate from endocrine cells in the submucosaOriginate from endocrine cells in the submucosa
Langhans in 1867 and Lubarsch in 1888 described Langhans in 1867 and Lubarsch in 1888 described unusual tumors in the small bowelunusual tumors in the small bowel
In 1907 In 1907 OberndorferOberndorfer referred to them as referred to them as KarzinoideKarzinoide or carcinomaor carcinoma--like, because of their relative indolent like, because of their relative indolent nature compared with carcinomas nature compared with carcinomas
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History/TimelineHistory/Timeline
In 1897, Nikolai Kulchitsky In 1897, Nikolai Kulchitsky described the described the ‘‘uniqueunique’’ cells of the intestinal cells of the intestinal epitheliumepithelium
Eponymously referred to Eponymously referred to as Kulchitsky cellsas Kulchitsky cells
Currently referred to as Currently referred to as enterochromaffin (EC) enterochromaffin (EC) cellscells
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1907 Oberndorfer coins the term “karzinoide” to describe SB submucosal tumors
1914 Gosset and Masson suggest that carcinoids may arise from EC cells
1978 Use of somatostatin to control carcinoid flushing
1982 Synthesis of somatostatin analogues
1985 First successful use of somatostatin analogues in carcinoid disease
1973 Isolation and sequencing of “somatotropin-release inhibitor factor”
Somatostatin scintigraphy 1989
Peptide receptor radiotherapy trials begin 1992
Depot SST analogues 1998
WHO classification Gastrointestinal Neuroendocrine Tumors 2000
Timeline/From Timeline/From KarzinoideKarzinoide to NETto NET
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IntroductionIntroductionCarcinoids are histologically and biochemically Carcinoids are histologically and biochemically diverse tumors diverse tumors
Classification is based on: Classification is based on: –– Anatomical location, with carcinoids being more Anatomical location, with carcinoids being more
commonly located in the ileumcommonly located in the ileum–– Embryologic origin: Foregut, Midgut, and Hindgut Embryologic origin: Foregut, Midgut, and Hindgut
Carcinoid Carcinoid
WHO classification published in 2000:WHO classification published in 2000:–– Neuroendocrine tumor instead of carcinoidNeuroendocrine tumor instead of carcinoid
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WHO Histological Typing of WHO Histological Typing of Neuroendocrine TumorsNeuroendocrine Tumors
1.1. Well differentiated neuroendocrine tumorWell differentiated neuroendocrine tumor–– Benign or low grade malignantBenign or low grade malignant–– MucosaMucosa--Submucosa, <1Submucosa, <1--2cm2cm
2.2. Well differentiated neuroendocrine carcinomaWell differentiated neuroendocrine carcinoma–– Low grade malignantLow grade malignant–– Muscularis propria or beyond, or metastasisMuscularis propria or beyond, or metastasis
3.3. Poorly differentiated endocrine (small cell) carcinomaPoorly differentiated endocrine (small cell) carcinoma–– High grade malignantHigh grade malignant
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Small Bowel Carcinoid: EpidemiologySmall Bowel Carcinoid: EpidemiologyData from both the NCDB and the SEER databases Data from both the NCDB and the SEER databases 67,843 patients with small bowel malignancies67,843 patients with small bowel malignancies–– 37.4% of patients had carcinoid tumors37.4% of patients had carcinoid tumors–– 36.9% had adenocarcinomas36.9% had adenocarcinomas–– Stromal tumors or lymphomas Stromal tumors or lymphomas
Increase by 4% per year since 1973, surpassing Increase by 4% per year since 1973, surpassing adenocarcinomas as the most common small bowel tumoradenocarcinomas as the most common small bowel tumor
Bilimoria et al. Ann Surg, 249 (1), 2009
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Increased incidence of Carcinoid TumorsIncreased incidence of Carcinoid Tumors US population 1973US population 1973––20052005
Data from SEER database, US National Cancer InstituteData from SEER database, US National Cancer Institute
Modlin et al, Lancet Oncol 2008;9: 61-72
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Small Bowel CarcinoidSmall Bowel Carcinoid
Introduction, History, EpidemiologyMacroscopic and Microscopic AppearanceClinical Presentation and DiagnosisTreatment of PrimaryTreatment of Advanced/MetastaticF/U and Prognosis
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Macroscopic AppearanceMacroscopic AppearanceCarcinoids are white, Carcinoids are white, yellow, or gray firm yellow, or gray firm submucosal nodules in submucosal nodules in the wall of the intestinethe wall of the intestine
They may protrude into They may protrude into the lumen as polypsthe lumen as polyps
Overlying mucosa may Overlying mucosa may be intact or ulceratedbe intact or ulcerated
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Macroscopic AppearanceMacroscopic Appearance
The primary lesions are smallThe primary lesions are small
The metastatic deposits in the The metastatic deposits in the lymph nodes, mesentery, and lymph nodes, mesentery, and liver may be quite large liver may be quite large
Involvement of the subserosa Involvement of the subserosa and adjacent mesentery and adjacent mesentery stimulates an intense stimulates an intense desmoplastic reaction desmoplastic reaction
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Macroscopic AppearanceMacroscopic AppearanceIntense desmoplastic reaction results in Intense desmoplastic reaction results in dense fibrosis that may lead to:dense fibrosis that may lead to:
–– Mesenteric fibrosis Mesenteric fibrosis
–– Intestinal kinksIntestinal kinks
–– RetractionRetractionpartial or intermittent bowel obstructionpartial or intermittent bowel obstructionischemia and venous congestion when affecting ischemia and venous congestion when affecting mesenteric vesselsmesenteric vessels
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Levy A D, Sobin L H Radiographics 2007;27:237-257©2007 by Radiological Society of North America
Small Bowel Carcinoid: MicroscopySmall Bowel Carcinoid: MicroscopyRounded, submucosal, nodular configurationRounded, submucosal, nodular configurationNests of tumor cells in the submucosa with surrounding Nests of tumor cells in the submucosa with surrounding fibrosis and Infiltrative pattern of growth fibrosis and Infiltrative pattern of growth Uniform nuclei and cytoplasmic secretory granules Uniform nuclei and cytoplasmic secretory granules Can be identified by silver impregnation staining or by IHC Can be identified by silver impregnation staining or by IHC staining for neuroendocrine markers (chromogranins)staining for neuroendocrine markers (chromogranins)
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Small Bowel CarcinoidSmall Bowel Carcinoid
Introduction, History, EpidemiologyMacroscopic and Microscopic AppearanceClinical Presentation and DiagnosisTreatment of PrimaryTreatment of Advanced/MetastaticF/U and Prognosis
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Small Bowel CarcinoidSmall Bowel Carcinoid
Median age of presentation is 66 Median age of presentation is 66 y/oy/o
Carcinoids location:Carcinoids location:–– ileum in 45%ileum in 45%–– duodenum in 18%duodenum in 18%–– jejunum 6%jejunum 6%–– diffuse/ undetermined in the remaining cases diffuse/ undetermined in the remaining cases
MulticentricMulticentric in up to 30% of patientsin up to 30% of patients
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Small Bowel CarcinoidSmall Bowel CarcinoidAssociated with non-carcinoid neoplasms in up to 29% of patients (17% operated patients, 36% necropsies)– 50% are adenocarcinomas of the GI tract
Tumors located in the duodenum and jejunum are more often adenocarcinomas
Tumors found in the ileum are more likely to be carcinoids
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Clinical PresentationClinical PresentationOften asymptomatic as they grow slowly in the Often asymptomatic as they grow slowly in the intestinal wallintestinal wall
Initially, symptoms are vague with long history of Initially, symptoms are vague with long history of episodic abdominal pain that progresses to episodic abdominal pain that progresses to cramping, abdominal distention, nausea and cramping, abdominal distention, nausea and vomiting, diarrhea, and weight lossvomiting, diarrhea, and weight loss
Ultimately, the primary tumor and mesenteric Ultimately, the primary tumor and mesenteric involvement may result in involvement may result in small bowel small bowel obstruction, ischemia, or bleedingobstruction, ischemia, or bleeding
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Clinical PresentationClinical PresentationExploration for SBO or ischemia: 30% to 50%Exploration for SBO or ischemia: 30% to 50%Vague abdominal symptomsVague abdominal symptomsDetection of liver metastasis on imaging/celiotomyDetection of liver metastasis on imaging/celiotomyCarcinoid syndromeCarcinoid syndromeOccult GI BleedOccult GI BleedOther sites of metastasis: bones, lungs, CNS, mediastinal Other sites of metastasis: bones, lungs, CNS, mediastinal and peripheral lymph nodes, ovaries, breast and skinand peripheral lymph nodes, ovaries, breast and skin
October 2006 January 2009
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Clinical Presentation: Carcinoid Clinical Presentation: Carcinoid SyndromeSyndrome
20% to 30% of patients with small bowel carcinoid develop 20% to 30% of patients with small bowel carcinoid develop signs of carcinoid syndrome: signs of carcinoid syndrome: –– flushingflushing–– secretory diarrheasecretory diarrhea–– palpitationspalpitations–– intolerance to some foods or alcoholintolerance to some foods or alcohol–– rightright--sided valvular heart diseasesided valvular heart disease–– bronchoconstriction bronchoconstriction
Associated with the release of various substances from Associated with the release of various substances from the tumor: Serotonin, histamine, dopamine, vasoactive the tumor: Serotonin, histamine, dopamine, vasoactive intestinal peptide, othersintestinal peptide, others
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Clinical Presentation: Carcinoid SyndromeClinical Presentation: Carcinoid Syndrome
The liver can detoxify substances released by The liver can detoxify substances released by the primary and mesenteric tumorsthe primary and mesenteric tumors
Carcinoid syndrome develops when vasoactive Carcinoid syndrome develops when vasoactive substances produced by the tumor enter the substances produced by the tumor enter the systemic circulation systemic circulation
The syndrome most commonly occurs:The syndrome most commonly occurs:–– metastatic involvement of the livermetastatic involvement of the liver–– large burden of retroperitoneal tumor involvementlarge burden of retroperitoneal tumor involvement
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Carcinoid Heart DiseaseCarcinoid Heart Disease30% of patients with carcinoid syndrome 30% of patients with carcinoid syndrome Caused by the effects of circulating serotonin Caused by the effects of circulating serotonin Characterized by fibrous plaques that Characterized by fibrous plaques that preferentially involve the right side of the heartpreferentially involve the right side of the heartThose with left sided disease are likely to have Those with left sided disease are likely to have rightright--toto--left cardiac shuntsleft cardiac shuntsMay require valve replacementMay require valve replacementResponsible for about 50% of Responsible for about 50% of deaths in these patients deaths in these patients
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Duodenal/Ampullary CarcinoidsDuodenal/Ampullary Carcinoids
Lower serotoninergic hormone levels than other Lower serotoninergic hormone levels than other carcinoidscarcinoidsWhen these tumors are >2 cm, they may develop When these tumors are >2 cm, they may develop metastases to regional lymph nodes or the liver in metastases to regional lymph nodes or the liver in 45% of patients45% of patientsApproximately 30% may be associated with Approximately 30% may be associated with neurofibromatosis, occasionally MEN I and/or neurofibromatosis, occasionally MEN I and/or pheochromocytomaspheochromocytomasShould be distinguished from duodenal Should be distinguished from duodenal gastrinomas, particularly in MEN I patientsgastrinomas, particularly in MEN I patients
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DiagnosisDiagnosis
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Biochemical Studies: 5Biochemical Studies: 5--HIAAHIAA
Elevated levels of the serotonin metabolite Elevated levels of the serotonin metabolite 55--hydroxyhydroxy--indolacetic acid (5indolacetic acid (5--HIAA) in 24HIAA) in 24-- hour urine hour urine
55--HIAAHIAASensitivity of 73% for localized diseaseSensitivity of 73% for localized diseaseSensitivity of 100% for metastatic diseaseSensitivity of 100% for metastatic diseaseSpecificity of 100% in predicting the presence Specificity of 100% in predicting the presence of carcinoidof carcinoid
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Biochemical Studies: Chromogranin A Biochemical Studies: Chromogranin A CgACgA is a glycoprotein released by neuroendocrine tumor is a glycoprotein released by neuroendocrine tumor cells, measured in the plasmacells, measured in the plasmaElevated in >80% of patients with carcinoid tumors but its Elevated in >80% of patients with carcinoid tumors but its specificity is low for small bowel carcinoidsspecificity is low for small bowel carcinoidsFalse positive:False positive:–– proton pump inhibitors, atrophic gastritis, renal impairment, orproton pump inhibitors, atrophic gastritis, renal impairment, or
inflammatory bowel diseaseinflammatory bowel disease
There is a correlation between There is a correlation between CgACgA levels, tumor load, and levels, tumor load, and prognosisprognosis11
CgACgA measurement is currently being used as a tumor measurement is currently being used as a tumor marker for monitoring of disease progress and surveillance marker for monitoring of disease progress and surveillance of recurrenceof recurrence22
1 Janson et al, Ann Oncol 1997;8:685-6902 Welin et al, Neuroendocrinology 2009;89:302-307
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Small Bowel Carcinoid: Imaging StudiesSmall Bowel Carcinoid: Imaging Studies
GI contrast studies: UGI, SBFT, enteroclysisGI contrast studies: UGI, SBFT, enteroclysisCT scanCT scanNuclear MedicineNuclear Medicine–– SPECTSPECT–– PETPETMRIMRIEUSEUS
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Imaging StudiesImaging StudiesPrimary small bowel carcinoid are often small, and Primary small bowel carcinoid are often small, and typically not seen on GI contrast studies or CT typically not seen on GI contrast studies or CT scanscan
CT scan may identify involvement of the mesentery CT scan may identify involvement of the mesentery and/or liverand/or liver
A mesenteric tumor with radiating densities is A mesenteric tumor with radiating densities is highly suggestive of mesenteric metastasis of highly suggestive of mesenteric metastasis of small bowel carcinoidsmall bowel carcinoid
Calcifications present in more than 50% of those Calcifications present in more than 50% of those lesions lesions
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Abdominal Computed Tomography Scan Abdominal Computed Tomography Scan Illustrating a Mesenteric Tumor with Radiating Illustrating a Mesenteric Tumor with Radiating
Densities and CalcificationsDensities and Calcifications
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Imaging Studies: CT ScanImaging Studies: CT Scan
Relationship to major mesenteric vessels Relationship to major mesenteric vessels Define the extent of liver involvementDefine the extent of liver involvementLiver metastases are hypervascular Liver metastases are hypervascular Tumor necrosis may produce central, nonTumor necrosis may produce central, non-- enhancing regions, giving lesions a rimenhancing regions, giving lesions a rim--like like enhancementenhancementMRI may better demonstrate the extent of liver MRI may better demonstrate the extent of liver metastasis metastasis
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Abdominal Computed Tomography Scan: Abdominal Computed Tomography Scan: Liver Metastases From Small Bowel CarcinoidLiver Metastases From Small Bowel Carcinoid
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Somatostatin Receptor Scintigraphy (SRS) Somatostatin Receptor Scintigraphy (SRS) Small bowel carcinoids Small bowel carcinoids overexpressoverexpress somatostatin receptors which have high affinity somatostatin receptors which have high affinity for octreotidefor octreotideOctreoscanOctreoscan is used to determine metastatic is used to determine metastatic diseasedisease90% sensitivity90% sensitivityChange management: Change management: 19%19%--33% of patients33% of patients**
Ahlman, Semin Oncol 1994;21:21-28Schillaci, J Nucl Med 2003;44:359-368
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New Imaging ModalitiesNew Imaging ModalitiesStandard Standard 1818FDGFDG--PET is less helpful in the setting PET is less helpful in the setting of wellof well--differentiated tumorsdifferentiated tumorsNETNET’’ss take up decarboxylate amine precursors take up decarboxylate amine precursors (APUD) such as (APUD) such as 1111CC--labeled and labeled and 1818FF--labeled labeled serotonin and levodopaserotonin and levodopaSpatial resolution of PET is better than SRSSpatial resolution of PET is better than SRS-- SPECT (3SPECT (3--fold, 0.5 cm vs. 1fold, 0.5 cm vs. 1--1.5 cm)1.5 cm)These studies have better sensitivity for primary These studies have better sensitivity for primary tumors and lymph node, pleural and bone tumors and lymph node, pleural and bone metastasismetastasis
Modlin et al, Lancet Oncol 2008;9: 61-72
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Comparison of Comparison of 6868GaGa--DOTATOC DOTATOC PET and 111InPET and 111In--DTPAOC DTPAOC
((OctreoscanOctreoscan) SPECT in patients ) SPECT in patients with neuroendocrine with neuroendocrine tumourstumours
PET can be performed 1 hr after PET can be performed 1 hr after injection vs. 4injection vs. 4--6h, 24h, 48h after 6h, 24h, 48h after tracer injection for SRStracer injection for SRSPET had improved identification, PET had improved identification, in particular, for skeletal and lung in particular, for skeletal and lung manifestationsmanifestations**
Quantification Quantification SUVsSUVs, may have a , may have a role in selection of patients for role in selection of patients for radionuclide treatmentradionuclide treatment
Buchmann, Eur J Nucl Med Mol Imaging. 2007;34(10):1617-26
68Ga-DOTATOC PET
111In-DTPAOC (Octreoscan) SPECT
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1818FF--DOPA PET scan: DOPA PET scan: Liver and Small Bowel Lesion Liver and Small Bowel Lesion
Koornstra et al Digestive and Liver Disease; 41, 2009
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Endoscopic Studies: Endoscopic Studies: Localization of the Primary Tumor Localization of the Primary Tumor Duodenal carcinoids: Duodenal carcinoids: –– EGDEGD–– Endoscopic ultrasound (EUS) to determine the extent Endoscopic ultrasound (EUS) to determine the extent
of disease/lymph node involvementof disease/lymph node involvement
IleoIleo--colonoscopy: colonoscopy: –– Rule out synchronous neoplastic disease Rule out synchronous neoplastic disease –– May identify carcinoid tumors in the terminal May identify carcinoid tumors in the terminal
ileum/ileocecal valveileum/ileocecal valve
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Capsule EndoscopyCapsule EndoscopyMay be useful after small bowel enteroclysis May be useful after small bowel enteroclysis studies have failed to detect the primary tumor studies have failed to detect the primary tumor It can be used to screen the small bowel in It can be used to screen the small bowel in patients with suspected small bowel carcinoidpatients with suspected small bowel carcinoid
11.4 mm
26.3 mm 26.3 mm
11.4 mm
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Double Balloon Enteroscopy Double Balloon Enteroscopy DBE can be performed through the oral and/or the anal DBE can be performed through the oral and/or the anal route route The combined approach allows for complete small bowel The combined approach allows for complete small bowel examination in 86% of patientsexamination in 86% of patientsDBE allows for direct access to the lesion for histological DBE allows for direct access to the lesion for histological diagnosis for India ink marking for intraoperative diagnosis for India ink marking for intraoperative localizationlocalization
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DBE: Small Bowel Carcinoid DBE: Small Bowel Carcinoid Detection of primary tumors when US, CT, EGD, Detection of primary tumors when US, CT, EGD, ileocolonoscopy unable to detectileocolonoscopy unable to detect17 DBE in 12 patients17 DBE in 12 patientsSubmucosal tumor ileum or jejunum in 7 patients (58%)Submucosal tumor ileum or jejunum in 7 patients (58%)6/7 patients underwent resection 6/7 patients underwent resection Only in 4 disease was confirmed/2 patients false positiveOnly in 4 disease was confirmed/2 patients false positiveDBE to be performed in selected cases, possibly based on a DBE to be performed in selected cases, possibly based on a positive previous workup positive previous workup
Bellutti et al, Dig Dis Sci 54, 2009
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Small Bowel CarcinoidSmall Bowel Carcinoid
Introduction, History, EpidemiologyMacroscopic and Microscopic AppearanceClinical Presentation and DiagnosisTreatment of PrimaryTreatment of Advanced/MetastaticF/U and Prognosis
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TreatmentTreatmentMultidisciplinary effortMultidisciplinary effortSurgical therapy is the primary treatment for most Surgical therapy is the primary treatment for most patientspatientsSpecific issues in the preSpecific issues in the pre--operative assessment operative assessment of patients with small bowel carcinoid:of patients with small bowel carcinoid:–– Determination of the extent of local and distant diseaseDetermination of the extent of local and distant disease–– Identification of synchronous carcinoid and nonIdentification of synchronous carcinoid and non--
carcinoid tumorcarcinoid tumor–– fluid and electrolyte repletionfluid and electrolyte repletion–– detection of cardiac abnormalitiesdetection of cardiac abnormalities–– pharmacological treatment of carcinoid syndromepharmacological treatment of carcinoid syndrome
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Pharmacological Treatment of Pharmacological Treatment of Carcinoid Syndrome Carcinoid Syndrome
The risk of carcinoid crisis is higher for patients The risk of carcinoid crisis is higher for patients with carcinoid syndrome, but all patients are at risk with carcinoid syndrome, but all patients are at risk Prophylactic measures:Prophylactic measures:–– Perioperative administration of octreotide (100mcg SubPerioperative administration of octreotide (100mcg Sub--
cutaneously TID)cutaneously TID)
Carcinoid crisis: Carcinoid crisis: –– Bolus intravenous octreotide (100mcg IV push) followed Bolus intravenous octreotide (100mcg IV push) followed
by infusionby infusion–– Antihistamines, hydrocortisone, and albuterol as neededAntihistamines, hydrocortisone, and albuterol as needed
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Treatment: Duodenal/Ampullary NETTreatment: Duodenal/Ampullary NET<1cm lesions may be locally treated by endoscopic <1cm lesions may be locally treated by endoscopic resection, provided that there is no evidence of lymph resection, provided that there is no evidence of lymph node involvementnode involvement** by imaging, SRS, and ideally, by imaging, SRS, and ideally, EUSEUS
Lesions between 1 and 2 cm and periampullary lesions Lesions between 1 and 2 cm and periampullary lesions may be amenable to transduodenal excision; the may be amenable to transduodenal excision; the concern again is for retained lymph node metastasesconcern again is for retained lymph node metastases**
Large, >2 cm duodenal carcinoids or lesions with Large, >2 cm duodenal carcinoids or lesions with associated lymph node involvement should be treated by associated lymph node involvement should be treated by duodenal resection which most often requires duodenal resection which most often requires pancreaticoduodenectomypancreaticoduodenectomy
*LN metastasis may not correlate well with size of the tumor
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Pancreaticoduodenectomy: LN involvement
Transduodenal Excision
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Treatment: Jejunal/Ileal CarcinoidsTreatment: Jejunal/Ileal Carcinoids
Inspection for synchronous Inspection for synchronous lesions lesions
The primary tumor and The primary tumor and mesenteric metastases mesenteric metastases should be removed by should be removed by wedge resection of the wedge resection of the mesentery and limited mesentery and limited intestinal resectionintestinal resection
Median survival increased Median survival increased from 4 to 7.4 years from 4 to 7.4 years
Hellman, WJS, 2002;26
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Treatment: Jejunal/Ileal CarcinoidsTreatment: Jejunal/Ileal CarcinoidsEmergency operation reEmergency operation re--operation as operation as needed after the patient has been evaluatedneeded after the patient has been evaluatedIn cases of severe desmoplastic reaction around In cases of severe desmoplastic reaction around the superior mesenteric vessels, radical the superior mesenteric vessels, radical resection may not be possibleresection may not be possibleWedge resection in the fibrotic and contracted Wedge resection in the fibrotic and contracted mesentery may compromise the superior mesentery may compromise the superior mesenteric vessels and demesenteric vessels and de--vascularize a large vascularize a large extent of small bowel leading to short bowel extent of small bowel leading to short bowel syndrome syndrome
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Resection of Terminal Ileum Primary Tumor Resection of Terminal Ileum Primary Tumor and Mesenteric Metastasis and Mesenteric Metastasis
Mesenteric tumor may Mesenteric tumor may extensively involve the extensively involve the mesenteric rootmesenteric rootMobilization of cecum, TI, Mobilization of cecum, TI, and mesenteric root allows and mesenteric root allows the tumor to be lifted, the tumor to be lifted, separated from duodenum, separated from duodenum, pancreas and mesenteric pancreas and mesenteric vesselsvesselsPreservation of intestinal Preservation of intestinal vascular supply and vascular supply and intestinal length intestinal length
From Åkerström et al, Best Pract Res Clin Gastroenterol 19:5, 717, 2005
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Treatment: Small Bowel CarcinoidsTreatment: Small Bowel Carcinoids
Intestinal resection should be reserved until Intestinal resection should be reserved until dissection of the mesenteric tumor is complete in dissection of the mesenteric tumor is complete in an effort to determine bowel viabilityan effort to determine bowel viabilityTumor multicentricity should not be a Tumor multicentricity should not be a contraindication for resectioncontraindication for resectionIn asymptomatic patients, prophylactic resection In asymptomatic patients, prophylactic resection of mesenteric tumor is recommended as it may of mesenteric tumor is recommended as it may later become more difficult to managelater become more difficult to manageCholecystectomy should be considered as many Cholecystectomy should be considered as many patients on long term somatostatin analogs will patients on long term somatostatin analogs will develop gallstonesdevelop gallstones
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Small Bowel CarcinoidSmall Bowel Carcinoid
Introduction, History, EpidemiologyMicroscopy and Macroscopic AppearanceClinical Presentation and DiagnosisTreatment of PrimaryTreatment of Advanced/MetastaticF/U and Prognosis
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Treatment of Metastatic Disease to LiverTreatment of Metastatic Disease to Liver
>60 % will have non>60 % will have non--localized disease at diagnosislocalized disease at diagnosis50% will present with liver metastases 50% will present with liver metastases Surgical resection remains the gold standardSurgical resection remains the gold standardThe European Neuroendocrine Tumor Society The European Neuroendocrine Tumor Society (ENETS) has established minimal requirements for (ENETS) has established minimal requirements for resection with curative intent:resection with curative intent:–– 1) resectable well1) resectable well--differentiated liver disease with acceptable differentiated liver disease with acceptable
morbidity (close to 30%) and <5% mortalitymorbidity (close to 30%) and <5% mortality–– 2) absence of right heart insufficiency2) absence of right heart insufficiency–– 3) absence of extra3) absence of extra--abdominal metastases or diffuse peritoneal abdominal metastases or diffuse peritoneal
carcinomatosiscarcinomatosis
Steinmuller et al Neuroendocrinology 2008;87:47-62
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Treatment of Metastatic Disease to LiverTreatment of Metastatic Disease to LiverSurvival rate of 60Survival rate of 60--80% at 5 years for patients 80% at 5 years for patients resected for cureresected for cure
Primary tumor should be removed with one or Primary tumor should be removed with one or twotwo--step proceduresstep procedures
If heart surgery is also required, it should be If heart surgery is also required, it should be undertaken first, about 3 months prior to liver undertaken first, about 3 months prior to liver resection resection
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Ablative procedures (RFA and cryotherapy)Ablative procedures (RFA and cryotherapy)TransTrans--catheter arterial embolization or catheter arterial embolization or chemoembolization (TACE):chemoembolization (TACE):–– Objective tumor responses can be seen in over 50% Objective tumor responses can be seen in over 50%
of patients as well as of patients as well as effective control of symptomseffective control of symptoms
Molecular targeted radionuclide therapyMolecular targeted radionuclide therapyPalliative debulking procedures for functional Palliative debulking procedures for functional symptoms that donsymptoms that don’’t respond to medical t respond to medical treatmenttreatmentLiver transplantation may be an option in very Liver transplantation may be an option in very well selected candidateswell selected candidates
Treatment of Metastatic Disease to Liver: Treatment of Metastatic Disease to Liver: Options for Unresectable DiseaseOptions for Unresectable Disease
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Biotherapy: LongBiotherapy: Long--acting somatostatin analogsacting somatostatin analogs
Effective in reducing hypersecretion related symptoms in Effective in reducing hypersecretion related symptoms in patients with carcinoid syndrome patients with carcinoid syndrome
A reduction of biochemical markers can be seen in 40A reduction of biochemical markers can be seen in 40-- 60% of patients and 60% of patients and symptomatic improvement in 40symptomatic improvement in 40--80%80%
The antiThe anti--proliferative effect of somatostatin analogs is proliferative effect of somatostatin analogs is limited with partial or complete responses seen in less than limited with partial or complete responses seen in less than 10% of patients10% of patients
Stabilization of progression of disease occurs in 24Stabilization of progression of disease occurs in 24--57% of 57% of patients with documented tumor growth before initiation of patients with documented tumor growth before initiation of treatmenttreatment
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Biotherapy: LongBiotherapy: Long--acting somatostatin analogsacting somatostatin analogs
Therapy is initiated with shortTherapy is initiated with short--acting analogues, acting analogues, followed by depot formulations that can be given followed by depot formulations that can be given every 4 weeksevery 4 weeks
Side effects: Side effects: –– Abdominal discomfortAbdominal discomfort–– SteatorrheaSteatorrhea–– MalabsorptionMalabsorption–– Gallstone formationGallstone formation
Monitoring: Symptoms, urinary 5Monitoring: Symptoms, urinary 5--HIAAHIAA
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Biotherapy: InterferonBiotherapy: Interferon--αα
InterferonInterferon--αα
treatment is recommended as treatment is recommended as secondsecond--line treatment of functioning tumors with a line treatment of functioning tumors with a low proliferation ratelow proliferation rate
Effect is not as rapid and its toxicities are more Effect is not as rapid and its toxicities are more pronounced than those of somatostatin analogspronounced than those of somatostatin analogs
Biochemical and symptoms control can be seen in Biochemical and symptoms control can be seen in up to 50% of patients up to 50% of patients
Partial tumor size responses of 10Partial tumor size responses of 10--15%15%
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Treatment Approach to Liver Metastases without Treatment Approach to Liver Metastases without Extrahepatic MetastasisExtrahepatic Metastasis
From Steinmüller et al: Neuroendocrinology 87: 47, 2008
RFA = radiofrequency ablation; RPVE = right portal vein embolization; RPVL = right portal vein ligation; LITT = laser-induced thermotherapy; TACE =trans-catheter arterial chemoembolization; TAE = trans-catheter arterial embolization.
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PeptidePeptide--Receptor Radionuclide Therapy Receptor Radionuclide Therapy (PRRT)(PRRT)
Targeting of somatostatin receptors with radiolabeled Targeting of somatostatin receptors with radiolabeled somatostatin analogs is a promising option for the somatostatin analogs is a promising option for the treatment of somatostatintreatment of somatostatin--receptorreceptor--positive endocrine positive endocrine tumors tumors Patients with metastatic or inoperable diseasePatients with metastatic or inoperable diseaseTreatment with somatostatin analogs labeled with Treatment with somatostatin analogs labeled with 111111In, In, 9090Y or Y or 177177Lu can result in symptomatic improvementLu can result in symptomatic improvement
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PeptidePeptide--Receptor Radionuclide Therapy Receptor Radionuclide Therapy (PRRT)(PRRT)
Tumor remission is seldom achieved with Tumor remission is seldom achieved with 111111InIn--labeled labeled analogs analogs Objective response with Objective response with 9090YY (yttrium)(yttrium)--DOTATOC: DOTATOC:
99––33% 33% Median duration of response of 30 monthsMedian duration of response of 30 months
Objective Objective responsrespons to to 177177Lu (Lutetium)Lu (Lutetium)--octreotateoctreotate::29%; stable disease was present in 35% and progressive disease i29%; stable disease was present in 35% and progressive disease in n 20% of patients 20% of patients median duration of response of 40 monthsmedian duration of response of 40 months
Treatment with Treatment with 177177LuLu--octreotate seems to confer a survival octreotate seems to confer a survival benefit of several yearsbenefit of several years
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PRRT: ENETS Consensus GuidelinesPRRT: ENETS Consensus Guidelines
Eligibility Eligibility –– Tumor uptake on Tumor uptake on octreoscanoctreoscan–– Inoperable diseaseInoperable disease–– Life expectancy at least 3Life expectancy at least 3--6 month6 month–– Performance statusPerformance status
ContraindicationsContraindications–– Pregnancy/lactationPregnancy/lactation–– Renal impairment Cr Cl <40Renal impairment Cr Cl <40--5050–– Hgb<8 g/dl, platelets<75K, WBC<2KHgb<8 g/dl, platelets<75K, WBC<2K–– Severe hepatic impairment, TB>3, alb <3, increased PTSevere hepatic impairment, TB>3, alb <3, increased PT–– Severe cardiac impairmentSevere cardiac impairment
Kwekkeboom et al, Neuroendocrinology, 90, 2009
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PeptidePeptide--Receptor Radionuclide Therapy Receptor Radionuclide Therapy (PRRT)(PRRT)
Predictive factors for tumor remission:Predictive factors for tumor remission:–– High tumoral uptake of radioactivity on SRS, PETHigh tumoral uptake of radioactivity on SRS, PET–– Limited numbers of liver metastasesLimited numbers of liver metastases
Adverse effects of PRRT are few and mostly mild with Adverse effects of PRRT are few and mostly mild with the use of renal protective agentsthe use of renal protective agents
Serious, delayed adverse effects, such as Serious, delayed adverse effects, such as myelomyelo-- dysplastic syndrome or renal failure, are raredysplastic syndrome or renal failure, are rare
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Improved tumor uptake of Improved tumor uptake of 177177LuLu--octreotateoctreotate versus that of 111inversus that of 111in--octreotideoctreotide
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Tumor Responses in Patients With GEPNETs, Treated With Different Radiolabeled Somatostatin Analogues
CLOSE
Tumor Response Center
(Reference) Ligand No of Patient CR PR MR SD PD CR + PR
Rotterdam5 [111In-DTPA0]octreotide 26 0 0 5 (19%) 11 (42%) 10 (38%) 0%
New Orleans7 [111In-DTPA0]octreotide 26 0 2 (8%) NA 21 (81%) 3 (12%) 8%
Basel[8] and [9] [90Y-DOTA°,Tyr3]octreotide 74 3 (4%) 15 (20%) NA 48 (65%) 8 (11%) 24%
Basel10 (90Y-DOTA0,Tyr3)octreotide 33 2 (6%) 9 (27%) NA 19 (57%) 3 (9%) 33%
Milan11 (90Y-DOTA0,Tyr3)octreotide 21 0 6 (29%) NA 11 (52%) 4 (19%) 29%
Rotterdam12 [90Y-DOTA0,Tyr3]octreotide 58 0 5 (9%) 7 (12%) 33 (61%) 10 (19%) 9%
Rotterdam13 [177Lu- DOTA0,Tyr3]octreotate 310 5 (2%) 86 (28%) 51 (16%) 107 (35%) 61 (20%) 29%
Adapted from Kwekkeboom DJ et al. J Nucl Med, 2005; 46: 625-665
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ChemotherapyChemotherapy
Combinations of streptozotocin (STZ) + Combinations of streptozotocin (STZ) + doxorubicin and/or 5doxorubicin and/or 5--fluorouracil (5fluorouracil (5--FU), FU), cisplatin + etoposide and dacarbazinecisplatin + etoposide and dacarbazine
The benefits and duration of responses to The benefits and duration of responses to chemotherapy for small bowel carcinoid chemotherapy for small bowel carcinoid are very limitedare very limited
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Chemotherapy vs. PRRTChemotherapy vs. PRRT
Kwekkeboom et al, Semin Nucl Med, 2010;40:78-88
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Overall survival in patientsOverall survival in patients from observational and interventional studies (blue bars) and infrom observational and interventional studies (blue bars) and in
similar patients with regard to tumor type and disease stagesimilar patients with regard to tumor type and disease stage treated with [treated with [177177LuLu--DOTA0, Tyr3]octreotate (red bars)DOTA0, Tyr3]octreotate (red bars)
Survival benefit of 40Survival benefit of 40--72 72 months in patients months in patients treated with [treated with [177177LuLu-- DOTA0, Tyr3]octreotateDOTA0, Tyr3]octreotate
Kwekkeboom et al, Semin Nucl Med 2010;40:78-88
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Small Bowel CarcinoidSmall Bowel Carcinoid
Introduction, History, EpidemiologyMacroscopic and Microscopic AppearanceClinical Presentation and DiagnosisTreatment of PrimaryTreatment of Advanced/MetastaticF/U and Prognosis
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CgACgA: Recurrent Disease Surveillance: Recurrent Disease Surveillance56 patients radically resected small bowel carcinoid56 patients radically resected small bowel carcinoidCgACgA, 5HIAA, radiologic examinations 1, 5HIAA, radiologic examinations 1--3 times/year3 times/year33/56 patients recurred, median 32 months (range 633/56 patients recurred, median 32 months (range 6--217)217)CgACgA was the first marker to become elevated in 28/33 (85%)was the first marker to become elevated in 28/33 (85%)CgACgA continued to be elevated for a median of 30 months continued to be elevated for a median of 30 months before radiologic confirmationbefore radiologic confirmation
Welin et al, Neuroendocrinology 2009;89:302-307
Suggested surveillance for recurrence in asymptomatic patients:
CgA twice per yearUS or CT annually
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CgACgA and Prognosisand Prognosis
There is a correlation between chromogranin A There is a correlation between chromogranin A levels, tumor load, and prognosislevels, tumor load, and prognosis252 patients with midgut carcinoid252 patients with midgut carcinoidPoor prognostic factorsPoor prognostic factors
Janson et al, Ann Oncol 1997;8:685-690
Univariate Multivariate
Age Age
CgA (>5000ug/L) CgA (>5000ug/L)
>5 liver metastasis
Carcinoid Syndrome
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Small Bowel Carcinoid: Prognostic FactorsSmall Bowel Carcinoid: Prognostic Factors
258 patients with small bowel carcinoid258 patients with small bowel carcinoidOverall 5Overall 5--year survival: 72%year survival: 72%–– Localized disease 94%Localized disease 94%–– Regional disease 85%Regional disease 85%–– Liver metastasis 63%Liver metastasis 63%
Strickland et al, Scandinavian Journal of Gastroenterology 2009, 1-8
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Therapeutic algorithm for gastrointestinal Therapeutic algorithm for gastrointestinal neuroendocrine tumors (NETs) neuroendocrine tumors (NETs)
Gustafsson, Current Opinion in Oncology. 20(1):1‐12, January 2008
En bloc resection of primary and lymphatic drainage
En bloc resection of primary and lymphatic drainage
Embolization +/chemo
Embolization +/chemo ResectionResection
Follow-up:CgA
OctreoscanCT/MRI5 HIAA
Follow-up:CgA
OctreoscanCT/MRI5 HIAA
Ablation/RFA/CryoAblation/RFA/Cryo
No metastasesNo metastasesLiver Metastases Residual disease Liver Metastases Residual disease
Cytotoxics: 5-FU, STZ, dacarb, othersCytotoxics: 5-FU, STZ, dacarb, others
PRRT PRRT
Pharmacotherapy: SST analogues, InterferonPharmacotherapy: SST analogues, Interferon
Liver transplant
Liver transplant RecurrenceRecurrence
LocalLocal
ResectionResection
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55--year overall survival from carcinoids at all sites, year overall survival from carcinoids at all sites, carcinoids of the digestive system, and carcinoids carcinoids of the digestive system, and carcinoids of the small intestine, US population 1973of the small intestine, US population 1973––2002 2002
Data from SEER database, US NCIData from SEER database, US NCI
Modlin et al, Lancet Oncol 2008;9: 61-72
70%
1993-97
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Requirements for an improvement in NET outcomeRequirements for an improvement in NET outcome
Refinement of universal classification and grading system Refinement of universal classification and grading system Elucidation of cell biology, development of cell lines and Elucidation of cell biology, development of cell lines and animal modelsanimal modelsIdentification of serum markers for early diagnosisIdentification of serum markers for early diagnosisDevelopment of molecular pathological profiling to define Development of molecular pathological profiling to define prognosisprognosisPrecise identification of topographic informationPrecise identification of topographic informationIdentification of molecular therapeutic targetsIdentification of molecular therapeutic targetsDevelopment of improved treatment for residual diseaseDevelopment of improved treatment for residual diseaseEstablishment of centers of excellence and Establishment of centers of excellence and multidisciplinary teamsmultidisciplinary teamsConstruction of central clinical and tissue databasesConstruction of central clinical and tissue databasesGovernment focus on clinical and research funding for an Government focus on clinical and research funding for an orphan diseaseorphan disease
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Volcan Osorno, Llanquihue, Chile
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SummarySummary
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EC-cell carcinoid of the distal ileum in a 45-year-old woman who complained of crampy abdominal pain
Levy A D, Sobin L H Radiographics 2007;27:237-257©2007 by Radiological Society of North America
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Multifocal ileal carcinoids with intussusception in a 43-year-old woman who complained of abdominal pain and nausea
Levy A D, Sobin L H Radiographics 2007;27:237-257©2007 by Radiological Society of North America
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Figure 13a. EC-cell small bowel carcinoid in a 59-year-old woman who complained of a 4-year history of flushing and diarrhea
Levy A D, Sobin L H Radiographics 2007;27:237-257©2007 by Radiological Society of North America
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EC-cell carcinoid of the ileum in a 50-year-old man with abdominal pain
Levy A D, Sobin L H Radiographics 2007;27:237-257©2007 by Radiological Society of North America
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Siegfried Oberndorfer (1876-1944) (top left) presented his observations of multiple “benign carcinomas” (Karzinoide) of the small bowel at the German Pathological Society meeting of 1907 in Dresden (top).
P. Masson and A. Gosset (bottom left and right, respectively) demonstrated the argentaffin staining properties of appendiceal carcinoid tumors in 1914 and suggested that gut enterochromaffin (EC) cells (lower left; bottom right) formed a diffuse endocrine organ. In 1928, they described these cells to be neural in origin and proposed them as progenitors of neuroendocrine tumors of the gut (carcinoids).
The first description of the diffuse neuroendocrine system (DNES) was provided in 1938 by F. Feyrter (bottom), who described argentaffin or argyrophil “clear cells” (“Helle Zellen”) in the gut and pancreas and proposed that such cells produced hormonesthat acted locally.
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Case Study #1 Case Study #1 Submucosal MassSubmucosal Mass
History: 72History: 72--year old woman, year old woman, unexplained iron deficiency anemia. unexplained iron deficiency anemia. Hgb 10, MCV 82, RDW 13. Three cards Hgb 10, MCV 82, RDW 13. Three cards for FOBT all positive.for FOBT all positive.History of note for GaucherHistory of note for Gaucher’’s with known s with known platelet dysfunctionplatelet dysfunctionNormal EGD and colonoscopy 4 months Normal EGD and colonoscopy 4 months earlier earlier Family history of celiac diseaseFamily history of celiac disease
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PillCamPillCam Capsule FindingsCapsule Findings Submucosal MassSubmucosal Mass
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ConclusionConclusion
Capsule endoscopy shows multiple Capsule endoscopy shows multiple submucosal masses. Some are submucosal masses. Some are ulcerated and bleeding. These are ulcerated and bleeding. These are located in the midlocated in the mid--small bowel. A small bowel. A preresumptivepreresumptive diagnosis of multicentric diagnosis of multicentric carcinoid is made. carcinoid is made. A CT scan is negative as is an A CT scan is negative as is an octreatideoctreatide scan.scan.The patient undergoes surgery guided The patient undergoes surgery guided by intraoperative endoscopy. Multiple by intraoperative endoscopy. Multiple carcinoid tumors are discovered and a carcinoid tumors are discovered and a midmid--small bowel resection is performedsmall bowel resection is performed
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Small Bowel Carcinoid: Small Bowel Carcinoid: EpidemiologyEpidemiology
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Levy A D, Sobin L H Radiographics 2007;27:237-257©2007 by Radiological Society of North America
Macroscopic Appearance: Macroscopic Appearance: Desmoplastic ReactionDesmoplastic Reaction
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Ileal carcinoid that was discovered incidentally in a 67-year-old woman who underwent preoperative CT for endometrial carcinoma
Levy A D, Sobin L H Radiographics 2007;27:237-257©2007 by Radiological Society of North America
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Additional ImagingAdditional Imaging
Echocardiogram should be performed in Echocardiogram should be performed in patients with carcinoid syndrome to patients with carcinoid syndrome to evaluate for valvular disease and evaluate for valvular disease and congestive heart diseasecongestive heart disease
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These techniques can be used effectively as antiThese techniques can be used effectively as anti--tumor tumor treatment and in relieving symptoms in patients with liver treatment and in relieving symptoms in patients with liver metastases either as sole therapy or in combination with metastases either as sole therapy or in combination with resectionresectionRFA has the potential to be delivered percutaneously RFA has the potential to be delivered percutaneously under image guidance, which may be useful for nonunder image guidance, which may be useful for non-- operative candidatesoperative candidatesThe use of RFA is not recommended for patients with The use of RFA is not recommended for patients with tumors over 5 cm or near vital structures, large vessels tumors over 5 cm or near vital structures, large vessels and central bile ductsand central bile ducts
Treatment of Metastatic Disease to Liver: Treatment of Metastatic Disease to Liver: Other OptionsOther Options
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Clinical Presentation: Clinical Presentation: Bowel ObstructionBowel Obstruction
October 2006 January 2009
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Small Bowel Carcinoid: MicroscopySmall Bowel Carcinoid: Microscopy
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Potential sidePotential side--effects of PRRT, deduced from the effects of PRRT, deduced from the normal distribution of radioactivitynormal distribution of radioactivity
during diagnostic somatostatin receptor imagingduring diagnostic somatostatin receptor imaging
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Moldin et al, Am J Gastroenterol 2004;99:2466–2478Kidd et al, World J Gastroenterology 2007;13: 5208-5216
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Treatment Response for Treatment Response for Gastrointestinal NETGastrointestinal NET
Radiofrequency, cryoablation, and chemoembolization of liver metastases. PRRT=peptide receptor radionuclide therapy. HL=human leucocyte interferon
Modlin et al, Lancet Oncol 2008;9: 61-72
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Treatment: Duodenal CarcinoidsTreatment: Duodenal CarcinoidsShould be removed unless:Should be removed unless:–– widely metastatic disease, markedly limited life expectancy or widely metastatic disease, markedly limited life expectancy or
increased surgical risk even in the face of metastatic disease, increased surgical risk even in the face of metastatic disease,
May be resected when present with complicationsMay be resected when present with complications–– uncontrollable bleeding uncontrollable bleeding –– liver only, potentially resectable metastasesliver only, potentially resectable metastases
There are different options for resection, and there is still There are different options for resection, and there is still considerable controversy on the selection of treatment considerable controversy on the selection of treatment modalities for these lesions modalities for these lesions
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Methods for identification of primary and Methods for identification of primary and metastatic GEPmetastatic GEP--NET: NET:
Data pooled from 41 studiesData pooled from 41 studies
Modlin et al, Lancet Oncol 2008;9: 61-72