Rebekah White, MD; James C. Yao, MD; Tumors · Endoscopic resection Local excision (transduodenal)...

© JNCCN—Journal of the National Comprehensive Cancer Network | Volume 10 Number 6 | June 2012

724

Manisha H. Shah, MD; Stephen Shibata, MD; Jonathan R. Strosberg, MD; Jean-Nicolas Vauthey, MD; Rebekah White, MD; James C. Yao, MD; Deborah A. Freedman-Cass, PhD; and Mary A. Dwyer, MS

OverviewNeuroendocrine tumors are thought to arise from cells throughout the diffuse endocrine system. They comprise a broad family of tumors, the most com-mon of which are carcinoid and pancreatic neuro-endocrine tumors. Other neuroendocrine tumors in-clude those arising in the parathyroid, adrenal, and pituitary glands, and in calcitonin-producing cells of the thyroid (causing medullary thyroid carcinoma).

An analysis of the SEER database estimated that the incidence of neuroendocrine tumors in the Unit-

NCCN

Neuroendocrine TumorsClinical Practice Guidelines in Oncology

Matthew H. Kulke, MD; Al B. Benson III, MD; Emily Bergsland, MD; Jordan D. Berlin, MD; Lawrence S. Blaszkowsky, MD; Michael A. Choti, MD, MBA; Orlo H. Clark, MD; Gerard M. Doherty, MD; James Eason, MD; Lyska Emerson, MD; Paul F. Engstrom, MD; Whitney S. Goldner, MD; Martin J. Heslin, MD; Fouad Kandeel, MD, PhD; Pamela L. Kunz, MD; Boris W. Kuvshinoff II, MD, MBA; Jeffrey F. Moley, MD; Venu G. Pillarisetty, MD; Leonard Saltz, MD; David E. Schteingart, MD;

AbstractNeuroendocrine tumors comprise a broad family of tumors, the most common of which are carcinoid and pancreatic neuroendocrine tumors. The NCCN Neuroendocrine Tumors Guidelines discuss the diagnosis and management of both sporadic and hereditary neuroendocrine tumors. Most of the recommendations pertain to well-differentiated, low- to intermediate-grade tumors. This updated version of the NCCN Guidelines includes a new section on pathology for diagnosis and reporting and revised recommendations for the surgi-cal management of neuroendocrine tumors of the pancreas. (JNCCN 2012;10:724–764)

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.

Clinical trials: NCCN believes that the best management for any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.

Please NoteThe NCCN Clinical Practice Guidelines in Oncol-ogy (NCCN Guidelines®) are a statement of consen-sus 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 Na-tional Comprehensive Cancer Network® (NCCN®) makes no representation or warranties of any kind regarding their content, use, or application and dis-claims any responsibility for their applications or use in any way.

© National Comprehensive Cancer Network, Inc. 2012, All rights reserved. The NCCN Guidelines and the illustra-tions herein may not be reproduced in any form without the express written permission of NCCN.Disclosures for the NCCN Neuroendocrine Tumors Panel

At the beginning of each NCCN Guidelines panel meeting, panel members review all potential conflicts of interest. NCCN, in keep-ing with its commitment to public transparency, publishes these disclosures for panel members, staff, and NCCN itself.

Individual disclosures for the NCCN Neuroendocrine Tumors Panel members can be found on page 764. (The most recent version of these guidelines and accompanying disclosures are available on the NCCN Web site at NCCN.org.)

These guidelines are also available on the Internet. For the latest update, visit NCCN.org.

Neuroendocrine Tumors

NCCNGuidelines®


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Journal of the National Comprehensive Cancer Network

Text continues on p. 746

ed States was 5.25 cases per 100,000 people in 2004.1 This analysis suggested that the diagnosed incidence of neuroendocrine tumors is increasing, and that the prevalence of individuals with neuroendocrine tu-mors in the United States may exceed 100,000.1

Most neuroendocrine tumors seem to be spo-radic; 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 types 1 (MEN 1) and 2 (MEN 2). MEN 1, associated with mutations in the menin gene, is characterized by multiple tumors of the parathyroid, pituitary, and pancreatic glands.2 MEN 2, associat-ed with mutations in the RET proto-oncogene, is characterized by the development of medullary thy-

roid cancer, pheochromocytoma (often bilateral), and hyperparathyroidism.3 Neuroendocrine tumors have also been associated with von Hippel-Lindau disease, tuberous sclerosis complex, and neurofibro-matosis.4,5

Patients with neuroendocrine tumors may or may not have symptoms attributable to hormonal hyperse-cretion. These symptoms include intermittent flushing and diarrhea in patients with carcinoid syndrome,6 hy-pertension in patients with pheochromocytoma,7 and symptoms attributable to secretion of insulin, glucagon, gastrin, and other peptides in patients with pancreatic neuroendocrine tumors.8 Patients with hormonal symp-toms are considered to have “functional” tumors, and those without symptoms are considered to have “non-functional” tumors.

NCCN Neuroendocrine Tumors Panel Members*Matthew H. Kulke, MD/Chair†

Dana-Farber/Brigham and Women’s Cancer CenterAl 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

Gerard M. Doherty, MD¶University of Michigan Comprehensive Cancer Center

James Eason, MD St. Jude Children’s Research Hospital/ University of Tennessee Cancer Institute

Lyska Emerson, MD≠ Huntsman Cancer Institute at the University of Utah

Paul F. Engstrom, MD†Fox Chase Cancer Center

Whitney S. Goldner, MDðUNMC Eppley Cancer Center at The Nebraska Medical Center

Martin J. Heslin, MD¶University of Alabama at Birmingham Comprehensive Cancer Center

Fouad Kandeel, MD, PhDðCity of Hope Comprehensive Cancer Center

Pamela L. Kunz, MD†Stanford Cancer Institute

Boris W. Kuvshinoff II, MD, MBA¶Roswell Park Cancer Institute

Jeffrey F. Moley, MD¶ Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine

Venu G. Pillarisetty, MD¶University of Washington/Seattle Cancer Care Alliance

Leonard Saltz, MD†ÞMemorial Sloan-Kettering Cancer Center

David E. Schteingart, MDðÞUniversity of Michigan Comprehensive Cancer Center

Manisha H. Shah, MD†The Ohio State University Comprehensive Cancer Center – James Cancer Hospital and Solove Research Institute

Stephen Shibata, MD†City of Hope Comprehensive Cancer Center

*Jonathan R. Strosberg, MD†H. Lee Moffitt Cancer Center & Research Institute

Jean-Nicolas Vauthey, MD¶The University of Texas MD Anderson Cancer Center

Rebekah White, MD¶Duke Cancer Institute

James C. Yao, MD†The University of Texas MD Anderson Cancer Center

NCCN Staff: Mary A. Dwyer, MS, and Deborah A. Freedman-Cass, PhD

KEY:

*Writing Committee Member

Specialties: †Medical Oncology; ¶Surgery/Surgical Oncology; ≠Pathology; ðEndocrinology; ÞInternal Medicine


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Neuroendocrine Tumors Version 1.2012

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

DIAGNOSIS AND CLINICAL PRESENTATIONSa

Carcinoid tumorsb

Clinical presentations:

Appendix (See page 728)Rectal (See page 728)Gastric (See page 729)Bronchopulmonary, thymus (See page 730)Atypical lung carcinoidRecurrent or metastatic disease (See page 731)

Neuroendocrine tumors of the pancreas (islet cell tumors)Clinical presentations:

Nonfunctioning pancreatic tumors (See page 732)Gastrinoma (See page 732)Insulinoma (See page 733)Glucagonoma (See page 733)VIPoma (See page 734)Recurrent disease (See page 735)Metastatic disease (See page 736)

Neuroendocrine tumors of unknown primary (See NUP-1*)

Adrenal gland tumors (See page 737)

Pheochromocytoma/paraganglioma (See PHEO-1*)

Poorly differentiated (high-grade or anaplastic)/small cell (See ANAP-1*)

•••••

•••••••

Jejunal, ileal, colon (See page 727)Duodenal (See page 727)

•••

b

b

c

aSee Principles of Pathology for Diagnosis and Reporting of Neuroendocrine Tumors (pages 742 and 743).bc

Guidelines pertain to well-differentiated tumors. For poorly differentiated/high-grade/anaplastic or small cell carcinomas, see ANAP-1*Includes adrenal cortical tumors and incidentaloma.

.

Multiple endocrine neoplasia, type 1 (MEN1)Clinical prese

†

†

ntations:

(See MEN1-1*)

VIPoma, pancreatic polypeptidoma, somatostatinoma,(See MEN1-4*)

Adrenal gland tumor (See page 737)Bronchopulmonary carcinoid, (See CARC-5*)Lipomas, skin angiomas

Multiple endocrine neoplasia, type 2 )

•••••

•

•••

•

•••••

Hyperparathyroidism (See MEN1-3*)GastrinomaGlucagonoma (See MEN1-2*)Insulinoma (See MEN1-3*)

nonfunctioning tumorPituitary tumor (See MEN1-5*)

ProlactinomaCushing diseaseAcromegalyTSH-producing adenomasNonfunctioning adenoma

thymus

(MEN2; See MEN2-1*Clinical presentations:

Medullary thyroid carcinoma (See MEN2-1* and NCCN ClinicalPractice Guidelines in Oncology [NCCN Guidelines] for ThyroidCarcinoma )PheochromocytomaHyperparathyroidism (MEN2A)Marfanoid habitus (MEN2B)Mucosal neuromas (MEN2B)Lichen planus amyloidosis (MEN2A)

Merkel cell carcinoma (See NCCN Guidelines for Merkel CellCarcinoma )

•••••

SURVEILLANCEf,g

abc

See Principles of Pathology for Diagnosis and Reporting of Neuroendocrine Tumors (pages 742 and 743).See Immunohistochemistry and Laboratory Studies Potentially Indicated in the Workup of Neuroendocrine Tumors (page 744).See Surgical Principles for Management of Neuroendocrine Tumors (page 745).

PRIMARY TREATMENT OFNONMETASTATIC DISEASE(If metastatic disease discovered,

c

see page 731)

CLINICALLOCATION

EVALUATIONa,b

Jejunal/ileal/colon

Recommended:

As appropriate:OctreoscanColonoscopySmall-bowelimaging

•

•••

Abdominal/ pelvicmultiphasic CT orMRI

•

• Consider prophylacticcholecystectomy whenappropriate

e

Bowel resection withregionallymphadenectomyd

3-12 mo postresection:•••

•

H&PConsider 5-HIAAConsider chromogranin A(category 3)Consider abdominal/pelvic multi-phasic CT or MRI

Metastaticdisease

See Recurrent or MetastaticDisease (page 731)

Locoregionaldisease

> 1 y postresection:6-12 mo thereafter

Consider 5-HIAAConsider chromogranin A(category 3)

••••

•

H&P

Imaging studies asclinically indicated

defg

Should include careful examination of the entire bowel, because multiple synchronous lesions may be present.If possible future need for octreotide.Earlier, if symptoms.Octreoscan and PET scan not recommended for routine surveillance.

Duodenal

Recommended:Abdominal/pelvicmultiphasic CT orMRI

As appropriate:Octreoscan

•

•• EGD/endoscopic

ultrasound (EUS)

••

•

Endoscopic resectionLocal excision(transduodenal) lymphnode sampling

±

Pancreatoduodenectomy

Metastaticdisease


Locoregionaldisease

*Available online, in these guidelines, at NCCN.org.To view the most recent version of these guidelines, visit NCCN.org.†

NCCN Clinical Practice Guidelines in Oncology


727


Version 2.2012, 03-09-12 ©2012 National Comprehensive Cancer Network, Inc. All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®.

DIAGNOSIS AND CLINICAL PRESENTATIONSa

Carcinoid tumorsb

Clinical presentations:

Appendix (See page 728)Rectal (See page 728)Gastric (See page 729)Bronchopulmonary, thymus (See page 730)Atypical lung carcinoidRecurrent or metastatic disease (See page 731)

Neuroendocrine tumors of the pancreas (islet cell tumors)Clinical presentations:

Nonfunctioning pancreatic tumors (See page 732)Gastrinoma (See page 732)Insulinoma (See page 733)Glucagonoma (See page 733)VIPoma (See page 734)Recurrent disease (See page 735)Metastatic disease (See page 736)

Neuroendocrine tumors of unknown primary (See NUP-1*)

Adrenal gland tumors (See page 737)

Pheochromocytoma/paraganglioma (See PHEO-1*)

Poorly differentiated (high-grade or anaplastic)/small cell (See ANAP-1*)

•••••

•••••••

Jejunal, ileal, colon (See page 727)Duodenal (See page 727)

•••

b

b

c

aSee Principles of Pathology for Diagnosis and Reporting of Neuroendocrine Tumors (pages 742 and 743).bc

Guidelines pertain to well-differentiated tumors. For poorly differentiated/high-grade/anaplastic or small cell carcinomas, see ANAP-1*Includes adrenal cortical tumors and incidentaloma.

.

Multiple endocrine neoplasia, type 1 (MEN1)Clinical prese

†

†

ntations:

(See MEN1-1*)

VIPoma, pancreatic polypeptidoma, somatostatinoma,(See MEN1-4*)

Adrenal gland tumor (See page 737)Bronchopulmonary carcinoid, (See CARC-5*)Lipomas, skin angiomas

Multiple endocrine neoplasia, type 2 )

•••••

•

•••

•

•••••

Hyperparathyroidism (See MEN1-3*)GastrinomaGlucagonoma (See MEN1-2*)Insulinoma (See MEN1-3*)

nonfunctioning tumorPituitary tumor (See MEN1-5*)

ProlactinomaCushing diseaseAcromegalyTSH-producing adenomasNonfunctioning adenoma

thymus

(MEN2; See MEN2-1*Clinical presentations:

Medullary thyroid carcinoma (See MEN2-1* and NCCN ClinicalPractice Guidelines in Oncology [NCCN Guidelines] for ThyroidCarcinoma )PheochromocytomaHyperparathyroidism (MEN2A)Marfanoid habitus (MEN2B)Mucosal neuromas (MEN2B)Lichen planus amyloidosis (MEN2A)

Merkel cell carcinoma (See NCCN Guidelines for Merkel CellCarcinoma )

•••••

SURVEILLANCEf,g

abc



c

see page 731)

CLINICALLOCATION

EVALUATIONa,b

Jejunal/ileal/colon

Recommended:

As appropriate:OctreoscanColonoscopySmall-bowelimaging

•

•••

Abdominal/ pelvicmultiphasic CT orMRI

•

• Consider prophylacticcholecystectomy whenappropriate

e

Bowel resection withregionallymphadenectomyd

3-12 mo postresection:•••

•

H&PConsider 5-HIAAConsider chromogranin A(category 3)Consider abdominal/pelvic multi-phasic CT or MRI

Metastaticdisease


Locoregionaldisease


Consider 5-HIAAConsider chromogranin A(category 3)

••••

•

H&P


defg

Should include careful examination of the entire bowel, because multiple synchronous lesions may be present.If possible future need for octreotide.Earlier, if symptoms.Octreoscan and PET scan not recommended for routine surveillance.

Duodenal

Recommended:Abdominal/pelvicmultiphasic CT orMRI

As appropriate:Octreoscan

•

•• EGD/endoscopic

ultrasound (EUS)

••

•

Endoscopic resectionLocal excision(transduodenal) lymphnode sampling

±


Metastaticdisease


Locoregionaldisease

*Available online, in these guidelines, at NCCN.org.To view the most recent version of these guidelines, visit NCCN.org.†

CARCINOID TUMORS


728



SURVEILLANCEf,gEVALUATIONa,b

abc

See Principles of Pathology for Diagnosis and Reporting of Neuroendocrine Tumors (pages 742 and 743).See Stains and Laboratory Studies Potentially Indicated in the Workup of Neuroendocrine Tumors (page 744).See Surgical Principles for Management of Neuroendocrine Tumors (page 745).


c

see page 731)

CLINICALLOCATION

Appendixh Abdominal/pelvicCT or MRImultiphasic

2 cm andconfined totheappendix

> 2 cm orincompleteresection(nodes,margins)

Simpleappendectomyi As clinically indicated

Re-explorationRight hemicolectomy

Metastaticdisease


3-12 mo postresection:H&P

Consider abdominal CT/MRI

Consider 5-HIAAConsider chromogranin A (category 3)

multiphasic



••••

H&P

Imaging studies as clinically indicated

fEarlier, if symptoms.Octreoscan and PET scan are not recommended for routine surveillance.Some appendiceal carcinoids will have mixed histology, including elements of adenocarcinoma. Such tumors should be managed according to coloncancer guidelines

Some institutions will consider more aggressive treatments for 1- to 2-cm tumors with poor prognostic features. See Discussion for details.

gh

ijFor 1- to 2-cm tumors, consider examination under anesthesia (EUA) and/or EUS with radical resection if muscularis propria invasion or node-positive.

. See NCCN Guidelines for Colon Cancer (to view the most recent version of these guidelines, visit NCCN.org).

Rectal

Recommended:ColonoscopyAbdominal/pelvic multi-phasic CT orMRI

As appropriate:OctreoscanEUS

2 cmj

> 2 cm

Resection (transanalor endoscopicexcision, if possible)

Low anterior resectionorAbdominoperinealresection (APR)

< 1 cm: No follow-up required1 to 2 cm: Proctoscopy at 6 and 12mo, then as clinically indicated

Metastaticdisease



Consider abdominal/pelvic CTor MRI

Consider chromogranin A (category 3)multiphasic


Consider chromogranin A (category 3)•

•

H&P

Imaging studies as clinically indicated•

Gastric

Recommended:EGD

As appropriate:

Octreoscan forpatients withnormal gastrinB level ifhypergastrinemia

Gastrin levelMultiphasic CT orMRI for patientswith normalgastrin

EUS

k

12

Hyper-gastrinemicpatientsl

Patients withnormal gastrin

Tumor2 cm

Solitaryormultiple

Observe

Endoscopicresection +biopsy oftumor(s) andadjacent mucosaorOctreotide forZollinger-Ellisonpatients(category 2B)

m

Surgicalresection

Endoscopicresection, ifpossibleor

Radicalgastricresection +lymph noderemoval

SURVEILLANCEf,g

abc

gklm


Octreoscan and PET scan are not recommended for routine surveillance.Gastrin levels need to be completed while fasting and off protein pump inhibitors for 1 week.If gastric pH is low or clinical or radiographic evidence, see gastrinoma on page 732 or MEN1-1 (available online, in these guidelines, at NCCN.org).Octreotide, 150-250 mcg, SC TID or octreotide LAR, 20-30 mg, IM every 4 weeks. Dose and frequenc

fEarlier, if symptoms.

y may be further increased for symptomcontrol as needed. Therapeutic levels of octreotide would not be expected to be reached for 10-14 d after LAR injection. Short-acting octreotidecan be added to octreotide LAR for rapid relief of symptoms or for breakthrough symptoms.

Tumor> 2 cmSolitaryormultiple

H&P andmarkers,

Years 1-3:every 6-12 mowith EGDYears 4+:Annuallythereafter

Imaging studiesas clinicallyindicated

b

•

•

Newlesion(s) orincreasingtumors,considerantrectomy


Locoregionaldisease

Metastaticdisease

EVALUATIONa,b PRIMARY TREATMENT OFNONMETASTATIC DISEASE(If metastatic diseasediscovered, see

c

page 731)


CT or MRI

Consider chromogranin A(category 3)Multiphasic


Consider chromogranin A(category 3)

•

•

H&P


•

H&P every 6-12 moor

CLINICALLOCATION

CARCINOID TUMORS



729




abc

See Principles of Pathology for Diagnosis and Reporting of Neuroendocrine Tumors (pages 742 and 743).See Stains and Laboratory Studies Potentially Indicated in the Workup of Neuroendocrine Tumors (page 744).See Surgical Principles for Management of Neuroendocrine Tumors (page 745).


c

see page 731)

CLINICALLOCATION

Appendixh Abdominal/pelvicCT or MRImultiphasic

2 cm andconfined totheappendix

> 2 cm orincompleteresection(nodes,margins)

Simpleappendectomyi As clinically indicated

Re-explorationRight hemicolectomy

Metastaticdisease



Consider abdominal CT/MRI


multiphasic



••••

H&P

Imaging studies as clinically indicated

fEarlier, if symptoms.Octreoscan and PET scan are not recommended for routine surveillance.Some appendiceal carcinoids will have mixed histology, including elements of adenocarcinoma. Such tumors should be managed according to coloncancer guidelines

Some institutions will consider more aggressive treatments for 1- to 2-cm tumors with poor prognostic features. See Discussion for details.

gh

ijFor 1- to 2-cm tumors, consider examination under anesthesia (EUA) and/or EUS with radical resection if muscularis propria invasion or node-positive.

. See NCCN Guidelines for Colon Cancer (to view the most recent version of these guidelines, visit NCCN.org).

Rectal

Recommended:ColonoscopyAbdominal/pelvic multi-phasic CT orMRI

As appropriate:OctreoscanEUS

2 cmj

> 2 cm

Resection (transanalor endoscopicexcision, if possible)

Low anterior resectionorAbdominoperinealresection (APR)

< 1 cm: No follow-up required1 to 2 cm: Proctoscopy at 6 and 12mo, then as clinically indicated

Metastaticdisease



Consider abdominal/pelvic CTor MRI

Consider chromogranin A (category 3)multiphasic


Consider chromogranin A (category 3)•

•

H&P

Imaging studies as clinically indicated•

Gastric

Recommended:EGD

As appropriate:

Octreoscan forpatients withnormal gastrinB level ifhypergastrinemia

Gastrin levelMultiphasic CT orMRI for patientswith normalgastrin

EUS

k

12

Hyper-gastrinemicpatientsl

Patients withnormal gastrin

Tumor2 cm

Solitaryormultiple

Observe

Endoscopicresection +biopsy oftumor(s) andadjacent mucosaorOctreotide forZollinger-Ellisonpatients(category 2B)

m

Surgicalresection

Endoscopicresection, ifpossibleor

Radicalgastricresection +lymph noderemoval

SURVEILLANCEf,g

abc

gklm


Octreoscan and PET scan are not recommended for routine surveillance.Gastrin levels need to be completed while fasting and off protein pump inhibitors for 1 week.If gastric pH is low or clinical or radiographic evidence, see gastrinoma on page 732 or MEN1-1 (available online, in these guidelines, at NCCN.org).Octreotide, 150-250 mcg, SC TID or octreotide LAR, 20-30 mg, IM every 4 weeks. Dose and frequenc

fEarlier, if symptoms.

y may be further increased for symptomcontrol as needed. Therapeutic levels of octreotide would not be expected to be reached for 10-14 d after LAR injection. Short-acting octreotidecan be added to octreotide LAR for rapid relief of symptoms or for breakthrough symptoms.

Tumor> 2 cmSolitaryormultiple

H&P andmarkers,

Years 1-3:every 6-12 mowith EGDYears 4+:Annuallythereafter

Imaging studiesas clinicallyindicated

b

•

•

Newlesion(s) orincreasingtumors,considerantrectomy


Locoregionaldisease

Metastaticdisease

EVALUATIONa,b PRIMARY TREATMENT OFNONMETASTATIC DISEASE(If metastatic diseasediscovered, see

c

page 731)


CT or MRI

Consider chromogranin A(category 3)Multiphasic


Consider chromogranin A(category 3)

•

•

H&P


•

H&P every 6-12 moor

CLINICALLOCATION

CARCINOID TUMORS


730



Thymusn

Recommended:Chest/CT and

CT orMRI

As appropriate:OctreoscanBronchoscopyACTH/cortisol

•

•••

mediastinalabdominal

multiphasic

Localizeddisease

Localizeddisease

Locoregionaldisease

Locoregionaldisease

Metastaticdisease

Metastaticdisease

Resect

Resect

See( )

Recurrent or MetastaticDisease facing page

Completeresection

Incompleteresection

RT± chemotherapy(category 3 foraddition ofchemotherapy)

o

Broncho-pulmonary

Recommended:

multiphasicAs appropriate:

•

•••

Chest CT andabdominal

CT or MRI

OctreoscanBronchoscopyACTH/cortisol

See NCCN Guidelines for Small Cell Lung Cancer; LungNeuroendocrine Tumor algorithm (to view the mostrecent version of these guidelines, visit NCCN.org)


See(

Recurrent or MetastaticDisease facing page)

abc


fEarlier, if symptoms.gno

Octreoscan and PET scan are not recommended for routine surveillance.Thymic carcinoids are often associated with MEN1.Consider 5-fluorouracil or capecitabine at radiosensitizing doses. Cisplatin or carboplatin with etoposide may be appropriate for patients with atypical orpoorly differentiated tumors.

PRIMARY TREATMENT OFNONMETASTATIC DISEASEc

(If metastatic disease discovered,see facing page)


Chest/mediastinalCT or MRI

•

•

• Consider chromogranin A(category 3)

multi-phasic


Consider chromograninA (category 3)

•• H&P


•

•

CLINICALLOCATION

MANAGEMENT OF LOCOREGIONAL UNRESECTABLE DISEASE AND/OR DISTANT METASTASESc

cSee Surgical Principles for Management of Neuroendocrine Tumors (pages 742 and 743).pq

rs

tu

Resection of a small asymptomatic (relatively stable) primary in the presence of unresectable metastatic disease is not indicated.Octreotide, 150-250 mcg, SC TID or octreotide LAR, 20-30 mg, IM every 4 weeks. Dose and frequency may be further increased forsymptom 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. See PROMID study: Rinke A,Muller HH, Schade-Bittinger C, et al. Placebo-controlled, double-blind, prospective, randomized study on the effect of octreotide LAR in thecontrol of tumor growth in patients with metastatic neuroendocrine midgut tumors: a report from the PROMID Study Group. J Clin Oncol2009;27:4656-4663.

If signs and symptoms of heart disease or planning major surgery.Includes ablative techniques such as radiofrequency, microwave, and cryotherapy. There are no randomized clinical trials, and prospectivedata for these interventions are limited. However, data on the use of these interventions are emerging.

Only if near-complete resection can be achieved.Anticancer agents such as capecitabine, dacarbazine, 5-fluorouracil, interferon, and temozolomide can be used in patients with progressivemetastases for whom no other treatment options exist.

Distantmetastases•

•

•

Imaging:MultiphasicCT or MRIConsideroctreoscan

Consider5-HIAAConsiderchromogranin A(category 3)

•

•

Observe withmarkers andscans every3-12 moorOctreotideq

• OctreotideEchocardiogram

qr•

Octreotide, if not already receivingandConsider hepatic regional therapy(arterial embolization,chemoembolization, radioembolization[category 2B])orConsider cytoreductive surgery/ablativetherapy (category 2B)orConsider everolimus (10 mg/d)(category 3)orConsider cytotoxic chemotherapy(category 3), if no other options feasible

s,t

u

Asymptomatic,low tumor burden

p

Clinicallysignificanttumor burden

Carcinoidsyndrome

Octreotideq

If completeresection possible Resect primary + metastases

Clinicallysignificantprogressivedisease

Locally symptomaticfrom primary tumor

Consider resectionof primary tumor

CARCINOID TUMORS



731



Thymusn

Recommended:Chest/CT and

CT orMRI

As appropriate:OctreoscanBronchoscopyACTH/cortisol

•

•••

mediastinalabdominal

multiphasic

Localizeddisease

Localizeddisease

Locoregionaldisease

Locoregionaldisease

Metastaticdisease

Metastaticdisease

Resect

Resect

See( )

Recurrent or MetastaticDisease facing page

Completeresection

Incompleteresection

RT± chemotherapy(category 3 foraddition ofchemotherapy)

o

Broncho-pulmonary

Recommended:

multiphasicAs appropriate:

•

•••

Chest CT andabdominal

CT or MRI

OctreoscanBronchoscopyACTH/cortisol

See NCCN Guidelines for Small Cell Lung Cancer; LungNeuroendocrine Tumor algorithm (to view the mostrecent version of these guidelines, visit NCCN.org)


See(

Recurrent or MetastaticDisease facing page)

abc


fEarlier, if symptoms.gno

Octreoscan and PET scan are not recommended for routine surveillance.Thymic carcinoids are often associated with MEN1.Consider 5-fluorouracil or capecitabine at radiosensitizing doses. Cisplatin or carboplatin with etoposide may be appropriate for patients with atypical orpoorly differentiated tumors.

PRIMARY TREATMENT OFNONMETASTATIC DISEASEc

(If metastatic disease discovered,see facing page)


Chest/mediastinalCT or MRI

•

•

• Consider chromogranin A(category 3)

multi-phasic


Consider chromograninA (category 3)

•• H&P


•

•

CLINICALLOCATION

MANAGEMENT OF LOCOREGIONAL UNRESECTABLE DISEASE AND/OR DISTANT METASTASESc

cSee Surgical Principles for Management of Neuroendocrine Tumors (pages 742 and 743).pq

rs

tu

Resection of a small asymptomatic (relatively stable) primary in the presence of unresectable metastatic disease is not indicated.Octreotide, 150-250 mcg, SC TID or octreotide LAR, 20-30 mg, IM every 4 weeks. Dose and frequency may be further increased forsymptom 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. See PROMID study: Rinke A,Muller HH, Schade-Bittinger C, et al. Placebo-controlled, double-blind, prospective, randomized study on the effect of octreotide LAR in thecontrol of tumor growth in patients with metastatic neuroendocrine midgut tumors: a report from the PROMID Study Group. J Clin Oncol2009;27:4656-4663.

If signs and symptoms of heart disease or planning major surgery.Includes ablative techniques such as radiofrequency, microwave, and cryotherapy. There are no randomized clinical trials, and prospectivedata for these interventions are limited. However, data on the use of these interventions are emerging.

Only if near-complete resection can be achieved.Anticancer agents such as capecitabine, dacarbazine, 5-fluorouracil, interferon, and temozolomide can be used in patients with progressivemetastases for whom no other treatment options exist.

Distantmetastases•

•

•

Imaging:MultiphasicCT or MRIConsideroctreoscan

Consider5-HIAAConsiderchromogranin A(category 3)

•

•

Observe withmarkers andscans every3-12 moorOctreotideq

• OctreotideEchocardiogram

qr•

Octreotide, if not already receivingandConsider hepatic regional therapy(arterial embolization,chemoembolization, radioembolization[category 2B])orConsider cytoreductive surgery/ablativetherapy (category 2B)orConsider everolimus (10 mg/d)(category 3)orConsider cytotoxic chemotherapy(category 3), if no other options feasible

s,t

u

Asymptomatic,low tumor burden

p

Clinicallysignificanttumor burden

Carcinoidsyndrome

Octreotideq

If completeresection possible Resect primary + metastases

Clinicallysignificantprogressivedisease

Locally symptomaticfrom primary tumor

Consider resectionof primary tumor

CARCINOID TUMORS


732



SeeSurveillance(page 735)

CLINICALDIAGNOSIS

EVALUATIONb,c,d

Nonfunctioningpancreatictumorsa

Metastaticdisease

See Metastases(page 736)

Locoregionaldiseasee

aFor rare tumors, such as somatostatinoma, ACTHoma, PTH-rP-secreting tumors, and PPoma, follow the nonfunctioning pancreatictumor pathway.

b

g

h

i

j

k

Preoperative trivalent vaccine (i.e., pneumococcus, haemophilus influenzae b,and meningococcal group C) if considering surgery with possiblesplenectomy.

Neuroendocrine tumors of the pancreas that are 1-2 cm have a smal, but realrisk of lymph node metastases. Therefore, lymph node resection should beconsidered.

Gastrin levels need to be measured while fasting and off proton pumpinhibitors for 1 week.

Octreotide, 150-250 mcg, SC TID or octreotide LAR, 20-30 mg, IM every 4weeks. Dose and frequency may be further increased for symptom control asneeded. Therapeutic levels of octreotide would not be expected to bereached for 10-14 d after LAR injection. Short-acting octreotide can be addedto octreotide LAR for rapid relief of symptoms or for breakthrough symptoms.

Not adjacent to the main pancreatic duct.

See Principles of Pathology for Diagnosis and Reporting ofNeuroendocrine Tumors (pages 742 and 743).

See Immunohistochemistry and Laboratory Studies PotentiallyIndicated in the Workup of Neuroendocrine Tumors (page 744).

Consider MEN1 family history for all patients with pancreaticneuroendocrine tumors.

Risks and benefits of surgical resection should be carefully weighed inpatients with small lesions.

See Surgical Principles for Management of Neuroendocrine Tumors(page 745).

c

d

e

f

MANAGEMENT OF NONMETASTATIC DISEASE(If metastatic disease discovered,

PRIMARY f,g

see page 736)Enucleation ± regionalnodesorDistal pancreatectomy ±regionalnodes/splenectomy

h

Small (< 2 cm)and peripheral

Deeper, larger(> 2 cm), orinvasive tumors

PancreatoduodenectomyHead

Distal Distal pancreatectomy +splenectomy

Recommended:Multiphasic CTor MRI

OctreoscanPancreaticpolypeptide(category 3)Chromogranin A(category 3)

•

••

•

As appropriate:


Gastrinoma(usuallyduodenalor head ofpancreas)

Head

For deeper orinvasive tumors andthose in proximity tothe main pancreaticduct


Distal Distal pancreatectomy± splenectomyg

OccultNo primary tumoror metastases onimaging

ObserveorExploratory surgery including

; localresection/enucleation oftumor(s) + periduodenal node

duodenotomy andintraoperative ultrasound

dissection

Enucleation of tumor+ periduodenal nodedissection

Exophytic orperipheral tumorsby imagingk

Recommended:Gastrin levels(basal,stimulated asindicated)Multiphasic CTor MRI

As appropriate:OctreoscanEUSChromogranin A(category 3)

•

•

•••

i

Duodenum

Duodenotomy andintraoperative ultrasound; localresection/enucleation oftumor(s) + periduodenal nodedissection

•

•

Manage gastrichypersecretionwith

Consideroctreotide

protonpump inhibitors

j


Insulinoma

Stabilizeglucose levelswith diet and/ordiazoxide

Tumorenucleation,considerlaparoscopicresection

CLINICALDIAGNOSIS

EVALUATIONb,c,d

Locoregionaldisease

Metastaticdisease

SeeMetastases(page 736)


f,gPRIMARYsee page 736)

Asappropriate:Octreoscanl

Head

Distal

Deeper orinvasivetumors andthose inproximity tothe mainpancreaticduct

Exophyticorperipheraltumors byimagingk

Pancreato-duodenectomy

Distalpancreatectomy(spleen-preserving ),considerlaparoscopicresection

m

Splenectomy should be performed for larger tumors involving splenicvessels.

b

c

d

f

g

j

kl

n

o

See Principles of Pathology for Diagnosis and Reporting ofNeuroendocrine Tumors (pages 742 and 743).See Immunohistochemistry and Laboratory Studies PotentiallyIndicated in the Workup of Neuroendocrine Tumors (page 744).Consider MEN1 family history for all patients with pancreaticneuroendocrine tumors.See Surgical Principles for Management of Neuroendocrine Tumors(page 745).Preoperative trivalent vaccine (i.e., pneumococcus, haemophilusinfluenzae b, and meningococcal group C) if considering surgerywith possible splenectomy.

Octreotide, 150-250 mcg, SC TID or octreotide LAR, 20-30 mg, IMevery 4 weeks. Dose and frequency may be further increased forsymptom 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 ofsymptoms or for breakthrough symptoms.Not adjacent to the main pancreatic duct.Octreoscan only if octreotide is planned. Octreotide should only be givenif tumor demonstrates somatostatin receptors. In the absence ofsomatostatin receptors, octreotide can profoundly worsenhypoglycemia. (See Discussion for details).

Small (< 2 cm) peripheral glucagonomas are rare; enucleation/localexcision + peripancreatic lymph dissection may be considered.

Consider perioperative anticoagulation.

m

Head orDistal

Recommended:Multiphasic CT orMRI

As appropriate:

48- to 7

Chromogranin A(category 3)

•

••

•

EUS2-h

observed orinpatient fast,insulin/glucoseratio, if diagnosisuncertain

Glucagonoma(usually tail)

Distal pancreatectomy+ peripancreatic lymphnode dissection +splenectomy

o

Stabilize

with IV fluidsandoctreotide

glucose levels

j

Locoregionaldisease

Metastaticdisease


Recommended:Glucagon/bloodglucoseMultiphasiccontrast-enhancedCT or MRI

As appropriate:OctreoscanChromogranin A(category 3)

•

•

••


Head(rare)n

Distaln

Pancreatoduodenectomy+ peripancreatic lymphnodes

PANCREAS (ISLET CELL TUMORS)



733




CLINICALDIAGNOSIS

EVALUATIONb,c,d

Nonfunctioningpancreatictumorsa

Metastaticdisease


Locoregionaldiseasee

aFor rare tumors, such as somatostatinoma, ACTHoma, PTH-rP-secreting tumors, and PPoma, follow the nonfunctioning pancreatictumor pathway.

b

g

h

i

j

k

Preoperative trivalent vaccine (i.e., pneumococcus, haemophilus influenzae b,and meningococcal group C) if considering surgery with possiblesplenectomy.

Neuroendocrine tumors of the pancreas that are 1-2 cm have a smal, but realrisk of lymph node metastases. Therefore, lymph node resection should beconsidered.

Gastrin levels need to be measured while fasting and off proton pumpinhibitors for 1 week.

Octreotide, 150-250 mcg, SC TID or octreotide LAR, 20-30 mg, IM every 4weeks. Dose and frequency may be further increased for symptom control asneeded. Therapeutic levels of octreotide would not be expected to bereached for 10-14 d after LAR injection. Short-acting octreotide can be addedto octreotide LAR for rapid relief of symptoms or for breakthrough symptoms.

Not adjacent to the main pancreatic duct.

See Principles of Pathology for Diagnosis and Reporting ofNeuroendocrine Tumors (pages 742 and 743).

See Immunohistochemistry and Laboratory Studies PotentiallyIndicated in the Workup of Neuroendocrine Tumors (page 744).

Consider MEN1 family history for all patients with pancreaticneuroendocrine tumors.

Risks and benefits of surgical resection should be carefully weighed inpatients with small lesions.

See Surgical Principles for Management of Neuroendocrine Tumors(page 745).

c

d

e

f


PRIMARY f,g

see page 736)Enucleation ± regionalnodesorDistal pancreatectomy ±regionalnodes/splenectomy

h

Small (< 2 cm)and peripheral

Deeper, larger(> 2 cm), orinvasive tumors

PancreatoduodenectomyHead

Distal Distal pancreatectomy +splenectomy

Recommended:Multiphasic CTor MRI

OctreoscanPancreaticpolypeptide(category 3)Chromogranin A(category 3)

•

••

•

As appropriate:


Gastrinoma(usuallyduodenalor head ofpancreas)

Head

For deeper orinvasive tumors andthose in proximity tothe main pancreaticduct


Distal Distal pancreatectomy± splenectomyg

OccultNo primary tumoror metastases onimaging

ObserveorExploratory surgery including

; localresection/enucleation oftumor(s) + periduodenal node

duodenotomy andintraoperative ultrasound

dissection

Enucleation of tumor+ periduodenal nodedissection

Exophytic orperipheral tumorsby imagingk

Recommended:Gastrin levels(basal,stimulated asindicated)Multiphasic CTor MRI

As appropriate:OctreoscanEUSChromogranin A(category 3)

•

•

•••

i

Duodenum

Duodenotomy andintraoperative ultrasound; localresection/enucleation oftumor(s) + periduodenal nodedissection

•

•

Manage gastrichypersecretionwith

Consideroctreotide

protonpump inhibitors

j


Insulinoma

Stabilizeglucose levelswith diet and/ordiazoxide

Tumorenucleation,considerlaparoscopicresection

CLINICALDIAGNOSIS

EVALUATIONb,c,d

Locoregionaldisease

Metastaticdisease




Asappropriate:Octreoscanl

Head

Distal

Deeper orinvasivetumors andthose inproximity tothe mainpancreaticduct

Exophyticorperipheraltumors byimagingk

Pancreato-duodenectomy

Distalpancreatectomy(spleen-preserving ),considerlaparoscopicresection

m

Splenectomy should be performed for larger tumors involving splenicvessels.

b

c

d

f

g

j

kl

n

o

See Principles of Pathology for Diagnosis and Reporting ofNeuroendocrine Tumors (pages 742 and 743).See Immunohistochemistry and Laboratory Studies PotentiallyIndicated in the Workup of Neuroendocrine Tumors (page 744).Consider MEN1 family history for all patients with pancreaticneuroendocrine tumors.See Surgical Principles for Management of Neuroendocrine Tumors(page 745).Preoperative trivalent vaccine (i.e., pneumococcus, haemophilusinfluenzae b, and meningococcal group C) if considering surgerywith possible splenectomy.

Octreotide, 150-250 mcg, SC TID or octreotide LAR, 20-30 mg, IMevery 4 weeks. Dose and frequency may be further increased forsymptom 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 ofsymptoms or for breakthrough symptoms.Not adjacent to the main pancreatic duct.Octreoscan only if octreotide is planned. Octreotide should only be givenif tumor demonstrates somatostatin receptors. In the absence ofsomatostatin receptors, octreotide can profoundly worsenhypoglycemia. (See Discussion for details).

Small (< 2 cm) peripheral glucagonomas are rare; enucleation/localexcision + peripancreatic lymph dissection may be considered.

Consider perioperative anticoagulation.

m

Head orDistal

Recommended:Multiphasic CT orMRI

As appropriate:

48- to 7

Chromogranin A(category 3)

•

••

•

EUS2-h

observed orinpatient fast,insulin/glucoseratio, if diagnosisuncertain

Glucagonoma(usually tail)

Distal pancreatectomy+ peripancreatic lymphnode dissection +splenectomy

o

Stabilize

with IV fluidsandoctreotide

glucose levels

j

Locoregionaldisease

Metastaticdisease


Recommended:Glucagon/bloodglucoseMultiphasiccontrast-enhancedCT or MRI

As appropriate:OctreoscanChromogranin A(category 3)

•

•

••


Head(rare)n

Distaln




734



CLINICALDIAGNOSIS

EVALUATIONb,c,d MANAGEMENT OF NONMETASTATIC DISEASE(If metastatic disease discovered,


bcdfg

j

p

See Principles of Pathology for Diagnosis and Reporting of Neuroendocrine Tumors (pages 742 and 743).See Stains and Laboratory Studies Potentially Indicated in the Workup of Neuroendocrine Tumors (page 744).Consider MEN1 family history for all patients with pancreatic neuroendocrine tumors.See Surgical Principles for Management of Neuroendocrine Tumors (page 745).Preoperative trivalent vaccine (i.e., pneumococcus, haemophilus influenzae b, and meningococcal group C) if considering surgery with possiblesplenectomy.

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 asneeded. Therapeutic levels of octreotide would not be expected to be reached for 10-14 d after LAR injection. Short-acting octreotide can be added tooctreotide LAR for rapid relief of symptoms or for breakthrough symptoms.Small (< 2 cm), peripheral VIPomas are rare; enucleation/local excision + peripancreatic lymph node dissection may be considered.

SeeSurveillance(facing page)

VIPoma

Distal pancreatectomy +peripancreatic lymphnode dissection +splenectomy

•

•

Stabilize with IVfluids andoctreotideCorrect electrolyteimbalance(K , Mg , HCO )

j

+ 2+3-

Locoregionaldisease

Metastaticdisease


Headp

Distalp


Recommended:ElectrolytesVIP levelsMultiphasic C

As appropriate:Chromogranin A(category 3)Octreoscan

••• T or

MRI

•

•

SURVEILLANCEq,r RECURRENT DISEASE

Locoregionaldisease

Resectable Resection

Unresectable

Distantmetastases

See Management ofDistant

Metastases

LocoregionalUnresectable Disease and/or

(page 736)

MANAGEMENT OF RECURRENT DISEASEf

cf

r

See Stains and Laboratory Studies Potentially Indicated in the Workup of Neuroendocrine Tumors (page 744).See Surgical Principles for Management of Neuroendocrine Tumors (page 745).

Octreoscan and PET scan are not recommended for routine surveillance.qEarlier, if symptoms.

3-12 mo postresection:H&P and consider markers

T or MRI

•

•

from preoperativeevaluation as indicatedMultiphasic C

c

> 1 y postresection:6-12 mo thereafter•••

H&P and consider markersImaging studies as clinicallyindicated

c

See Management of

DistantMetastases

LocoregionalUnresectable Diseaseand/or

(page 736)




735



CLINICALDIAGNOSIS

EVALUATIONb,c,d MANAGEMENT OF NONMETASTATIC DISEASE(If metastatic disease discovered,


bcdfg

j

p

See Principles of Pathology for Diagnosis and Reporting of Neuroendocrine Tumors (pages 742 and 743).See Stains and Laboratory Studies Potentially Indicated in the Workup of Neuroendocrine Tumors (page 744).Consider MEN1 family history for all patients with pancreatic neuroendocrine tumors.See Surgical Principles for Management of Neuroendocrine Tumors (page 745).Preoperative trivalent vaccine (i.e., pneumococcus, haemophilus influenzae b, and meningococcal group C) if considering surgery with possiblesplenectomy.

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 asneeded. Therapeutic levels of octreotide would not be expected to be reached for 10-14 d after LAR injection. Short-acting octreotide can be added tooctreotide LAR for rapid relief of symptoms or for breakthrough symptoms.Small (< 2 cm), peripheral VIPomas are rare; enucleation/local excision + peripancreatic lymph node dissection may be considered.

SeeSurveillance(facing page)

VIPoma

Distal pancreatectomy +peripancreatic lymphnode dissection +splenectomy

•

•

Stabilize with IVfluids andoctreotideCorrect electrolyteimbalance(K , Mg , HCO )

j

+ 2+3-

Locoregionaldisease

Metastaticdisease


Headp

Distalp


Recommended:ElectrolytesVIP levelsMultiphasic C

As appropriate:Chromogranin A(category 3)Octreoscan

••• T or

MRI

•

•

SURVEILLANCEq,r RECURRENT DISEASE

Locoregionaldisease

Resectable Resection

Unresectable

Distantmetastases

See Management ofDistant

Metastases

LocoregionalUnresectable Disease and/or

(page 736)

MANAGEMENT OF RECURRENT DISEASEf

cf

r

See Stains and Laboratory Studies Potentially Indicated in the Workup of Neuroendocrine Tumors (page 744).See Surgical Principles for Management of Neuroendocrine Tumors (page 745).

Octreoscan and PET scan are not recommended for routine surveillance.qEarlier, if symptoms.

3-12 mo postresection:H&P and consider markers

T or MRI

•

•

from preoperativeevaluation as indicatedMultiphasic C

c

> 1 y postresection:6-12 mo thereafter•••

H&P and consider markersImaging studies as clinicallyindicated

c

See Management of

DistantMetastases

LocoregionalUnresectable Diseaseand/or

(page 736)



736



MANAGEMENT OF LOCOREGIONAL UNRESECTABLE DISEASE AND/OR DISTANT METASTASESf

fs

tu

vw

See Surgical Principles for Management of Neuroendocrine Tumors (page 745).Staged or synchronous resection when possible. When performing staged pancreatoduodenectomy and liver resection, consider hepatectomy beforepancreatic resection in order to reduce risk of perihepatic sepsis. De Jong MC, Farnell MB, Sclabas G, et al. Liver-directed therapy for hepatic metastasesin patients undergoing pancreaticoduodenectomy: a dual-center analysis. Ann Surg 2010;252:142-148.

The following agents have been used: capecitabine, dacarbazine, doxorubicin, 5-FU, streptozocin, and temozolomide.Includes ablative techniques such as radiofrequency, microwave, and cryotherapy. There are no randomized clinical trials and prospective data for theseinterventions are limited, but data on their use are emerging.

Octreotide should be used with caution in patients with insulinoma as it may transiently worsen hypoglycemia (see discussion).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 asneeded. Therapeutic levels of octreotide would not be expected to be reached for 10-14 d after LAR injection. Short-acting octreotide can be added tooctreotide LAR for rapid relief of symptoms or for breakthrough symptoms. Octreotide can be used alone or in combination with other agents.

Asymptomatic, lowtumor burden, andstable disease

Observe with markers andscans every 3-12 mo

SymptomaticorClinically significanttumor burdenorClinically significantprogressive disease

Everolimus (10 mg/d)orSunitinib (37.5 mg/d)orCytotoxic chemotherapyorHepatic regional therapy (arterial embolization,chemoembolization, radioembolization[category 2B])orCytoreductive surgery/ablative therapy(category 2B)orConsider octreotide if not already receiving(category 2B)

t

u

v,w

If completeresection possible Resect metastases + primarys

Locoregionalunresectable diseaseand/orDistant metastases

Clinically significantprogressive disease,see below


Manage clinically significantsymptoms as appropriate(pages 732-734)

CLINICALPRESENTATION

EVALUATIONa,b

Adrenalglandtumoronimaging

History ofcurrent malignancywith risk of orsuspicion of adrenalmetastasis

prior or

CLINICAL DIAGNOSIS

Hyperaldosteronism

Cushing syndrome

Nonfunctioning tumor

PheochromocytomaElevated plasmafreemetanephrines orconfirmedelevation of urinemetanephrines

•

f

andcatecholamines

SeePheochromocytomaGuidelines(PHEO-1; availableonline, in theseguidelines, atNCCN.org)

See Additional Evaluation (page 738)

SeePrimaryTreatment(page 738)

See PrimaryTreatment(page 739)


abc

See Principles of Pathology for Diagnosis and Reporting of Neuroendocrine Tumors (pages 742 and 743).See Immunohistochemistry and Laboratory Studies Potentially Indicated in the Workup of Neuroendocrine Tumors (page 744).If unenhanced is < +10 HU, then the tumor is probably benign. If unenhanced is > +10 HU, then use enhanced and washout. 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. Adrenalmasses: characterization with combined unenhanced and delayed enhanced CT. Radiology 2002;222:629-633.)

• HyperaldosteronismPlasma aldosterone, reninactivityElectrolytes

e

• Cushing syndromeSerum ACTH, cortisol, andDHEA-s with one of thefollowing:

24-h urine for free cortisol

Overnight 1 mgdexamethasonesuppression test with8 am plasma cortisolRepeated (2-3) midnightsalivary cortisols

• PheochromocytomaFractionated plasma-freemetanephrinesFractionated urinemetanephrines andcatecholamines forconfirmation

f

Functionalevaluation

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

cd

No history of

currentmalignancy

prior or

Morphologicevaluation

and

de

f

Chemical shift imaging showing signal drop out.If hyperaldosteronism, confirmatory testing with saline suppression test or salt loading test may be indicated. Funder JW, Carey RM, FardellaC, et al. Case detection, diagnosis, and treatment of patients with primary aldosteronism: an endocrine society clinical practice guideline. JClin Endocrinol Metab 2008;93:3266-3281.Review concurrent medication(s) for those that may interfere with plasma metanephrines evaluation. Elevations that are 4 times above theupper limit of normal are diagnostic.




737



MANAGEMENT OF LOCOREGIONAL UNRESECTABLE DISEASE AND/OR DISTANT METASTASESf

fs

tu

vw

See Surgical Principles for Management of Neuroendocrine Tumors (page 745).Staged or synchronous resection when possible. When performing staged pancreatoduodenectomy and liver resection, consider hepatectomy beforepancreatic resection in order to reduce risk of perihepatic sepsis. De Jong MC, Farnell MB, Sclabas G, et al. Liver-directed therapy for hepatic metastasesin patients undergoing pancreaticoduodenectomy: a dual-center analysis. Ann Surg 2010;252:142-148.

The following agents have been used: capecitabine, dacarbazine, doxorubicin, 5-FU, streptozocin, and temozolomide.Includes ablative techniques such as radiofrequency, microwave, and cryotherapy. There are no randomized clinical trials and prospective data for theseinterventions are limited, but data on their use are emerging.

Octreotide should be used with caution in patients with insulinoma as it may transiently worsen hypoglycemia (see discussion).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 asneeded. Therapeutic levels of octreotide would not be expected to be reached for 10-14 d after LAR injection. Short-acting octreotide can be added tooctreotide LAR for rapid relief of symptoms or for breakthrough symptoms. Octreotide can be used alone or in combination with other agents.

Asymptomatic, lowtumor burden, andstable disease

Observe with markers andscans every 3-12 mo

SymptomaticorClinically significanttumor burdenorClinically significantprogressive disease

Everolimus (10 mg/d)orSunitinib (37.5 mg/d)orCytotoxic chemotherapyorHepatic regional therapy (arterial embolization,chemoembolization, radioembolization[category 2B])orCytoreductive surgery/ablative therapy(category 2B)orConsider octreotide if not already receiving(category 2B)

t

u

v,w

If completeresection possible Resect metastases + primarys

Locoregionalunresectable diseaseand/orDistant metastases



Manage clinically significantsymptoms as appropriate(pages 732-734)

CLINICALPRESENTATION

EVALUATIONa,b

Adrenalglandtumoronimaging

History ofcurrent malignancywith risk of orsuspicion of adrenalmetastasis

prior or

CLINICAL DIAGNOSIS

Hyperaldosteronism

Cushing syndrome

Nonfunctioning tumor

PheochromocytomaElevated plasmafreemetanephrines orconfirmedelevation of urinemetanephrines

•

f

andcatecholamines

SeePheochromocytomaGuidelines(PHEO-1; availableonline, in theseguidelines, atNCCN.org)

See Additional Evaluation (page 738)

SeePrimaryTreatment(page 738)



abc

See Principles of Pathology for Diagnosis and Reporting of Neuroendocrine Tumors (pages 742 and 743).See Immunohistochemistry and Laboratory Studies Potentially Indicated in the Workup of Neuroendocrine Tumors (page 744).If unenhanced is < +10 HU, then the tumor is probably benign. If unenhanced is > +10 HU, then use enhanced and washout. 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. Adrenalmasses: characterization with combined unenhanced and delayed enhanced CT. Radiology 2002;222:629-633.)

• HyperaldosteronismPlasma aldosterone, reninactivityElectrolytes

e

• Cushing syndromeSerum ACTH, cortisol, andDHEA-s with one of thefollowing:

24-h urine for free cortisol

Overnight 1 mgdexamethasonesuppression test with8 am plasma cortisolRepeated (2-3) midnightsalivary cortisols

• PheochromocytomaFractionated plasma-freemetanephrinesFractionated urinemetanephrines andcatecholamines forconfirmation

f

Functionalevaluation

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

cd

No history of

currentmalignancy

prior or

Morphologicevaluation

and

de

f

Chemical shift imaging showing signal drop out.If hyperaldosteronism, confirmatory testing with saline suppression test or salt loading test may be indicated. Funder JW, Carey RM, FardellaC, et al. Case detection, diagnosis, and treatment of patients with primary aldosteronism: an endocrine society clinical practice guideline. JClin Endocrinol Metab 2008;93:3266-3281.Review concurrent medication(s) for those that may interfere with plasma metanephrines evaluation. Elevations that are 4 times above theupper limit of normal are diagnostic.

ADRENAL GLAND TUMORS


738



Image-guidedneedle biopsy

CLINICAL DIAGNOSIS

Hyperaldosteronism,suspect benign

Hyperaldosteronism,suspect malignantg

ADDITIONAL EVALUATION

Not a surgicalcandidate

Surgical candidate Consider adrenal veinsampling for aldosteronei

PRIMARY TREATMENTj

Unilateralaldosteroneproduction

Adrenalectomy,laparoscopic preferred

Bilateralaldosteroneproduction

Medical management ofhypertension andhypokalemia withspironolactone or eplerenone

Metastasis from othersite discovered

Adrenal cortical tissue

See NCCN disease-specific treatmentguidelines, available atNCCN.org

See Evaluation (page 737)

Open adrenalectomy

gSuspect malignancies with irregular/inhomogeneous morphology, or secretion of more than one hormone.lipid-poor, do not washout, tumor > 3 cm,

Cortisol measurement in the catheterization samples is used to confirm proper catheter placement.

h

i

Can proceed with adrenal biopsy if the clinical suspicion for pheochromocytoma is low and if plasma metanephrines are less than 2 times the upper limitof normal.

Adrenal vein sampling is considered the standard for distinguishing single unilateral adenomas from bilateral hyperplasia. CT imaging is not alwaysreliable. Some NCCN institutions recommend sampling in all cases of primary aldosteronism. However, it may be reasonable to exclude adrenal veinsampling in patients aged < 40 y.

jSee Surgical Principles for Management of Neuroendocrine Tumors (page 745).

Rule outpheochromocytomah

History ofcurrent malignancy withrisk of or suspicion ofadrenal metastasis

prior or

ACTH-independentCushingsyndrome

ACTH-dependentCushing syndrome

CLINICALDIAGNOSIS

ADDITIONALEVALUATION

PRIMARY TREATMENTj

Tumor < 5 cm,contralateral glandnormal,circumscribed tumor

Tumor < 5 cm,contralateralgland abnormal

Tumor > 5 cm orinhomogeneous,irregular margins,local invasion

Imaging of chest,abdomen, andpelvis to evaluatefor metastases andlocal invasion

Assess and treat forpituitary ACTH productionor ectopic sources of ACTHproduction

••

Adrenalectomy, laparoscopic preferredPostoperative corticosteroid supplementationuntil hypothalamic-pituitary-adrenal (HPA) axisrecovery

Adrenalveinsamplingfor cortisol

Asymmetriccortisolproduction

Symmetriccortisolproduction

•

•

Unilateral adrenalectomy with removal of mostactive side, laparoscopic preferredPostoperative corticosteroid supplementationuntil HPA axis recovery

Medical management ofhypercortisolism frompresumed multinodularhyperplasia of the adrenalwith ketoconazole, mitotanek

Bilateraladrenalectomy ifsevere Cushingsyndrome andmedical failure

Adrenalectomyfor suspectedcarcinoma(laparoscopicgenerally notappropriate)

l

Apparent localizeddisease, locallyresectabledisease, orregionallyadvanced disease See

AdrenalCarcinoma(page 741)

jSee Surgical Principles for Management of Neuroendocrine Tumors (page 745).kConsider octreotide if Octreoscan is positive.lMay require removal of adjacent structures (i.e., liver, kidney, pancreas, spleen, diaphragm) for complete resection.

If ectopic, remove primary tumor if possibleorIf primary tumor unresectable, then bilaterallaparoscopic adrenalectomy or medicalmanagement (as described above)

Metastatic disease




739



Image-guidedneedle biopsy

CLINICAL DIAGNOSIS

Hyperaldosteronism,suspect benign

Hyperaldosteronism,suspect malignantg

ADDITIONAL EVALUATION

Not a surgicalcandidate

Surgical candidate Consider adrenal veinsampling for aldosteronei

PRIMARY TREATMENTj

Unilateralaldosteroneproduction

Adrenalectomy,laparoscopic preferred

Bilateralaldosteroneproduction

Medical management ofhypertension andhypokalemia withspironolactone or eplerenone

Metastasis from othersite discovered

Adrenal cortical tissue

See NCCN disease-specific treatmentguidelines, available atNCCN.org

See Evaluation (page 737)

Open adrenalectomy

gSuspect malignancies with irregular/inhomogeneous morphology, or secretion of more than one hormone.lipid-poor, do not washout, tumor > 3 cm,

Cortisol measurement in the catheterization samples is used to confirm proper catheter placement.

h

i

Can proceed with adrenal biopsy if the clinical suspicion for pheochromocytoma is low and if plasma metanephrines are less than 2 times the upper limitof normal.

Adrenal vein sampling is considered the standard for distinguishing single unilateral adenomas from bilateral hyperplasia. CT imaging is not alwaysreliable. Some NCCN institutions recommend sampling in all cases of primary aldosteronism. However, it may be reasonable to exclude adrenal veinsampling in patients aged < 40 y.

jSee Surgical Principles for Management of Neuroendocrine Tumors (page 745).

Rule outpheochromocytomah

History ofcurrent malignancy withrisk of or suspicion ofadrenal metastasis

prior or

ACTH-independentCushingsyndrome

ACTH-dependentCushing syndrome

CLINICALDIAGNOSIS

ADDITIONALEVALUATION

PRIMARY TREATMENTj

Tumor < 5 cm,contralateral glandnormal,circumscribed tumor

Tumor < 5 cm,contralateralgland abnormal

Tumor > 5 cm orinhomogeneous,irregular margins,local invasion

Imaging of chest,abdomen, andpelvis to evaluatefor metastases andlocal invasion

Assess and treat forpituitary ACTH productionor ectopic sources of ACTHproduction

••

Adrenalectomy, laparoscopic preferredPostoperative corticosteroid supplementationuntil hypothalamic-pituitary-adrenal (HPA) axisrecovery

Adrenalveinsamplingfor cortisol

Asymmetriccortisolproduction

Symmetriccortisolproduction

•

•

Unilateral adrenalectomy with removal of mostactive side, laparoscopic preferredPostoperative corticosteroid supplementationuntil HPA axis recovery

Medical management ofhypercortisolism frompresumed multinodularhyperplasia of the adrenalwith ketoconazole, mitotanek

Bilateraladrenalectomy ifsevere Cushingsyndrome andmedical failure

Adrenalectomyfor suspectedcarcinoma(laparoscopicgenerally notappropriate)

l

Apparent localizeddisease, locallyresectabledisease, orregionallyadvanced disease See

AdrenalCarcinoma(page 741)

jSee Surgical Principles for Management of Neuroendocrine Tumors (page 745).kConsider octreotide if Octreoscan is positive.lMay require removal of adjacent structures (i.e., liver, kidney, pancreas, spleen, diaphragm) for complete resection.

If ectopic, remove primary tumor if possibleorIf primary tumor unresectable, then bilaterallaparoscopic adrenalectomy or medicalmanagement (as described above)

Metastatic disease



740



Nonfunctioningtumor

CLINICAL DIAGNOSIS ADDITIONAL EVALUATION PRIMARY TREATMENTj

Benign-appearingadenoma (< 4 cm) by CTor MRI criteriaorMyelolipoma byradiographic features (anysize) without symptoms

cd

Suspectedcarcinoma

Repeat imagingin 6-12 mo

Unchanged

Enlarging(> 1 cm in 1 y)

No further follow-up

Consider adrenalectomyorShort-interval follow-up

Benign-appearingadenoma of intermediatesize (4-6 cm) by CT orMRI criteria

cd


Unchanged


Repeat imaging in 6-12 mo

c

djmn

If unenhanced is < +10 HU, then the tumor is probably benign. If unenhanced is > +10 HU, then use enhanced and wash-out. If > 60% washout 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 withcombined unenhanced and delayed enhanced CT. Radiology 2002;222:629-633.)Chemical shift imaging showing signal drop out.

See Surgical Principles for Management of Neuroendocrine Tumors (page 745).Aggressive features such as inhomogeneous, irregular margins, and local invasion.If size is resectable by laparoscopy, may explore laparoscopically with planned conversion for evidence of local invasion.

Imaging of chest, abdomen, andpelvis to evaluate for metastasesand local invasion

See AdrenalCarcinoma(page 741)

Intermediate size tumor (4-6 cm)with aggressive featuresm

Large tumor (> 6 cm)with aggressivefeatures

Adrenalectomy forsuspected carcinoman


Adrenalcarcinomao

Localizeddisease

Metastaticdisease

Low-gradetumor

Low-gradetumor

High-gradetumor

High-gradetumor

Consider imaging every 3-6mo and biomarkers (if tumorinitially functional)

FOLLOW-UPTREATMENTj

• Consider externalbeam RT to tumorbedConsider adjuvantmitotane therapy(category 3)

Imaging every 3-6 mo andbiomarkers (if tumorinitially functional)

Consider observation with imaging every 3 mo andbiomarkers (if tumor initially functional)Consider resection of primary tumor and metastases if> 90% removable, particularly if functionalConsider systemic therapy, preferably in clinical trial

orStreptozocin ± mitotane

orMitotane monotherapy

Cisplatin or carboplatin + etoposide ± doxorubicin ±mitotane

q

Consider systemic therapy, preferably in clinical trialCisplatin or carboplatin + etoposide ± doxorubicin ±mitotane



q

ADRENAL CARCINOMA

jlopq

See Surgical Principles for Management of Neuroendocrine Tumors (page 745).May require removal of adjacent structures (i.e., liver, kidney, pancreas, spleen, diaphragm) for complete resection.Cross-sectional imaging to stage disease.Increased risk for local recurrence and peritoneal spread when done laparoscopically.Monitor mitotane blood levels. Some institutions recommend target levels of 14-20 mcg/mL if tolerated. Steady-state levels may be reachedseveral months after initiation of mitotane. Mitotane therapy requires steroid replacement therapy.

• Resect tumor andadjacent lymphnodes

Openadrenalectomyrecommendedl,p

Consider adjuvantmitotane therapy(category 3)

•

•

•

•➤

➤

➤

➤

➤

➤

➤




741



Nonfunctioningtumor

CLINICAL DIAGNOSIS ADDITIONAL EVALUATION PRIMARY TREATMENTj

Benign-appearingadenoma (< 4 cm) by CTor MRI criteriaorMyelolipoma byradiographic features (anysize) without symptoms

cd

Suspectedcarcinoma


Unchanged


No further follow-up

Consider adrenalectomyorShort-interval follow-up

Benign-appearingadenoma of intermediatesize (4-6 cm) by CT orMRI criteria

cd


Unchanged


Repeat imaging in 6-12 mo

c

djmn

If unenhanced is < +10 HU, then the tumor is probably benign. If unenhanced is > +10 HU, then use enhanced and wash-out. If > 60% washout 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 withcombined unenhanced and delayed enhanced CT. Radiology 2002;222:629-633.)Chemical shift imaging showing signal drop out.

See Surgical Principles for Management of Neuroendocrine Tumors (page 745).Aggressive features such as inhomogeneous, irregular margins, and local invasion.If size is resectable by laparoscopy, may explore laparoscopically with planned conversion for evidence of local invasion.

Imaging of chest, abdomen, andpelvis to evaluate for metastasesand local invasion


Intermediate size tumor (4-6 cm)with aggressive featuresm

Large tumor (> 6 cm)with aggressivefeatures

Adrenalectomy forsuspected carcinoman


Adrenalcarcinomao

Localizeddisease

Metastaticdisease

Low-gradetumor

Low-gradetumor

High-gradetumor

High-gradetumor

Consider imaging every 3-6mo and biomarkers (if tumorinitially functional)

FOLLOW-UPTREATMENTj

• Consider externalbeam RT to tumorbedConsider adjuvantmitotane therapy(category 3)

Imaging every 3-6 mo andbiomarkers (if tumorinitially functional)

Consider observation with imaging every 3 mo andbiomarkers (if tumor initially functional)Consider resection of primary tumor and metastases if> 90% removable, particularly if functionalConsider systemic therapy, preferably in clinical trial



Cisplatin or carboplatin + etoposide ± doxorubicin ±mitotane

q

Consider systemic therapy, preferably in clinical trialCisplatin or carboplatin + etoposide ± doxorubicin ±mitotane



q

ADRENAL CARCINOMA

jlopq

See Surgical Principles for Management of Neuroendocrine Tumors (page 745).May require removal of adjacent structures (i.e., liver, kidney, pancreas, spleen, diaphragm) for complete resection.Cross-sectional imaging to stage disease.Increased risk for local recurrence and peritoneal spread when done laparoscopically.Monitor mitotane blood levels. Some institutions recommend target levels of 14-20 mcg/mL if tolerated. Steady-state levels may be reachedseveral months after initiation of mitotane. Mitotane therapy requires steroid replacement therapy.

• Resect tumor andadjacent lymphnodes

Openadrenalectomyrecommendedl,p

Consider adjuvantmitotane therapy(category 3)

•

•

•

•➤

➤

➤

➤

➤

➤

➤



742



Required information:Anatomic site of tumor

Size of tumorPresence of multicentric diseasePresence of vascular invasionPresence of perineural invasion

Lymph node metastases to include the number of positive nodes and total number of nodes examinedMargin status (report as positive or negative)Assign TNM stage per the AJCC TNM system (

)

Optional information:Ki-67 labeling indexImmunohistochemical staining for general neuroendocrine markersImmunohistochemical staining for specific peptide markersPresence of nonischemic tumor necrosisPresence of unusual histologic features (e.g., oncocytic, clear cell, gland forming)Exact distance of tumor to margin(s) if less than 0.5 cmBackground pathology of organ (i.e., PanIN, ECL cell hyperplasia)

DiagnosisGrade (see Table 1)Mitotic rate

Presence of other pathologic components (e.g., non-neuroendocrine components)

See Staging, in these guidelines, available online, atNCCN.org [ST-1–ST-4]

Grade Mitotic Count (per 10 HPF) Ki-67 Index (%) Differentiation

Low-grade (G1)

Intermediate-grade (G2)

High-grade (G3)

< 2 3

2-20 3-20

> 20 > 20

Well-differentiated NET


Poorly differentiatedneuroendocrine carcinoma

Table 1

PRINCIPLES OF PATHOLOGY FOR DIAGNOSIS AND REPORTING OF NEUROENDOCRINE TUMORS PRINCIPLES OF PATHOLOGY FOR DIAGNOSIS AND REPORTING OF NEUROENDOCRINE TUMORS (Cont.)

Functional status

Immunohistochemistry and other ancillary technique

Functional status of a NET need not be included in the pathology report. However, if a specific clinical situation suggests thatcorrelation with histologic evidence of peptide hormone may be helpful, then histochemical or immunohistochemical studiesmay be performed and included in the report. Functioning NETs should have the same pathologic diagnosis as thenonfunctioning NETs at the same anatomic site, because the functional status is based on clinical findings and should notalter the pathologic diagnosis. However, a note may be added with additional information of the functional status of a tumor.

Immunohistochemistry and other ancillary techniques may not be required to diagnose well-differentiated NETs whensufficient tumor material is available for histologic review. Specific markers that may be used to establish neuroendocrinedifferentiation include chromogranin A, synaptophysin, and CD56, although the last marker has proven to be lessspecific. In less well-differentiated tumors or tumors of unknown origin, it may be helpful (or required in the case of poorlydifferentiated neuroendocrine carcinomas) to use immunohistochemistry panels. Although not entirely specific, lung origin isfavored by thyroid transcription factor 1 (TTF-1), intestinal or pancreatic origin by CDX2, and pancreatic origin by Isl1.

Many classification schemes have been proposed for NETs. The most recent WHO classification systemepresents an attempt to unify European and American approaches. Multiple site-specific grading systems also exist; and

therefore, the specific classification and grading scheme being used should be reported in parentheses after the diagnosis toavoid confusion with overlapping terminology and criteria used in other systems. The raw data used to derive the gradeshould 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 isinappropriate for pathology reporting.

Mitotic count should be based on counting mitoses in at least 40 fields at 40x magnification in the areas of highest mitoticdensity, and should be reported as the number of mitoses per 10 HPF or per 2 mm . Ten HPF is equivalent to 2 mm on manymicroscopes, although the field size may vary slightly. Note that in cases where an accurate mitotic rate is precluded byinadequate tissue, such as in small biopsy samples, the Ki-67 index is the preferred method of establishing the proliferativerate.

Ki-67 index is reported as the percentage of positive tumor cells in the area of highest nuclear labeling. Althoughrecommendations have been to count 2000 tumor cells to determine the Ki-67 index, this is not practical in routine clinicalpractice. It is therefore currently acceptable to estimate the labeling index, despite the recognition that estimation is subject tolimitations in reproducibility. If both mitotic rate and Ki-67 index are used and these are discordant, it is currentlyrecommended that the higher grade be assigned.

recently

is suggested andr

1

2-87

1,9

2 23

910

Classification and grade

Mitotic rate

Ki-67 index

1

2

3

4

5

6

789

10

Klimstra DS, Modlin IR, Coppola D, et al. The pathologic classification of neuroendocrine tumors: a review of nomenclature, grading andstaging systems. Pancreas 2010;39:707-712.

Kloppel G, Perren A, Heitz PU. The gastroenteropancreatic neuroendocrine cell system and its tumours: the WHO classification. Ann N YAcad Sci 2004;1014:13-27.

Rindi 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.

Strosberg JR, Coppola D, Klimstra DS, et al. The NANETS consensus guidelines for the diagnosis and management of poorlydifferentiated (high-grade) extrapulmonary neuroendocrine carcinomas. Pancreas 2010;39:799-800.

Boudreaux JP, Klimstra DS, Hassan MM, et al. The NANETS consensus guideline for the diagnosis and management of neuroendocrinetumors: well-differentiated neuroendocrine tumors of the jejunum, ileum, appendix, and cecum. Pancreas 2010;39:753-766.

Anthony LB, Strosberg JR, Klimstra DS, et al. The NANETS consensus guidelines for the diagnosis and management of gastrointestinalneuroendocrine tumors (NETs): well-differentiated NETs of the distal colon and rectum. Pancreas 2010;39:767-774.

Bosman F, Carneiro F, Hruban R, Theise ND. WHO Classification of Tumours of the Digestive System. Lyon, France: IARC Press; 2010.Oberg K, Castellano D. Current knowledge on diagnosis and staging of neuroendocrine tumors. Cancer Metastasis Rev 2011;30S:S3-7.Klimstra DS, Modlin IR, Adsay NV, et al. Pathology reporting of neuroendocrine tumors: application of the Delphic consensus process tothe development of a minimum pathology data set. Am J Surg Pathol 2010;34:300-313.Rindi G, Bordi C, La Rosa S, et al. Gastroenteropancreatic (neuro)endocrine neoplasms: the histology report. Dig Liver Dis 2011;43S:S356-360.

REFERENCES

See additional information on facing page

Abbreviations: HPF, high-power field; NET neuroendocrine tumor.



743



Required information:Anatomic site of tumor

Size of tumorPresence of multicentric diseasePresence of vascular invasionPresence of perineural invasion

Lymph node metastases to include the number of positive nodes and total number of nodes examinedMargin status (report as positive or negative)Assign TNM stage per the AJCC TNM system (

)

Optional information:Ki-67 labeling indexImmunohistochemical staining for general neuroendocrine markersImmunohistochemical staining for specific peptide markersPresence of nonischemic tumor necrosisPresence of unusual histologic features (e.g., oncocytic, clear cell, gland forming)Exact distance of tumor to margin(s) if less than 0.5 cmBackground pathology of organ (i.e., PanIN, ECL cell hyperplasia)

DiagnosisGrade (see Table 1)Mitotic rate

Presence of other pathologic components (e.g., non-neuroendocrine components)

See Staging, in these guidelines, available online, atNCCN.org [ST-1–ST-4]

Grade Mitotic Count (per 10 HPF) Ki-67 Index (%) Differentiation

Low-grade (G1)

Intermediate-grade (G2)

High-grade (G3)

< 2 3

2-20 3-20

> 20 > 20



Poorly differentiatedneuroendocrine carcinoma

Table 1

PRINCIPLES OF PATHOLOGY FOR DIAGNOSIS AND REPORTING OF NEUROENDOCRINE TUMORS PRINCIPLES OF PATHOLOGY FOR DIAGNOSIS AND REPORTING OF NEUROENDOCRINE TUMORS (Cont.)

Functional status

Immunohistochemistry and other ancillary technique

Functional status of a NET need not be included in the pathology report. However, if a specific clinical situation suggests thatcorrelation with histologic evidence of peptide hormone may be helpful, then histochemical or immunohistochemical studiesmay be performed and included in the report. Functioning NETs should have the same pathologic diagnosis as thenonfunctioning NETs at the same anatomic site, because the functional status is based on clinical findings and should notalter the pathologic diagnosis. However, a note may be added with additional information of the functional status of a tumor.

Immunohistochemistry and other ancillary techniques may not be required to diagnose well-differentiated NETs whensufficient tumor material is available for histologic review. Specific markers that may be used to establish neuroendocrinedifferentiation include chromogranin A, synaptophysin, and CD56, although the last marker has proven to be lessspecific. In less well-differentiated tumors or tumors of unknown origin, it may be helpful (or required in the case of poorlydifferentiated neuroendocrine carcinomas) to use immunohistochemistry panels. Although not entirely specific, lung origin isfavored by thyroid transcription factor 1 (TTF-1), intestinal or pancreatic origin by CDX2, and pancreatic origin by Isl1.

Many classification schemes have been proposed for NETs. The most recent WHO classification systemepresents an attempt to unify European and American approaches. Multiple site-specific grading systems also exist; and

therefore, the specific classification and grading scheme being used should be reported in parentheses after the diagnosis toavoid confusion with overlapping terminology and criteria used in other systems. The raw data used to derive the gradeshould 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 isinappropriate for pathology reporting.

Mitotic count should be based on counting mitoses in at least 40 fields at 40x magnification in the areas of highest mitoticdensity, and should be reported as the number of mitoses per 10 HPF or per 2 mm . Ten HPF is equivalent to 2 mm on manymicroscopes, although the field size may vary slightly. Note that in cases where an accurate mitotic rate is precluded byinadequate tissue, such as in small biopsy samples, the Ki-67 index is the preferred method of establishing the proliferativerate.

Ki-67 index is reported as the percentage of positive tumor cells in the area of highest nuclear labeling. Althoughrecommendations have been to count 2000 tumor cells to determine the Ki-67 index, this is not practical in routine clinicalpractice. It is therefore currently acceptable to estimate the labeling index, despite the recognition that estimation is subject tolimitations in reproducibility. If both mitotic rate and Ki-67 index are used and these are discordant, it is currentlyrecommended that the higher grade be assigned.

recently

is suggested andr

1

2-87

1,9

2 23

910

Classification and grade

Mitotic rate

Ki-67 index

1

2

3

4

5

6

789

10

Klimstra DS, Modlin IR, Coppola D, et al. The pathologic classification of neuroendocrine tumors: a review of nomenclature, grading andstaging systems. Pancreas 2010;39:707-712.

Kloppel G, Perren A, Heitz PU. The gastroenteropancreatic neuroendocrine cell system and its tumours: the WHO classification. Ann N YAcad Sci 2004;1014:13-27.

Rindi 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.

Strosberg JR, Coppola D, Klimstra DS, et al. The NANETS consensus guidelines for the diagnosis and management of poorlydifferentiated (high-grade) extrapulmonary neuroendocrine carcinomas. Pancreas 2010;39:799-800.

Boudreaux JP, Klimstra DS, Hassan MM, et al. The NANETS consensus guideline for the diagnosis and management of neuroendocrinetumors: well-differentiated neuroendocrine tumors of the jejunum, ileum, appendix, and cecum. Pancreas 2010;39:753-766.

Anthony LB, Strosberg JR, Klimstra DS, et al. The NANETS consensus guidelines for the diagnosis and management of gastrointestinalneuroendocrine tumors (NETs): well-differentiated NETs of the distal colon and rectum. Pancreas 2010;39:767-774.

Bosman F, Carneiro F, Hruban R, Theise ND. WHO Classification of Tumours of the Digestive System. Lyon, France: IARC Press; 2010.Oberg K, Castellano D. Current knowledge on diagnosis and staging of neuroendocrine tumors. Cancer Metastasis Rev 2011;30S:S3-7.Klimstra DS, Modlin IR, Adsay NV, et al. Pathology reporting of neuroendocrine tumors: application of the Delphic consensus process tothe development of a minimum pathology data set. Am J Surg Pathol 2010;34:300-313.Rindi G, Bordi C, La Rosa S, et al. Gastroenteropancreatic (neuro)endocrine neoplasms: the histology report. Dig Liver Dis 2011;43S:S356-360.

REFERENCES

See additional information on facing page

Abbreviations: HPF, high-power field; NET neuroendocrine tumor.


744



IMMUNOHISTOCHEMICAL AND LABORATORY STUDIES POTENTIALLY INDICATED INTHE WORKUP OF NEUROENDOCRINE TUMORS1

HORMONE-RELATED STUDIES (blood markers)

Chromogranin A (category 3)

Carcinoid tumors5-HIAA (24-h urine)Chromogranin A (category 3)

pancNET

IMMUNOHISTOCHEMICAL STUDIES2

Chromogranin ASynaptophysinCytokeratinKi-67 (MIB-1) and/or mitotic rate

Metanephrines (plasma and urine)Catecholamines (urine)Dopamine (urine) (optional)

PituitaryGrowth hormone/IGF-1ProlactinLH/FSHTSHAlpha subunitsACTH

Ectopic hormonesACTHGRHGHRH

Pheochromocytoma/paraganglioma

Chromogranin A: Impaired renal or hepatic function or treatment with proton pump inhibitors may result in artifactual elevations.Urine 5-HIAA

GastrinVIP

: 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 smokingfor this time period.

: 8-h fast.: 8-h fast.

1For most of the blood studies, an 8-h fast is rderingphysicians should be aware that s

generally recommended in addition to certain dietary adjustments depending on the test ordered. Oome medications can also affect the results, but medications do not necessarily need to be discontinued if they are

medically necessary. Below are examples:

2Immunohistochemistry and other ancillary techniques may not be required to diagnose well-differentiated NETs when sufficient tumor material is available forhistologic review. Specific markers that may be used to establish neuroendocrine differentiation include chromogranin A, synaptophysin, and CD56,although the last marker has recently proven to be less specific. In less well-differentiated tumors or tumors of unknown origin, it may be helpful (or requiredin the case of poorly differentiated neuroendocrine carcinomas) to use immunohistochemistry panels. Although not entirely specific, lung origin is favored bythyroid transcription factor 1 (TTF-1), intestinal or pancreatic origin by CDX2, and pancreatic origin by Isl1.

CalcitoninPTH-related peptide

GastrinomaGastrin

InsulinomaProinsulinInsulin/glucose ratioC-peptide

VIPomaVIP

GlucagonomaGlucagonBlood glucoseCBC

Other pancreasSomatostatinPancreatic polypeptide

�

SURGICAL PRINCIPLES FOR MANAGEMENT OF NEUROENDOCRINE TUMORS

Patients with localized pancNETs should be resected. Exceptions include patients with other life-limiting comorbidities,high surgical risk, or widely metastatic disease. Peripheral insulinomas and small (< 2 cm), nonfunctional tumors arecandidates for open or laparoscopic enucleation/local resection or spleen-preserving distal pancreatectomy. Virtually allinsulinomas should be resected regardless of size because of the metabolic (hypoglycemic) complications. NonfunctionalpancNETs 1-2 cm in size have a small (7%-26%) but measurable risk of lymph node metastases; therefore, lymph noderesection should be considered.Resection for larger (> 2 cm) or malignant-appearing nonfunctional and functional pancNETs (i.e., glucagonoma, VIPoma,somatistatinoma) should include total removal of the tumor with negative margins (including adjacent organs) and regionallymph nodes. Tumors of the head are generally treated with (Whipple procedure); tumors of thebody and tail are treated with distal pancreatectomy and splenectomy or spleen-preserving surgery.Surgical treatment of pancNETs in patients with MEN1 is not well defined. Gastrinomas, nonfunctioning pancNETs, andinsulinomas are common. Resection of dominant tumors (> 2-2.5 cm) helps symptom management (insulinoma) and maydecrease the risk of developing metastatic disease (gastrinoma).Distal pancreatectomy with enucleation of tumors from the head of the pancreas is recommended for MEN1insulinoma. Duodenotomy, excision of usually multiple tumors, and lymph node resection are recommended for patientswith MEN1 gastrinoma. Enucleation or a Whipple procedure is recommended for gastrinomas in the head of the pancreas.Resection of gastrointestinal carcinoid should include both adequate regional lymph node resection (including all palpabledisease 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 hasregressed 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 subtotalresection of a large proportion of the tumor (typically > 90%); however, experienced judgment is required formanagement of patients with an unresectable tumor and/or distant metastases. Planned cytoreductive, incomplete (R2)resection of advanced disease in patients with asymptomatic or nonfunctional 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.

Octreotide therapy should be administered parenterally prior to induction of anesthesia in patients with functional carcinoidtumors to prevent carcinoid crisis.

In general, laparoscopic resection is preferable for patients suspected to have small (< 6 cm), benign, functional adrenaltumors. An open exploration is recommended for tumors that have a high risk of being malignant.

pancreatoduodenectomy

Liver-directed therapies (e.g., liver resection, thermal ablation, chemoembolization) for hepatic metastases from NETsfollowing pancreatoduodenectomy are associated with increased risk for perihepatic sepsis and liver abscess.

All patients who might require splenectomy should receive preoperative trivalent vaccine (i.e., pneumococcus,haemophilus influenzae b, meningococcal group C).

patients with

➤

➤

➤

➤

➤

➤

➤

➤

➤

➤

➤

➤

➤

➤

➤

➤

➤

➤

➤

➤

➤

➤

➤

➤

➤

➤



745



IMMUNOHISTOCHEMICAL AND LABORATORY STUDIES POTENTIALLY INDICATED INTHE WORKUP OF NEUROENDOCRINE TUMORS1

HORMONE-RELATED STUDIES (blood markers)

Chromogranin A (category 3)

Carcinoid tumors5-HIAA (24-h urine)Chromogranin A (category 3)

pancNET

IMMUNOHISTOCHEMICAL STUDIES2

Chromogranin ASynaptophysinCytokeratinKi-67 (MIB-1) and/or mitotic rate

Metanephrines (plasma and urine)Catecholamines (urine)Dopamine (urine) (optional)

PituitaryGrowth hormone/IGF-1ProlactinLH/FSHTSHAlpha subunitsACTH

Ectopic hormonesACTHGRHGHRH

Pheochromocytoma/paraganglioma

Chromogranin A: Impaired renal or hepatic function or treatment with proton pump inhibitors may result in artifactual elevations.Urine 5-HIAA

GastrinVIP

: 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 smokingfor this time period.

: 8-h fast.: 8-h fast.

1For most of the blood studies, an 8-h fast is rderingphysicians should be aware that s

generally recommended in addition to certain dietary adjustments depending on the test ordered. Oome medications can also affect the results, but medications do not necessarily need to be discontinued if they are

medically necessary. Below are examples:

2Immunohistochemistry and other ancillary techniques may not be required to diagnose well-differentiated NETs when sufficient tumor material is available forhistologic review. Specific markers that may be used to establish neuroendocrine differentiation include chromogranin A, synaptophysin, and CD56,although the last marker has recently proven to be less specific. In less well-differentiated tumors or tumors of unknown origin, it may be helpful (or requiredin the case of poorly differentiated neuroendocrine carcinomas) to use immunohistochemistry panels. Although not entirely specific, lung origin is favored bythyroid transcription factor 1 (TTF-1), intestinal or pancreatic origin by CDX2, and pancreatic origin by Isl1.

CalcitoninPTH-related peptide

GastrinomaGastrin

InsulinomaProinsulinInsulin/glucose ratioC-peptide

VIPomaVIP

GlucagonomaGlucagonBlood glucoseCBC

Other pancreasSomatostatinPancreatic polypeptide

�

SURGICAL PRINCIPLES FOR MANAGEMENT OF NEUROENDOCRINE TUMORS

Patients with localized pancNETs should be resected. Exceptions include patients with other life-limiting comorbidities,high surgical risk, or widely metastatic disease. Peripheral insulinomas and small (< 2 cm), nonfunctional tumors arecandidates for open or laparoscopic enucleation/local resection or spleen-preserving distal pancreatectomy. Virtually allinsulinomas should be resected regardless of size because of the metabolic (hypoglycemic) complications. NonfunctionalpancNETs 1-2 cm in size have a small (7%-26%) but measurable risk of lymph node metastases; therefore, lymph noderesection should be considered.Resection for larger (> 2 cm) or malignant-appearing nonfunctional and functional pancNETs (i.e., glucagonoma, VIPoma,somatistatinoma) should include total removal of the tumor with negative margins (including adjacent organs) and regionallymph nodes. Tumors of the head are generally treated with (Whipple procedure); tumors of thebody and tail are treated with distal pancreatectomy and splenectomy or spleen-preserving surgery.Surgical treatment of pancNETs in patients with MEN1 is not well defined. Gastrinomas, nonfunctioning pancNETs, andinsulinomas are common. Resection of dominant tumors (> 2-2.5 cm) helps symptom management (insulinoma) and maydecrease the risk of developing metastatic disease (gastrinoma).Distal pancreatectomy with enucleation of tumors from the head of the pancreas is recommended for MEN1insulinoma. Duodenotomy, excision of usually multiple tumors, and lymph node resection are recommended for patientswith MEN1 gastrinoma. Enucleation or a Whipple procedure is recommended for gastrinomas in the head of the pancreas.Resection of gastrointestinal carcinoid should include both adequate regional lymph node resection (including all palpabledisease 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 hasregressed 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 subtotalresection of a large proportion of the tumor (typically > 90%); however, experienced judgment is required formanagement of patients with an unresectable tumor and/or distant metastases. Planned cytoreductive, incomplete (R2)resection of advanced disease in patients with asymptomatic or nonfunctional 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.

Octreotide therapy should be administered parenterally prior to induction of anesthesia in patients with functional carcinoidtumors to prevent carcinoid crisis.

In general, laparoscopic resection is preferable for patients suspected to have small (< 6 cm), benign, functional adrenaltumors. An open exploration is recommended for tumors that have a high risk of being malignant.

pancreatoduodenectomy

Liver-directed therapies (e.g., liver resection, thermal ablation, chemoembolization) for hepatic metastases from NETsfollowing pancreatoduodenectomy are associated with increased risk for perihepatic sepsis and liver abscess.

All patients who might require splenectomy should receive preoperative trivalent vaccine (i.e., pneumococcus,haemophilus influenzae b, meningococcal group C).

patients with

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Text continued from p. 725

Appropriate diagnosis and treatment of neuro-endocrine tumors often involves collaboration be-tween specialists in multiple disciplines, using spe-cific biochemical, radiologic, and surgical methods. Specialists include pathologists, endocrinologists, radiologists (including nuclear medicine specialists), and medical, radiation, and surgical oncologists.

These NCCN 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 guide-line sections pertain to well-differentiated, low- to intermediate-grade tumors; for poorly differenti-ated/high-grade/anaplastic or small cell carcinomas, please refer to Poorly Differentiated (High Grade or Anaplastic)/Small Cell (available online, in these guidelines, at NCCN.org [ANAP-1]) and Poorly Differentiated Neuroendocrine Tumors or Small Cell Tumors (available online, in these guidelines, at NCCN.org [MS-20]). 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 TumorsNeuroendocrine tumors are generally subclassified by site of origin and histologic characteristics. Pan-creatic neuroendocrine tumors arise in endocrine tissues of the pancreas; carcinoid tumors most com-monly arise in the lungs and bronchi, small intes-tine, appendix, rectum, or thymus.

Neuroendocrine tumors are classified histologi-cally 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, intermediate-grade (G2); and poorly differentiated, high-grade (G3). The latter are also sometimes referred to as high-grade neuroendocrine carcinomas or small cell carcinoma.8 These tumors are characterized by a high mitotic rate and an ag-gressive clinical course.9,10

Tumor differentiation and grade often correlate with mitotic count and Ki-67 proliferation index. In most cases, well differentiated, low-grade tumors have a mitotic count of less than 2/10 high-power field (HPF) and 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 a Ki-67 index of 3% to 20%. In high-grade tumors, the mitotic count usually exceeds 20/10 HPF and the Ki-67 index exceeds 20%. Most commonly used his-tologic classification schemes, including both the European Neuroendocrine Tumor Society (ENETS) and WHO systems, incorporate mitotic rate and Ki-67 index.8,11 Numerous studies have confirmed that increased mitotic rate and high Ki-67 index are associated with a more aggressive clinical course and worse prognosis.12,13

Neuroendocrine tumors are staged according to the American Joint Committee on Cancer (AJCC) tu-mor (T), node (N), metastasis (M) staging system. The AJCC introduced its first TNM staging system for the classification of neuroendocrine tumors in the 7th edi-tion AJCC Cancer Staging Manual.14 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.15–19

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 as-sociated with worse prognosis.14

The TNM staging system for the classification of pancreatic neuroendocrine tumors in the 7th edition AJCC Cancer Staging Manual is the same as for exo-crine pancreatic carcinoma.14 The primary tumor (T) is differentiated based on size and involvement of major vessels or other organs (see the staging table, available online, in these guidelines, at NCCN.org [ST-1]). A re-cent retrospective analysis of 425 patients with pancre-atic neuroendocrine tumors treated at H. Lee Moffitt Cancer Center & Research Institute 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).20 Although the trends of this analysis are consistent with population-based studies, the survival rates were significantly higher than those seen in population-based studies.21,22 For example, in the SEER database analysis of pancreatic neuroendo-crine tumors, the 5-year survival rate for patients with metastatic disease was only 19.5%.22

In addition to information on histologic clas-sification and stage, the margin status (positive or negative) and the presence of vascular or perineu-




747

ral invasion should be indicated on the pathol-ogy report, because they may also have prognostic significance.23,24

Sporadic Neuroendocrine Tumors

Carcinoid Tumors Approximately one-third of carcinoid tumors arise in the lungs or thymus, and two-thirds arise in the gas-trointestinal tract. Sites of origin within the gastro-intestinal 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, opposite page).

Carcinoid tumors may secrete various hormones and vasoactive peptides. Bronchial carcinoids have been associated with adrenocorticotropic hormone (ACTH) production and are a cause of Cushing syn-drome.25 Carcinoid tumors arising in the small in-testine or appendix are more commonly associated with carcinoid syndrome, related to the secretion of serotonin, histamine, or tachykinins into the sys-temic circulation causing episodic flushing and di-arrhea.26 Additionally, 10% to 30% of patients with carcinoid syndrome develop valvular cardiac com-plications consisting of tricuspid regurgitation and/or pulmonary stenosis.26

The metabolic products released by intestinal carcinoid tumors are rapidly destroyed by liver en-zymes in the portal circulation, thus the classical syndrome, occurring in approximately 8% of patients with carcinoid tumors,27 is not usually observed un-less liver metastases or rarely retroperitoneal disease have occurred, in which case hepatic metastases re-lease metabolic products directly into the systemic circulation via the hepatic veins.

These NCCN Guidelines address 7 major sub-types of carcinoid tumors: 1) jejunal/ileal/colon, 2) duodenal, 3) appendix, 4) rectal, 5) gastric, 6) bronchopulmonary, and 7) thymus.Evaluation of Carcinoid Tumors: Patients who pres-ent with suspected carcinoid tumors should be eval-uated with imaging studies to assess disease burden and possible primary location. Commonly used tech-niques include CT and MRI. Carcinoid tumors are highly vascular and can appear isodense with liver on CT scan, depending on contrast phase. Multiphase

CT or MRI scans should therefore be used for evalu-ation of liver metastasis. Because most carcinoid tumors express high-affinity receptors for somatosta-tin,26,28 radiolabeled somatostatin receptor scintigra-phy, performed using the radiolabeled somatostatin analog [111In-DTPA]-octreotide (Octreoscan) 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 as appropriate for duodenal and gastric carcinoids; proctoscopic ex-amination for rectal carcinoids; and bronchoscopy as appropriate for bronchopulmonary and thymic carcinoids.Management of Locoregional Disease: The man-agement of locoregional carcinoid tumors depends on tumor size and primary site, and the general con-dition of the patient. Resection is the primary treat-ment approach for most localized carcinoid tumors. Specific recommendations for management of carci-noid tumor subtypes are described below. Gastric Carcinoid Tumors: Three types of gastric carcinoid tumors are generally recognized: type 1 gastric carcinoids (associated with chronic atrophic gastritis), type 2 (associated with Zollinger-Ellison syndrome), and type 3 (sporadic).29 Types 1 and 2 gastric carcinoids are both associated with hyper-gastrinemia; the major difference between them is that patients with type 1 gastric carcinoids gener-ally have atrophic gastritis and absent acid secre-tion, whereas those with type 2 gastric carcinoids have evidence of acid hypersecretion secondary to gastrinoma (Zollinger-Ellison syndrome).29 For hypergastrinemic patients whose tumors are 2 cm or smaller and either solitary or multiple, options include 1) endoscopic resection, if feasible, with bi-opsy of the tumor and adjacent mucosa; 2) observa-tion; or 3) octreotide for patients with gastrinoma and Zollinger-Ellison syndrome (category 2B rec-ommendation). For hypergastrinemic patients with tumors larger than 2 cm and either solitary or mul-tiple, 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.




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Thymic Carcinoid Tumors: Localized and locoregional carcinoid tumors in the thymus are treated with sur-gical resection, generally without adjuvant therapy. After incomplete resection of locoregional disease, however, radiation therapy (RT) alone is recom-mended; the addition of chemotherapy can also be considered (category 3). If chemotherapy is offered, capecitabine or 5-fluorouracil at radiosensitizing dos-es may be considered. Cisplatin or carboplatin with etoposide may be appropriate for patients with atypi-cal or poorly differentiated tumors.Bronchopulmonary Carcinoid Tumors: For localized or locoregional bronchopulmonary tumors, please re-fer to the Lung Neuroendocrine Tumors algorithm, which is part of the NCCN Clinical Practice Guide-lines in Oncology (NCCN Guidelines) for Small Cell Lung Cancer (to view the most recent version of these guidelines, visit NCCN.org).Carcinoid Tumors of the Duodenum, Small Intestine, and Colon: For localized lesions arising in the duo-denum, endoscopic resection is recommended if fea-sible. Transduodenal local excision with or without lymph node sampling and pancreatoduodenectomy are other options for primary treatment of nonmeta-static duodenal carcinoid tumors.

For patients presenting with tumors in the jeju-num, 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 le-sions may be present. If future treatment with octreo-tide is 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.30

Appendiceal Carcinoid Tumors: Most appendiceal carci-noid tumors are identified incidentally, during appen-dectomy 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 suf-ficient, because metastases are uncommon.31,32

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 metasta-ses can develop in some patients with appendiceal carcinoids 2 cm or smaller.33 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 smaller than 2 cm are at risk for locoregional or dis-tant metastases. These patients should be staged with abdominal/pelvic CT or MRI scans. If no distant dis-ease is identified, they should undergo reexploration with a right hemicolectomy. Additionally, a small proportion of appendiceal carcinoids may also con-tain evidence of adenocarcinoma (i.e., “adenocar-cinoid” or “goblet cell carcinoid”). These tumors should be managed according to the NCCN Guide-lines for Colon Cancer (available at NCCN.org).Carcinoid Tumors of the Rectum:The treatment of rec-tal 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 an-esthesia 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 pro-pria, or those associated with lymph node metastases should be treated with low anterior resection or, in rare cases, an abdominoperineal resection.34

Surveillance: Surveillance of carcinoid tumors should include complete patient history and physi-cal examination (H&P) and consideration of imag-ing studies, such as CT (abdominal and/or pelvic triple-phase) and MRI. Most patients with carcinoid tumors of the jejunum/ileum/colon, duodenum, rec-tum, 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 every 6 to 12 months thereafter.

Chromogranin A may be used as a tumor marker (category 3); although not diagnostic, elevated levels have been associated with recurrence.35 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 cau-tion that rising chromogranin A levels in an asymptom-atic patient with a tumor that looks stable on imaging does not necessarily indicate that a patient should be initiated on a new therapy.

5-Hydroxyindoleacetic acid (5-HIAA), a me-tabolite of serotonin, in a 24-hour urine sample may




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also be considered as a biochemical marker in some cases, particularly in patients with small-intestinal carcinoid tumors. During monitoring of patients af-ter 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 tu-mor 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, pineap-ples, plums, tomatoes, hickory nuts, plantain, kiwi, dates, grapefruit, honeydew, or walnuts for 48 hours before the start of urine collection. Additionally, pa-tients should avoid coffee, alcohol, and smoking for this period. Medications that can increase 5-HIAA include acetaminophen, ephedrine, diazepam, nico-tine, glyceryl guaiacolate (an ingredient found in some cough medicines), and phenobarbital.

Somatostatin receptor scintigraphy (Octreoscan) 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 rec-tal tumors (< 1 cm), prognosis is excellent and no follow-up is usually required. Follow-up endoscopies 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 tu-mors (≤ 2 cm, without aggressive features), follow-up examinations are done as clinically indicated. Some institutions recommend a follow-up examination 1 year after simple appendectomy and then with de-creasing frequency.

Follow-up recommendations also differ to some extent for patients with gastric carcinoid tumors. Hypergastrinemic (type 1 or 2) patients with small gastric carcinoid tumors who did not require endo-scopic resection or treatment should be evaluated with H&P every 6 to 12 months. Imaging studies or surveillance may be performed on these patients as clinically indicated. Follow-up endoscopies are rec-ommended for patients with type 1 and type 2 gastric carcinoid tumors. Surveillance every 6 to 12 months for the first 3 years and annually thereafter is appro-

priate if no evidence of recurrence or progression is seen. 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 in-creasing tumor burden is observed.Management of Locoregional Unresectable and/or Metastatic Carcinoid Tumors: Baseline imag-ing recommendations for patients suspected to have distant metastatic disease include multi-phase tech-nique CT or MRI.36,37 Baseline levels of chromo-granin A (category 3) or 5-HIAA may also be con-sidered to monitor subsequent progression (discussed previously). Octreoscan can also be considered both to assess sites of metastases and to assess somatostatin receptor status if treatment with octreotide is being considered. The most common sites of metastases from intestinal carcinoids include regional/mesen-teric lymph nodes, liver, and bones.

In some cases, patients with limited hepatic me-tastases or other sites of disease can undergo com-plete resection. In these patients, resection of the primary tumor and metastases should be performed. A recent study of 172 patients who underwent he-patic resection of metastatic neuroendocrine tumors showed that long-term survival can be achieved in many cases: the reported 10-year overall survival rate was 50.4%.38 Resection of the primary site in the set-ting of unresectable metastases is generally not indi-cated if the primary site remains asymptomatic and is relatively stable. However, it is not uncommon for patients with small bowel primary tumors to experi-ence symptoms of intermittent abdominal pain from episodic bowel obstruction or bowel ischemia related to the primary tumor and surrounding fibrosis. Pallia-tive small bowel resection is recommended in these patients.

Patients who have metastatic carcinoid tumors and carcinoid syndrome should be treated with oc-treotide.30 The long-acting release (LAR) formula-tion is used for the chronic management of patients with carcinoid syndrome. Standard doses of octreo-tide 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 to 14 days after LAR in-jection. Short-acting octreotide (usually 150–250 mcg subcutaneously 3 times daily) can be added to octreotide LAR for rapid relief of symptoms or for




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breakthrough symptoms.39–41 A cardiology consul-tation 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.30 Cardiac heart disease is frequent in patients with carcinoid syndrome; in one study, 59% of patients with carcinoid syndrome were diagnosed with tricuspid regurgitation.42,43 A recent study of 250 patients with carcinoid syndrome showed that patients with 5-HIAA levels of 300 mcmol or greater (57 mg) over 24 hours and with 3 or more flushing episodes per day were more likely to have carcinoid heart disease.44

In patients who have clinically significant tu-mor burden, initiation of octreotide LAR is rec-ommended. The recommendation to consider oc-treotide in these patients is based on the results of the PROMID study, a placebo-controlled phase III trial of 85 patients with metastatic midgut car-cinoid tumors, which showed median times to tumor progression of 14.3 and 6 months in the octreotide LAR and placebo groups, respectively (P = .000072).45 After 6 months of treatment, sta-ble disease was observed in 66.7% of patients in the octreotide LAR group and 37.2% of patients in the placebo group.

No clear consensus exists on the timing of octreo-tide initiation in asymptomatic patients with meta-static carcinoid with low tumor burden. Although initiation of octreotide can be considered in these pa-tients, deferring initiation of octreotide until evidence of tumor progression is seen may also be appropriate.

Patients with clinically significant progression of metastatic carcinoid tumors can pursue several options. In general, these patients should be started on treat-ment with octreotide if they are not already receiving it. For patients with hepatic-predominant disease, cy-toreductive surgery or ablative therapies such as radio-frequency ablation (RFA) or cryoablation may be con-sidered if near-complete treatment of tumor burden can be achieved (category 2B).46,47 For unresectable liver metastases, hepatic regional therapy (arterial emboli-zation,48 chemoembolization,49,50 or radioembolization [category 2B])50–56 are recommended.

Interferon alpha has been shown in several large series to be associated with an antitumor effect, and can also be considered in patients with progressive metastatic carcinoid tumors (category 3).40,57–61 In

general, responses to cytotoxic chemotherapy regi-mens are rare in patients with advanced, well-differ-entiated carcinoid tumors, and these regimens have not been shown to result in improved progression-free survival. The panel lists cytotoxic chemotherapy for carcinoid tumors as a category 3 recommendation.Everolimus for Advanced Carcinoid Tumors: For patients with progressive metastatic carcinoid tu-mors, everolimus can also be considered (category 3). Everolimus is an inhibitor of mammalian target of rapamycin (mTOR), which has been the subject of recent trials in patients with advanced neuroen-docrine tumors. It was well tolerated and showed promising antitumor effects in patients with ad-vanced carcinoid tumors when given with octreo-tide LAR in a phase II trial.62 In the randomized phase III RADIANT-2 trial, 429 patients with ad-vanced carcinoid tumors and carcinoid syndrome were randomized to receive octreotide LAR with everolimus or placebo.63 Based on central review, patients receiving octreotide plus everolimus had a median progression-free survival of 16.4 months, compared with 11.3 months for patients receiving octreotide alone (P = .026). This difference in the primary end point of progression-free survival did not, however, meet the predefined threshold for statistical significance. Adverse events associated with everolimus included stomatitis, rash, fatigue, and diarrhea.63 Other side effects have also been described.64 The panel lists consideration of evero-limus for carcinoid tumors after progression as a category 3 recommendation.Radiolabeled Somatostatin Analogs for Advanced Car-cinoid Tumors: Treatment with radiolabeled soma-tostatin analogues has been reported to result in tu-mor responses in patients with advanced carcinoid tumors.65–69 This approach remains investigational, and randomized trials to further evaluate the rela-tive benefit and potential toxicities of radiopeptide therapy in advanced carcinoid are needed.70 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.71–75 Although some highly se-lected patients have experienced long-term survival, the panel acknowledged the considerable associated risks and deemed liver transplantation to be inves-tigational and not part of routine care at this time.




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Neuroendocrine Tumors of the Pancreas (Islet Cell Tumors)According to a population-based study, malignant pancreatic endocrine tumors account for approxi-mately 1% of pancreatic cancers by incidence and 10% of pancreatic cancers by prevalence.76 Although the peak incidence of occurrence is be-tween ages 40 and 69 years, a significant number of patients diagnosed with pancreatic neuroendo-crine tumors are younger than 35 years.76,77 Based on an analysis of pancreatic neuroendocrine tu-mors in the SEER database from 1973 to 2000, the annual incidence per 1 million was 1.8 in women and 2.6 in men.22 An estimated 40% to 91% of pancreatic neuroendocrine tumors are nonfunctional. The remainder manifest with clinically evident hormonal symptoms.8,22 The characteristics of functional endocrine tumors of the pancreas are summarized in Table 1.77 Of these functioning tumors, up to 70% are insulinomas, and approximately 90% of these are benign. Ap-proximately 15% are glucagonomas. Gastrinomas and somatostatinomas account for another 10%; most (80%–90%) of these are associated with a relatively high risk for metastases.77 The remain-ing rare islet cell tumors include vasoactive intes-tinal polypeptide tumor (VIPoma) and pancreatic

polypeptidoma (PPoma). Islet cell tumors occur-ring in patients with MEN 1 are typically multiple and require different treatment strategies from those used for patients with sporadic pancreatic endocrine tumors, which are usually solitary (see next section). Gastrinoma and insulinoma are the most common pancreatic islet cell tumors in pa-tients with MEN 1.78

Evaluation of Neuroendocrine Tumors of the Pancreas: Family history should be considered to rule out MEN 1 syndromes. For nonfunctioning islet cell tumors, the recommended evaluation in-cludes multiphasic CT or MRI scan. Serum chro-mogranin A (category 3) and PPoma (category 3) may be tested as clinically appropriate. Function-al tumors may give significant clinical symptoms even when very small, and lesion identification can therefore be difficult.79 Multiphasic, contrast-enhanced CT or MRI is recommended, and Oc-treoscan and EUS can also be considered.

Chromogranin A levels are elevated in 60% or more of patients with either functioning or nonfunctioning pancreatic endocrine tumors.80–82 Care should be taken in measuring chromogranin A and interpreting the results, because spuriously elevated levels of chromogranin A have been re-ported in patients using proton pump inhibitors,

Table 1 Characteristics of Neuroendocrine Tumors of the Pancreas

Tumor Major Clinical Symptom Predominant HormoneIslet Cell Type

Malignant Potential Other Clinical Features

Gastrinoma Recurrent peptic ulcer disease

Gastrin γ Very high Diarrhea/steatorrhea

Insulinoma Hypoglycemia (fasting or nocturnal)

Insulin β Low Catecholamine excess

Glucagonoma Diabetes mellitus, migratory necrolytic erythema

Glucagon α Very high Panhypoaminoaciduria, thromboembolism, weight loss

VIPoma Watery diarrhea, hypokalemia, achlorhydria (WDHA syndrome)

Vasoactive intestinal polypeptide

δ High Metabolic acidosis, hyperglycemia, hypercalcemia, flushing

Somatostatinoma Diabetes mellitus Diarrhea/steatorrhea

Somatostatin δ Very high Hypochlorhydria, weight loss, gall bladder disease

PPoma Hepatomegaly, abdominal pain

PP PP cells Very high Occasional watery diarrhea

Abbreviations: PP, pancreatic polypeptide; PPoma, pancreatic polypeptidoma; VIPoma, vasoactive intestinal polypeptide tumor. Adapted with modifications from Skarin AT. Atlas of Diagnostic Oncology. Philadelphia: Elsevier Science; 2003. Copyright 2003, with permission from Elsevier.77




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those with renal or liver failure, those with hyper-tension, and those with chronic gastritis. Gastrinomas: Gastrinoma is often suspected in pa-tients 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 gas-trin levels.83 Diagnosis of gastrinoma can be con-founded by the concurrent use of proton pump in-hibitors, which will elevate serum gastrin levels. Importantly, most patients who are found to have an elevated level of serum gastrin do not have a gastri-noma, 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. In addition, imaging studies (multiphasic CT/MRI scan) often aid not only in localizing the tumor but also in confirming the diagnosis. Other tests, such as an Octreoscan, EUS, and chromogranin A levels (category 3), may be performed as appropriate. Ap-proximately 70% of patients with MEN 1 and gastri-noma have tumors situated in the duodenum.Insulinomas: Insulinomas are generally small tumors that are best localized with EUS, which has been shown to localize approximately 82% of pancreatic endocrine tumors.84 Insulinomas can also be local-ized by injecting calcium into selective pancreatic arteries and measuring the insulin levels in the right (usually) or left hepatic vein (Imamura-Doppman procedure).85 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, de-termining 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 secre-tion of insulin at the time of hypoglycemia, indicate the presence of these tumors.86–88 Patients with insu-linoma also have elevated levels of C-peptide.86 Test-ing for urinary sulfonylurea helps rule out factitious hypoglycemia.

CT or MRI scans should be performed to rule out metastatic disease. Ninety percent of insulino-mas pursue an indolent course and can be cured sur-

gically. Insulinomas are less consistently octreotide-avid than other pancreatic neuroendocrine tumors, and Octreoscan may consequently be less useful as an imaging technique in insulinomas than in other tumor subtypes. Octreoscan should be performed only if octreotide is being considered as a treatment. Octreotide should only be administered to patients whose tumors are Octreoscan-positive, because in the absence of somatostatin receptors, octreotide can profoundly worsen hypoglycemia (see Preopera-tive Management, below).89

Glucagonomas and VIPomas: For patients with re-cent-onset diabetes, cachexia, and/or a necrolytic er-ythematous skin rash, the panel recommends a blood test for glucagon and blood glucose, multiphase contrast-enhanced CT or MRI, and Octreoscan as appropriate. For VIPomas with characteristic watery diarrhea, testing for vasoactive intestinal polypep-tide (VIP) and electrolytes is recommended. A CT or MRI scan may be useful for identifying large tu-mors or metastatic disease, and is recommended rou-tinely for suspected VIPoma. Octreoscan can also be considered as appropriate.Primary Treatment of Locoregional Resectable Neu-roendocrine Tumors of the Pancreas: 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 endo-crine tumors. Before excision, however, any symp-toms of hormonal excess must be treated. Octreotide can be considered 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 coun-terregulatory hormones, such as growth hormone, glucagon, and catecholamines. In this situation, oc-treotide can precipitously worsen hypoglycemia, and can result in fatal complications in some cases.89

For gastrinomas, gastrin hypersecretion may be treated with proton pump inhibitors. VIPomas and glucagonomas are generally sensitive to octreotide.30 Because severe weight loss is common in patients with glucagonoma, total parenteral nutrition (TPN) may also be considered. All patients who might re-quire splenectomy should receive preoperative tri-




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valent vaccine (i.e., pneumococcus, haemophilus influenzae b, and meningococcus group c).Surgical Management of Nonfunctioning Pancreatic Neuroendocrine Tumors: Patients with localized pancreatic neuroendocrine tumors should generally undergo surgical resection, absent any contraindica-tions. Exceptions include patients with other life-limiting comorbidities, high surgical risk, or widely metastatic disease. 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.

Results of a recent retrospective analysis of 139 consecutive patients with incidentally found, nonfunctional pancreatic neuroendocrine tumors showed that even small tumors can be aggressive, including those originally classified as benign.90 In general, resection together with lymph node dissec-tion should be considered, because pancreatic neuro-endocrine tumors that are 1 to 2 cm have a small but real risk of lymph node metastases.91,92

However, another retrospective study of patients with incidentally discovered, nonfunctioning, early-stage pancreatic neuroendocrine tumors who opted against surgical resection suggested that in some cases these tumors can be safely followed, and some panel members have recommended interval follow-up and monitoring for selected patients with inci-dentally discovered small (≤ 1.5 cm) pancreatic neu-roendocrine tumors.93 Surgical Management of Gastrinomas: The treatment approach for gastrinoma usually depends on the re-sults of preoperative localization studies and on find-ings during exploratory laparotomy. In patients with occult gastrinoma (i.e., no primary tumor or me-tastasis 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.

Gastrinomas in the duodenum are treated with duodenotomy and intraoperative ultrasound with lo-cal resection or enucleation of tumors and periduo-denal 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 pancre-atic 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 treat-ed with distal pancreatectomy with or without 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 pancreatoduo-denectomy for tumors in the head of the pancreas or distal pancreatectomy with preservation of the spleen for smaller tumors not involving splenic ves-sels may be considered. Distal pancreatectomy can be performed laparoscopically.Surgical Management of Glucagonomas: Most gluca-gonomas are malignant and calcified and located in the tail of the pancreas, with regional node involve-ment. The recommended treatment is distal pancre-atectomy with resection of the peripancreatic lymph nodes and splenectomy. For tumors in the pancreatic head, pancreatoduodenectomy with resection of the peripancreatic lymph nodes is recommended. Small (< 2 cm) peripheral glucagonomas are rare; enucle-ation or local excision with peripancreatic lymph dissection may be considered for small peripheral tumors of the head or distal pancreas. For glucagono-mas, perioperative anticoagulation should be con-sidered 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. Pancre-atoduodenectomy 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 peripancre-atic lymph dissection may be considered for small peripheral tumors of the head or distal pancreas.Surgical Management of Rare Tumors: The treat-ment recommendations for rare tumors, such as somatostatinoma, adrenocorticotropin hormone–secreting tumor (ACTHoma), parathyroid hor-




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mone-related protein (PTH-rP)–secreting tumors, and PPoma, are similar to those for nonfunctioning tumors. Tumors that are small (< 2 cm) and periph-eral can be enucleated with or without removal of regional nodes, or distal pancreatectomy can be per-formed with or without removal of regional nodes and with or without splenectomy. Deeper, larger (> 2 cm), or invasive tumors are treated with pan-creatoduodenectomy if they are located in the head of the pancreas, and with distal pancreatectomy and splenectomy if they are distally localized. Resection for larger (> 2 cm) or malignant-appearing tumors should include total removal of the tumor with nega-tive margins (including adjacent organs) and region-al lymph nodes. Surveillance: Disease recurrence has been ob-served in 21% to 42% of patients with pancreatic neuroendocrine tumors and can occur after many years.94–96 Patients should undergo follow-up 3 to 12 months after resection, or earlier if the patient presents with symptoms, and every 6 to 12 months thereafter with an H&P, appropriate tumor mark-ers, and imaging studies such as CT/MRI as clini-cally indicated. Octreoscan and PET scan are not recommended for routine surveillance. Surgical re-section is recommended for resectable locoregional or oligometastatic recurrence.Management of Locoregional Unresectable and/or Metastatic Neuroendocrine Tumors of the Pan-creas: Patients with malignant neuroendocrine tu-mors of the pancreas frequently present with liver metastases. In patients with limited hepatic disease, surgical excision of both the primary tumor and liv-er metastases should be considered when possible and can be performed in a staged or synchronous fashion. When performing staged pancreatoduode-nectomy and liver resection, hepatectomy should be considered before pancreatic resection to reduce the risk of perihepatic sepsis from the contaminat-ed biliary tree.97 Although resection may provide clinical benefit, most patients with metastatic dis-ease will experience recurrence.98 Additional resec-tion or ablation may be possible; a recent study of 172 patients who had liver resection of metastatic neuroendocrine tumors (55 with the primary tumor in the pancreas) showed that significant long-term survival can be achieved after recurrence in many patients, with a 10-year overall survival rate of 50.4%.38

Unfortunately, most patients with advanced pancreatic neuroendocrine tumors have unresect-able disease. For patients with unresectable disease who are asymptomatic and have low tumor burden and stable disease, observation is recommended with marker assessment and imaging every 3 to 12 months until clinically significant disease progression occurs.

For unresectable symptomatic patients, those who initially present with clinically significant tu-mor burden, or those with clinically significant dis-ease progression, several different options can be considered. Systemic options include treatment with biologically targeted agents (everolimus or sunitinib, category 2A), treatment with cytotoxic chemo-therapy (category 2A), or treatment with octreotide (category 2B). These options, and hepatic-directed therapies, are discussed in more detail in the follow-ing sections.Biologically Targeted Therapies: The biologically tar-geted agents everolimus and sunitinib have recently been confirmed to have antitumor activity and to improve progression-free survival in patients with advanced pancreatic neuroendocrine tumors. Evero-limus, administered orally at a dose of 10 mg once daily, was evaluated in a multicenter study (RA-DIANT-3) enrolling 410 patients with advanced, progressive pancreatic neuroendocrine tumors.61 In this study, the median progression-free survival du-ration for patients randomized to everolimus was 11.0 months, compared with 4.6 months for patients receiving placebo, (P < .001). Subset analyses of RADIANT-3 showed that the progression-free sur-vival effect of everolimus is independent of prior or concurrent somatostatin analog therapy or prior chemotherapy.99,100 Adverse events associated with everolimus include stomatitis, hyperglycemia, and, in rare cases, pneumonitis.61 Other side effects have also been described.64

Sunitinib, administered orally at a dose of 37.5 mg once daily, was compared with placebo in a mul-ticenter randomized study of patients with advanced progressive metastatic pancreatic neuroendocrine tumors.101 The study was designed to enroll 340 pa-tients but was discontinued after enrollment of 171 patients, before the predefined efficacy analysis. At discontinuation, patients who received sunitinib had a median progression-free survival duration of 11.4 months, compared with 5.5 months for patients re-ceiving placebo (P < .001). The objective response




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rate seen with sunitinib was 9.3%.101 A large propor-tion of patients on the placebo arm subsequently received sunitinib at progression, and no significant difference in overall survival was observed between the arms.102 Adverse events associated with sunitinib include fatigue and, in rare cases, congestive heart failure.103 Other side effects have also been described.Somatostatin Analogs: Patients with symptoms of hormone secretion should, in most cases, receive treatment with octreotide and/or other medication to manage their symptoms as previously described. Patients without hormone-related symptoms who have a positive Octreoscan can also be considered for treatment with octreotide (category 2B). Al-though no randomized studies to date have shown an antitumor effect of octreotide in pancreatic neu-roendocrine tumors, the PROMID trial showed an improvement in its primary end point of time to tu-mor progression (14.3 vs. 6 months; P = .000072) in carcinoid tumors of the midgut.45 The ongoing phase III CLARINET study is comparing lanreotide with placebo in patients with locally advanced or meta-static nonfunctioning pancreatic or intestinal neu-roendocrine tumors (ClinicalTrials.gov identifier: NCT00353496). Cytotoxic Chemotherapy: Cytotoxic chemotherapy is another option (category 2A) for patients with un-resectable or metastatic pancreatic neuroendocrine tumors. Streptozocin is FDA approved for use in pa-tients with advanced pancreatic neuroendocrine tu-mors. The combination of doxorubicin and strepto-zocin was initially reported to be associated with an overall response rate of 69% and a survival benefit in a relatively small randomized study of patients with advanced pancreatic neuroendocrine tumors.104 A more recent retrospective review from MD Ander-son Cancer Center reported an objective response rate of 39% with the combination of 5-FU, doxo-rubicin, and streptozocin.105 More recently, oral te-More recently, oral te-mozolomide-based therapy has become increasingly used in patients with advanced pancreatic neuroen-docrine tumors. Temozolomide has been administe-red using different schedules and either alone or in combination with other agents.106–110 A retrospective series reported that the combination of temozolomi-de with capecitabine was associated with an objec-tive radiographic response rate of 70% and a median progression-free survival of 18 months.110 Hepatic-Directed Therapies: Hepatic-directed thera-

pies may be considered in patients with hepatic-predominant disease. The panel also lists cytore-ductive surgery or ablative therapy (radiofrequency ablation, cryotherapy, microwave46,47) as category 2B recommendations for these patients. Although some groups report that the risks of cytoreductive surgery outweigh its benefits,111 others have reported good outcomes.112,113 No high-level evidence exists assess-ing cytoreductive surgery.114

Additional options include hepatic regional therapies, such as arterial embolization,115 radioem-bolization (category 2B),51–56 and chemoemboliza-tion.116 To date, no randomized clinical trials have assessed the effectiveness of these therapies, and pro-spective data for these interventions are limited.Liver Transplantation: Liver transplantation has been performed in patients with pancreatic neuroendo-crine tumors whose metastases are confined to the liver.71–75,117 Although some highly selected patients have experienced long-term survival, the panel ac-knowledged the considerable associated risks and deemed liver transplantation to be investigational and not part of routine care at this time.

Adrenal Gland Tumors Adrenocortical carcinomas (ACCs) are rare (inci-dence, 1–2 per million).118–120 A bimodal age distri-bution is seen, with peak incidences in early child-hood and the fourth to fifth decades of life. The female-to-male ratio is approximately 1.5 to 1.121,122 Most cases are sporadic; however, ACCs have been observed in association with several hereditary syn-dromes, including Li-Fraumeni syndrome, Beckwith-Wiedemann syndrome, and MEN 1.2,123–126 The un-derlying mechanisms of carcinogenesis in sporadic ACCs have not been fully elucidated; however, in-activating somatic mutations of the p53 tumor sup-pressor gene (chromosome 17p13127,128) and altera-tions at the 11p15 locus (site of the IGF-2 gene129,130) seem to occur frequently.

Approximately 60% of patients present with evidence of adrenal steroid hormone excess, with or without virilization.118,131–133 Signs and symptoms associated with hypersecretion of cortisol, called Cushing syndrome, include weight gain, weakness (primarily in proximal muscles), hypertension, psy-chiatric disturbances, hirsutism, centripetal obesity, purple striae, buffalo hump, supraclavicular fat pad enlargement, hyperglycemia, and hypokalemia. Aldosterone-secreting tumors may present with hy-




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pertension, weakness, and hypokalemia. Androgen-secreting tumors in women may induce hirsutism, deepening of the voice, and oligo/amenorrhea.131 In men, estrogen-secreting tumors may induce gyneco-mastia and testicular atrophy. Hormonally inactive ACCs typically produce symptoms related to tumor burden, including abdominal pain, back pain, early satiety, and weight loss.131,134

Evaluation and Treatment of Adrenal Gland Tu-mors: Evaluation of patients with adrenal gland tumors should take into account whether patients have a history of prior malignancy, which may raise suspicion that the tumor is metastatic. In these pa-tients, an image-guided needle biopsy is recommend-ed after a functioning adrenal neoplasm (in particu-lar pheochromocytoma) is ruled out. If the clinical suspicion for pheochromocytoma is low and plasma metanephrines are less than 2 times the upper limit of normal, it is reasonable to proceed with an adrenal biopsy. If the tumor is determined to be a metastasis from another site, treatment should be according to the appropriate NCCN disease-specific treatment guideline (to see the NCCN Guidelines Table of Contents, visit NCCN.org). If biopsy reveals adre-nal cortical tissue, than morphologic and functional evaluation should proceed as described here.

The morphologic evaluation should include an adrenal protocol CT or MRI to determine the size, heterogeneity, lipid content (MRI), contrast wash-out (CT), and margin characteristics. Functional evaluation should include evaluation for hyperaldo-steronism, Cushing syndrome, and pheochromocy-toma, as described here. Functional Evaluation for Pheochromocytoma: A pheo-chromocytoma should be excluded with fraction-ated plasma free metanephrine, and measurements of 24-hour urine fractionated metanephrines and catecholamines for confirmation. Elevated levels of metanephrines are suggestive of pheochromocy-toma.135,136 Concurrent medications should be re-viewed before metanephrine testing for those that interfere with plasma metanephrines evaluation, including acetaminophen, certain beta- and alpha-adrenoreceptor blocking drugs, serotonin-reuptake inhibitors, and monoamine oxidase inhibitors.137 Elevations in metanephrine levels that are 4 times above the upper limit for normal are diagnostic. Treatment of pheochromocytoma is discussed in the full guidelines, available at NCCN.org.

Evaluation and Treatment of Hyperaldosteronism: When hyperaldosteronism (also called primary al-dosteronism) is suspected, plasma aldosterone and renin activity should be assessed. Patients with pri-mary aldosteronism have elevated plasma levels of aldosterone and low levels of renin activity. The plasma aldosterone-to-renin ratio in patients with primary hyperaldosteronism is usually greater than 30.138 Confirmatory testing with the saline suppres-sion test or salt loading test may be indicated, be-cause both false-positives and false-negatives can occur. Electrolytes should also be measured, because excessive aldosterone production causes both reten-tion of sodium and excretion of potassium. The En-docrine Society has developed detailed guidelines for the detection, diagnosis, and treatment of primary aldosteronism.139

Hyperaldosteronism is rarely malignant, but ma-lignancy should be suspected if the tumor has an ir-regular morphology, is lipid-poor, does not wash out on contrast-enhanced CT, is larger than 3 cm, or is secreting more than one hormone. When malignant hyperaldosteronism is suspected, an open adrenal-ectomy is recommended, because these tumors are prone to rupture.140,141

Benign hyperaldosteronism is much more com-mon and can be caused by a unilateral adrenal ad-enoma or bilateral adrenal hyperplasia. Adrenal vein sampling for aldosterone is considered the standard for distinguishing these 2 causes of benign hyperal-dosteronism and should be considered if the patient is a surgical candidate, because CT imaging is not always reliable. It may be reasonable, however, to exclude adrenal vein sampling in patients younger than 40 years when imaging only shows one affected gland, because bilateral hyperplasia is rare in this population. Laparoscopic adrenalectomy is recom-mended for adenoma, whereas medical management with spironolactone or eplerenone for hypertension and hypokalemia is recommended for patients with bilateral adrenal hyperplasia and for nonsurgical candidates.Evaluation and Treatment of Cushing Syndrome: When patients present with symptoms of Cushing syndrome, levels of serum ACTH, cortisol, and the sex steroid dehydroepiandrosterone sulfate (DHEA-S) are assessed. A confirmatory test (dexametha-sone suppression [except when ACTH is already suppressed], repeated midnight salivary cortisol, or




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24-hour urine) is recommended if cortisol levels are elevated.131,142 Elevated levels of cortisol are indica-tive of Cushing syndrome. Patients who experience symptoms secondary to increased adrenocortical steroid levels may require treatment for palliation of symptoms, such as hypertension, hyperglycemia, hypokalemia, and muscle atrophy.

Elevated levels of ACTH indicate that exces-sive cortisol secretion is not coming from the adrenal gland. Pituitary tumors, which are usually benign, and ectopic tumors in the lung, thyroid, pancreas, or bow-el are probable sources. If an ectopic tumor is found, it should be removed if possible. If the primary tumor is unresectable, a bilateral laparoscopic adrenalectomy or medical management (see following discussion) is recommended.

Cushing syndrome can also be caused by a be-nign adrenal tumor (adrenal adenoma) or a ma-lignant adrenal tumor, neither of which produce ACTH. Malignancy should be suspected if the tu-mor is larger than 5 cm or is inhomogeneous with ir-regular margins and/or local invasion. Imaging of the chest, abdomen, and pelvis is required to evaluate for metastases and local invasion. For malignant disease, see later discussion of adrenal carcinoma. Benign adrenal tumors are removed through laparoscopic adrenalectomy, when feasible. Postoperative corti-costeroid supplementation is required until recovery of the hypothalamus-pituitary-adrenal (HPA) axis.

ACTH-independent Cushing syndrome can also rarely be caused by bilateral multinodal hyperplasia. When the tumor appears benign and the contralat-eral gland appears abnormal, adrenal vein sampling of cortisol production determines treatment. If cor-tisol production is asymmetric, the laparoscopic uni-lateral adrenalectomy with removal of the most ac-tive side is recommended, again with postoperative corticosteroid supplementation. If cortisol produc-tion is symmetric, medical management is indicated.

Medical management of hypercortisolism is achieved with adrenostatic agents, including keto-conazole and mitotane. Ketoconazole is most com-monly used (at doses of 400–1200 mg/d) because of its easy availability and relatively tolerable toxicity profile. Octreotide can also be considered for ecto-pic Cushing syndrome if the tumor is Octreoscan-positive, although it may be less effective in con-trolling ectopic ACTH secretion than it is in other contexts. Bilateral adrenalectomy is recommended

when medical management of severe ectopic Cush-ing syndrome fails.Treatment of Nonfunctioning, Benign Adrenal Tumors: Adrenal tumors that do not secrete hormones are of-ten discovered incidentally during scans for unrelated reasons and are thus sometimes called incidentalomas. Most nonfunctioning tumors are benign and can be left untreated. Masses showing radiographic features of myelolipoma are considered benign. In addition, tumors smaller than 4 cm that are homogenous, with smooth margins, and that appear lipid-rich according to CT or MRI criteria are also usually benign. If no change in size is noted on repeat imaging in 6 to 12 months, no further follow-up is required. Adrenal-ectomy can be considered if more than 1 cm growth of the mass occurs in 1 year. Alternatively, these masses can be observed with short-interval follow-up. Larger tumors (4–6 cm) with benign-appearing features can also be left untreated, but repeat imag-ing is recommended sooner (3–6 months). Without evidence of growth, repeat imaging can be performed in 6 to 12 months. If these larger tumors continue to grow, however, malignancy should be suspected and adrenalectomy is recommended. This procedure can be performed laparoscopically, with a planned conversion to an open procedure if evidence of local invasion is observed during surgery. Evaluation and Treatment of Adrenal Carcinoma: Ad-renal carcinoma should be strongly suspected in nonfunctioning tumors larger than 4 cm with irregu-lar margins or that are internally heterogenous.143 On CT scans with intravenous contrast, adjacent lymph nodes or liver metastases may be present. On unenhanced CTs, the Hounsfield unit (HU) number is typically higher in carcinomas than in adenomas, and a threshold value of 10 HU has been proposed as a means of distinguishing benign from malignant ad-renal tumors.144 If the HU attenuation value is great-er than 10 on unenhanced CT, then enhanced CT and washout at 15 minutes is recommended. If the enhancement washout value is greater than 60% at 15 minutes, the tumor is likely benign.143 Chemical-shift MRI is highly sensitive and specific for differ-entiation of benign from malignant adrenal tumors, because most benign tumors contain fat, whereas most malignant tumors do not. MRIs more clearly document local invasion and involvement of the in-ferior vena cava than CT scans.145,146 Whether CT or MRI scans are performed, they should be performed




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after an adrenal protocol to determine size, heteroge-neity, lipid content (MRI), contrast washout (CT), and margin characteristics.

Imaging of the chest, abdomen, and pelvis is also recommended to evaluate for metastatic disease and lo-cal invasion when the primary tumor is larger than 6 cm. Treatment of Nonmetastatic Adrenal Carcinoma: Sur-gical resection of the tumor with removal of adjacent lymph nodes is recommended in patients with local-ized adrenal carcinoma, and may require removal of adjacent structures such as the liver, kidney, pancre-as, spleen, and/or diaphragm for complete resection. Open adrenalectomy is preferred in tumors with a high risk of being malignant because of increased risk for local recurrence and peritoneal spread when per-formed laparoscopically.140,141

Because of the rarity of ACCs, no randomized, prospective trials of adjuvant therapy have been published. Most retrospective reports have examined the use of adjuvant mitotane, an oral adrenocorti-colytic agent.147–149 The largest study retrospectively analyzed 177 patients with resected ACC (stages I-III) treated in Italy and Germany.150 In the Italian cohort, nearly half of the patients received adjuvant mitotane (47/102 patients) at doses ranging from 1 to 5 g/d, whereas none of the 75 German patients received adjuvant mitotane. The median duration of treatment was 29 months. In follow-up, disease-free and overall survivals were significantly longer in those treated with mitotane versus the controls, suggesting that adjuvant mitotane may be an effec-tive postoperative strategy. The randomized phase III ADIUVO trial is currently underway to assess the efficacy of adjuvant mitotane in patients with ACCs considered to be at low to intermediate risk for progression (ClinicalTrials.gov identifier: NCT00777244). Disease-free survival is the primary end point.

Based on the available data, adjuvant mito-tane therapy can be considered after resection of adrenal carcinoma (category 3). Because of the adrenolytic effects of mitotane, lifelong replace-ment doses of corticosteroids (hydrocortisone or prednisone) should be prescribed to prevent ad-renal insufficiency. Because of the potential risks and uncertain benefits of adjuvant mitotane, several NCCN Member Institutions do not ad-vocate its use for patients with resected adrenal carcinomas.

For patients with high-grade adrenal carcinoma, adjuvant radiation therapy to the tumor bed can also be considered, particularly if concern exists regard-ing tumor spillage or close margins after surgery. Follow-up imaging and biomarkers (for functioning tumors) should be performed every 3 to 6 months.Management of Metastatic Adrenal Carcinoma: For low-grade tumors, resection may be considered if greater than 90% of the tumor and metastases can be removed. In low-grade tumors, observation with imaging and relevant biomarkers every 3 months can also be considered, with systemic treatment initiated at tumor progression. Otherwise, systemic therapy should be initiated. For high-grade tumors, systemic chemotherapy is generally initiated without further observation. Choices of systemic therapy for ad-vanced adrenal carcinoma are mitotane monothera-py or various combinations of cisplatin, carboplatin, etoposide, doxorubicin, streptozocin, and mitotane.

Mitotane monotherapy has been studied in the setting of locally advanced or metastatic disease.151–153 Partial response rates are thought to be 10% to 30% at most.154 Several studies have evaluated the com-bination of mitotane with other cytotoxic agents, including cisplatin and etoposide. One of the larger studies analyzed the combination of mitotane (4 g/d) with cisplatin, etoposide, and doxorubicin in 72 pa-tients with unresectable adrenal carcinoma, yielding an overall response rate of 49% (according to WHO criteria) and a complete hormonal response in 16 of 42 patients with functioning tumors.155 Another study examined the combination of mitotane with streptozocin and reported an objective response rate of 36%.156 Of 12 patients in this study with advanced disease, 3 (25%) were converted to a resectable status with this therapy and remained disease-free or with stable disease 3 to 18 years after surgery; 1 (8%) had stable disease for 3 months, and the oth-er 8 (67%) showed no response. Analysis of results from an international randomized trial comparing treatment of metastatic adrenocortical carcinoma with etoposide, doxorubicin, cisplatin, and mitotane versus treatment with streptozotocin and mitotane (FIRM-ACT) is underway (ClinicalTrials.gov iden-tifier: NCT00094497).157 The toxicity of concurrent chemotherapy plus mitotane should be considered when making treatment decisions.

The optimal doses and duration of mitotane treatment for metastatic disease have not yet been




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standardized, but some institutions recommend tar-get levels of 14 to 20 mcg/mL if tolerated. Higher doses may be difficult for patients to tolerate, where-as lower doses may be less effective.154 Steady-state levels may be reached several months after initia-tion of mitotane. Because of the adrenolytic effects of mitotane, replacement doses of corticosteroids (hydrocortisone or prednisone) should be prescribed to prevent adrenal insufficiency.

Future Trial DesignRecent successes have shown that large randomized controlled trials studying treatments for neuroendo-crine tumors can provide practice-changing results. The NCI recently convened a task force to set pri-orities for future studies and to recommend appropri-ate standards for trials in this disease.158 Among their recommendations are the following:• Pancreatic neuroendocrine tumors should be

studied separately from tumors in other loca-tions.

• Well-differentiated and poorly differentiated neuroendocrine tumors should be studied in separate trials.

• Progression-free survival is an appropriate pri-mary end point for phase III trials and many phase II trials.

• Trials studying treatment for hormonal symp-toms are as critical as those assessing effects on tumor progression and should include quality-of-life end points.Rigorous studies will allow continued progress in

the development of improved treatments for patients with neuroendocrine tumors.

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The NCCN guidelines staff have no conflicts to disclose.

Individual Disclosures for the NCCN Neuroendocrine Tumors Panel

Panel Member Clinical Research SupportAdvisory Boards, Speakers Bureau, Expert Witness, or Consultant

Patent, Equity, or Royalty Other

Date Completed

Al B. Benson III, MD Abbott Laboratories; Amgen Inc.; AstraZeneca Pharmaceuticals LP; Bayer HealthCare; Eli Lilly and Company; Genentech, Inc.; General Electric; Genomic Health, Inc.; National Cancer Institute; and Onyx Pharmaceuticals, Inc.

Abbott Laboratories; Amgen Inc.; AstraZeneca Pharmaceuticals LP; Bayer HealthCare; Eli Lilly and Company; General Electric; Genomic Health, Inc.; National Cancer Institute; and Onyx Pharmaceuticals, Inc.

None None 8/11/11

Emily Bergsland, MD Genentech, Inc.; Novartis Pharmaceuticals Corporation; and sanofi-aventis U.S.

Novartis Pharmaceuticals Corporation

None None 9/28/11

Jordan D. Berlin, MD Abbott Laboratories; Amgen Inc.; Bayer HealthCare; Genentech, Inc.; ImClone Systems Incorporated; Novartis Pharmaceuticals Corporation; and Pfizer Inc.

Amgen Inc.; AstraZeneca Pharmaceuticals LP; Celgene Corporation; Novartis Pharmaceuticals Corporation; Clovis Oncology; Otsuka Pharmaceutical Co., Ltd; and Roche Laboratories, Inc.

None None 1/5/12

Lawrence S. Blaszkowsky, MD Genentech, Inc.; and GlaxoSmithKline None None None 9/28/11

Michael A. Choti, MD, MBA Ipsen Bristol-Myers Squibb Company; Genentech, Inc.; and sanofi-aventis U.S.

None None 6/1/11

Orlo H. Clark, MD XOMA Corporation XOMA Corporation None None 12/7/11

Gerald M. Doherty, MD None Novartis Pharmaceuticals Corporation

None None 6/2/11

James Eason, MD None None None None 1/30/12

Lyska Emerson, MD None None None None 7/6/11

Paul F. Engstrom, MD None None None None 2/16/12

Whitney S. Goldner, MD None None None None 11/3/11

Martin J. Heslin, MD None None None None 9/2/11

Fouad Kandeel, MD, PhD Molecular Insight Pharmaceuticals Molecular Insights Pharmaceuticals None None 7/13/11

Matthew H. Kulke, MD None Novartis Pharmaceuticals Corporation; Ipsen; Lexicon Pharmaceuticals, Inc.; and Pfizer Inc.

None None 7/6/11

Pamela L. Kunz, MD Genentech, Inc. None None None 9/28/11

Boris W. Kuvshinoff II, MD, MBA

None None None None 9/5/11

Jeffrey F. Moley, MD None None None None 10/28/11

Venu G. Pillarisetty, MD None None None None 3/8/11

Leonard Saltz, MD Amgen Inc.; Bayer HealthCare; Bristol-Myers Squibb Company; CureTech Ltd.; Eli Lilly and Company; Genentech, Inc.; ImClone Systems Incorporated; National Cancer Institute; OSI Pharmaceuticals, Inc.; Pfizer Inc.; Roche Laboratories, Inc.; Synta Pharmaceuticals Corp.; and Taiho Parmaceuticals Co., Ltd.

Abbott Laboratories; CureTech Ltd.; Genentech, Inc.; Genomic Health, Inc.; Genzyme Corporation; Merck & Co., Inc.; Novartis Pharmaceuticals Corporation; Asuragen, Inc.; Roche Laboratories, Inc.; and YM BioScience Inc.

None None 7/24/11

David E. Schteingart, MD Corcept Therapeutics None None None 4/9/12

Manisha H. Shah, MD ImClone Systems Incorporated; National Cancer Institute; and Novartis Pharmaceuticals Corporation

Novartis Pharmaceuticals Corporation

None None 7/12/11

Stephen Shibata, MD None Genentech, Inc.; and Genomic Health, Inc.

None None 6/22/11

Jonathan R. Strosberg, MD Genentech, Inc.; Novartis Pharmaceuticals Corporation; and Pfizer Inc.

Genentech, Inc.; Novartis Pharmaceuticals Corporation; Endo Pharmaceuticals; and Pfizer Inc.

None None 11/10/11

Jean-Nicolas Vauthey, MD None None None None 6/2/11

Rebekah White, MD None None None None 2/3/12

James C. Yao, MD Genentech, Inc.; National Cancer Institute; Novartis Pharmaceuticals Corporation; Ipsen; Lexicon Pharmaceuticals, Inc.; and Roche Laboratories, Inc.

National Cancer Institute; Novartis Pharmaceuticals Corporation; and Pfizer Inc.

None None 7/14/11

Rebekah White, MD; James C. Yao, MD; Tumors · Endoscopic resection Local excision (transduodenal)...

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