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NCCN临床实践指南:神经内分泌肿瘤(2014.V2)_图文


NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines?)

Neuroendocrine Tumors
Version 2.2014 NCCN.org

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NCCN Guidelines Version 2.2014 Panel Members Neuroendocrine Tumors
* Matthew H. Kulke, MD/Chair ? Dana-Farber/Brigham and Women’s Cancer Center Manisha H. Shah, MD/ Vice Chair ? The Ohio State University Comprehensive Cancer Center - James Cancer Hospital and Solove Research Institute Al B. Benson, III, MD ? Robert H. Lurie Comprehensive Cancer Center of Northwestern University Emily Bergsland, MD ? UCSF Helen Diller Family Comprehensive Cancer Center Jordan D. Berlin, MD ? Vanderbilt-Ingram Cancer Center Lawrence S. Blaszkowsky, MD ? Massachusetts General Hospital Cancer Center Michael A. Choti, MD, MBA ? The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Orlo H. Clark, MD ? UCSF Helen Diller Family Comprehensive Cancer Center Lyska Emerson, MD ≠ Huntsman Cancer Institute at the University of Utah Paul F. Engstrom, MD ? Fox Chase Cancer Center Paul Fanta, MD UC San Diego Moores Cancer Center Whitney S. Goldner, MD ? Fred & Pamela Buffett Cancer Center at The Nebraska Medical Center Martin J. Heslin, MD ? University of Alabama at Birmingham Comprehensive Cancer Center Fouad Kandeel, MD, PhD ? City of Hope Comprehensive Cancer Center Pamela L. Kunz, MD ? Stanford Cancer Institute Boris W. Kuvshinoff, II, MD, MBA ? Roswell Park Cancer Institute Christopher Lieu, MD ? University of Colorado Cancer Center Jeffrey F. Moley, MD ? Siteman Cancer Center at BarnesJewish Hospital and Washington University School of Medicine Gitonga Munene, MD St. Jude Children`s Research Hospital/ The University of Tennessee Health Science Center

NCCN Guidelines Index Neuroendocrine TOC Discussion

Venu G. Pillarisetty, MD ? University of Washington Medical Center/ Seattle Cancer Care Alliance Leonard Saltz, MD ? ? Memorial Sloan-Kettering Cancer Center David E. Schteingart, MD ? ? University of Michigan Comprehensive Cancer Center Julie Ann Sosa, MD ? ? Duke Cancer Institute Jonathan R. Strosberg, MD ? Moffitt Cancer Center Jean-Nicolas Vauthey, MD ? The University of Texas MD Anderson Cancer Center James C. Yao, MD ? The University of Texas MD Anderson Cancer Center NCCN Jennifer Burns Deborah Freedman-Cass, PhD

NCCN Guidelines Panel Disclosures

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? Surgery/Surgical oncology ? Medical oncology ? Endocrinology ≠ Pathology ? Internal medicine * Writing committee member

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NCCN Guidelines Version 2.2014 Table of Contents Neuroendocrine Tumors
NCCN Neuroendocrine Tumors Panel Members Summary of the Guidelines Updates Neuroendocrine Tumors, Clinical Presentations and Diagnosis (NE-1) Carcinoid Tumors (CARC-1) Neuroendocrine Tumors of the Pancreas (PanNET-1) Neuroendocrine Tumors of Unknown Primary (NUP-1) Adrenal Gland Tumors (AGT-1) Pheochromocytoma/Paraganglioma (PHEO-1) Poorly Differentiated (High Grade)/Large or Small Cell (HGNET-1) Multiple Endocrine Neoplasia, Type 1 (MEN1-1) Multiple Endocrine Neoplasia, Type 2 (MEN2-1) Principles of Pathology for Diagnosis and Reporting of Neuroendocrine Tumors (NE-A) Serum Hormone Evaluation Potentially Indicated in the Workup of Neuroendocrine Tumors (NE-B) Surgical Principles for Management of Neuroendocrine Tumors (NE-C) Staging (ST-1)

NCCN Guidelines Index Neuroendocrine TOC Discussion

Clinical Trials: NCCN believes that the best management for any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged. To find clinical trials online at NCCN Member Institutions, click here: nccn.org/clinical_trials/physician.html. NCCN Categories of Evidence and Consensus: All recommendations are category 2A unless otherwise specified. See NCCN Categories of Evidence and Consensus.

The NCCN Guidelines? are a statement of evidence and consensus of the authors regarding their views of currently accepted approaches to treatment. Any clinician seeking to apply or consult the NCCN Guidelines is expected to use independent medical judgment in the context of individual clinical circumstances to determine any patient’s care or treatment. The National Comprehensive Cancer Network? (NCCN?) makes no representations or warranties of any kind regarding their content, use or application and disclaims any responsibility for their application or use in any way. The NCCN Guidelines are copyrighted by National Comprehensive Cancer Network?. All rights reserved. The NCCN Guidelines and the illustrations herein may not be reproduced in any form without the express written permission of NCCN. ?2013.
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NCCN Guidelines Version 2.2014 Updates Neuroendocrine Tumors
Updates in Version 2.2014 of the NCCN Guidelines for Neuroendocrine Tumors from Version 1.2014 include: MS-1 ? The Discussion section was updated to reflect the changes in the algorithm. Updates in Version 1.2014 of the NCCN Guidelines for Neuroendocrine Tumors from Version 2.2013 include:
Global ? “24-hour urine 5-HIAA” replaced “5-HIAA” ? “Islet cell tumor” was removed from Neuroendocrine Tumors ? “Somatostatin scintigraphy” replaced “Octreoscan” Neuroendocrine Tumors NE-1 ? Multiple endocrine neoplasia, type 1 List was revised to include only those tumor types described on MEN1-2 ? Multiple endocrine neoplasia, type 2 List was revised to include only those tumor types described on MEN2-2 Carcinoid Tumors CARC-1 ? Footnote “d” was modified: “ Should include: ? Careful examination of the entire bowel, as multiple synchronous lesions may be present. ? Assessment of the proximity to or involvement of the superior mesenteric artery and superior mesenteric vein.” CARC-5 ? Footnote “q” was added: “Prior to evaluating ACTH, confirm hypercortisolemia using one of the following: ??Overnight 1 mg dexamethasone suppression test with 8 am plasma cortisol ??Repeated (2-3) midnight salivary cortisols ??24-hour urine free cortisol” CARC-6 ? Footnote “s” was added: “Noncurative debulking surgery might be considered in select cases.” Neuroendocrine Tumors of the Pancreas PanNET-1 ? Footnote “a” was revised: “For rare tumors secreting hormones such as somatostatin, ACTH, PTHrP, and PP, follow the nonfunctioning pancreatic tumor pathway.” PanNET-2 ? Footnote “n” was added: “There is some disagreement among panel members regarding the role of splenectomy in all cases.”

NCCN Guidelines Index Neuroendocrine TOC Discussion

PanNET-4 ? Management of Primary Non-Metastatic Disease Footnote “r” was added to “Pancreatoduodenectomy + peripancreatic lymph nodes.” ? Footnote Footnote “r” was revised: “Hypercoaguable state has been described. Consider Perioperative anticoagulation can be considered.” PanNET-6 ? Surveillance: “>1 y postresection up to 10 y” was modified: “>1 y postresection up to a maximum of 10 y” PanNET-7 ? Footnote “v” was added: “Noncurative debulking surgery might be considered in select cases.” Neuroendocrine Tumors of Unknown Primary NUP-1 ? Initial Workup 4th bullet revised: “Consider FDG-PET scan, and brain imaging in poorly differentiated tumors only.” Adrenal Gland Tumors AGT-1 ? Evaluation Cushing’s syndrome was revised: Serum ACTH, cortisol, and DHEA-s with one of the following: ? Overnight 1 mg dexamethasone suppression test with 8 am plasma cortisol ? Repeated (2-3) midnight salivary cortisols ? 24-hour urine free cortisol” Pheochromocytoma was revised: Plasma free or 24-hour urine fractionated metanephrines Fractionated urine metanephrines and catecholamines for confirmation ? Clinical diagnosis Bullet and text under Pheochromocytoma was removed: “Elevated plasma-free metanephrines or confirmed elevation of urine metanephrines and catecholamines.”

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NCCN Guidelines Version 2.2014 Updates Neuroendocrine Tumors
Updates in Version 1.2014 of the NCCN Guidelines for Neuroendocrine Tumors from Version 2.2013 include:
Adrenal Gland Tumors AGT-1 (Continuted) ? Footnotes Footnote “e” was added: ??“Prior to evaluating ACTH, confirm hypercortisolemia using one of the following: ? Overnight 1 mg dexamethasone suppression test with 8 am plasma cortisol ? Repeated (2-3) midnight salivary cortisols ? 24-hour urine free cortisol” Footnote “g” was added: “For cervical paraganglioma, consider measuring dopamine.” Footnote was removed: “Chemical shift imaging demonstrating signal drop out.” AGT-4 ? Additional Evaluation Suspected carcimona: “Imaging of chest, abdomen, and pelvis to evaluate for metastases” was moved and is now recommended for tumors of all sizes. ? Footnotes Footnote was removed: “Chemical shift imaging demonstrating signal drop out.” Pheochromocytoma PHEO-1 ? Evaluation: 1st bullet was modified: “Plasma free or 24-hour urine fractionated metanephrine and normetanephrine or urine metanephrine” ? Footnote “d” was added: “For cervical paraganglioma, consider measuring dopamine.” PHEO-2 ? Surveillance: “FDG” was added to “PET scan.” Poorly Differentiated (High Grade)/Large or Small Cell HGNET-1 ? Footnote “b” was revised, “Cisplatin or carboplatin and etoposide are generally recommended as primary treatment. Evolving data suggest that tumors with intermediate Ki-67 level in the 20-50% range may not respond as well to platinum/ etoposide as patients with small cell histology or extremely high Ki-67. Clinical judgement should be used. See NCCN Guidelines for Small Cell Lung Cancer.” Multiple Endocrine Neoplasia, Type 1 MEN1-3 ? Footnote “h” was revised: “Surveillance is indicated for all MEN tumors regardless of patient’s tumor type. For patients at risk for bronchial or thymic carcinoid tumors, chest imaging can be considered every 1-3 y (Thakker RV, Newey PJ, Walls GV, et al. Clinical practice guidelines for multiple endocrine neoplasia type 1 (MEN1). J Clin Endocrinol Metab 2012;97:2990-3011).”
?

NCCN Guidelines Index Neuroendocrine TOC Discussion

MEN1-A ? The table was removed and replaced with the following text: The most common MEN1 neoplasm is parathyroid hyperplasia (affecting 98% of patients), followed by islet cell tumors of the pancreas (50%), pituitary adenomas (35%), and/or lung/thymus carcinoid tumors (10%). Type 2 gastric carcinoid tumors occur frequently in MEN1 patients with gastrinoma. A higher incidence of adrenal tumors is also observed in MEN1. MEN1-B ? 3rd bullet, 1st sub-bullet was revised: “Insulinoma causing symptomatic hypoglycemia Symptomatic functional tumors refractory to medical management.” Multiple Endocrine Neoplasia, Type 2 MEN2-1 ? First bullet was revised: “MEN2 is subdivided into MEN2A and MEN2B. Medullary thyroid cancer (MTC) occurs in ~100% of nearly all patients with MEN2A...” MEN2-2 ? Clinical Evaluation Pheochromocytoma: Recommended, 1st sub-bullet was modified: “Plasma free or 24-hour urine fractionated metanephrine and normetanephrine or urine metanephrine” ? Footnotes Footnote “g” was added: “For cervical paraganglioma, consider measuring dopamine.” MEN2-A ? The table was removed and replaced with the following text: The most common MEN2A neoplasm is medullary carcinoma of the thyroid (affecting 98% of patients), followed by adrenal pheochromocytoma (50%), and/or parathyroid hyperplasia (25%). The most common MEN2B neoplasm is medullary carcinoma of the thyroid (98%), followed by mucosal neuroma or intestinal ganglioneuroma (95%), adrenal pheochromocytoma (50%), and/or parathyroid hyperplasia (<1%). ? Text was moved from footnote “a” into the bulleted list on the page. ? Reference was added: Moore FD, Scoinski MA, Joste NE. Endocrine Tumors and Malignancies. In: Skarin A, ed. Atlas of Diagnostic Oncology (ed 3rd). Philadelphia: Elsevier Science Limited; 2003.

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NCCN Guidelines Version 2.2014 Updates Neuroendocrine Tumors
Updates in Version 1.2014 of the NCCN Guidelines for Neuroendocrine Tumors from Version 2.2013 include:
Principles of Pathology For Diagnosis and Reporting of Neuroendocrine Tumors NE-A 1 of 4 ? Table 1 was significantly revised to reflect the grading classification systems for gastroenteropancreatic (GEP) neuroendocrine tumors and lung and thymus neuroendocrine tumors. ? Reference added below Table 1: Adapted from Bosman FT, Carneiro F, Hruban RH, Theise ND. World Health Organization Classification of Tumours of the Digestive System. IARC, Lyon, 2010; and Travis WD, Brambilla E, Muller-Hermelink HK, Harris CC. World Health Organization Classification of Tumours of the Lung, Pleura, Thymus and Heart. Lyon: IARC;2004. ? Footnotes Text from footnote “a” was revised and relocated to a text box below Table 1: “Table 1 should be used as a general guide. Some tumors may not fall into a single category. Definitions vary between lung, thymus, and GEP-NETs in some classification systems. It is recognized that occasionally a morphologically “well-differentiated” NET may have a proliferation index by Ki-67, which technically falls into the “highgrade” category by this measure alone. Clinical judgment should be used in such discordant cases. In general, this discordance should not cause a reclassification of a well-differentiated NET as a “poorly differentiated NEC.” In these cases, the tumor should be reported as a well-differentiated NET (so-called “atypical carcinoid” terminology in lung and thymus) with the specific mitotic rate and Ki-67 proliferation index included in the report as additional information. (See NE-A 3 of 4.)” NE-A 2 of 4 ? Immunohistochemistry and other ancillary techniques 2nd bullet revised: “Specific markers that may be used to establish neuroendocrine differentiation include chromogranin A, synaptophysin, and CD56, although the last marker CD56 has recently proven to be less specific.” ? Classification and grade 1st bullet, 2nd sentence revised: “The most recent WHO classification system is suggested for GEP NETs and represents an attempt to unify European and American approaches.”

NCCN Guidelines Index Neuroendocrine TOC Discussion

NE-A 3 of 4 ? Ki-67 Index 2nd bullet was revised: “If both mitotic rate and Ki-67 index are used and these are discordant, it is currently recommended that the higher grade be assigned used to assign classification.” 3rd bullet was added: “It is recognized that occasionally a morphologically “well-differentiated” NET may have a proliferation index by Ki-67, which technically falls into the “high-grade” category by this measure alone. Clinical judgment should be used in such discordant cases. In general, this discordance should not cause a reclassification of a well-differentiated NET as a “poorly differentiated NEC.” In these cases, the tumor should be reported as a welldifferentiated NET (so-called “atypical carcinoid” terminology in lung and thymus) with the specific mitotic rate and Ki-67 proliferation index included in the report as additional information.” 4th bullet was revised: “The pathologist should report the actual parameters used to assign grade (ie, mitotic rate and proliferation index) so that retrospective reviews may be done and clinicians have the necessary information to make informed treatment decisions. Clinical judgment must be applied in these circumstances. 5th bullet, reference “3” was added. NE-A 4 of 4 ? Reference “3” was updated: “Travis WD, Brambilla E, Muller-Hermelink HK, Harris CC. World Health Organization Classification of Tumours of the Lung, Pleura, Thymus and Heart. Lyon: IARC;2004.” Serum Hormone Evaluation Potentially Indicated in the Workup of Neuroendocrine Tumors NE-B ? Pheochromocytoma/paraganglioma Removed catecholamines and dopamine. ? Footnote Footnote “2” was revised: “Should be considered with cervical paraganglioma. For cervical paraganglioma, consider measuring dopamine.” Surgical Principles for Management of Neuroendocrine Tumors NE-C ? 8th bullet was revised: “Octreotide therapy should be administered parenerally proir to induction of anesthesia in patients with functional carcinoid tumors to prevent carcinoid crisis.”

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NCCN Guidelines Version 2.2014 Neuroendocrine Tumors
Carcinoid tumorsb Clinical presentations: ? Jejunal, ileal, colon (See CARC-1) ? Duodenal (See CARC-1) ? Appendix (See CARC-2) ? Rectal (See CARC-3) ? Gastric (See CARC-4) ? Bronchopulmonary, thymus (See CARC-5) ? Atypical lung carcinoid ? Locoregional unresectable disease and/or distant metastases (See CARC-6) Neuroendocrine tumors of the pancreasb Clinical presentations: ? Nonfunctioning pancreatic tumors (See PanNET-1) ? Gastrinoma (See PanNET-2) ? Insulinoma (See PanNET-3) ? Glucagonoma (See PanNET-4) ? VIPoma (See PanNET-5) ? Recurrent disease (See PanNET-6) ? Locoregional unresectable disease and/or distant metastases (See PanNET-7) Neuroendocrine tumors of unknown primary (See NUP-1)b Adrenal gland tumors (See AGT-1)c Pheochromocytoma/paraganglioma (See PHEO-1) Poorly differentiated (high grade) neuroendocrine tumors/ Large or small cell carcinoma other than lung (See HGNET-1) CLINICAL PRESENTATIONS AND DIAGNOSISa Multiple endocrine neoplasia, type 1 (See MEN1-1) ? Parathyroid ? Pancreatic neuroendocrine tumors (PanNET) ? Pituitary tumor

NCCN Guidelines Index Neuroendocrine TOC Discussion

Multiple endocrine neoplasia, type 2 (See MEN2-1) ? Medullary thyroid carcinoma (Also see NCCN Guidelines for Thyroid Carcinoma) ? Parathyroid ? Pheochromocytoma Merkel cell carcinoma (See NCCN Guidelines for Merkel Cell Carcinoma)

aSee Principles of Pathology for Diagnosis and Reporting of Neuroendocrine Tumors (NE-A). bGuidelines pertain to well-differentiated tumors. For poorly differentiated/high-grade/large or small cIncludes adrenal cortical tumors and incidentaloma.

cell carcinomas, see HGNET-1.

Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.
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NE-1

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NCCN Guidelines Version 2.2014 Carcinoid Tumors
CLINICAL LOCATION EVALUATIONa,b PRIMARY TREATMENT OF NON-METASTATIC DISEASEc ? Bowel resection with regional lymphadenectomyd ? Consider prophylactic cholecystectomye when appropriate Metastatic Disease (CARC-6)

NCCN Guidelines Index Neuroendocrine TOC Discussion SURVEILLANCEg,h

Jejunal/ileal/ colon

Recommended: ? Abdominal/pelvic multiphasic CT or MRI As appropriate: ? Somatostatin scintigraphy ? Colonoscopy ? Small-bowel imaging ? Chest CT

Locoregional disease

Metastatic disease

3-12 mo postresection: ? H&P ? Consider 24-hour urine 5-HIAA ? Consider chromogranin A (category 3) ? Consider abdominal/pelvic multiphasic CT or MRI >1 y postresection up to 10 y: ? Every 6-12 mo H&P Consider 24-hour urine 5-HIAA  Consider chromogranin A (category 3) Consider multiphasic CT or MRI

Duodenal

Recommended: ? Abdominal/pelvic multiphasic CT or MRI As appropriate: ? Somatostatin scintigraphy ? EGD/endoscopic ultrasound (EUS) ? Chest CT

Locoregional disease

? Endoscopic resectionf ? Local excision (transduodenal) ± lymph node sampling ? Pancreatoduodenectomy

Metastatic disease

Metastatic Disease (CARC-6)
d Should

a See

Principles of Pathology for Diagnosis and Reporting of Neuroendocrine Tumors (NE-A). b See Serum Hormone Evaluation Potentially Indicated in the Workup of Neuroendocrine Tumors (NE-B). cSee Surgical Principles for Management of Neuroendocrine Tumors (NE-C).

include: ? Careful examination of the entire bowel, as multiple synchronous lesions may be present. ? Assessment of the proximity to or involvement of the superior mesenteric artery and superior mesenteric vein. eIf possible future need for octreotide. fIf endoscopic resection performed, follow-up EGD as appropriate. gEarlier, if symptoms. hSomatostatin scintigraphy and PET scan are not recommended for routine surveillance.

Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.
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Carc-1

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NCCN Guidelines Version 2.2014 Carcinoid Tumors
CLINICAL LOCATION ≤2 cm and confined to the appendix EVALUATIONa,b PRIMARY TREATMENT OF NON-METASTATIC DISEASEc

NCCN Guidelines Index Neuroendocrine TOC Discussion SURVEILLANCEg,h

Simple appendectomyj

As clinically indicated 3-12 mo postresection: ? H&P ? Consider 24-hour urine 5-HIAA ? Consider chromogranin A (category 3) ? Consider abdominal multiphasic CT/ MRI >1 y postresection up to 10 y: ? Every 6-12 mo H&P Consider 24-hour urine 5-HIAA Consider chromogranin A (category 3) Consider multiphasic CT or MRI

Appendixi

>2 cm or incomplete resection (nodes, margins)

Recommended: ? Abdominal/pelvic multiphasic CT or MRI As appropriate: ? Chest CT

? Re-exploration ? Right hemicolectomy

Metastatic disease

Metastatic Disease (CARC-6)

gEarlier, if symptoms. hSomatostatin scintigraphy a See

Principles of Pathology for Diagnosis and Reporting of Neuroendocrine Tumors (NE-A). b See Serum Hormone Evaluation Potentially Indicated in the Workup of Neuroendocrine Tumors (NE-B). cSee Surgical Principles for Management of Neuroendocrine Tumors (NE-C).

and PET scan are not recommended for routine surveillance. i Some appendiceal carcinoids will have mixed histology, including elements of adenocarcinoma. Such tumors should be managed according to colon cancer guidelines. See NCCN Guidelines for Colon Cancer. j Some institutions will consider more aggressive treatments for 1- to 2-cm tumors with poor prognostic features. See Discussion for details.

Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.
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Carc-2

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NCCN Guidelines Version 2.2014 Carcinoid Tumors
CLINICAL LOCATION EVALUATIONa,b PRIMARY TREATMENT OF NON-METASTATIC DISEASEc SURVEILLANCEg,h

NCCN Guidelines Index Neuroendocrine TOC Discussion

≤2 cmk Recommended: ? Colonoscopy ? Abdominal/ ? Pelvic multi-phasic CT or MRI ? Endorectal MRI or EUS As appropriate: ? Somatostatin scintigraphy ? Chest CT

Resection (transanal or endoscopic excision, if possible)

? <1 cm: No follow-up required ? 1-≤2 cm: Endoscopy with rectal MRI or EUS at 6 and 12 mo, then as clinically indicated 3-12 mo postresection: ? H&P ? Consider chromogranin A (category 3) ? Consider abdominal/pelvic multiphasic CT or MRI >1 y postresection up to 10 y: ? Every 6-12 mo H&P Consider chromogranin A (category 3) Consider multiphasic CT or MRI

Rectal

≥2 cm

? Low anterior resection ? or ? Abdominoperineal resection (APR)

Metastatic disease

Metastatic Disease (CARC-6)

a See

Principles of Pathology for Diagnosis and Reporting of Neuroendocrine Tumors (NE-A). b See Serum Hormone Evaluation Potentially Indicated in the Workup of Neuroendocrine Tumors (NE-B). cSee Surgical Principles for Management of Neuroendocrine Tumors (NE-C).

gEarlier, if symptoms. hSomatostatin scintigraphy

and PET scan are not recommended for routine surveillance. k For 1- to 2-cm tumors, consider examination under anesthesia (EUA) and/or EUS with radical resection if muscularis propria invasion or node positive.

Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.
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carc-3

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NCCN Guidelines Version 2.2014 Carcinoid Tumors
CLINICAL EVALUATIONa,b LOCATION PRIMARY TREATMENT OF NON-METASTATIC DISEASEc Observe or Endoscopic resection + biopsy of tumor(s) and adjacent mucosa or Octreotiden,o for Zollinger-Ellison patients (category 2B) Endoscopic resection, if possible or Surgical resection ? Radical gastric resection + lymph node removal ? Consider endoscopic or wedge resection for tumors ≤2 cm

NCCN Guidelines Index Neuroendocrine TOC Discussion SURVEILLANCEg,h H&P every 6-12 mo up to 10 y ? H&P and markers,b Years 1-3: every 6-12 mo with EGD Years 4+: Annually with EGD ? Imaging studies as clinically indicated New lesion(s) or increasing tumors, consider antrectomy

? Tumor ≤2 cm ? Solitary or multiple Hypergastrinemic patientsm Recommended: ? EGD ? Gastrin levell ? Multiphasic CT or MRI for patients with normal gastrin As appropriate: ? EUS ? Chest CT ? Somatostatin scintigraphy for patients with normal gastrin ? B12 level if hypergastrinemia ? Tumor >2 cm ? Solitary or multiple

Locoregional disease

Gastric

Patients with normal gastrin Metastatic disease Metastatic Disease (CARC-6)

3-12 mo postresection: ? H&P ? Consider chromogranin A (category 3) ? Multiphasic CT or MRI >1 y postresection up to 10 y: ? Every 6-12 mo H&P Consider chromogranin A (category 3) Consider multiphasic CT or MRI

a See

Principles of Pathology for Diagnosis and Reporting of Neuroendocrine Tumors (NE-A). b See Serum Hormone Evaluation Potentially Indicated in the Workup of Neuroendocrine Tumors (NE-B). cSee Surgical Principles for Management of Neuroendocrine Tumors (NE-C). gEarlier, if symptoms. h Somatostatin scintigraphy and PET scan are not recommended for routine surveillance.

l Gastrin levels need to be completed while fasting and off protein pump inhibitors for 1 week. mIf gastric pH is low or there is clinical or radiographic evidence, see gastrinoma on PanNET-2. n For symptom control, octreotide 150-250 mcg SC TID or octreotide LAR 20-30 mg IM every 4 weeks.

Dose and frequency may be further increased for symptom control as needed. Therapeutic levels of octreotide would not be expected to be reached for 10-14 d after LAR injection. Short-acting octreotide can be added to octreotide LAR for rapid relief of symptoms or for breakthrough symptoms. o Lanreotide is approved for symptom control in Europe. Lanreotide has a similar mechanism of action as octreotide and may be preferable in patients who have difficulty tolerating an IM versus SC injection.

Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.
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carc-4

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NCCN Guidelines Version 2.2014 Carcinoid Tumors
CLINICAL LOCATION EVALUATIONa,b Recommended: ? Chest CT and abdominal multiphasic CT or MRI As appropriate: ? Somatostatin scintigraphy ? Bronchoscopy ? ACTH/cortisolq Localized disease Locoregional disease Metastatic disease Localized disease PRIMARY TREATMENT OF NON-METASTATIC DISEASEc See NCCN Guidelines for Small Cell Lung Cancer; Lung Neuroendocrine Tumor algorithm

NCCN Guidelines Index Neuroendocrine TOC Discussion SURVEILLANCEg,h

Brochopulmonary

Metastatic Disease (CARC-6) 3-12 mo postresection: ? H&P ? Consider chromogranin A (category 3) ? Chest/mediastinal multiphasic CT or MRI >1 y postresection up to 10 y: ? Every 6-12 mo H&P Consider chromogranin A (category 3) Consider CT or MRI

Thymusp

Recommended: ? Chest/mediastinal multiphasic CT and abdominal multiphasic CT or MRI As appropriate: ? Somatostatin scintigraphy ? Bronchoscopy ? ACTH/cortisolq

Resect Complete Resection

Locoregional disease

Resect Incomplete Resection

Metastatic disease

RT ± chemotherapyr (category 3 for addition of chemotherapy)

Metastatic Disease (CARC-6)
p Thymic

a See

Principles of Pathology for Diagnosis and Reporting of Neuroendocrine Tumors (NE-A). b See Serum Hormone Evaluation Potentially Indicated in the Workup of Neuroendocrine Tumors (NE-B). cSee Surgical Principles for Management of Neuroendocrine Tumors (NE-C). gEarlier, if symptoms. hSomatostatin scintigraphy and PET scan are not recommended for routine surveillance.

carcinoids are often associated with MEN1. See Multiple Endocrine Neoplasia, Type 1 (MEN1-1). qPrior to evaluating ACTH, confirm hypercortisolemia using one of the following: ? Overnight 1 mg dexamethasone suppression test with 8 am plasma cortisol ? Repeated (2-3) midnight salivary cortisols ? 24-hour urine free cortisol r Consider 5-FU or capecitabine at radiosensitizing doses. Cisplatin or carboplatin with etoposide may be appropriate for patients with atypical or poorly differentiated tumors.

Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.
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Carc-5

Printed by Maria Chen on 12/23/2013 10:02:46 PM. For personal use only. Not approved for distribution. Copyright ? 2013 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 2.2014 Carcinoid Tumors
MANAGEMENT OF LOCOREGIONAL UNRESECTABLE DISEASE AND/OR DISTANT METASTASESc If complete resection possiblec,s Locoregional unresectable disease and/or distant metastases ? Imaging: Multiphasic CT or MRI Consider Somatostatin scintigraphy ? Consider 24-hour urine 5-HIAA ? Consider chromogranin A (category 3) Resect primary + metastases Observe with markers and scans every 3-12 mo or Octreotideu Consider resection of primary tumor Clinically significant progressive disease

NCCN Guidelines Index Neuroendocrine TOC Discussion

Asymptomatic,t low tumor burden

Locally symptomatic from primary tumor Clinically significant tumor burden

Octreotideu

Octreotide, if not already receiving and Consider hepatic regional therapy (arterial embolization, chemoembolization, radioembolization [category 2B]) or Consider cytoreductive surgery/ablative therapyw,x (category 2B) or Consider everolimus (10 mg/d) (category 3) or Consider cytotoxic chemotherapyy (category 3), if no other options feasible

Carcinoid Syndrome

? Octreotiden,o ? Echocardiogramv
tResection

of a small asymptomatic (relatively stable) primary in the presence of unresectable metastatic disease is not indicated. cSee Surgical Principles for Management of Neuroendocrine Tumors (NE-C). uFor tumor control, the PROMID study (J Clin Oncol 2009;27:4656-4663) used n For symptom control, octreotide 150-250 mcg SC TID or octreotide LAR 20-30 octreotide LAR 30 mg IM every 4 weeks. mg IM every 4 weeks. Dose and frequency may be further increased for symptom vIf signs and symptoms of heart disease or planning major surgery. wIncludes ablative techniques such as radiofrequency, microwave, and cryotherapy. control as needed. Therapeutic levels of octreotide would not be expected to be reached for 10-14 d after LAR injection. Short-acting octreotide can be added to There are no randomized clinical trials and prospective data for these interventions octreotide LAR for rapid relief of symptoms or for breakthrough symptoms. are limited. However, data on the use of these interventions are emerging. o xOnly if near complete resection can be achieved. Lanreotide is approved for symptom control in Europe. Lanreotide has a similar yAnticancer agents such as capecitabine, dacarbazine, 5-FU, interferon, oxaliplatin, mechanism of action as octreotide and may be preferable in patients who have difficulty tolerating an IM versus SC injection. and temozolomide can be used in patients with progressive metastases for whom sNoncurative debulking surgery might be considered in select cases. there are no other treatment options. See Discussion for details.
Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.
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carc-6

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NCCN Guidelines Version 2.2014
CLINICAL LOCATION EVALUATIONb,c,d

Neuroendocrine Tumors of the Pancreas

NCCN Guidelines Index Neuroendocrine TOC Discussion

MANAGEMENT OF PRIMARY NON-METASTATIC DISEASEf,g Enucleation ± regional nodesh or Distal pancreatectomy ± regional nodes/splenectomy or Pancreatoduodenectomy ± regional nodes or Consider observation in selected casesi Head Pancreatoduodenectomy + regional nodes Distal pancreatectomy + splenectomy + regional nodes

Small (<2 cm)

Nonfunctioning pancreatic tumorsa

Recommended: ? Multiphasic CT or MRI As appropriate: ? Somatostatin scintigraphy ? EUS ? Pancreatic polypeptide (category 3) ? Chromogranin A (category 3)

Locoregional diseasee

See Surveillance (PanNET-6)

Larger (>2 cm), or invasive tumors

Distal

Metastatic disease

See Metastases (PanNET-7)
fSee Surgical Principles for Management of Neuroendocrine Tumors (NE-C). gPreoperative trivalent vaccine (ie, pneumococcus, haemophilus influenzae

aFor

tumors secreting hormones such as somatostatin, ACTH, PTHrP, and PP, follow the nonfunctioning pancreatic tumor pathway. bSee Principles of Pathology for Diagnosis and Reporting of Neuroendocrine Tumors (NE-A). cSee Serum Hormone Evaluation Potentially Indicated in the Workup of Neuroendocrine Tumors (NE-B). dFor all patients with PanNET, evaluate personal and family history for possibility of MEN1 and see Multiple Endocrine Neoplasia, Type 1 (MEN1-1). eRisks and benefits of surgical resection should be carefully weighed in patients with small lesions.

b, meningococcal group C), if considering surgery with possible splenectomy. hNeuroendocrine tumors of the pancreas that are 1-2 cm have a small, but real risk of lymph node metastases. Therefore, lymph node resection should be considered. iSelected cases: tumors <1 cm, incidently discovered. Decision based on estimated surgical risk, site of tumor, and patient comorbidities.

Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.
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PanNET-1

Printed by Maria Chen on 12/23/2013 10:02:46 PM. For personal use only. Not approved for distribution. Copyright ? 2013 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 2.2014
CLINICAL LOCATION EVALUATIONb,c,d

Neuroendocrine Tumors of the Pancreas

NCCN Guidelines Index Neuroendocrine TOC Discussion

MANAGEMENT OF PRIMARY NON-METASTATIC DISEASEf,g Observe or Occult Exploratory surgery No primary tumor including duodenotomy and or metastases on intraoperative ultrasound; imaging local resection/enucleation of tumor(s) + periduodenal node dissection ? Manage gastric hypersecretion with proton pump inhibitors ? Consider octreotidek,l Duodenum Duodenotomy and intraoperative ultrasound; local resection/enucleation of tumor(s) + periduodenal node dissection Enucleation of tumor + periduodenal node dissection

Gastrinoma (usually duodenal or head of pancreas)

Recommended: ? Gastrin levelsj (basal, stimulated as indicated) ? Multiphasic CT or MRI As appropriate: ? Somatostatin scintigraphy ? EUS ? Chromogranin A (category 3)

Locoregional disease

Head

Exophytic or peripheral tumors by imagingm For deeper or invasive tumors and those in proximity to the main pancreatic duct

See Surveillance (PanNET-6)

Metastatic disease

See Metastases (PanNET-7) Distal
kFor

Pancreatoduodenectomy Distal pancreatectomy ± splenectomyg,n

bSee

Principles of Pathology for Diagnosis and Reporting of Neuroendocrine Tumors (NE-A). cSee Serum Hormone Evaluation Potentially Indicated in the Workup of Neuroendocrine Tumors (NE-B). dFor all patients with PanNET, evaluate personal and family history for possibility of MEN1 and see Multiple Endocrine Neoplasia, Type 1 (MEN1-1). fSee Surgical Principles for Management of Neuroendocrine Tumors (NE-C). gPreoperative trivalent vaccine (ie, pneumococcus, haemophilus influenzae b, meningococcal group C), if considering surgery with possible splenectomy. jGastrin levels need to be completed while fasting and off proton pump inhibitors for 1 week.

symptom control, octreotide 150-250 mcg SC TID or octreotide LAR 20-30 mg IM every 4 weeks. Dose and frequency may be further increased for symptom control as needed. Therapeutic levels of octreotide would not be expected to be reached for 10-14 d after LAR injection. Short-acting octreotide can be added to octreotide LAR for rapid relief of symptoms or for breakthrough symptoms. lLanreotide is approved for symptom control in Europe. Lanreotide has a similar mechanism of action as octreotide and may be preferable in patients who have difficulty tolerating an IM versus SC injection. mNot adjacent to the main pancreatic duct. nThere is some disagreement among panel members regarding the role of splenectomy in all cases.

Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.
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PanNET-2

Printed by Maria Chen on 12/23/2013 10:02:46 PM. For personal use only. Not approved for distribution. Copyright ? 2013 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 2.2014
CLINICAL LOCATION EVALUATIONb,c,d

Neuroendocrine Tumors of the Pancreas

NCCN Guidelines Index Neuroendocrine TOC Discussion

MANAGEMENT OF PRIMARY NON-METASTATIC DISEASEf,g

Locoregional disease Recommended: ? Multiphasic CT or MRI As appropriate: ? EUS ? 48-72-hr observed fast, insulin/glucose ratio, if diagnosis uncertain ? Chromogranin A (category 3) Metastatic disease

Stabilize glucose levels with diet and/or diazoxide

Exophytic or peripheral tumors by imagingm

Head or Distal

Tumor enucleation, consider laparoscopic resection

Insulinoma

Deeper or invasive tumors and those in proximity to the main pancreatic duct As appropriate: Somatostatin scintigraphyo See Metastases (PanNET-7)

Head

Pancreatoduodenectomy Distal pancreatectomy (spleenpreservingp), consider laparoscopic resction

See Surveillance (PanNET-6)

Distal

bSee

Principles of Pathology for Diagnosis and Reporting of Neuroendocrine Tumors (NE-A). cSee Serum Hormone Evaluation Potentially Indicated in the Workup of Neuroendocrine Tumors (NE-B). dFor all patients with PanNET, evaluate personal and family history for possibility of MEN1 and see Multiple Endocrine Neoplasia, Type 1 (MEN1-1). fSee Surgical Principles for Management of Neuroendocrine Tumors (NE-C).

gPreoperative

trivalent vaccine (ie, pneumococcus, haemophilus influenzae b, meningococcal group C), if considering surgery with possible splenectomy. mNot adjacent to the main pancreatic duct. oSomatostatin scintigraphy only if octreotide is planned. Octreotide should only be given if tumor demonstrates somatostatin receptors. In the absence of somatostatin receptors, octreotide can profoundly worsen hypoglycemia. (See Discussion for details). pSplenectomy should be performed for larger tumors involving splenic vessels.

Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.
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PanNET-3

Printed by Maria Chen on 12/23/2013 10:02:46 PM. For personal use only. Not approved for distribution. Copyright ? 2013 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 2.2014
CLINICAL LOCATION EVALUATIONb,c,d

Neuroendocrine Tumors of the Pancreas

NCCN Guidelines Index Neuroendocrine TOC Discussion

MANAGEMENT OF PRIMARY NON-METASTATIC DISEASEf,g

Glucagonoma (usually tail)

Recommended: ? Glucagon/blood glucose ? Multiphasic contrastenhanced CT or MRI As appropriate: ? Somatostatin scintigraphy ? EUS ? Chromogranin A (category 3)

Locoregional disease

Stabilize glucose levels with IV fluids and octreotidek,l

Head (rare)q

Pancreatoduodenectomyr + peripancreatic lymph nodes See Surveillance (PanNET-6)

Distalq

Distal pancreatectomyr + peripancreatic lymph node dissection + splenectomy

Metastatic disease

See Metastases (PanNET-7)

kFor bSee

Principles of Pathology for Diagnosis and Reporting of Neuroendocrine Tumors (NE-A). cSee Serum Hormone Evaluation Potentially Indicated in the Workup of Neuroendocrine Tumors (NE-B). dFor all patients with PanNET, evaluate personal and family history for possibility of MEN1 and see Multiple Endocrine Neoplasia, Type 1 (MEN1-1). fSee Surgical Principles for Management of Neuroendocrine Tumors (NE-C). gPreoperative trivalent vaccine (ie, pneumococcus, haemophilus influenzae b, meningococcal group C), if considering surgery with possible splenectomy.

symptom control, octreotide 150-250 mcg SC TID or octreotide LAR 20-30 mg IM every 4 weeks. Dose and frequency may be further increased for symptom control as needed. Therapeutic levels of octreotide would not be expected to be reached for 10-14 d after LAR injection. Short-acting octreotide can be added to octreotide LAR for rapid relief of symptoms or for breakthrough symptoms. lLanreotide is approved for symptom control in Europe. Lanreotide has a similar mechanism of action as octreotide and may be preferable in patients who have difficulty tolerating an IM versus SC injection. qSmall (<2 cm), peripheral glucagonomas are rare; enucleation/local excision + peripancreatic lymph dissection may be considered. rHypercoaguable state has been described. Perioperative anticoagulation can be considered..

Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.
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PanNET-4

Printed by Maria Chen on 12/23/2013 10:02:46 PM. For personal use only. Not approved for distribution. Copyright ? 2013 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 2.2014
CLINICAL LOCATION EVALUATIONb,c,d

Neuroendocrine Tumors of the Pancreas

NCCN Guidelines Index Neuroendocrine TOC Discussion

MANAGEMENT OF PRIMARY NON-METASTATIC DISEASEf,g

VIPoma

Recommended: ? Electrolytes ? VIP levels ? Multiphasic CT or MRI As appropriate: ? Somatostatin scintigraphy ? EUS ? Chromogranin A (category 3)

Locoregional disease

? Stabilize with IV fluids and octreotidek,l ? Correct electrolyte imbalance (K+, Mg2+, HCO3-)

Heads

Pancreatoduodenectomy + peripancreatic lymph nodes See Surveillance (PanNET-6)

Distals

Distal pancreatectomy + peripancreatic lymph node dissection + splenectomy

Metastatic disease

See Metastases (PanNET-7)

bSee

Principles of Pathology for Diagnosis and Reporting of Neuroendocrine Tumors (NE-A). cSee Serum Hormone Evaluation Potentially Indicated in the Workup of Neuroendocrine Tumors (NE-B). dFor all patients with PanNET, evaluate personal and family history for possibility of MEN1 and see Multiple Endocrine Neoplasia, Type 1 (MEN1-1). fSee Surgical Principles for Management of Neuroendocrine Tumors (NE-C). gPreoperative trivalent vaccine (ie, pneumococcus, haemophilus influenzae b, meningococcal group C), if considering surgery with possible splenectomy.

kFor

symptom control, octreotide 150-250 mcg SC TID or octreotide LAR 20-30 mg IM every 4 weeks. Dose and frequency may be further increased for symptom control as needed. Therapeutic levels of octreotide would not be expected to be reached for 10-14 d after LAR injection. Short-acting octreotide can be added to octreotide LAR for rapid relief of symptoms or for breakthrough symptoms. lLanreotide is approved for symptom control in Europe. Lanreotide has a similar mechanism of action as octreotide and may be preferable in patients who have difficulty tolerating an IM versus SC injection. sSmall (<2 cm), peripheral VIPomas are rare; enucleation/local excision + peripancreatic lymph dissection may be considered.

Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.
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PanNET-5

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NCCN Guidelines Version 2.2014
SURVEILLANCEt,u RECURRENT DISEASE

Neuroendocrine Tumors of the Pancreas

NCCN Guidelines Index Neuroendocrine TOC Discussion

MANAGEMENT OF RECURRENT DISEASEf

Resectable Locoregional disease Unresectable

Resection See Management of Locoregional Unresectable Disease and/or Distant Metastases (PanNET-7)

3-12 mo postresection: ? H&P and consider markers from preoperative evaluation as indicatedc ? Multiphasic CT or MRI >1 y postresection to a maximum of 10 y: ? Every 6-12 mo H&P Consider markersc Consider multiphasic CT or MRI

Distant metastases

See Management of Locoregional Unresectable Disease and/or Distant Metastases (PanNET-7)

cSee Serum Hormone Evaluation Potentially Indicated in the Workup of Neuroendocrine Tumors fSee Surgical Principles for Management of Neuroendocrine Tumors (NE-C). tEarlier, if symptoms. uSomatostatin scintigraphy and PET scan are not recommended for routine surveillance.

(NE-B).

Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.
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PanNET-6

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NCCN Guidelines Version 2.2014

Neuroendocrine Tumors of the Pancreas
MANAGEMENT OF LOCOREGIONAL UNRESECTABLE DISEASE AND/OR DISTANT METASTASESf If complete resection possiblef,v Resect metastases + primaryw

NCCN Guidelines Index Neuroendocrine TOC Discussion

Clinically significant progressive disease, see below

Locoregional unresectable disease and/or Distant metastases

Asymptomatic, low tumor burden, and stable disease

Observe with markers and scans every 3-12 mo

Clinically significant progressive disease, see below Everolimus (10 mg/d) or Sunitinib (37.5 mg/d) or Cytotoxic chemotherapyx or Hepatic regional therapy (ie, arterial embolization, chemoembolization, radioembolization [category 2B]) or Cytoreductive surgery/ablative therapyy (category 2B) or Consider octreotidez if not already receiving (category 2B)

Symptomatic or Clinically significant tumor burden or Clinically significant progressive disease

Manage clinically significant symptoms as appropriate (PanNET-1, PanNET-2, PanNET-3, PanNET-4, and PanNET-5)

fSee Surgical Principles for Management of Neuroendocrine Tumors (NE-C). vNoncurative debulking surgery might be considered in select cases. wStaged or synchronous resection when possible. When performing staged pancreatoduodenectomy

and liver resection, consider hepatectomy prior to pancreatic resection in order to reduce risk of perihepatic sepsis. De Jong MC, Farnell MB, Sclabas G, et al. Liver-directed therapy for hepatic metastases in patients undergoing pancreaticoduodenectomy: A dual-center analysis. Ann Surg 2010;252:142-148. xThe following agents have been used: capecitabine, dacarbazine, doxorubicin, 5-FU, streptozocin, and temozolomide. yIncludes ablative techniques such as radiofrequency, microwave, and cryotherapy. There are no randomized clinical trials and prospective data for these interventions are limited, but data on their use are emerging. zOctreotide should be used with caution in patients with insulinoma as it may transiently worsen hypoglycemia (See Discussion for details).
Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.
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PanNET-7

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NCCN Guidelines Version 2.2014 Neuroendocrine Tumors of Unknown Primary
INITIAL WORKUPb,c

NCCN Guidelines Index Neuroendocrine TOC Discussion

Poorly differentiatede,f Primary not discoveredd Welldifferentiatede,f

See Primary Treatment for poorly differentiated (high-grade) neuroendocrine tumor (HGNET-1)

Biopsy-proven neuroendocrine tumors (NET) of unknown primarya

Tumor-directed localizing studies: ? Multiphasic CT or MRI ? Consider somatostatin scintigraphy, ultrasound, or EUS ? Bone scan, if symptoms ? Consider FDG-PET scan, and brain imaging in poorly differentiated tumors only ? Consider EGD and/or colonoscopy

See Carcinoid Tumors (CARC-6)

Primary found

See specific tumor type (NE-1)

aConsider

possibility of functioning adrenal neoplasms and suspected carcinoid tumor syndrome prior to biopsy. Alpha blockade is required prior to biopsy or manipulation for suspected pheochromocytoma or paraganglioma (See PHEO-1). Octreotide premedication is required before biopsy in a suspected functioning carcinoid tumor. bSequence of initial workup may vary. cSee Principles of Pathology for Diagnosis and Reporting of Neuroendocrine Tumors (NE-A). dConsider small bowel primary tumor based on symptoms and associated radiologic findings. eIndicate well- or poorly differentiated. Klimstra DS, Modlin IR, Coppola D, et al. The pathologic classification of neuroendocrine tumors: a review of nomenclature, grading and staging systems. Pancreas 2010;39:707-712. fSee Serum Hormone Evaluation Potentially Indicated in the Workup of Neuroendocrine Tumors (NE-B).
Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.
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NUP-1

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NCCN Guidelines Version 2.2014 Adrenal Gland Tumors
CLINICAL PRESENTATION History of prior or current malignancy with risk of or suspicion of adrenal metastasis Adrenal gland tumor on imaging No history of prior or current malignancy Morphologic evaluation Evaluationa,b CLINICAL DIAGNOSIS

NCCN Guidelines Index Neuroendocrine TOC Discussion

See Additional Evaluation (AGT-2) See Primary Treatment (AGT-2)

Adrenal protocol (CTc scan or MRI) to determine size, heterogeneity, lipid content (MRI), contrast washout (CT), and margin characteristics

Hyperaldosteronism

Cushing’s syndrome and ? Hyperaldosteronism Plasma aldosterone, renin activityd Electrolytes ? Cushing’s syndrome Serum ACTH, cortisol, and DHEA-se ? Pheochromocytoma Plasmaf or 24-hour urine fractionated metanephrinesg
dIf

See Primary Treatment (AGT-3)

Non-functioning tumor

See Primary Treatment (AGT-4)

Functional evaluation

Pheochromocytoma

See Pheochromocytoma Guidelines (PHEO-1)

hyperaldosteronism, confirmatory testing with saline suppression test or salt loading test may be indicated. Funder JW, Carey RM, Fardella C, et al. Case detection, diagnosis, and Principles of Pathology for Diagnosis and Reporting of Neuroendocrine treatment of patients with primary aldosteronism: An endocrine society clinical practice Tumors (NE-A). bSee Serum Hormone Evaluation Potentially Indicated in the Workup of guideline. J Clin Endocrinol Metab 2008;93:3266-3281. ePrior to evaluating ACTH, confirm hypercortisolemia using one of the following: Neuroendocrine Tumors (NE-B). cIf unenhanced is <+10 HU, then the tumor is probably benign. If unenhanced ? Overnight 1 mg dexamethasone suppression test with 8 am plasma cortisol ? Repeated (2-3) midnight salivary cortisols is >+10 HU, then use enhanced and wash-out. If >60% wash-out in 15 min, ? 24-hour urine free cortisol the tumor is likely to be benign; if >60%, the tumor is possibly malignant. (Caoili E, Korobkin M, Francis I, et al. Adrenal masses: characterization with fReview concurrent medication(s) for those that may interfere with plasma metanephrines combined unenhanced and delayed enhanced CT. Radiology 2002;222:629- evaluation. Elevations that are 4 times above the upper limit of normal are diagnostic. gFor cervical paraganglioma, consider measuring dopamine. 633.)
aSee Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.
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AGT-1

Printed by Maria Chen on 12/23/2013 10:02:46 PM. For personal use only. Not approved for distribution. Copyright ? 2013 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 2.2014 Adrenal Gland Tumors
CLINICAL DIAGNOSIS ADDITIONAL EVALUATION Adrenal cortical tissue

NCCN Guidelines Index Neuroendocrine TOC Discussion PRIMARY TREATMENTl See Evaluation (AGT-1)

History of prior or current malignancy with risk of or suspicion of adrenal metastasis

Rule out pheochromocytomai

Considerj image-guided needle biopsy

Metastasis from other site discovered

See NCCN disease-specific treatment guidelines

Not a surgical candidate Hyperaldosteronism, suspect benign Surgical candidate Consider adrenal vein samplingk for aldosterone Bilateral aldosterone production Unilateral aldosterone production

Medical management of hypertension and hypokalemia with spironolactone or eplerenone

Adrenalectomy, laparoscopic preferred Open adrenalectomy

Hyperaldosteronism, suspect malignanth

hSuspect malignancies with irregular/inhomogeneous morphology, lipid-poor, do not wash-out, tumor >3 cm, or secretion of more than one hormone. iCan proceed with adrenal biopsy if the clinical suspicion for pheochromocytoma is low and if plasma metanephrines are less than 2 times the upper limit of normal. jFalse negatives are possible; may consider proceeding directly to surgery in selected cases. kAdrenal vein sampling can be considered for distinguishing single unilateral adenomas from bilateral hyperplasia. CT imaging is not always reliable. Some NCCN

Member Institutions recommend sampling in all cases of primary aldosteronism. However, it may be reasonable to exclude adrenal vein sampling in patients <40 y. Cortisol measurement in the catheterization samples is used to confirm proper catheter placement. lSee Surgical Principles for Management of Neuroendocrine Tumors (NE-C).
Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.
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agt-2

Printed by Maria Chen on 12/23/2013 10:02:46 PM. For personal use only. Not approved for distribution. Copyright ? 2013 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 2.2014 Adrenal Gland Tumors
CLINICAL DIAGNOSIS Tumor <5 cm, contralateral gland normal, circumscribed tumor, and other benign imaging characteristics Asymmetric cortisol production Adrenal vein sampling for cortisol Symmetric cortisol production ADDITIONAL EVALUATION PRIMARY TREATMENTl

NCCN Guidelines Index Neuroendocrine TOC Discussion

? Adrenalectomy, laparoscopic preferred ? Postoperative corticosteroid supplementation until hypothalamic-pituitary-adrenal (HPA) axis recovery ? Unilateral adrenalectomy with removal of most active side, laparoscopic preferred ? Postoperative corticosteroid supplementation until HPA axis recovery Medical management of hypercortisolism from presumed multinodular hyperplasia of the adrenal with ketoconazole, mitotanem Adrenalectomy for suspected carcinoman (laparoscopic generally not appropriate) Bilateral adrenalectomy if severe Cushing’s syndrome and medical failure

ACTHindependent Cushing’s syndrome

Tumor <5 cm, benign imaging characteristics, and contralateral gland abnormal

Tumor >5 cm or inhomogeneous, irregular margins, local invasion, or other malignant imaging characteristics

Imaging of chest, abdomen, and pelvis to evaluate for metastases and local invasion

Apparent localized disease, locally resectable disease, or regionally advanced disease Metastatic disease

See Adrenal Carcinoma (AGT-5)

ACTH-dependent Cushing’s syndrome

Assess and treat for pituitary ACTH production or ectopic sources of ACTH production

lSee Surgical Principles for Management of Neuroendocrine Tumors (NE-C). mConsider octreotide if Somatostatin scintigraphy is positive. nMay require removal of adjacent structures (ie, liver, kidney, pancreas, spleen,

If ectopic, remove primary tumor if possible or If primary tumor unresectable, then bilateral laparoscopic adrenalectomy or medical management (as described above)

diaphragm) for complete resection.

Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.
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agt-3

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NCCN Guidelines Version 2.2014 Adrenal Gland Tumors
CLINICAL DIAGNOSIS ADDITIONAL EVALUATION Benign-appearing adenoma (<4 cm) by CTc or MRI criteria or Myelolipoma by radiographic features (any size) without symptoms Unchanged Repeat imaging in 6-12 mo Enlarging (>1 cm in 1 y)

NCCN Guidelines Index Neuroendocrine TOC Discussion PRIMARY TREATMENTl No further follow-up

Consider adrenalectomy or Short-interval follow-up

Non-functioning tumor

Benign-appearing adenoma of intermediate size (4-6 cm) by CTc or MRI criteria

Unchanged Repeat imaging in 3-6 mo Enlarging (>1 cm in 1 y) Intermediate-size tumor (4-6 cm) with aggressive featureso Large tumor (>6 cm) with aggressive features

Repeat imaging in 6-12 mo

Suspected carcinoma

Imaging of chest, abdomen, and pelvis to evaluate for metastases and local invasion

Adrenalectomy for suspected carcinomap

See Adrenal Carcinoma (AGT-5)

See Adrenal Carcinoma (AGT-5)

cIf

unenhanced is <+10 HU, then the tumor is probably benign. If unenhanced is >+10 HU, then use enhanced and wash-out. If >60% wash-out in 15 min, the tumor is likely to be benign; if <60%, the tumor is possibly malignant. (Caoili E, Korobkin M, Francis I, et al. Adrenal masses: characterization with combined unenhanced and delayed enhanced CT. Radiology 2002;222:629-633.) lSee Surgical Principles for Management of Neuroendocrine Tumors (NE-C). oAggressive features such as inhomogeneous, irregular margins, and local invasion. pIf size is resectable by laparoscopy, may explore laparoscopically with planned conversion for evidence of local invasion. The decision for open versus laparoscopic surgery is based on tumor size and degree of concern regarding potential malignancy.
Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.
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agt-4

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NCCN Guidelines Version 2.2014 Adrenal Gland Tumors
ADRENAL CARCINOMA TREATMENTl ? If high risk for local recurrence:v Consider external-beam RT to tumor bed Consider adjuvant mitotane therapy (category 3)

NCCN Guidelines Index Neuroendocrine TOC Discussion FOLLOW-UP

Localized disease

? Resect tumor and adjacent lymph nodes Open adrenalectomy recommendedn,r

? Every 3-12 mo up to 5 y Consider imaging and biomarkers, if tumor initially functional

Adrenal carcinomaq

Metastatic disease

? Consider observation with imaging for clinically indolent disease every 3 mo and biomarkers (if tumor initially functional) ? Consider resection of primary tumor and metastases if >90% removable, particularly if functional ? Consider systemic therapy,s,t preferably in clinical trial Cisplatin or carboplatin + etoposide ± doxorubicin ± mitotaneu or Streptozocin ± mitotaneu or Mitotaneu monotherapy

lSee Surgical Principles for Management of Neuroendocrine Tumors (NE-C). nMay require removal of adjacent structures (ie, liver, kidney, pancreas, spleen, diaphragm) for complete resection. qCross-sectional imaging to stage disease. rIncreased risk for local recurrence and peritoneal spread when done laparoscopically. sMonitor mitotane blood levels. Some institutions recommend target levels of 14-20 mcg/mL if tolerated. Steady-state

levels may be reached several months after initiation of mitotane. Mitotane therapy requires steroid replacement therapy. tSee Discussion for further information regarding the phase III FIRM-ACT trial. (Fassnacht M, Terzolo M, Allolio B, et al; FIRM-ACT Study Group. Combination chemotherapy in advanced adrenocortical carcinoma. N Eng J Med 2012;366:2189-2197.) uMitotane may have more benefit for control of hormone symptoms than control of tumor. vHigh-risk local recurrence features include: positive margins, rupture of capsule, large size, and high grade.
Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.
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agt-5

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NCCN Guidelines Version 2.2014 Pheochromocytoma/Paraganglioma
TUMOR TYPE EVALUATIONa,b TREATMENT

NCCN Guidelines Index Neuroendocrine TOC Discussion

Pheochromocytoma/ paraganglioma

Recommended: ? Plasma or 24-hour urine fractionated metanephrinesc,d ? Chest/abdominal multiphasic CT or MRI ? Genetic counselinge As appropriate: ? Bone scan, if bone symptoms ? MIBG scan/Somatostatin scintigraphy, if suspect multiple tumors or CT negative

Alpha blockadef with aggressive volume repletion ± alpha-methyltyrosine ± beta blockade preoperative (beta blockade only after alpha blockade)g

See Primary Treatment (PHEO-2)

aSee Principles of Pathology for Diagnosis and Reporting of Neuroendocrine Tumors (NE-A). bSee Serum Hormone Evaluation Potentially Indicated in the Workup of Neuroendocrine Tumors (NE-B). cReview concurrent medication(s) for those that may interfere with plasma metanephrines evaluation. Elevations

that are 4 times above the upper limit of normal are diagnostic. dFor cervical paraganglioma, consider measuring dopamine. eGenetic counseling and genetic testing are recommended when appropriate (See Discussion). fPhenoxybenzamine or doxazosin can be considered. gOther effective agents can be used for alpha and beta blockade. Rapid-acting intravenous alpha-adrenergic antagonists (eg, phentolamine) and rapid-acting intravenous beta blockers (eg, esmolol) are primarily used in the operating room. Selective alpha1-blocking agents, such as prazosin, terazosin, and doxazosin, are alternative medications when long-term therapy is required for metastatic pheochromocytoma. Noncardioselective (propranolol, nadolol, or labetalol) or cardioselective (atenolol and metoprolol) beta blockers can be used after initiation of alpha blockade. The calcium channel blocker nicardipine may be used to provide additional blood pressure control or may be substituted in patients who cannot tolerate beta blockers.
Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.
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pheo-1

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NCCN Guidelines Version 2.2014 Pheochromocytoma/Paraganglioma
PRIMARY TREATMENTh SURVEILLANCEi

NCCN Guidelines Index Neuroendocrine TOC Discussion

Resectable

Resect (laparoscopic preferred when safe and feasible)

3-12 mo postresection: ? H&P, blood pressure, and markersb ? Consider CT or MRI or FDG-PET scan >1 y postresection up to 10 y: ? H&P, blood pressure, and markersb Years 1-3: every 6-12 mo Years 4+ up to 10 y: annually ? Consider CT or MRI or FDG-PET scan ? Genetic counseling and testing as clinically indicated

Locally unresectable

Cytoreductive (R2) resection, if possible ± RT + alpha blockade ± alpha-methyltyrosine ± beta blockade Cytoreductive (R2) resection when possible + continuous alpha blockade ± alpha-methyltyrosine ± beta blockade (optional) or Clinical trial or Systemic chemotherapy (eg, dacarbazine, cyclophosphamide, vincristine) or 131I-MIBG (requires prior positive MIBG scan with dosimetry) ? Every 3-12 mo H&P, blood pressure, and markersb Consider CT or MRI or FDG-PET scan ? Genetic counseling and testing as clinically indicated

Distant metastases

bSee Serum Hormone Evaluation Potentially Indicated in the Workup of Neuroendocrine hSee Surgical Principles for Management of Neuroendocrine Tumors (NE-C). iEarlier, if symptoms.

Tumors (NE-B).

Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.
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pheo-2

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NCCN Guidelines Version 2.2014
TUMOR TYPE EVALUATION

Poorly Differentiated (High Grade)/Large or Small Cell
PRIMARY TREATMENTa Resection + chemotherapy with small cell lung cancer regimenb ± RT or Consider definitive chemoradiation (See NCCN Guidelines for Small Cell Lung Cancer)b

NCCN Guidelines Index Neuroendocrine TOC Discussion SURVEILLANCEe

Resectable

H&P + appropriate imaging studies: ? Every 3 mo for 1 y, then every 6 mo

Poorly differentiated (high-grade) NET or Large or small cell carcinoma other than lung

Recommended: ? Chest/abdominal/ pelvic CT As appropriate: ? Brain MRI or CT ? FDG-PET scan ? Other scans as indicated ? Plasma ACTH or other biochemical markers

Locoregional, unresectable

RT + chemotherapy with small cell lung cancer regimenb ? Consider octreotide therapyc,d if hormone secreting H&P + appropriate imaging studies: ? Every 3 mo

Metastatic

Chemotherapy with small cell lung cancer regimenb ? Consider octreotide therapyc,d if hormone secreting

aSee Surgical Principles for Management of Neuroendocrine Tumors (NE-C). bCisplatin or carboplatin and etoposide are generally recommended as primary

treatment. Evolving data suggest that tumors with intermediate Ki-67 level in the 20%50% range may not respond as well to platinum/etoposide as patients with small cell histology or extremely high Ki-67. Clinical judgement should be used. See NCCN Guidelines for Small Cell Lung Cancer. cFor symptom control, octreotide 150-250 mcg SC TID or octreotide LAR 20-30 mg IM every 4 weeks. Dose and frequency may be further increased for symptom control as needed. Therapeutic levels of octreotide would not be expected to be reached for 10-14 d after LAR injection. Short-acting octreotide can be added to octreotide LAR for rapid relief of symptoms or for breakthrough symptoms. dLanreotide is approved for symptom control in Europe. Lanreotide has a similar mechanism of action as octreotide and may be preferable in patients who have difficulty tolerating an IM versus SC injection. eEarlier, if symptoms.
Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.
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hgnet-1

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NCCN Guidelines Version 2.2014 Multiple Endocrine Neoplasia, Type 1
DIAGNOSIS OF OR CLINICAL SUSPICION OF MEN1

NCCN Guidelines Index Neuroendocrine TOC Discussion

? A clinical diagnosis for MEN1 includes two or more MEN1-associated tumors: multi-gland parathyroid hyperplasia; pancreatic NET; or pituitary tumors.a,b See Tumors in Patients with MEN1 (MEN1-A) MEN1 may also be associated with carcinoid tumors of the lung and thymus, adrenal tumors, multiple lipomas, and cutaneous angiomas.a,b Patients with MEN1 are more likely to have multiple PanNETs than those with sporadic tumors. ? For patients known or suspected to have MEN1, a clinical evaluation includes: See MEN1 Clinical Evaluation and Primary Treatment (MEN1-2) 1) Biochemical tests evaluating hormone levels; 2) Imaging tests needed to localize the site of the tumor or hyperplasia; and 3) Genetic counseling and testing ? Genetic counseling and MEN1 genetic testing should be offered to the following: An individual with a clinical diagnosis or suspicion of MEN1a,b,c,d An at-risk relative of an individual with a known germline MEN1 mutationa ? MEN1 clinical evaluation should be offered to the following: Individuals with a clinical diagnosis or suspicion of MEN1 even with a negative MEN1 genetic test At-risk relatives even if MEN1 mutation has not been identified in the affected family member or if MEN1 genetic testing has not been performed in the affected or at-risk family member

aThakker bGiusti F,

RV, Newey PJ, Walls GV, et al. Clinical practice guidelines for multiple endocrine neoplasia type 1 (MEN1). J Clin Endocrinol Metab 2012;97:2990-3011. Marini F, Brandi ML. (Updated September 6, 2012) Multiple Endocrine Neoplasia Type 1. In: GeneReviews at GeneTests: Medical Genetics Information Resource (database online). Copyright, University of Washington, Seattle. 1997-2013. Available at http://www.genetests.org. Accessed October 3, 2013. cA germline MEN1 mutation is seldom found in individuals with a single MEN1-associated tumor and no family history. (Ellard S, Hattersley AT, Brewer CM, Vaidya B. Detection of an MEN1 gene mutation depends on clinical features and supports current referral criteria for diagnostic molecular genetic testing. Clin Endocrinol (Oxf). 2005;62:169-175.) d10% of cases have de novo MEN1 mutations.
Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.
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men1-1

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NCCN Guidelines Version 2.2014 Multiple Endocrine Neoplasia, Type 1
CLINICAL EVALUATIONe Parathyroid: ? Recommended Serum calcium Parathyroid hormone (PTH) ? As appropriate 24-hour urine calcium Neck ultrasound Parathyroid sestamibi scan TREATMENT

NCCN Guidelines Index Neuroendocrine TOC Discussion

Subtotal parathyroidectomy ± cryopreservation of parathyroids ± thymectomy or Total parathyroidectomy with autotransplantation ± cryopreservation of parathyroids ± thymectomy

See MEN1 Surveillance (MEN1-3)

Diagnosis of or clinical suspicion of MEN1 (See MEN1-1)

Pancreatic neuroendocrine tumors (PanNET): ? Recommended Gastrin levelsf (basal, stimulated as indicated) Pancreatic polypeptide (category 3) Chromogranin A (category 3) Multiphasic CT or MRI ? As appropriate Glucagon, VIP, insulin, fasting glucose depending on symptoms EUS Somatostatin scintigraphy Pituitary: ? Recommended Pituitary MRI Prolactin, IGF-1 (category 2B) ? As appropriate Other pituitary hormones evaluating functioning pituitary tumorsg

See Treatment of PanNETs Specific to MEN1 Patients (MEN1-B) and See appropriate sporadic PanNET workup and treatment (PanNET-1 through PanNET-5)

See MEN1 Surveillance (MEN1-3)

Consider referral to endocrinology for further workup

See MEN1 Surveillance (MEN1-3)

eFor MEN1 genetic testing recommendations, see MEN1-1. fGastrin levels need to be completed while fasting and off proton pump inhibitors gPotential hormones secreted include ACTH, FSH, LH, TSH, GH, and prolactin.

for 1 week.

Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.
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men1-2

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NCCN Guidelines Version 2.2014 Multiple Endocrine Neoplasia, Type 1
MEN1 SURVEILLANCEh ? If calcium rises: Serum PTH Reimage with neck ultrasound and/or parathyroid sestamibi scan Consider MRI neck

NCCN Guidelines Index Neuroendocrine TOC Discussion

Parathyroid: ? Calcium annually

Consider referral to endocrinology

PanNET: ? Serum gastrin annuallyi ? Serum chromogranin Ai and/or pancreatic polypeptide annually (category 3) ? Follow other previously elevated serum hormones or as symptoms indicate ? Consider imaging with multiphasic abdominal CT, MRI scan every 1-3 y ? Consider serial EUS

See appropriate sporadic PanNET workup and treatment (PanNET-1 through PanNET-5)

Pituitary: ? MRI of pituitary every 3-5 y ? Repeat prolactin, IGF-1, and other previously abnormal pituitary hormones annually or as symptoms indicate

If tumor grows or hormones increase, consider referral to endocrinology

hSurveillance

is indicated for all MEN tumors regardless of patient’s tumor type. For patients at risk for bronchial or thymic carcinoid tumors, chest imaging can be considered every 1-3 y (Thakker RV, Newey PJ, Walls GV, et al. Clinical practice guidelines for multiple endocrine neoplasia type 1 (MEN1). J Clin Endocrinol Metab 2012;97:2990-3011). iSerum gastrin and chromogranin A will be elevated in patients using proton pump inhibitors.
Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.
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men1-3

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NCCN Guidelines Version 2.2014 Multiple Endocrine Neoplasia, Type 1
TUMORS IN PATIENTS WITH MEN1

NCCN Guidelines Index Neuroendocrine TOC Discussion

? The most common MEN1 neoplasm is parathyroid hyperplasia (affecting 98% of patients), followed by islet cell tumors of the pancreas (50%), pituitary adenomas (35%), and/or lung/thymus carcinoid tumors (10%a). ? Type 2 gastric carcinoid tumors occur frequently in MEN1 patients with gastrinoma. ? A higher incidence of adrenal tumors is also observed in MEN1.

aGiusti

F, Marini F, Brandi ML. (Updated September 6, 2012) Multiple Endocrine Neoplasia Type 1. In: GeneReviews at GeneTests: Medical Genetics Information Resource (database online). Copyright, University of Washington, Seattle. 1997-2013. Available at http://www.genetests.org. Accessed October 3, 2013.
Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.

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men1-A

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NCCN Guidelines Version 2.2014 Multiple Endocrine Neoplasia, Type 1
TREATMENT OF PanNETs SPECIFIC TO MEN1 PATIENTS

NCCN Guidelines Index Neuroendocrine TOC Discussion

? In general, surgical management of patients with MEN1 is similar to those with sporadic tumors. Refer to the relevant site-specific recommendations earlier in these guidelines. (See PanNET-1 through PanNET-5) ? However, one notable exception is the multi-focality of pancreaticoduodenal NETs in patients with MEN1. ? Decision to resect a pancreatic or duodenal NET in the setting of multifocal disease is complex. If surgery is performed to resect hormonally functional tumor(s), attempts should be made to preoperatively localize the site of the functional tumor. Surgical resection can be considered in the following scenarios: Symptomatic functional tumors refractory to medical management Tumor larger than 1-2 cm in size Tumor with relatively rapid rate of growth over 6-12 months Endoscopy with EUS is recommended prior to pancreatic surgery in order to preoperatively assess and localize tumors. ? MEN1-associated metastatic pancreatic NETs are often slower growing than metastatic sporadic tumors. Observation can be considered for non-functioning indolent tumors. ? A consultation with an endocrinologist for all patients with MEN1 should be considered.

Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.
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men1-B

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NCCN Guidelines Version 2.2014 Multiple Endocrine Neoplasia, Type 2
DIAGNOSIS OF OR CLINICAL SUSPICION OF MEN2

NCCN Guidelines Index Neuroendocrine TOC Discussion

? MEN2 is subdivided into MEN2A and MEN2B. Medullary thyroid cancer (MTC) occurs in nearly all patients with MEN2A and MEN2B and is often the first manifestation of the syndrome. See Tumors in Patients with MEN2 (MEN2-A) A clinical diagnosis of MEN2A includes two or more MEN2A-associated cancers (MTC, pheochromocytoma, or parathyroid adenoma/ hyperplasia) in a single individual or in close relativesa,b A clinical diagnosis of MEN2B includes the presence of MTC, pheochromocytoma, mucosal neuromas of the lips and tongue, medullated corneal nerve fibers, distinctive facies with enlarged lips, “marfanoid” body habitus, or inability to cry tearsa,b ? For patients known or suspected to have MEN2, a clinical evaluation includes: See MEN2 Clinical Evaluation and Primary Treatment (MEN2-2) 1) Biochemical tests evaluating hormone levels; 2) Imaging tests needed to localize MEN2-associated tumors; and 3) Genetic counseling and testing ? Genetic counseling and RET genetic testing should be offered to the following: An individual with a diagnosis of MTC or clinical diagnosis of MEN2 or primary C-cell hyperplasiaa,b,c An at-risk relative of an individual with a known germline RET mutationa,b ??Genetic testing of at-risk family members at a very early age.a,b See NCCN Guidelines for Thyroid Carcinoma: Medullary Thyroid Cancer section. ? MEN2 clinical evaluation should be offered to the following: Individuals with a clinical diagnosis or suspicion of MEN2 even with negative RET genetic test At-risk relatives even if RET mutation has not been identified in the affected family memberb or if RET genetic testing has not been performed in the affected or at-risk family member

aMoline

J, Eng C. (Updated January 10, 2013) Multiple Endocrine Neoplasia Type 2. In: GeneReviews at GeneTests: Medical Genetics Information Resource (database online). Copyright, University of Washington, Seattle. 1997-2013. Available at http://www.genetests.org. Accessed April 13, 2013. bKloos RT, Eng C, Evans D, et al. Medullary thyroid cancer: Management guidelines of the American Thyroid Association. Thyroid 2009;19:565-612. c50% of cases have de novo RET mutations; therefore, even if a family history is not suggestive of a hereditary syndrome, genetic testing for RET mutations should still be performed on the affected individual.
Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.
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men2-1

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NCCN Guidelines Version 2.2014 Multiple Endocrine Neoplasia, Type 2
CLINICAL EVALUATIONd Medullary thyroid cancer: ? Calcitonin, CEA ? Neck ultrasound of both thyroid and cervical lymph nodes Parathyroid: ? Recommended Serum calcium PTH ? As appropriate 24-hour urine calcium Neck ultrasound Parathyroid sestamibi scan Pheochromocytoma:e,f ? Recommended: Plasma or 24-hour urine fractionated metanephrinesg MRI or multiphasic CT of abdomen ? As appropriate: MIBG scan/somatostatin scintigraphy TREATMENT

NCCN Guidelines Index Neuroendocrine TOC Discussion SURVEILLANCEi

See NCCN Guidelines for Thyroid Carcinoma 3-6 mo postresection: ? H&P, blood pressure, and markersj >6 mo postresection up to 10 y: ? H&P, blood pressure, and markersj Years 1-3: every 6 mo Years 4+: annually ? Consider CT or MRI

Four-gland identification: Selective parathyroid resectionh

Diagnosis of or clinical suspicion of MEN2 (See MEN2-1)

Refer to endocrinology for medical preparation for adrenalectomy and Adrenalectomy ? Involved side only, laparoscopic procedure preferred as appropriate

See Pheochromocytoma Guidelines (PHEO-1)

dFor RET genetic testing recommendations, see MEN2-1. eEvaluation of pheochromocytoma should be done before the administration of any anesthetic or invasive procedure. fMore likely to be multifocal. gFor cervical paraganglioma, consider measuring dopamine. hSubtotal parathyroidectomy is recommended when all the parathyroid glands are abnormal. Some thyroid surgeons recommend

parathyroid autotransplantation, but others believe the risk of hypoparathyroidism (~6%) is too high to warrant this procedure. iEarlier, if symptoms. jSee Serum Hormone Evaluation Potentially Indicated in the Workup of Neuroendocrine Tumors (NE-B).

total parathyroidectomy with

Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.
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men2-2

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NCCN Guidelines Version 2.2014 Multiple Endocrine Neoplasia, Type 2
TUMORS IN PATIENTS WITH MEN2

NCCN Guidelines Index Neuroendocrine TOC Discussion

? The most common MEN2A neoplasm is medullary carcinoma of the thyroid (affecting 98% of patients), followed by adrenal pheochromocytoma (50%), and/or parathyroid hyperplasia (25%).a ? The most common MEN2B neoplasm is medullary carcinoma of the thyroid (98%), followed by mucosal neuroma or intestinal ganglioneuroma (95%), adrenal pheochromocytoma (50%), and/or parathyroid hyperplasia (<1%).a ? Other physical exam findings for MEN2 patients include: Ectopic lenses (type 2B) Marfanoid features (type 2B) Lichen planus amyloidosis (type 2A) Hirschsprung’s disease (megacolon)

aMoore

2003.

FD, Scoinski MA, Joste NE. Endocrine Tumors and Malignancies. In: Skarin A, ed. Atlas of Diagnostic Oncology (ed 3rd). Philadelphia: Elsevier Science Limited;

Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.
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men2-A

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NCCN Guidelines Version 2.2014 Neuroendocrine Tumors
Required information: ? Anatomic site of tumor ? Diagnosis ? Grade (See Table 1) ? Mitotic rate and/or Ki-67 ? Size of tumor ? Presence of multicentric disease ? Presence of vascular invasion ? Presence of perineural invasion ? Presence of other pathologic components (eg, non-neuroendocrine components) ? Lymph node metastases to include the number of positive nodes and total number of nodes examined ? Margin status (report as positive or negative) ? Assign TNM stage per the AJCC TNM system (See Staging) Table 1 Grade Low Grade (G1) Intermediate Grade (G2) High Grade (G3) Gastroenteropancreatic (GEP) NETs <2 mitoses/10 HPF AND/OR <3% Ki-67 index 2-20 mitoses/10 HPF AND/OR 3-20% Ki-67 index >20 mitoses/10 HPF AND/OR >20% Ki-67 index

NCCN Guidelines Index Neuroendocrine TOC Discussion

PRINCIPLES OF PATHOLOGY FOR DIAGNOSIS AND REPORTING OF NEUROENDOCRINE TUMORS Optional information: ? Immunohistochemical staining for general neuroendocrine markers ? Immunohistochemical staining for specific peptide markers ? Presence of nonischemic tumor necrosis ? Presence of unusual histologic features (eg, oncocytic, clear cell, gland forming) ? Exact distance of tumor to margin(s) if less than 0.5 cm ? Background pathology of organ (ie, PanIN, ECL cell hyperplasia)

Lung and Thymus <2 mitoses/10 HPF AND no necrosis 2-10 mitoses/10 HPF AND/OR foci of necrosis >10 mitoses/10 HPF

Differentiation Well-differentiated NET Well-differentiated NET Poorly differentiated neuroendocrine carcinoma

Adapted from Bosman FT, Carneiro F, Hruban RH, Theise ND. World Health Organization Classification of Tumours of the Digestive System. IARC, Lyon, 2010; and Travis WD, Brambilla E, Muller-Hermelink HK, Harris CC. World Health Organization Classification of Tumours of the Lung, Pleura, Thymus and Heart. Lyon: IARC; 2004. Table 1 should be used as a general guide. Definitions vary between lung, thymus, and GEP-NETs in some classification systems. It is recognized that occasionally a morphologically “well-differentiated” NET may have a proliferation index by Ki-67, which technically falls into the “high-grade” category by this measure alone. Clinical judgment should be used in such discordant cases. In general, this discordance should not cause a reclassification of a welldifferentiated NET as a “poorly differentiated NEC.” In these cases, the tumor should be reported as a well-differentiated NET (so-called “atypical carcinoid” terminology in lung and thymus) with the specific mitotic rate and Ki-67 proliferation index included in the report as additional information (See NE-A 3 of 4). See additional information on next page
Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.
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NCCN Guidelines Index Neuroendocrine TOC Discussion

PRINCIPLES OF PATHOLOGY FOR DIAGNOSIS AND REPORTING OF NEUROENDOCRINE TUMORS Functional status ? Functional status of a NET need not be included in the pathology report. However, if a specific clinical situation suggests that correlation with histologic evidence of peptide hormone may be helpful, then histochemical or immunohistochemical studies may be performed and included in the report. ? Functioning NETs should have the same pathologic diagnosis as the non-functioning NETs at the same anatomic site, since the functional status is based upon clinical findings and should not alter the pathologic diagnosis. However, a note may be added with additional information of the immunoreactivity of specific peptide hormone. Immunohistochemistry and other ancillary techniques ? Immunohistochemistry and other ancillary techniques may not be required to diagnose well-differentiated NETs when sufficient tumor material is available for histologic review. ? Specific markers that may be used to establish neuroendocrine differentiation include chromogranin A, synaptophysin, and CD56, although CD56 has recently proven to be less specific. In less well-differentiated tumors or tumors of unknown origin, it may be helpful (or required in the case of poorly differentiated neuroendocrine carcinomas) to utilize immunohistochemistry panels. ? Although not entirely specific, lung origin is favored by thyroid transcription factor 1 (TTF-1); intestinal or pancreatic origin by CDX2; and pancreatic and rectal NETs by Isl1 and PAX8.1,2 Classification and grade ? Many classification schemes have been proposed for NETs.3-9 The most recent WHO classification system is suggested for GEP NETs and represents an attempt to unify European and American approaches.8 Multiple site-specific grading systems also exist. ? Therefore, the specific classification and grading scheme being utilized should be reported in parentheses after the diagnosis to avoid confusion with overlapping terminology and criteria used in other systems. ? The raw data used to derive the grade should be reported. ? Regardless of the system used, it is most important to realize that the term “neuroendocrine tumor” or “neuroendocrine carcinoma” without any further qualification as to grade is inadequate for prognostication and therapy and is inappropriate for pathology reporting.1,10 Continued on next page See References on NE-A 4 of 4

Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.
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NCCN Guidelines Index Neuroendocrine TOC Discussion

PRINCIPLES OF PATHOLOGY FOR DIAGNOSIS AND REPORTING OF NEUROENDOCRINE TUMORS Mitotic rate ? Mitotic rate should be based upon counting mitoses in at least 40 fields at 40x magnification in the areas of highest mitotic density, and should be reported as the number of mitoses per 10 HPF or per 2 mm2. Ten HPF is equivalent to 2 mm2 on many microscopes, although the field size may vary slightly.4 ? Note that in cases where an accurate mitotic rate is precluded by inadequate tissue, such as in small biopsy samples including FNA, the Ki67 index is the preferred method of establishing the proliferative rate. Ki-67 index ? Ki-67 index is reported as the percentage of positive tumor cells in the area of highest nuclear labeling. Although recommendations have been to count 2000 tumor cells in order to determine the Ki-67 index, this is not practical in routine clinical practice. It is therefore currently acceptable to estimate the labeling index, despite the recognition that estimation is subject to limitations in reproducibility.10 ? If both mitotic rate and Ki-67 index are used and these are discordant, it is currently recommended that the higher grade be used to assign classification.11 ? It is recognized that occasionally a morphologically “well-differentiated” NET may have a proliferation index by Ki-67, which technically falls into the “high-grade” category by this measure alone. Clinical judgment should be used in such discordant cases. In general, this discordance should not cause a reclassification of a well-differentiated NET as a “poorly differentiated NEC.” In these cases, the tumor should be reported as a well-differentiated NET (so-called “atypical carcinoid” terminology in lung and thymus) with the specific mitotic rate and Ki-67 proliferation index included in the report as additional information. ? The pathologist should report the actual parameters used to assign grade (ie, mitotic rate, proliferation index) so clinicians have the necessary information to make informed treatment decisions. ? Although the 2004 WHO3 does not utilize Ki-67 as part of its grading system for thymus and lung NETs, it may be quite useful in the setting of small biopsies and cytology specimens when there is insufficient tissue for an accurate mitotic count. The Ki-67 index cut-points are not currently well-defined but tend to parallel those proposed in GEP-NETs, and generally the data suggest that Ki-67 proliferation rates of <20% exclude small cell lung carcinoma.12 See References on NE-A 4 of 4

Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.
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REFERENCES

NCCN Guidelines Index Neuroendocrine TOC Discussion

PRINCIPLES OF PATHOLOGY FOR DIAGNOSIS AND REPORTING OF NEUROENDOCRINE TUMORS

1Klimstra

DS, Modlin IR, Coppola D, et al. The pathologic classification of neuroendocrine tumors: a review of nomenclature, grading and staging systems. Pancreas 2010;39:707-712. 2Koo J, Mertens RB, Mirocha JM, et al. Value of Islet 1 and PAX8 in identifying metastatic neuroendocrine tumors of pancreatic origin. Modern Pathology 2012; 25:893-901. 3Travis WD, Brambilla E, Muller-Hermelink HK, Harris CC. World Health Organization Classification of Tumours of the Lung, Pleura, Thymus and Heart. Lyon: IARC;2004. 4Rindi G, Kloppel G, Alhman H, et al. TNM staging of foregut (neuro)endocrine tumors: a consensus proposal including a grading system. Virchows Arch 2006;449:395-401. 5Strosberg JR, Coppola D, Klimstra DS et al. The NANETS consensus guidelines for the diagnosis and management of poorly differentiated (high-grade) extrapulmonary neuroendocrine carcinomas. Pancreas 2010;39,799-800. 6Boudreaux JP, Klimstra DS, Hassan MM et al. The NANETS consensus guideline for the diagnosis and management of neuroendocrine tumors: well-differentiated neuroendocrine tumors of the jejunum, ileum, appendix, and cecum. Pancreas 2010;39,753-766. 7Anthony LB, Strosberg JR, Klimstra DS et al. The NANETS consensus guidelines for the diagnosis and management of gastrointestinal neuroendocrine tumors (NETs): well-differentiated NETs of the distal colon and rectum. Pancreas 2010;39,767-774. 8Bosman F, Carneiro F, Hruban R, and Theise ND. WHO Classification of tumours of the digestive system. Lyon, France: IARC Press; 2010. 9Oberg K and Castellano D. Current knowledge on diagnosis and staging of neuroendocrine tumors. Cancer Metastasis Rev 2011;30S,S3-S7. 10Klimstra DS, Modlin IR, Adsay NV, et al. Pathology reporting of neuroendocrine tumors: application of the Delphic consensus process to the development of a minimum pathology data set. Am J Surg Pathol 2010;34:300-313. 11Rindi G, Bordi C, La Rosa S, et al. Gastroenteropancreatic (neuro)endocrine neoplasms: The histology report. Digestive and Liver Disease 2011;43S;S356-S360. 12Rekhtman N. Neuroendocrine tumors of the lung. An Update. Arch Pathol Lab Med 2010;134:1628-1638.

Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.
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NCCN Guidelines Version 2.2014 Neuroendocrine Tumors
SERUM HORMONE EVALUATION POTENTIALLY INDICATED IN THE WORKUP OF NEUROENDOCRINE TUMORS1 HORMONE-RELATED STUDIES (blood markers) ? Carcinoid tumors 5-HIAA (24-hour urine) Chromogranin A (category 3) ? PanNET Chromogranin A (category 3) ? Gastrinoma Gastrin ? Insulinoma Proinsulin Insulin/glucose ratio C-peptide ? VIPoma VIP ? Glucagonoma Glucagon Blood glucose CBC ? Other pancreas Somatostatin Pancreatic polypeptide Calcitonin PTH-related peptide
1For

NCCN Guidelines Index Neuroendocrine TOC Discussion

? Pheochromocytoma/paraganglioma Metanephrines (plasma and urine)2 ? Pituitary Growth hormone/IGF-1 Prolactin LH/FSH TSH Alpha subunits ACTH ? Ectopic hormones ACTH GRH GHRH

most of the blood studies, an 8-hour fast is generally recommended in addition to certain dietary adjustments depending on the test ordered. Ordering physicians should be aware that some medications can also affect the results, but medications do not necessarily need to be discontinued if they are medically necessary. Below are examples: Chromogranin A: Impaired renal or hepatic function or treatment with proton pump inhibitors may result in artifactual elevations. Urine 5-HIAA: Patients should not eat avocados, bananas, cantaloupe, eggplant, pineapples, plums, tomatoes, hickory nuts, plantains, kiwi, dates, grapefruit, honeydew, or walnuts for a 48-hour period prior to start of urine collection. Additionally, patients should avoid coffee, alcohol, and smoking for this time period. Gastrin: ≥8 hour fast. False elevations may occur, especially in patients on proton pump inhibitors. VIP: 8-hour fast. 2For cervical paraganglioma, consider measuring dopamine.
Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.
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SURGICAL PRINCIPLES FOR MANAGEMENT OF NEUROENDOCRINE TUMORS

NCCN Guidelines Index Neuroendocrine TOC Discussion

? Patients with localized PanNETs should be resected. Exceptions include patients with other life-limiting comorbidities, high surgical risk, or widely metastatic disease. Peripheral insulinomas and small (<2 cm), non-functional tumors are candidates for open or laparoscopic enucleation/local resection or spleen-preserving distal pancreatectomy. Virtually all insulinomas should be resected regardless of size because of the metabolic (hypoglycemic) complications. Non-functional PanNETs 1-2 cm in size have a small (7%-26%), but measurable risk of lymph node metastases; therefore, lymph node resection should be considered. ? Resection for larger (>2 cm) or malignant-appearing non-functional and functional PanNETs (ie, glucagonoma, VIPoma, somatistatinoma) should include total removal of the tumor with negative margins (including adjacent organs) and regional lymph nodes. Tumors of the head are generally treated with pancreatoduodenectomy (Whipple procedure); tumors of the body and tail are treated with distal pancreatectomy and splenectomy or spleen-preserving surgery. Generally surgery will include splenectomy, but with benign insulinoma spleen preservation should be considered. ? Resection of gastrointestinal carcinoid should include adequate regional lymph node resection (including all palpable disease where feasible) and thorough exploration of synchronous primary tumors (15%-30% incidence). ? Resection of recurrent locoregional disease, isolated distant metastases, or a previously unresectable tumor that has regressed should be considered for selected patients with adequate performance status. ? Patients with symptomatic recurrence from local effects or hormone hypersecretion can be effectively palliated by subtotal resection of a large proportion of the tumor (typically more than 90%); however, experienced judgment is required for management of patients with an unresectable tumor and/or distant metastases. Planned cytoreductive, incomplete (R2) resection of advanced disease in patients with asymptomatic or non-functional disease is controversial. ? Cholecystectomy is recommended when performing surgery for advanced NETs in patients anticipated to receive long-term octreotide therapy, as these patients are at higher risk of developing biliary symptoms and cholecystitis. ? Liver-directed therapies (eg, liver resection, thermal ablation, chemoembolization) for hepatic metastases from NETs following pancreatoduodenectomy are associated with increased risk for perihepatic sepsis and liver abscess. ? Octreotide therapy should be administered prior to induction of anesthesia in patients with functional carcinoid tumors to prevent carcinoid crisis. ? All patients who might require splenectomy should receive preoperative trivalent vaccine (ie, pneumococcus, haemophilus influenzae b, meningococcal group C). ? In general, laparoscopic resection is preferable for patients suspected to have small (<6 cm), clinically benign, functional adrenal tumors. An open exploration is recommended for tumors that have a high risk of being malignant. ? For MEN1-related surgical principles, see MEN1-B.

Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.
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NCCN Guidelines Version 2.2014 Staging Neuroendocrine Tumors
Staging

NCCN Guidelines Index Neuroendocrine TOC Discussion

American Joint Committee on Cancer (AJCC) TNM Staging System for Neuroendocrine Tumors (gastric, small bowel, colonic, rectal, and ampulla of Vater carcinoid tumors [well-differentiated neuroendocrine tumors and well-differentiated neuroendocrine carcinomas]) (7th ed., 2010) Stomach TNM Primary Tumor (T) TX Primary tumor cannot be assessed T0 No evidence of primary tumor Tis  Carcinoma in situ/dysplasia (tumor size less than 0.5 mm), confined to mucosa T1  Tumor invades lamina propria or submucosa and 1 cm or less in size T2 Tumor invades muscularis propria or more than 1 cm in size T3 Tumor penetrates subserosa T4  Tumor invades visceral peritoneum (serosal) or other organs or adjacent structures For any T, add (m) for multiple tumors Regional Lymph Nodes (N) NX Regional lymph nodes cannot be assessed N0 No regional lymph node metastasis N1 Regional lymph node metastasis Distant Metastases (M) M0 No distant metastases M1 Distant metastasis Duodenum/Ampulla/Jejunum/Ileum TNM Primary Tumor (T) TX Primary tumor cannot be assessed T0 No evidence of primary tumor T1  Tumor invades lamina propria or submucosa and size 1 cm or less* (small intestinal tumors); tumor 1 cm or less (ampullary tumors) Tumor invades muscularis propria or size > 1 cm (small intestinal T2  tumors); tumor > 1 cm (ampullary tumors) T3  Tumor invades through the muscularis propria into subserosal tissue without penetration of overlying serosa (jejunal or ileal tumors) or invades pancreas or retroperitoneum (ampullary or duodenal tumors) or into non-peritonealized tissues T4 Tumor invades visceral peritoneum (serosa) or invades other organs For any T, add (m) for multiple tumors Regional Lymph Nodes (N) NX Regional lymph nodes cannot be assessed N0 No regional lymph node metastasis N1 Regional lymph node metastasis Distant Metastases (M) M0 No distant metastases M1 Distant metastasis
* Note: Tumor limited to ampulla of Vater for ampullary gangliocytic paraganglioma.

Continued on next page
Used with the permission of the American Joint Committee on Cancer (AJCC), Chicago, Illinois. The original and primary source for this information is the AJCC Cancer Staging Manual, Seventh Edition (2010) published by Springer Science + Business Media, LLC (SBM). (For complete information and data supporting the staging tables, visit www.springer.com.) Any citation or quotation of this material must be credited to the AJCC as its primary source. The inclusion of this information herein does not authorize any reuse or further distribution without the expressed, written permission of Springer SBM, on behalf of the AJCC.
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NCCN Guidelines Version 2.2014 Staging Neuroendocrine Tumors
Staging

NCCN Guidelines Index Neuroendocrine TOC Discussion

American Joint Committee on Cancer (AJCC) TNM Staging System for Neuroendocrine Tumors (gastric, small bowel, colonic, rectal, and ampulla of Vater carcinoid tumors [well-differentiated neuroendocrine tumors and well-differentiated neuroendocrine carcinomas]) (7th ed., 2010) Colon or Rectum TNM Primary Tumor (T) TX Primary tumor cannot be assessed T0 No evidence of primary tumor T1  Tumor invades lamina propria or submucosa and size 2 cm or less T1a Tumor size less than 1 cm in greatest dimension T1b Tumor size 1–2 cm in greatest dimension T2  Tumor invades muscularis propria or size more than 2 cm with invasion of lamina propria or submucosa T3  Tumor invades through the muscularis propria into the subserosa, or into non-peritonealized pericolic or perirectal tissues T4 Tumor invades peritoneum or other organs For any T, add (m) for multiple tumors Regional Lymph Nodes (N) NX Regional lymph nodes cannot be assessed N0 No regional lymph node metastasis N1 Regional lymph node metastasis Distant Metastases (M) M0 No distant metastases M1 Distant metastasis

ANATOMIC STAGE/PROGNOSTIC GROUPS Stage 0 Tis N0 M0 Stage I Stage IIA Stage IIB Stage IIIA Stage IIIB Stage IV T1 T2 T3 T4 N0 N0 N0 N0 M0 M0 M0 M0 M0

Any T N1

Any T Any N M1

Continued on next page
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NCCN Guidelines Version 2.2014 Staging Neuroendocrine Tumors
Staging
American Joint Committee on Cancer (AJCC) TNM Staging System for Neuroendocrine Tumors (pancreatic) (7th ed., 2010) All pancreatic neuroendocrine tumors should be staged using this staging system. Pancreatic TNM Primary Tumor (T) TX Primary tumor cannot be assessed T0 No evidence of primary tumor Tis Carcinoma in situ* T1 Tumor limited to the pancreas, 2 cm or less in greatest dimension Tumor limited to the pancreas, more than 2 cm in greatest dimension T2  T3  Tumor extends beyond the pancreas but without involvement of the celiac axis or the superior mesenteric artery T4  Tumor involves the celiac axis or the superior mesenteric artery (unresectable primary tumor) Regional Lymph Nodes (N) NX Regional lymph nodes cannot be assessed N0 No regional lymph node metastasis N1 Regional lymph node metastasis Distant Metastases (M) M0 No distant metastases M1 Distant metastasis * This also includes the “PanInIII” classification.

NCCN Guidelines Index Neuroendocrine TOC Discussion

ANATOMIC STAGE/PROGNOSTIC GROUPS Tis N0 M0 Stage 0 Stage IA Stage IB Stage IIA Stage IIB Stage III Stage IV T1 T2 T3 T1 T2 T3 T4 N0 N0 N0 N1 N1 N1 Any N M0 M0 M0 M0 M0 M0 M0 M1

Any T Any N

Continued on next page

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NCCN Guidelines Version 2.2014 Staging Neuroendocrine Tumors
Staging
American Joint Committee on Cancer (AJCC) TNM Staging System for Neuroendocrine Tumors (appendiceal carcinoid) (7th ed., 2010) Appendiceal Carcinoid TNM Primary Tumor (T) TX Primary tumor cannot be assessed T0 No evidence of primary tumor T1 Tumor 2 cm or less in greatest dimension T1a Tumor 1 cm or less in greatest dimension T1b Tumor more than 1 cm but not more than 2 cm Tumor more than 2 cm but not more than 4 cm or with extension to T2  the cecum T3 Tumor more than 4 cm or with extension to the ileum T4  Tumor directly invades other adjacent organs or structures, e.g., abdominal wall and skeletal muscle* Regional Lymph Nodes (N) NX Regional lymph nodes cannot be assessed N0 No regional lymph node metastasis N1 Regional lymph node metastasis Distant Metastases (M) M0 No distant metastases M1 Distant metastasis

NCCN Guidelines Index Neuroendocrine TOC Discussion

ANATOMIC STAGE/PROGNOSTIC GROUPS T1 N0 M0 Stage I Stage II Stage III Stage IV T2, T3 N0 T4 Any T Any T N0 N1 Any N M0 M0 M0 M1

pTNM Pathologic Classification. The pT, pN, and pM categories correspond to the T, N, and M categories except that pM0 does not exist as a category. pN0. Histological examination of a regional lymphadenectomy specimen will ordinarily include 12 or more lymph nodes. If the lymph nodes are negative, but the number ordinarily examined is not met, classify as pN0.

Note: Tumor that is adherent to other organs or structures, grossly, is classified cT4. However, if no tumor is present in the adhesion, microscopically, the classification should be classified pT1-3 depending on the anatomical depth of wall invasion. *Penetration of the mesoappendix does not seem to be as important a prognostic factor as the size of the primary tumor and is not separately categorized

Continued on next page
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NCCN Guidelines Version 2.2014 Staging Neuroendocrine Tumors
Staging
American Joint Committee on Cancer (AJCC) TNM Staging System for Neuroendocrine Tumors (adrenal) (7th ed., 2010) Adrenal TNM Primary Tumor (T) TX Primary tumor cannot be assessed T0 No evidence of primary tumor T1  Tumor 5 cm or less in greatest dimension, no extra-adrenal invasion T2 Tumor greater than 5 cm, no extra-adrenal invasion T3 Tumor of any size with local invasion, but not invading adjacent organs* T4 Tumor of any size with invasion of adjacent organs* Regional Lymph Nodes (N) NX Nodes cannot be assessed N0 No regional lymph node metastasis N1 Metastasis in regional lymph node(s) Distant Metastases (M) M0 No distant metastases M1 Distant metastasis
* Note : Adjacent organs include kidney, diaphragm, great vessels, pancreas, spleen, and liver.

NCCN Guidelines Index Neuroendocrine TOC Discussion

ANATOMIC STAGE/PROGNOSTIC GROUPS T1 N0 M0 Stage I Stage II Stage III Stage IV T2 T1 T2 T3 N0 N1 N1 N0 M0 M0 M0 M0

T3 N1 M0 T4 N0 M0 T4 N1 M0 Any T Any N M1

pTNM Pathologic Classification. The pT, pN, and pM categories correspond to the T, N, and M categories except that pM0 does not exist as a category. pN0. Histological examination of a regional lymphadenectomy specimen will ordinarily include 12 or more lymph nodes. If the lymph nodes are negative, but the number ordinarily examined is not met, classify as pN0.

Used with the permission of the American Joint Committee on Cancer (AJCC), Chicago, Illinois. The original and primary source for this information is the AJCC Cancer Staging Manual, Seventh Edition (2010) published by Springer Science + Business Media, LLC (SBM). (For complete information and data supporting the staging tables, visit www.springer.com.) Any citation or quotation of this material must be credited to the AJCC as its primary source. The inclusion of this information herein does not authorize any reuse or further distribution without the expressed, written permission of Springer SBM, on behalf of the AJCC.
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NCCN Guidelines Version 2.2014 Neuroendocrine Tumors
Discussion
NCCN Categories of Evidence and Consensus Category 1: Based upon high-level evidence, there is uniform NCCN consensus that the intervention is appropriate. Category 2A: Based upon lower-level evidence, there is uniform NCCN consensus that the intervention is appropriate. Category 2B: Based upon lower-level evidence, there is NCCN consensus that the intervention is appropriate. Category 3: Based upon any level of evidence, there is major NCCN disagreement that the intervention is appropriate. All recommendations are category 2A unless otherwise noted.

NCCN Guidelines Index Neuroendocrine Tumors Table of Contents Discussion

Table of Contents
Overview....................................................................................... MS-2? Histologic Classification and Staging of Neuroendocrine Tumors . MS-2? Histologic Classification ............................................................. MS-3? Staging ...................................................................................... MS-4? Pathologic Reporting ................................................................. MS-4? Other Potential Prognostic Markers .............................................. MS-4? Sporadic Neuroendocrine Tumors ................................................ MS-5? Carcinoid Tumors ...................................................................... MS-5? Evaluation of Carcinoid Tumors ............................................. MS-5? Management of Locoregional Disease ................................... MS-5? Surveillance of Carcinoid Tumors .......................................... MS-7? Management of Locoregional Unresectable and/or Metastatic Carcinoid Tumors .................................................................. MS-8? Neuroendocrine Tumors of the Pancreas ................................ MS-11? Evaluation of Neuroendocrine Tumors of the Pancreas ....... MS-12? Primary Treatment of Locoregional Resectable Neuroendocrine Tumors of the Pancreas ....................................................... MS-14?

Surveillance of Pancreatic Neuroendocrine Tumors ............ MS-16? Management of Locoregional Unresectable and/or Metastatic Neuroendocrine Tumors of the Pancreas ............................. MS-16? Neuroendocrine Tumors of Unknown Primary ......................... MS-18? Evaluation of Neuroendocrine Tumors of Unknown Primary MS-19? Primary Treatment of Neuroendocrine Tumors of Unknown Primary ................................................................................ MS-19? Adrenal Gland Tumors ............................................................ MS-19? Evaluation and Treatment of Adrenal Gland Tumors............ MS-20? Pheochromocytomas/Paragangliomas .................................... MS-24? Evaluation for Pheochromocytoma/Paragangliomas ............ MS-24? Genetic Counseling/Testing in Pheochromocytomas/Paragangliomas ................................. MS-25? Primary Treatment of Pheochromocytomas/Paragangliomas… ............................................................................................ MS-25? Surveillance of Pheochromocytomas/Paragangliomas ......... MS-26? Poorly Differentiated Neuroendocrine Tumors/Large or Small Cell Tumors .................................................................................... MS-26? Evaluation of Poorly Differentiated/Large or Small Cell Tumors ............................................................................................ MS-26? Primary Treatment of Poorly Differentiated/Large or Small Cell Tumors ................................................................................ MS-26? Surveillance of Poorly Differentiated/Large or Small Cell Tumors ............................................................................................ MS-27? Multiple Endocrine Neoplasia ..................................................... MS-27? MEN1 ...................................................................................... MS-27? Evaluation of MEN1 Syndromes .......................................... MS-28? Genetic Counseling/Testing in MEN1 .................................. MS-29? Primary Treatment of MEN1 Syndromes .............................. MS-29? MEN1 Surveillance .............................................................. MS-30? MEN2 and Familial MTC ......................................................... MS-31? Evaluation of MEN2A, MEN2B, and Familial MTC ............... MS-31? Genetic Counseling/Testing in MEN2 .................................. MS-32? Primary Treatment of MEN2A, MEN2B, and Familial MTC .. MS-32? MEN2 Surveillance .............................................................. MS-33? Future Trial Design ..................................................................... MS-33? References ................................................................................. MS-34?

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NCCN Guidelines Version 2.2014 Neuroendocrine Tumors
Overview
Neuroendocrine tumors are thought to arise from cells throughout the diffuse endocrine system. They comprise a broad family of tumors, the most common of which are carcinoid tumors (most commonly arising in the lungs and bronchi, small intestine, appendix, rectum, or thymus) and pancreatic neuroendocrine tumors. Other neuroendocrine tumors include those arising in the parathyroid, adrenal, and pituitary glands, and in calcitonin-producing cells of the thyroid (causing medullary thyroid carcinoma [MTC]). An analysis of the SEER database estimated that the incidence of neuroendocrine tumors in the United States was 5.25 cases per 100,000 people in the year 2004.1 This analysis suggested that the diagnosed incidence of neuroendocrine tumors is increasing, and that the prevalence of individuals with neuroendocrine tumors in the United States may exceed 100,000.1 A recent independent analysis of the SEER database also found that the incidence of gastrointestinal neuroendocrine tumors increased from 1975 to 2008.2 Most neuroendocrine tumors seem to be sporadic; risk factors for sporadic neuroendocrine tumors are poorly understood. Neuroendocrine tumors may also arise in the context of inherited genetic syndromes, including multiple endocrine neoplasia (MEN) types 1 and 2. Multiple endocrine neoplasia type 1 (MEN1), associated with mutations in the menin gene, is characterized by multiple tumors of the parathyroid, pituitary, and pancreatic glands.3 Multiple endocrine neoplasia type 2 (MEN2), associated with mutations in the RET protooncogene, is characterized by the development of medullary thyroid cancer, pheochromocytoma (often bilateral), and hyperparathyroidism.4 Neuroendocrine tumors have also been associated with von HippelLindau disease, tuberous sclerosis complex, and neurofibromatosis.5,6

NCCN Guidelines Index Neuroendocrine Tumors Table of Contents Discussion

Patients with neuroendocrine tumors may or may not have symptoms attributable to hormonal hypersecretion. These symptoms include intermittent flushing and diarrhea in patients with carcinoid syndrome,7 hypertension in patients with pheochromocytoma,8 and symptoms attributable to secretion of insulin, glucagon, gastrin, and other peptides in patients with pancreatic neuroendocrine tumors.9 Patients with hormonal symptoms are considered to have “functional” tumors, and those without symptoms are considered to have “nonfunctional” tumors. Appropriate diagnosis and treatment of neuroendocrine tumors often involves collaboration between specialists in multiple disciplines, using specific biochemical, radiologic, and surgical methods. Specialists include pathologists, endocrinologists, radiologists (including nuclear medicine specialists), and medical, radiation, and surgical oncologists. These guidelines discuss the diagnosis and management of both sporadic and hereditary neuroendocrine tumors and are intended to assist with clinical decision-making. Most of the guideline sections pertain to well-differentiated, low- to intermediate-grade tumors, although poorly differentiated/high-grade/large or small cell carcinomas are also addressed (see Poorly Differentiated Neuroendocrine Tumors/Large or Small Cell Tumors, below). Medical practitioners should note that unusual patient scenarios (presenting in <5% of patients) are not specifically discussed in these guidelines.

Histologic Classification and Staging of Neuroendocrine Tumors
Neuroendocrine tumors are generally subclassified by site of origin, stage, and histologic characteristics.

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NCCN Guidelines Version 2.2014 Neuroendocrine Tumors
Histologic Classification Neuroendocrine tumors are classified histologically based on tumor differentiation (well or poorly differentiated) and tumor grade (grades 1– 3). Most neuroendocrine tumors fall into 3 broad histologic categories: well-differentiated, low-grade (G1); well-differentiated, intermediategrade (G2); and poorly differentiated, high-grade (G3). Tumor differentiation and tumor grade often correlate with mitotic count and Ki-67 proliferation index. In fact, most commonly used histologic classification schemes, including both the European Neuroendocrine Tumor Society and WHO systems, incorporate mitotic rate and Ki-67 index.9-11 Numerous studies have confirmed that increased mitotic rate and high Ki-67 index are associated with a more aggressive clinical course and worse prognosis.12-15 In most cases, well-differentiated, lowgrade tumors have a mitotic count of less than 2/10 high-power field (HPF) and/or a Ki-67 index of less than 3%. Well-differentiated, intermediate-grade tumors usually have a mitotic count of 2 to 20/10 HPF and/or a Ki-67 index of 3% to 20%. In high-grade tumors, the mitotic count usually exceeds 20/10 HPF and/or the Ki-67 index exceeds 20%. Grade is generally defined by mitotic count and/or Ki-67 index, whichever is higher. In some cases, however, tumors may not fall clearly into one category. For example, a morphologically welldifferentiated neuroendocrine tumor with a low mitotic index may have a Ki-67 proliferation index that falls into the high-grade category. While technically classified as a high-grade tumor, clinical judgement should be used in making treatment decisions for such cases. A key recommendation is that tumor differentiation, mitotic rate, and Ki-67 index should all be included in the pathology report. Doing so allows the

NCCN Guidelines Index Neuroendocrine Tumors Table of Contents Discussion

treating physician to factor these data into the clinical picture to make appropriate treatment decisions. The classification of lung and thymus carcinoids varies from that of gastroenteropancreatic neuroendocrine tumors in some classification systems, and in particular does not include Ki-67 and includes the assessment of necrosis. Well-differentiated neuroendocrine tumors of the lung and thymus are either considered typical (low-grade, <2 mitoses/HPF and no necrosis) or atypical (2-10 mitosis/HPF and/or foci of necrosis). Poorly-differentiated neuroendocrine carcinomas are of either small cell or large cell cytology, with >10 mitoses/HPF.16,17 Considerable debate remains as to the most appropriate Ki-67 proliferative threshold for the determination of tumor grade and consequent treatment decisions.18,19 A retrospective database review of 252 patients with high-grade gastrointestinal neuroendocrine carcinoma suggested that platinum-based chemotherapy is most active in those with a Ki-67 index of ≥55%.20 These results suggest that a higher Ki-67 cutoff than is currently recommended may be more appropriate to classify tumors as high-grade. Conversely, for low-grade tumors, some studies have suggested that the currently accepted cutoff may be too low. An analysis of data from 274 patients with pancreatic neuroendocrine tumors found that a 5% Ki-67 cutoff (rather than 2%) was the optimal prognostic indicator.21 A comparable analysis based on 691 patients with jejunal-ileocecal neuroendocrine tumors similarly found that a threshold of 5 mitoses/10 HPF provided better prognostic information than one of 2 mitoses/10 HPF.22 The panel recommends that the current histologic grading system be used more as a general guide, in conjunction with clinical judgement, when treatment decisions are made.

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NCCN Guidelines Version 2.2014 Neuroendocrine Tumors
Staging Neuroendocrine tumors are staged according to the AJCC tumor (T), node (N), metastasis (M) staging system. The AJCC introduced its first TNM staging system for the classification of neuroendocrine tumors in its 7th edition of the AJCC Cancer Staging Manual.23 Carcinoids of the stomach, duodenum/ampulla/jejunum/ileum, colon/rectum, and appendix have separate staging systems. The association of tumor stage with prognosis has been confirmed in analyses of the SEER database and the National Cancer Database.24-29 A recent analysis of 691 patients with jejunal-ileocecal neuroendocrine tumors treated at the Moffitt Cancer Center between 2000 and 2010 revealed 5-year survival rates of 100%, 100%, 91%, and 72% for stages I through IV, respectively, further validating the TNM staging system.22 Of note, however, this analysis also suggested that, unlike other malignancies, primary tumor size and depth of invasion had little bearing on survival in early-stage disease.19 Similar results were reported in a recent analysis of 6792 small intestine neuroendocrine tumors in the SEER database, which found that outcomes were similar for patients with T1 and T2 tumors.30 Carcinoids of the lungs and bronchi are staged in the same manner as more common lung carcinomas. As in lung carcinoma, more advanced tumor stage for carcinoid tumors of the lungs and bronchi is associated with worse prognosis.23 The TNM staging system for the classification of pancreatic neuroendocrine tumors in the 7th edition of the AJCC Cancer Staging Manual is the same as for exocrine pancreatic carcinoma.23 The primary tumor (T) is differentiated based on size and involvement of major vessels or other organs (see Staging in the guidelines). A recent retrospective analysis of 425 patients with pancreatic neuroendocrine

NCCN Guidelines Index Neuroendocrine Tumors Table of Contents Discussion

tumors treated at the Moffitt Cancer Center between 1999 and 2010 validated this system, with 5-year overall survival rates of 92%, 84%, 81%, and 57% for stages I through IV, respectively (P < .001).31 Although the trends of this analysis are consistent with populationbased studies, the survival rates from this analysis were significantly higher than those seen in population-based studies.32,33 For example, in the SEER database analysis of pancreatic neuroendocrine tumors, the 5-year survival rate for patients with metastatic disease was only 19.5%.33 Pathologic Reporting In addition to information on histologic classification and stage, the margin status (positive or negative) and the presence of vascular or perineural invasion should be included in the pathology report, because they may also have prognostic significance.34,35

Other Potential Prognostic Markers
The molecular basis of neuroendocrine tumors remains poorly understood, and molecular predictors of outcome remain investigational. A recent study found that overexpression of mammalian target of rapamycin (mTOR) or its downstream targets was associated with shorter overall survival in 195 neuroendocrine tissue samples (15% were located in the pancreas; 85% were gastrointestinal carcinoids).36 Circulating tumor cells (CTC) have also been studied as possible prognostic markers, based on the idea that tumor cells in the blood would be indicative of more disseminated disease. A recent study found that the presence of ≥1 CTC in 7.5 mL of blood was independently associated with worse PFS and overall survival in patients with varyingly pre-treated metastatic neuroendocrine tumors from various primary sites.37 MS-4

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NCCN Guidelines Version 2.2014 Neuroendocrine Tumors
More research is required before these and other new molecular assays are routinely used in the clinic.

NCCN Guidelines Index Neuroendocrine Tumors Table of Contents Discussion

These guidelines address 7 major subtypes of carcinoid tumors: 1) jejunal/ileal/colon, 2) duodenal, 3) appendix, 4) rectal, 5) gastric, 6) bronchopulmonary, and 7) thymus.
Evaluation of Carcinoid Tumors

Sporadic Neuroendocrine Tumors
Carcinoid Tumors Approximately one-third of carcinoid tumors arise in the lungs or thymus, and two-thirds arise in the gastrointestinal tract. Sites of origin within the gastrointestinal tract include the stomach, small intestine, appendix, and rectum.1 The prognosis for patients with carcinoid tumors varies according to the stage at diagnosis, histologic classification, and primary site of the tumor (see Histologic Classification and Staging of Neuroendocrine Tumors, above). Carcinoid tumors may secrete various hormones and vasoactive peptides. Bronchial and thymic carcinoids have been associated with adrenocorticotropic hormone (ACTH) production and are a cause of Cushing’s syndrome.38,39 Carcinoid tumors arising in the small intestine or appendix are more commonly associated with carcinoid syndrome, related to the secretion of serotonin, histamine, or tachykinins into the systemic circulation causing episodic flushing and diarrhea.40 Approximately 50% to 66% of patients with carcinoid syndrome develop valvular cardiac complications consisting of tricuspid regurgitation and/or pulmonary stenosis.41 The metabolic products released by intestinal carcinoid tumors are rapidly destroyed by liver enzymes in the portal circulation. Thus, the classical syndrome, occurring in approximately 8% to 28% of patients with carcinoid tumors,42,43 is not usually observed unless liver metastases or rarely retroperitoneal disease have occurred, in which case hepatic metastases release metabolic products directly into the systemic circulation via the hepatic veins.

Patients who present with suspected carcinoid tumors should be evaluated with imaging studies to assess disease burden and possible primary location. Commonly used techniques include CT and MRI. Carcinoid tumors are highly vascular and can appear isodense with liver on conventional CT scan, depending on contrast phase. Multiphase CT or MRI scans should therefore be used for evaluation of liver metastasis. Chest CT is also recommended as appropriate to assess for lung metastases. Because most carcinoid tumors express highaffinity receptors for somatostatin,40,44 radiolabeled somatostatin receptor scintigraphy, performed using the radiolabeled somatostatin analog [111In-DTPA]-octreotide may also be used in the initial evaluation of patients with carcinoid tumor. Additional recommendations vary by disease site and include colonoscopy and small bowel imaging as appropriate for jejunal, ileal, and colon carcinoids; endoscopic ultrasound (EUS) and/or esophagogastroduodenoscopy (EGD) as appropriate for duodenal and gastric carcinoids; proctoscopic examination for rectal carcinoids; and bronchoscopy as appropriate for bronchopulmonary and thymic carcinoids. Details of the evaluation and diagnosis of a patient with Cushing’s syndrome from a bronchial carcinoid tumor have recently been published.45
Management of Locoregional Disease

The management of locoregional carcinoid tumors depends on tumor size and primary site and the general condition of the patient. Resection is the primary treatment approach for most localized carcinoid tumors. MS-5

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NCCN Guidelines Version 2.2014 Neuroendocrine Tumors
Although symptoms of hormone hypersecretion are more common in patients with metastatic disease, for patients with locoregional disease and symptoms of hormone hypersecretion, symptom control with a somatostatin analog is paramount (see Management of Locoregional Unresectable and/or Metastatic Carcinoid Tumors, below). Specific recommendations for management of carcinoid tumor subtypes are described here. Gastric Carcinoid Tumors Three types of gastric carcinoid tumors are generally recognized: type 1 (associated with chronic atrophic gastritis), type 2 (associated with Zollinger-Ellison syndrome), and type 3 (sporadic).46 Types 1 and 2 gastric carcinoids are both associated with hypergastrinemia; the major difference between them is that patients with type 1 gastric carcinoids generally have atrophic gastritis and absent acid secretion, whereas those with type 2 gastric carcinoids have evidence of acid hypersecretion secondary to gastrinoma (Zollinger-Ellison syndrome).46 For hypergastrinemic patients whose tumors are 2 cm or smaller and either solitary or multiple, options include: 1) endoscopic resection, if feasible, with biopsy of the tumor and adjacent mucosa; 2) observation; or 3) octreotide for symptom control in patients with gastrinoma and Zollinger-Ellison syndrome (category 2B recommendation). For hypergastrinemic patients with solitary or multiple tumors larger than 2 cm, endoscopic resection (if possible) or surgical resection is indicated. Patients with nonmetastatic gastric carcinoid and normal gastrin levels (type 3) have more aggressive tumors and are usually treated with radical resection of the tumor with regional lymphadenectomy. Alternatively, endoscopic or wedge resection can be considered for tumors ≤2 cm.47

NCCN Guidelines Index Neuroendocrine Tumors Table of Contents Discussion

Thymic Carcinoid Tumors Localized and locoregional carcinoid tumors in the thymus are treated with surgical resection, generally without adjuvant therapy. After incomplete resection of locoregional disease, however, radiation therapy (RT) alone is recommended; the addition of chemotherapy can also be considered (category 3). If chemotherapy is offered, capecitabine or 5-FU at radiosensitizing doses may be considered. Cisplatin or carboplatin with etoposide may be appropriate for patients with atypical or poorly differentiated tumors. Bronchopulmonary Carcinoid Tumors For localized or locoregional bronchopulmonary tumors, please refer to the Lung Neuroendocrine Tumors algorithm in the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Small Cell Lung Cancer (to view the most recent version of these guidelines, visit the NCCN website at www.NCCN.org). Carcinoid Tumors of the Duodenum, Small Intestine, and Colon For localized lesions arising in the duodenum, endoscopic resection is recommended if feasible. Transduodenal local excision with or without lymph node sampling and pancreatoduodenectomy are other options for primary treatment of nonmetastatic duodenal carcinoid tumors. If endoscopic resection was performed, follow-up upper endoscopy (EGD) should be performed as appropriate. For patients presenting with tumors in the jejunum, ileum, or colon, surgical resection of the bowel with regional lymphadenectomy is recommended. The surgical procedure should include careful examination of the entire bowel, because multiple synchronous lesions may be present. In addition, the proximity to or involvement of the superior mesenteric artery and superior mesenteric vein should be assessed during surgery. If future treatment with octreotide is

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NCCN Guidelines Version 2.2014 Neuroendocrine Tumors
anticipated, a prophylactic cholecystectomy should be considered given the association between long-term treatment with somatostatin analogs and the development of biliary symptoms and gallstones.48 Appendiceal Carcinoid Tumors Most appendiceal carcinoid tumors are identified incidentally, during appendectomy performed for appendicitis. Most appendiceal carcinoid tumors have well-differentiated histology, and for most appendiceal tumors 2 cm or smaller and confined to the appendix, simple appendectomy is sufficient because metastases are uncommon.49,50 However, some controversy exists regarding the management of appendiceal carcinoids measuring less than 2 cm with more aggressive histologic features. A recent population-based study analyzing the SEER database found evidence that lymph node metastases can develop in some patients with appendiceal carcinoids 2 cm or smaller.51 Some NCCN Member Institutions thus consider more aggressive treatment for 1- to 2-cm tumors with poor prognostic features, such as lymphovascular or mesoappendiceal invasion or atypical histologic features. Patients with an incomplete resection or tumors larger than 2 cm are at risk for locoregional or distant metastases. These patients should be staged with abdominal/pelvic CT or MRI scans. If no distant disease is identified, they should undergo reexploration with a right hemicolectomy. Additionally, a small proportion of appendiceal carcinoids may also contain evidence of adenocarcinoma (ie, “adenocarcinoid” or “goblet cell carcinoid”). These tumors should be managed according to the NCCN Guidelines for Colon Cancer (available at www.NCCN.org).

NCCN Guidelines Index Neuroendocrine Tumors Table of Contents Discussion

Carcinoid Tumors of the Rectum The treatment of rectal lesions is based on the size of the primary tumor. If the lesion is 2 cm or less, endoscopic or transanal excision is recommended. Given the higher risk of invasion with larger tumors, examination under anesthesia and/or EUS before the procedure should be considered for tumors 1 to 2 cm in size. Tumors larger than 2 cm, those with invasion of the muscularis propria, or those associated with lymph node metastases should be treated with low anterior resection or, in rare cases, an abdominoperineal resection.52 Surveillance of Carcinoid Tumors Surveillance of carcinoid tumors should include complete patient history and physical examination (H&P) and consideration of multiphasic CT or MRI (usually abdominal and/or pelvic). Most patients with carcinoid tumors of the jejunum/ileum/colon, duodenum, rectum, and thymus, and type 3 gastric carcinoid lesions with normal gastrin levels should be reevaluated 3 to 12 months after resection (earlier if the patient is symptomatic) and then every 6 to 12 months for up to 10 years. Chromogranin A may be used as a tumor marker (category 3); although not diagnostic, elevated levels have been associated with recurrence.53 In addition, an analysis of a large prospective database showed that chromogranin A levels elevated twice the normal limit or higher were associated with shorter survival times for patients with metastatic neuroendocrine tumors (HR, 2.8; 95% CI, 1.9-4.0; P < .001).54 Chromogranin A levels can be elevated in several concurrent medical conditions, including renal or hepatic insufficiency, and are also commonly elevated in the setting of concurrent proton pump inhibitors. Several panelists therefore caution that rising chromogranin A levels in an asymptomatic patient with a tumor that looks stable on imaging does not necessarily indicate that a patient should be initiated on a new therapy.

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NCCN Guidelines Version 2.2014 Neuroendocrine Tumors
5-Hydroxyindoleacetic acid (5-HIAA), a metabolite of serotonin, in a 24hour urine sample may also be considered as a biochemical marker in some cases, particularly in patients with small-intestinal carcinoid tumors. During monitoring of patients after treatment of a carcinoid tumor, decreasing levels of 5-HIAA indicate a response to treatment, whereas increasing or excessive concentration indicates that the treatment has not been successful. However, a patient with symptoms may still have a carcinoid tumor even if the concentration of 5-HIAA is normal. Diet and a variety of drugs can affect the 5-HIAA test. Therefore, patients should be advised not to eat avocados, bananas, cantaloupe, eggplant, pineapples, plums, tomatoes, hickory nuts, plantains, kiwi, dates, grapefruit, honeydew, or walnuts for 48 hours before the start of urine collection. Additionally, patients should avoid coffee, alcohol, and smoking for this period. Medications that can increase 5-HIAA include acetaminophen, ephedrine, diazepam, nicotine, glyceryl guaiacolate (an ingredient found in some cough medicines), and phenobarbital. Somatostatin receptor scintigraphy is not routinely recommended for surveillance after definitive resection, but may be indicated to assess disease location and disease burden for comparison in cases of subsequent possible recurrence. In specific cases, follow-up recommendations for patients with resected carcinoid tumors differ from the above general recommendations. For rectal tumors smaller than 1 cm, prognosis is excellent and no follow-up is usually required. Follow-up endoscopies with rectal MRI or EUS are recommended for rectal tumors that are between 1 and 2 cm, 6 and 12 months after primary therapy, and then as clinically indicated. For appendiceal tumors 2 cm or smaller without aggressive features, follow-up examinations are done as clinically indicated. Patients with

NCCN Guidelines Index Neuroendocrine Tumors Table of Contents Discussion

small, well-differentiated appendiceal carcinoids are at very low risk for recurrence,55,56 and some institutions recommend no follow-up in these patients. Other institutions recommend a follow-up examination 1 year after simple appendectomy and then with decreasing frequency. However, because recurrences have rarely been reported even after resection of small appendiceal tumors, any patients with symptoms of hormone hypersecretion should be more fully evaluated. Follow-up recommendations also differ to some extent for hypergastrinemic patients with type 1 or 2 gastric carcinoid tumors. Patients with type 1 or 2 gastric carcinoid tumors measuring less than 2 cm may, in some cases, simply be followed up with H&P every 6 to 12 months or as symptoms indicate. More commonly, patients with type 1 or type 2 gastric carcinoid tumors are managed with endoscopic resection of larger lesions, and follow-up endoscopies are recommended every 6 to 12 months for the first 3 years and annually thereafter if no evidence of progression is seen. Because gastrin levels remain persistently high in patients with atrophic gastritis, gastrin levels are generally uninformative in patients with type 1 gastric carcinoids. If clinically indicated, imaging studies should also be performed. Antrectomy to remove the source of gastrin production can be considered in patients with type 1 gastric carcinoids if new lesions or increasing tumor burden is observed.
Management of Locoregional Unresectable and/or Metastatic Carcinoid Tumors

Baseline imaging recommendations for patients suspected to have distant metastatic disease include multiphase technique CT or MRI.57,58 Baseline levels of chromogranin A (category 3) or 24-hour urine 5-HIAA may also be considered to monitor subsequent progression (discussed above). Somatostatin scintography can also be considered both to assess sites of metastases and to assess somatostatin receptor status

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NCCN Guidelines Version 2.2014 Neuroendocrine Tumors
if treatment with octreotide is being considered. The most common sites of metastases from intestinal carcinoids include regional/mesenteric lymph nodes, liver, and bones. Resection of Metastatic Disease In some cases, patients with limited hepatic metastases or other sites of disease can undergo complete resection of the primary tumor and metastases with curative intent. A recent study of 172 patients who underwent hepatic resection of metastatic neuroendocrine tumors showed that long-term survival can be achieved in selected cases: the reported 10-year overall survival rate was 50.4%.59 However, most patients with metastatic disease will eventually experience recurrence.60,61 Noncurative debulking surgery can also be considered in select cases, especially if the patient is symptomatic either from tumor bulk or hormone production. Resection of the primary site in the setting of unresectable metastases is generally not indicated if the primary site remains asymptomatic and is relatively stable. However, it is not uncommon for patients with small bowel primary tumors to experience symptoms of intermittent abdominal pain from episodic bowel obstruction or bowel ischemia related to the primary tumor and surrounding fibrosis. Palliative small bowel resection is recommended in these patients. Somatostatin Analogs for Symptom Control Patients who have metastatic carcinoid tumors and carcinoid syndrome should be treated with a somatostatin analog.48 The long-acting release (LAR) formulation of octreotide is commonly used for the chronic management of symptoms in patients with carcinoid syndrome. Standard doses of octreotide LAR are 20 to 30 mg intramuscularly every 4 weeks. Dose and frequency may be further increased for symptom control as needed. Therapeutic levels are not achieved for 10

NCCN Guidelines Index Neuroendocrine Tumors Table of Contents Discussion

to 14 days after LAR injection. Short-acting octreotide (usually 150–250 mcg subcutaneously 3 times daily) can be added to octreotide LAR for rapid relief of symptoms or for breakthrough symptoms.62-64 Lanreotide is a somatostatin analog approved for symptom control in Europe and for acromegaly in the United States that has a similar mechanism of action as octreotide. Studies have shown it to be effective at controlling symptoms in patients with carcinoid tumors, gastrinomas, or vasoactive intestinal peptide tumors (VIPomas).65-68 Because it is injected via a deep subcutaneous injection, it may be preferable in patients who have difficulty tolerating an intramuscular injection. A cardiology consultation and echocardiogram to assess whether the patient has carcinoid heart disease should also be considered in patients with carcinoid syndrome with signs and symptoms of heart disease or with planned major surgery.48 Cardiac heart disease is frequent in patients with carcinoid syndrome; in one study, 59% of patients with carcinoid syndrome were diagnosed with tricuspid regurgitation.69,70 A recent study of 250 patients with carcinoid syndrome showed that patients with 5-HIAA levels of 300 μmol or greater (57 mg) over 24 hours and with 3 or more flushing episodes per day were more likely to have carcinoid heart disease.71 In patients who have clinically significant tumor burden, initiation of octreotide LAR is recommended to potentially control tumor growth if they are not already receiving it. The recommendation to consider octreotide in these patients is based on the results of the PROMID study, a placebo-controlled phase III trial of 85 patients with metastatic midgut carcinoid tumors, which showed median times to tumor progression of 14.3 and 6 months in the octreotide LAR and placebo groups, respectively (P = .000072).72 After 6 months of treatment, stable

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NCCN Guidelines Version 2.2014 Neuroendocrine Tumors
disease was observed in 66.7% of patients in the octreotide LAR group and 37.2% of patients in the placebo group. Results of long-term survival of patients in the PROMID study were recently reported.73 Median OS for was not significantly different at 84 months in the placebo arm and not reached in the octreotide arm (HR, 0.85; 95% CI 0.46–1.56; P = .59). However, post-study treatment included octreotide in 38 of 43 patients in the placebo arm, possibly confounding interpretation of long-term survival results. No clear consensus exists on the timing of octreotide initiation in asymptomatic patients with metastatic carcinoid with low tumor burden. Although initiation of octreotide can be considered in these patients, deferring initiation of octreotide until evidence of tumor progression is seen may also be appropriate. The potential role of lanreotide in slowing tumor progression was recently evaluated. The CLARINET study randomized 204 patients with locally advanced or metastatic nonfunctioning pancreatic or intestinal neuroendocrine tumors to receive either lanreotide or placebo and followed patients for PFS. Preliminary results from this trial showed that treatment with lanreotide for 2 years resulted in an improvement in PFS over placebo (PFS, not reached vs. 18 months; HR, 0.47; 95% CI, 0.30–0.73; P = .0002).74 A final report from this study is pending. Patients with clinically significant progression of metastatic carcinoid tumors can pursue several other options, as discussed here. Hepatic-directed Therapies for Metastatic Carcinoid Tumors For patients with unresectable hepatic-predominant progressive disease, hepatic-directed therapies may be considered, mainly with the palliative goals of extending life and relieving hormonal symptoms.75-77

NCCN Guidelines Index Neuroendocrine Tumors Table of Contents Discussion

Cytoreductive surgery or ablative therapies such as radiofrequency ablation78 (RFA) or cryoablation may be considered if near-complete treatment of tumor burden can be achieved (category 2B).79,80 For unresectable liver metastases, hepatic regional therapy (arterial embolization,81 chemoembolization,82-84 or radioembolization [category 2B])84-90 is recommended. Systemic Therapy for Advanced Carcinoid Tumors Cytotoxic chemotherapy: The benefits associated with cytotoxic chemotherapy in advanced carcinoid appear, at best, to be modest. Tumor response rates are generally low, and no PFS benefit has been clearly demonstrated.91 Capecitabine was tested in patients with metastatic carcinoid tumors in a recent phase II trial; no objective responses were reported although 13 of 19 patients were reported to have experienced stable disease.92 The combination of capecitabine and oxaliplatin was assessed in a phase II study, with response rates of 23% in patients with poorly differentiated neuroendocrine tumors and 30% in well-differentiated disease.93 5-FU was assessed in the phase III E1281 trial in combination with streptozocin or doxorubicin.94 Response rates in both arms were around 16%. Dacarbazine was given as salvage therapy, with a response rate of 8%. Responses to temozolomide in advanced carcinoid are rare.95 The panel lists cytotoxic chemotherapy for carcinoid tumors as a category 3 recommendation. While some panelists believe the toxicity of systemic therapy does not warrant its wide-spread use in this population, others believe that it is an important alternative for patients without other options for treatment. Alpha Interferon: Interferon alpha has been shown in several large, non-randomized series to be associated with an antitumor effect in patients with advanced carcinoid. 63,96-99 Because of its potential side

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MS-10

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NCCN Guidelines Version 2.2014 Neuroendocrine Tumors
effects,63,96-99 interferon is usually reserved as a salvage therapy after failure of octreotide.91 Everolimus for Advanced Carcinoid Tumors For patients with progressive metastatic carcinoid tumors, everolimus can also be considered (category 3). Everolimus is an inhibitor of mTOR, which has been the subject of recent trials in patients with advanced neuroendocrine tumors. It was well tolerated and showed promising antitumor effects in patients with advanced carcinoid tumors when given with octreotide LAR in a phase II trial.100 In the randomized phase III RADIANT-2 trial, 429 patients with advanced carcinoid tumors and carcinoid syndrome were randomized to receive octreotide LAR with everolimus or placebo.101 Based on central review, patients receiving octreotide plus everolimus had a median PFS of 16.4 months, compared with 11.3 months for patients receiving octreotide alone (P = .026). This difference in the primary endpoint of PFS did not, however, meet the predefined threshold for statistical significance. Adverse events associated with everolimus included stomatitis, rash, fatigue, and diarrhea.101 Other side effects have also been described.102-104 Radiolabeled Somatostatin Analogs for Advanced Carcinoid Tumors Treatment with radiolabeled somatostatin analogues has been reported to result in tumor responses in patients with advanced carcinoid tumors.105-109 Numerous large, non-randomized cohort analyses have also reported encouraging survival rates with this approach.110,111 However, patients pursuing this form of therapy are often highly selected. At this time, this approach remains investigational, and randomized trials to further evaluate the relative benefit and potential toxicities of radiopeptide therapy in advanced carcinoid are needed.112

NCCN Guidelines Index Neuroendocrine Tumors Table of Contents Discussion

Liver Transplantation for Liver Metastases of Carcinoid Tumors Liver transplantation has been performed in patients with carcinoid tumors whose metastases are confined to the liver.113-118 Although some highly selected patients have experienced long-term survival, the panel acknowledged the considerable associated risks and a high rate of tumor recurrence, and deemed liver transplantation to be investigational and not part of routine care at this time. Neuroendocrine Tumors of the Pancreas According to a population-based study, malignant pancreatic endocrine tumors account for approximately 1% of pancreatic cancers by incidence and 10% of pancreatic cancers by prevalence.119 Although the peak incidence of occurrence is between ages 40 and 69 years, a significant number of patients diagnosed with pancreatic neuroendocrine tumors are younger than 35 years.119,120 Based on an analysis of pancreatic neuroendocrine tumors in the SEER database from 1973 to 2000, the annual incidence per 1 million was 1.8 in women and 2.6 in men.33 An estimated 40% to 91% of pancreatic neuroendocrine tumors are nonfunctional. The remainder manifest with clinically evident hormonal symptoms.9,33 Consistent with these numbers, recent analysis of the NCCN Neuroendocrine Outcomes Database found that 22% of patients with pancreatic neuroendocrine tumors had a hormonal syndrome.42 Of these functioning tumors, up to 70% are insulinomas, and approximately 90% of these are benign. Approximately 15% are glucagonomas. Gastrinomas and somatostatinomas account for another 10%; most (80%–90%) of these are associated with a relatively high risk for metastases.120 The remaining rare pancreatic neuroendocrine tumors include VIPoma, pancreatic polypeptidoma (PPoma), and the recently described cholecystokininoma (CCKoma).121

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NCCN Guidelines Version 2.2014 Neuroendocrine Tumors
The major clinical symptoms associated with functional neuroendocrine tumors of the pancreas depend on the hormone secreted.120 Insulinomas secrete insulin, resulting in fasting or nocturnal hypoglycemia. Gastrinomas secrete gastrin, and patients often present with recurrent peptide ulcers. The glucagon secreted by glucagonomas results in diabetes mellitus and/or migratory necrolytic erythema. Patients with somatostatinomas may also present with diabetes mellitus and/or diarrhea/steatorrhea from secretion of somatostatin. VIPomas are characterized by watery diarrhea, hypokalemia, and achlorhydria (WDHA syndrome) from secretion of vasoactive intestinal polypeptide (VIP). Pancreatic neuroendocrine tumors occurring in patients with MEN1 are typically multiple and require different treatment strategies from those used for patients with sporadic pancreatic endocrine tumors, which are usually solitary (see MEN1, below). Gastrinoma and insulinoma are the most common pancreatic neuroendocrine tumors in patients with MEN1.122
Evaluation of Neuroendocrine Tumors of the Pancreas

NCCN Guidelines Index Neuroendocrine Tumors Table of Contents Discussion

Chromogranin A levels are elevated in 60% or more of patients with either functioning or nonfunctioning pancreatic endocrine tumors.124-126 In addition, analysis of a large prospective database found that chromogranin A levels elevated twice the normal limit or higher were associated with shorter survival times for patients with metastatic neuroendocrine tumors (HR, 2.8; 95% CI, 1.9–4.0; P < .001).54 Chromogranin A levels also appear to be prognostic in patients treated with everolimus.127 Care should be taken in measuring chromogranin A and interpreting the results, because spuriously elevated levels of chromogranin A have been reported in patients using proton pump inhibitors, those with renal or liver failure, those with hypertension, and those with chronic gastritis. Gastrinomas Gastrinoma is often suspected in patients with severe gastroduodenal ulcer symptoms, such as dyspepsia, usually accompanied by diarrhea. Evaluation of a patient with suspected gastrinoma includes measurement of basal and stimulated gastrin levels.128 Diagnosis of gastrinoma can be confounded by the concurrent use of proton pump inhibitors, which will elevate serum gastrin levels. Importantly, most patients who are found to have an elevated level of serum gastrin do not have a gastrinoma but have achlorhydria or are receiving proton pump inhibitors or antacids. Gastrin levels (basal or stimulated) must be measured after the patient is off proton pump inhibitor therapy for at least 1 week. After excluding retained gastric antrum by history, a combination of fasting serum gastrin level >10 times elevated and a gastric pH <2 is diagnostic of a gastrinoma. Patients who have clinical manifestations suspicious for a gastrinoma and a gastric pH <2 but with <10 times elevation of serum gastrin levels require further testing.129 In addition, imaging studies (multiphasic CT/MRI scan) often aid not only in localizing the tumor but also in confirming the diagnosis. Other

Personal and family history should be evaluated for the possibility of MEN1 (see Multiple Endocrine Neoplasia, below). For nonfunctioning pancreatic neuroendocrine tumors, the recommended evaluation includes multiphasic CT or MRI scan. Serum chromogranin A (category 3) and pancreatic polypeptide (PP; category 3) may be tested as clinically appropriate. Functional tumors may give significant clinical symptoms even when very small, and lesion identification can therefore be difficult.123 Multiphasic, contrast-enhanced CT or MRI is recommended, and somatostatin scintography and EUS can also be considered.

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NCCN Guidelines Version 2.2014 Neuroendocrine Tumors
tests, such as somatostatin scintography, EUS, and chromogranin A levels (category 3), may be performed as appropriate. Approximately 70% of patients with MEN1 and gastrinoma have tumors situated in the duodenum. The New England Journal of Medicine recently published a case report outlining the diagnosis of gastrinoma in a patient presenting with severe, recurrent diarrhea.130 Insulinomas Insulinomas are generally small tumors that are best localized with EUS, which has been shown to localize approximately 82% of pancreatic endocrine tumors.131 Insulinomas can also be localized by injecting calcium into selective pancreatic arteries and measuring the insulin levels in the right (usually) or left hepatic vein (ImamuraDoppman procedure).132 Most experts recommend this test only for patients with persistent or recurrent insulinoma or when other localization tests are equivocal or negative. If the diagnosis of insulinoma is uncertain, determining the insulin/glucose ratio after a 48- to 72-hour observed or inpatient observed fast may also be helpful. An insulin level greater than 3 mcIU/mL (usually >6 mcIU/mL) when blood glucose is less than 40 to 45 mg/dL, with an insulin-to-glucose ratio of 0.3 or greater reflecting the inappropriate secretion of insulin at the time of hypoglycemia, indicate the presence of these tumors.133-135 Patients with insulinoma also have elevated levels of C-peptide.133 Testing for urinary sulfonylurea helps rule out factitious hypoglycemia. Multiphasic CT or MRI scans should be performed to rule out metastatic disease. Ninety percent of insulinomas pursue an indolent course and can be cured surgically. Insulinomas are less consistently octreotide-

NCCN Guidelines Index Neuroendocrine Tumors Table of Contents Discussion

avid than other pancreatic neuroendocrine tumors, and somatostatin scintography may consequently be less useful as an imaging technique in insulinomas than in other tumor subtypes. Somatostatin scintography should be performed only if octreotide is being considered as a treatment. Octreotide should only be administered to patients whose tumors are somatostatin scintography-positive, because in the absence of somatostatin receptors, octreotide can profoundly worsen hypoglycemia (see Preoperative Management, below).136 The New England Journal of Medicine recently published a case report describing the diagnosis of insulinoma in a lactating patient presenting with periodic numbness and prolonged episodes of confusion and lethargy.137 Glucagonomas and VIPomas For patients with recent-onset diabetes, cachexia, and/or a necrolytic erythematous skin rash, the panel recommends a blood test for glucagon and blood glucose and multiphase contrast-enhanced CT or MRI. Somatostatin scintography and EUS can be performed as appropriate. For suspected VIPomas with characteristic watery diarrhea, testing for VIP and electrolytes is recommended. A multiphase CT or MRI scan may be useful for identifying large tumors or metastatic disease, and is recommended routinely for suspected VIPoma. Somatostatin scintography and EUS can also be considered as appropriate. A recent case report describes the diagnosis and treatment of a patient with VIPoma.138

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NCCN Guidelines Version 2.2014 Neuroendocrine Tumors
Primary Treatment of Locoregional Resectable Neuroendocrine Tumors of the Pancreas

NCCN Guidelines Index Neuroendocrine Tumors Table of Contents Discussion

Resection is the primary treatment approach for localized pancreatic neuroendocrine tumors when possible, and can result in excellent outcomes. Exceptions include patients with other life-limiting comorbidities or high surgical risk. Preoperative Management Surgical resection is the optimal treatment for locoregional pancreatic endocrine tumors. Before excision, however, any symptoms of hormonal excess must be treated. Octreotide can be considered for symptom control in most pancreatic neuroendocrine tumor subtypes. For insulinomas, the panel advises stabilizing glucose levels with diet and/or diazoxide. Octreotide should be used with caution in patients with insulinoma because it can also suppress counterregulatory hormones, such as growth hormone (GH), glucagon, and catecholamines. In this situation, octreotide can precipitously worsen hypoglycemia, and can result in fatal complications in some cases.136 In each instance where octreotide is recommended for symptom control, lanreotide is an acceptable alternative, as discussed in more detail in Management of Locoregional Unresectable and/or Metastatic Carcinoid Tumors, above. For gastrinomas, gastrin hypersecretion may be treated with proton pump inhibitors. VIPomas and glucagonomas are generally sensitive to octreotide.48 Because severe weight loss is common in patients with glucagonoma, total parenteral nutrition may also be considered. All patients who might require splenectomy should receive preoperative trivalent vaccine (ie, pneumococcus, haemophilus influenzae b, meningococcus group c).

Surgical Management of Nonfunctioning Pancreatic Neuroendocrine Tumors Most patients with localized pancreatic neuroendocrine tumors should undergo surgical resection, absent any contraindications. Exceptions include patients with other life-limiting comorbidities, high surgical risk, or widely metastatic disease. Additionally, several studies have suggested that patients with incidentally discovered tumors <1 cm in size may in some cases be safely followed, depending on the site of the tumor.139,140 Other studies, including an analysis of the SEER database, suggest that some small tumors (measuring less than 2 cm in size in these studies), can pursue a more aggressive course.141-143 Therefore, the panel includes observation alone as an option for selected cases of incidentally discovered pancreatic neuroendocrine tumors measuring 1 cm, but recommends surgical resection for larger tumors absent contraindications. Resection for larger (>2 cm) or malignant-appearing nonfunctional tumors should include total removal of the tumor with negative margins (including adjacent organs) and regional lymph nodes. Lymph node resection should also be considered for tumors of 1 to 2 cm, because of the small but real risk of lymph node metastases.144,145 Surgical Management of Gastrinomas The treatment approach for gastrinoma usually depends on the results of preoperative localization studies and on findings during exploratory laparotomy. In patients with occult gastrinoma (ie, no primary tumor or metastasis is seen on imaging), the panel recommends either observation or exploratory surgery, including duodenotomy and intraoperative ultrasound with enucleation or local resection of tumors if identified at operation, and removal of periduodenal nodes.

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NCCN Guidelines Version 2.2014 Neuroendocrine Tumors
Gastrinomas in the duodenum are treated with duodenotomy and intraoperative ultrasound with local resection or enucleation of tumors and periduodenal node dissection. Gastrinomas in the head of the pancreas that are exophytic or peripheral as determined by imaging and are not immediately adjacent to the pancreatic duct should be enucleated. The periduodenal nodes should also be removed. Gastrinomas in the pancreatic head that are deeper or invasive and those with proximity to the main pancreatic duct should be managed with pancreatoduodenectomy. Gastrinomas in the distal pancreas are treated with distal pancreatectomy. The role of routine splenectomy in such cases is debated. Gastrinomas in some cases may be associated with lymph node metastases,146 which are removed with splenectomy. However, no firm data support splenectomy in all cases. A third alternative is the “Warshaw technique,” which, with resection of splenic vessels but preservation of the spleen,147 can achieve lymph node retrieval comparable to distal pancreatectomy with en-bloc splenectomy. Surgical Management of Insulinomas The primary treatment for exophytic or peripheral insulinomas, because they are primarily benign, is enucleation. This procedure can be performed laparoscopically for localized solitary tumors within the body and tail of the pancreas. Sporadic tumors are usually solitary, whereas familial tumors are multiple. If enucleation is not possible because of invasion or the location of the tumor within the pancreas, then pancreatoduodenectomy for tumors in the head of the pancreas or distal pancreatectomy with preservation of the spleen for smaller tumors not involving splenic vessels may be considered. Distal pancreatectomy can be performed laparoscopically.

NCCN Guidelines Index Neuroendocrine Tumors Table of Contents Discussion

Surgical Management of Glucagonomas Most glucagonomas are malignant and calcified and located in the tail of the pancreas, with regional node involvement. The recommended treatment is distal pancreatectomy with splenectomy and resection of the peripancreatic lymph nodes. For tumors in the pancreatic head, pancreatoduodenectomy with resection of the peripancreatic lymph nodes is recommended. Small (<2 cm) peripheral glucagonomas are rare; enucleation or local excision with peripancreatic lymph dissection may be considered for small peripheral tumors of the head or distal pancreas. A hypercoagulable state has been reported in 10% to 33% of patients with glucagonoma.148,149 Therefore, perioperative anticoagulation can be considered because of the increased risk of pulmonary emboli. Surgical Management of VIPomas Distal VIPomas are treated with distal pancreatectomy with resection of peripancreatic lymph nodes and spleen. Pancreatoduodenectomy with dissection of peripancreatic nodes is recommended for tumors in the head of the pancreas. Small (<2 cm) peripheral VIPomas are rare; enucleation or local excision with peripancreatic lymph dissection may be considered for small peripheral tumors of the head or distal pancreas. Surgical Management of Other Pancreatic Neuroendocrine Tumors The treatment recommendations for


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