(NCCN

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NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines

)

Neuroendocrine and

Adrenal Tumors

Version 2.2021 — June 18, 2021

Continue

NCCN.org

NCCN Guidelines for Patients

available at www.nccn.org/patients

NCCN Guidelines Version 2.2021

Neuroendocrine and Adrenal Tumors

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Table of Contents

Discussion

*Manisha H. Shah, MD/Chair †

The Ohio State University Comprehensive

Cancer Center - James Cancer Hospital

and Solove Research Institute

*Whitney S. Goldner, MD/Vice Chair ð

Fred & Pamela Buffett Cancer Center

*Al B. Benson, III, MD †

Robert H. Lurie Comprehensive Cancer

Center of Northwestern University

*Emily Bergsland, MD †

UCSF Helen Diller Family

Comprehensive Cancer Center

Lawrence S. Blaszkowsky, MD ‡

Massachusetts General Hospital

Cancer Center

*Pamela Brock, MS D

Ohio State University Comprehensive

Cancer Center - James Cancer Hospital

and Solove Research Institute

*Jennifer Chan, MD †

Dana-Farber/Brigham and Women’s

Cancer Center

*Satya Das MD, MSCI †

Vanderbilt-Ingram Cancer Center

Paxton V. Dickson, MD ¶

St. Jude Children's Research Hospital/

The University of Tennessee Health

Science Center

Paul Fanta, MD ‡ †

UC San Diego Moores Cancer Center

Thomas Giordano, MD, PhD ≠

University of Michigan

Rogel Cancer Center

*Thorvardur R. Halfdanarson, MD ‡ Þ †

Mayo Clinic Cancer Center

*Daniel Halperin, MD †

The University of Texas

MD Anderson Cancer Center

*Jin He, MD, PhD ¶

The Sidney Kimmel Comprehensive Cancer

Center at Johns Hopkins

*Anthony Heaney, MD, PhD ð

UCLA Jonsson Comprehensive

Cancer Center

Martin J. Heslin, MD ¶

O'Neal Comprehensive

Cancer Center at UAB

Fouad Kandeel, MD, PhD ð

City of Hope National Medical Center

Arash Kardan, MD ɸ

Case Comprehensive Cancer Center/

University Hospitals Seidman Cancer Center

and Cleveland Clinic Taussig Cancer Institute

Sajid A. Khan, MD ¶

Yale Cancer Center/Smilow

Cancer Hospital

Boris W. Kuvshinoff, II, MD, MBA

Roswell Park Comprehensive

Cancer Center

Christopher Lieu, MD †

University of Colorado Cancer Center

Kimberly Miller, RN ¥

Fred & Pamela Buffett Cancer Center

Venu G. Pillarisetty, MD ¶

Fred Hutchinson Cancer Research Center/

Seattle Cancer Care Alliance

Diane Reidy, MD †

Memorial Sloan Kettering Cancer Center

*Sarimar Agosto Salgado, MD ð Þ

UT Southwestern Simmons

Comprehensive Cancer Center

*Shagufta Shaheen, MD †

Stanford Cancer Institute

Heloisa P. Soares, MD, PhD †

Huntsman Cancer Institute

at the University of Utah

*Michael C. Soulen, MD ∩

Abramson Cancer Center at the

University of Pennsylvania

Jonathan R. Strosberg, MD †

Moffitt Cancer Center

Craig R. Sussman, MD ð Þ

Vanderbilt-Ingram Cancer Center

*Nikolaos A. Trikalinos, MD ‡ †

Siteman Cancer Center at Barnes-Jewish

Hospital and Washington University School of

Medicine

Nataliya A. Uboha, MD, PhD †

University of Wisconsin

Carbone Cancer Center

Namrata Vijayvergia, MD †

Fox Chase Cancer Center

*Terence Wong, MD, PhD ф f

Duke Cancer Institute

NCCN

Beth Lynn, RN, BS

Cindy Hochstetler, PhD

NCCN Guidelines Panel Disclosures

Continue

D Cancer genetics

ф Diagnostic radiology

ð Endocrinology

‡ Hematology/Hematology

oncology

Þ Internal medicine

∩ Interventional radiology

† Medical oncology

f Nuclear medicine

¥ Patient advocacy

≠ Pathology

¶ Surgery/Surgical oncology

* Discussion section

committee member

NCCN Guidelines Version 2.2021

Neuroendocrine and Adrenal Tumors

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NCCN Guidelines Index

Table of Contents

Discussion

NCCN Neuroendocrine Tumors Panel Members

Summary of the Guidelines Updates

Clinical Presentations and Diagnosis (CP-1)

N euroendocrine Tumors of the Gastrointestinal Tract (Well-Dierentiated Grade 1/2),

Lung, and Thymus (NET-1)

Neuroendocrine Tumors of the Pancreas (Well-Dierentiated Grade 1/2) (PanNET-1)

Neuroendocrine Tumors of Unknown Primary (Well-Dierentiated Grade 1/2) (NUP-1)

Well-Dierentiated, Grade 3 Neuroendocrine Tumors (WDG3-1)

Poorly Dierentiated Neuroendocrine Carcinoma/Large or Small Cell (other than lung) (PDNEC-1)

Adrenal Gland Tumors (AGT-1)

Pheochromocytoma/Paraganglioma (PHEO-1)

Multiple Endocrine Neoplasia, Type 1 (MEN1-1)

Multiple Endocrine Neoplasia, Type 2 (MEN2-1)

Principles of Pathology for Diagnosis and Reporting of Neuroendocrine Tumors (NE-A)

Principles of Imaging (NE-B)

Principles of Biochemical Testing (NE-C)

Surgical Principles for Management of Neuroendocrine Tumors (NE-D)

Principles of Genetic Risk Assessment and Counseling: Hereditary Endocrine Neoplasias (NE-E)

Principles of Systemic Anti-Tumor Therapy (NE-F)

Principles of Peptide Receptor Radionuclide Therapy (PRRT) with 177Lu-dotatate (NE-G)

Principles of Liver-Directed Therapy for Neuroendocrine Tumor Metastases (NE-H)

Principles of Hormone Control (NE-I)

Staging (ST-1)

Clinical Trials: NCCN believes that

the best management for any patient

with cancer is in a clinical trial.

Participation in clinical trials is

especially encouraged.

Find an NCCN Member Institution:

https://www.nccn.org/home/member-

institutions.

NCCN Categories of Evidence and

Consensus: All recommendations

are category 2A unless otherwise

indicated.

See NCCN Categories of Evidence

and Consensus.

NCCN Categories of Preference:

All recommendations are considered

appropriate.

See NCCN Categories of

Preference.

The NCCN Guidelines

are a statement of evidence and consensus of the authors regarding their views of currently accepted approaches to

treatment. Any clinician seeking to apply or consult the NCCN Guidelines is expected to use independent medical judgment in the context of individual

clinical circumstances to determine any patient’s care or treatment. The National Comprehensive Cancer Network

(NCCN

) makes no representations

or warranties of any kind regarding their content, use or application and disclaims any responsibility for their application or use in any way. The NCCN

Guidelines are copyrighted by National Comprehensive Cancer Network

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NCCN Guidelines Index

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Discussion

UPDATES

Global

• Footnotes added throughout:

SSR PET tracers include: 68Ga-DOTATATE, 64Cu-DOTATATE, 68Ga-

DOTATOC.

See Principles of Genetic Risk Assessment and Counseling (NE-E).

• Modied "somatostatin receptor-based imaging or SSR scintigraphy"

to "SSR-PET/CT or SSR-PET/MRI."

• Added "Well-Dierentiated Grade 1/2" to page headings where

applicable.

• Testing for inherited genetic syndromes revised: Genetic counseling

and testing for inherited genetic syndromes.

Neuroendocrine Tumors of the Gastrointestinal Tract (Well-Dierentiated

Grade 1/2, Lung and Thymus)

NET-1

• Footnote g revised:

Should include:

◊ Careful m

Manual examination palpation of the entire bowel, as

multiple synchronous lesions tumors may be present.

◊ Assessment of the Assess for proximity to or involvement of the

superior mesenteric artery and superior mesenteric vein.

NET-2

• Primary Treatment of Non-Metastatic Disease

Non-functioning NET and duodenal gastrinoma; revised: Local

excision (transduodenal) + lymph node sampling regional

lymphadenectomy.

NET-3

• Clinical Location, criteria modied:

T1 (conned to the appendix) Tumor ≤2 cm

T2–4 or Tumor >2 cm or Incomplete resection or Positive nodes/

margins or LVI.

• Evaluation:

Removed: Chest CT with or without contrast.

Removed: Biochemical evaluation as clinically indicated.

• Primary Treatment of Non-Metastatic Disease, removed: Re-exploration.

• Top pathway; surveillance modied: Surveillance as clinically indicated

No surveillance indicated.

Updates in Version 2.2021 of the NCCN Guidelines for Neuroendocrine and Adrenal Tumors from Version 1.2021 include:

Updates in Version 1.2021 of the NCCN Guidelines for Neuroendocrine and Adrenal Tumors from Version 2.2020 include:

Continued

NET-5

• Evaluation

Following Hypergastrinemic/Type 1, third bullet added: After

baseline gastrin, following gastrin and CgA levels is not

recommended.

• Primary Treatment/Surveillance

Normal gastrin/Type 3 options revised: Radical resection

with regional lymphadenectomy (preferred) or Consider

endoscopic or surgical wedge resection (if no evidence of

regional lymphadenopathy on EUS or other imaging).

• Footnote q added: May need multiple biopsies throughout the

entire stomach.

NET-6

• Evaluation

Bullet added: Consider genetic counseling and testing for

inherited genetic syndromes. (Also page NET-7)

• Primary Treatment of Non-Metastatic Disease

Locoregional disease (Stage IIIA/B):

◊ Incomplete resection and/or positive margins pathway;

revised: "carcinoid" added. (Also on NET-7)

◊ Low grade (typical carcinoid); revised: Consider observation

or Consider RT (category 3) ± cytotoxic chemotherapy.

• Footnote removed: Thymic neuroendocrine tumors are often

associated with MEN1. See Multiple Endocrine Neoplasia, Type

1 (MEN1-1).

NET-7

• Primary Therapy

Localized disease (Stage I–II) options revised: SBRT (if

surgery contraindicated) or If surgery contraindicated, thermal

ablation or SBRT (if surgery and RT is contraindicated).

• Footnote removed: Bronchopulmonary neuroendocrine tumors

are often associated with MEN1. See Multiple Endocrine

Neoplasia, Type 1 (MEN1-1). (Also on NET-10)

NE-C 2 of 3

• Cushing Syndrome, Testing, third bullet revised: Serum

Plasma ACTH

MS-1

• The Discussion section has been updated to reect the changes in the algorithm.

NCCN Guidelines Version 2.2021

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Discussion

UPDATES

Updates in Version 1.2021 of the NCCN Guidelines for Neuroendocrine and Adrenal Tumors from Version 2.2020 include:

Continued

NET-9

• Treatment, last column: Everolimus dose removed.

NET-10

• Footnote pp revised: For symptom control, consider addition of

focal therapy (ie, endobronchial therapy).

(ie, endobronchial therapy

debulking, ablation). (Also on NET-11)

NET-12

• Following Carcinoid syndrome poorly controlled, option revised:

Consider additional therapy for disease

symptom control.

• Footnote removed: Treatment with octreotide or lanreotide will likely

only benet those patients who are SSR positive.

• Footnote vv added: Evaluate for pancreatic exocrine deciency and

bile acid diarrhea.

Neuroendocrine Tumors of the Pancreas (Well-Dierentiated Grade 1/2)

PanNET-1

• Evaluation, rst bullet revised: Abdominal ± pelvis multiphasic CT or

MRI. (Also PanNET-2 through 5)

• Management of Primary Non-Metastatic Disease:

Small (≤2 cm) option revised: Observation in select cases

or Enucleation ± regional nodes

regional lymphadenectomy

or Distal pancreatectomy ± regional nodes/splenectomy or

Pancreatoduodenectomy ± regional nodes Resection ± regional

lymphadenectomy.

Larger (>2 cm), invasive, or node-positive tumors pathway revised:

◊ Head: Pancreatoduodenectomy + regional nodes regional

lymphadenectomy.

◊ Distal: Distal pancreatectomy + splenectomy + regional nodes

regional lymphadenectomy.

• Footnotes:

Removed: For all patients with PanNET, evaluate personal and

family history for possibility of MEN1 or other hereditary syndromes

as appropriate. See Multiple Endocrine Neoplasia, Type 1 (MEN-1).

(Also PanNET-2 through 5)

Footnote g revised: Observation can be considered for small (≤2

cm), low-grade, incidentally discovered, non-functional tumors.

Decision based on estimated surgical risk, site of tumor, and patient

comorbidities. (Sadot E, et al. Ann Surg Oncol 2016;23:1361-70.)

Follow surveillance recommendations on PanNET-6.

Footnote j added: As appropriate, central pancreatectomy or spleen-

preserving surgery should be considered.

PanNET-2

• Clinical location revised: Gastrinoma (usually duodenal

duodenum or head of pancreas)

• Evaluation, bullet moved from "as appropriate" to

"recommended": Genetic counseling and testing for inherited

genetic syndromes.

PanNET-3

• Management of Primary Non-Metastatic Disease, Locoregional

disease, following Head or Distal, option revised: Tumor

enucleation, consider minimally invasive resection.

PanNET-4

• Management of Primary Non-Metastatic Disease, following

Head, option revised: Pancreatoduodenectomy + peripancreatic

lymph nodes lymphadenectomy. (Also page PanNET-5)

• Management of Primary Non-Metastatic Disease, following

Distal, option revised: Distal pancreatoduodenectomy +

peripancreatic lymph nodes lymphadenectomy + splenectomy.

(Also page PanNET-5)

• PanNET-7

• Evaluation, bullet revised: Abdominal/

pelvic multiphasic CT

or MRI and chest CT (± contrast) as clinically indicated.

• Treatment, last column: Everolimus and Sunitinib dose

removed.

• Footnotes:

Footnote dd revised: For patients with insulinoma, octreotide

or lanreotide should be used only if SSR-based imaging

somatostatin scintigraphy is positive. If used...

Footnote gg revised: After any prior biliary instrumentation,

there are increased risks of infectious complications

associated with liver-directed therapies.

Neuroendocrine Tumors of Unknown Primary

NUP-1

• Initial Work-up, following Primary not discovered, heading

revised: Well-dierentiated grade 1/2.

• Footnote b added: Treat presumptively as

gastroenteropancreatic (GEP) NETs if it is unknown primary.

Neuroendocrine Tumors, Well-Dierentiated Grade 3

WDG3-1 through WDG3-4

• New algorithm added for Well-Dierentiated, Grade 3

Neuroendocrine Tumors.

NCCN Guidelines Version 2.2021

Neuroendocrine and Adrenal Tumors

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and this illustration may not be reproduced in any form without the express written permission of NCCN.

NCCN Guidelines Index

Table of Contents

Discussion

Updates in Version 1.2021 of the NCCN Guidelines for Neuroendocrine and Adrenal Tumors from Version 2.2020 include:

Continued

UPDATES

Adrenal Gland Tumors

AGT-1

• Footnotes added:

For benign-appearing lesions, refer to the following guidelines for the

management of adrenal incidentalomas: Zeiger MA, Thompson GB,

Duh QY, et al. The American Association of Clinical Endocrinologists

and American Association of Endocrine Surgeons medical guidelines

for the management of adrenal incidentalomas. Endocrine practice:

ocial journal of the American College of Endocrinology and the

American Association of Clinical Endocrinologists 2009;15 Suppl

1:1-20; Fassnacht M, Arlt W, Bancos I, et al. Management of adrenal

incidentalomas: European Society of Endocrinology Clinical Practice

Guideline in collaboration with the European Network for the Study

of Adrenal Tumors. Eur J Endocrinol 2016;175:G1-G34.

For benign-appearing lesions, refer to the Endocrine Society's

Clinical Practice Guidelines for the Treatment of Cushing's Syndrome

(Nieman LK, et al. J Clin Endocrinol Metab 2015;100:2807-2831).

AGT-2

• Top pathway, second column revised: Rule out pheochromocytoma

(See NE-C). Check plasma free or 23 hour urine fractionated

metanephrines (See NE-C).

• Footnote b added: See Principles of Biochemical Testing (NE-C). (Also

page AGT-4)

AGT-3

• Primary Treatment, top pathway, last column revised: Adrenalectomy

(minimally invasive preferred).

• Tumor >4 cm or inhomogeneous, irregular margins, local invasion, or

other malignant imaging characteristics pathway:

Additional evaluation:

◊ First bullet added: FDG-PET/CT.

◊ Third bullet revised: Abdominal/pelvic CT or MRI with contrast to

evaluate for metastases and local invasion.

Primary treatment, middle pathway revised: Open Adrenalectomy for

suspected carcinoma malignancy.

• Footnote removed: If size is resectable by laparoscopy, may explore

using a minimally invasive approach with planned conversion for

evidence of local invasion. The decision for open versus minimally

invasive surgery is based on tumor size and degree of concern

regarding potential malignancy, and local surgical expertise.

• Footnote j added: Some centers may use 6 cm as cuto.

Poorly Dierentiated Neuroendocrine Carcinoma/Large or Small

Cell

PDNEC-1

• Treatment, Metastatic pathway, following chemotherapy, option

revised: If progression, consider ipilimumab + nivolumab for

non-pancreatic NET (category 2B).

• Surveillance:

Top pathway revised: Every 3 mo 12 weeks for 1 y, then every

6 mo.

Bottom pathway revised: Every 3 mo 6–16 weeks.

• Footnotes:

Footnote a revised: This page is for PDNEC and not high-

grade NET. Not all high-grade (Ki-67 >20%) neuroendocrine

cancers neoplasms are poorly dierentiated. See WDG3-

1. NETs with Ki-67 index >20% may be characterized by

relatively well-dierentiated histology, particularly tumors

with Ki-67 index between 20%–50%. Tumors that fall into

the "well-dierentiated/ high-grade" category may respond

relatively poorly to cisplatin/etoposide or carboplatin/

etoposide, and respond more favorably to treatments

described for well-dierentiated NETs.

Footnote c revised: Somatostatin scintigraphy with SPECT/

CT is not part of the routine evaluation of poorly differentiated

neuroendocrine carcinomas, but may be considered for

morphologically well-differentiated tumors with higher

proliferation index, as appropriate. See Principles of Imaging

(NE-B). For options for well-differentiated tumors, see NET-10

or NET-11.

Footnote d revised: Pembrolizumab can be considered for

patients with mismatch repair-decient (dMMR), microsatellite

instability-high (MSI-H), or advanced tumor mutational

burden-high (TMB-H) tumors (as determined by an FDA-

approved test) that have progressed following prior treatment

and have no satisfactory alternative treatment options.

Footnote e revised: Combination of pembrolizumab immune

checkpoint inhibitors + chemotherapy is investigational

for all patients with extrapulmonary poorly dierentiated

neuroendocrine carcinomas.

Footnotes with chemotherapy options were removed and

replaced with a link to NE-F (4 of 4); where regimens are now

listed.

NCCN Guidelines Version 2.2021

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Discussion

Updates in Version 1.2021 of the NCCN Guidelines for Neuroendocrine and Adrenal Tumors from Version 2.2020 include:

Continued

UPDATES

AGT-4

• Additional Evaluation

Bullet added: FDG PET/CT.

Third bullet revised: Abdominal/pelvic CT or MRI with contrast

to evaluate for metastases and local invasion.

Last bullet added: Biochemical workup.

• Following evaluation:

Top pathway revised: Resectable disease (Intermediate-size

tumor (4–6 cm) with aggressive features.

Bottom pathway revised: Unresectable or suspected metastatic

disease Large tumor (>6 cm) with aggressive features.

• Primary Treatment:

Top pathway revised: Open adrenalectomy for suspected

carcinoma.

• Footnotes:

Removed: For benign-appearing lesions, refer to the following

guidelines for the management of adrenal incidentalomas...

Removed: Aggressive features such as inhomogeneous,

irregular margins, and local invasion.

AGT-5

• Workup

Second bullet revised: Consider tumor MSI, MMR and TMB

testing.

Bullet removed: Biochemical evaluation (See NE-C).

Second option revised: Locoregional unresectable or

Metastatic disease.

• Treatment, following Localized disease, footnotes removed from

"Consider adjuvant mitotane therapy (category 3).

• Treatment, following Locoregional unresectable or Metastatic

disease, options revised:

First bullet revised: Consider observation with chest CT

± contrast and abdominal/pelvic CT or MRI with contrast

for clinically indolent disease every 3 mo 12 weeks and

biomarkers (if tumor initially functional) .

Third bullet revised: Consider local therapy (ie, SBRT, thermal

ablative therapies, liver-directed therapy).

Fourth bullet revised: Consider systemic therapy preferably

in clinical trial (See Systemic Therapy for Metastatic

Adrenocortical Tumors [AGT-A]).

Chemotherapy options were removed and replaced with a link

to (AGT-A); where regimens are now listed.

AGT-5 (continued)

• Follow-up, following Locoregional unresectable or Metastatic disease,

added: Every 12 wk–12 mo up to 5 y (after 5 y as clinically indicated):

Second bullet revised: Abdominal/pelvic CT or MRI with contrast or

FDG-PET/CT.

• Footnotes revised:

Footnote n: Chest CT with or without contrast and abdominal/pelvic

CT or MRI with contrast to evaluate for metastases and local invasion

to stage disease, if not previously done. Staging workup, see AGT-4.

Footnote p: FDA-approved test recommended for determination

of TMB. Genetic counseling and testing for Lynch syndrome is

recommended for any patient with mismatch repair-decient

adrenocortical carcinoma.

• Footnotes added:

Footnote o: See Principles of Genetic Risk Assessment and

Counseling (NE-E).

Footnote s: If bulky disease, or <90% is removable, surgery can be

reconsidered following response to systemic therapy.

• Footnotes removed:

Monitor mitotane blood levels. Some institutions recommend

target levels of 14–20 mcg/mL if tolerated. Steady-state levels may

be reached several months after initiation of mitotane. Life-long

hydrocortisone replacement may be required with mitotane.

Mitotane may have more benet for control of hormone symptoms

than control of tumor.

See Discussion for further information regarding the phase III FIRM-

ACT trial. (Fassnacht et al. N Eng J Med 2012;366:2189-2197.)

AGT-A

• New page added: Systemic Therapy for Locoregional Unresectable/

Metastatic Adrenocortical Carcinoma.

NCCN Guidelines Version 2.2021

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NCCN Guidelines Index

Table of Contents

Discussion

Continued

UPDATES

Paraganglioma/Pheochromocytoma

PHEO-1

• Evaluation

Recommended;

◊ Bullet added: Adrenal protocol CT (abdomen/pelvis).

◊ Bullet removed: Abdominal/pelvic multiphasic CT or MRI.

As appropriate

◊ Bullet added: Abdominal/pelvic multiphasic CT or MRI.

• Footnote removed: A high incidence of inherited disease has been

reported in patients with pheochromocytoma/paraganglioma.

Certain genetic variants may require more frequent follow-up.

(See Discussion) (Also page PHEO-3)

• Footnote j revised: PET/CT or PET/MRI of skull base to mid-thigh

with IV contrast when possible. Data are limited on the optimal

timing of scans following administration of SSAs. (Also page

PHEO-3)

PHEO-3

• Surveillance

For resectable disease, bullet revised: Consider chest CT ±

contrast and abdominal/pelvic CT or MRI with contrast or FDG-

PET/CT.

For locally unresectable disease or distant metastases, bullet

revised: SSR-PET/CT or SSR-PET/MRI or SSR scintigraphy (eg,

68Ga-dotatate imaging preferred [PET/CT or PET/MRI] or SSR

scintigraphy).

Multiple Endocrine Neoplasia, Type 1

MEN1-1

• Page removed: Diagnosis of or Clinical Suspicion of MEN1

(formerly MEN1-1).

• Clinical diagnosis of MEN1 or clinical suspicion of MEN1 (See

MEN1-1)

• Bullet added: Genetic counseling and testing for inherited genetic

syndromes. (Also on MEN2-1)

• Footnotes removed:

For MEN1 genetic testing recommendations, see MEN1-1.

Preference of scan will depend on institutional practice/protocol.

Sestamibi scan may not be as sensitive as other imaging

options since often the patient has hyperplasia. See Principles of

Imaging (NE-B).

• Footnote b added: See Principles of Genetic Risk Assessment and

Counseling (NE-E). (Also on MEN2-1)

Updates in Version 1.2021 of the NCCN Guidelines for Neuroendocrine and Adrenal Tumors from Version 2.2020 include:

MEN1-2

• MEN1 Surveillance, Parathyroid pathway,

If calcium rises, third sub-bullet revised: Re-image with neck

ultrasound and/or parathyroid sestamibi with SPECT scan

(SPECT-CT preferred) or 4D-CT.

• Footnote a removed: Preference of scan will depend on institutional

practice/protocol. Sestamibi scan may not be as sensitive as

other imaging options since often the patient has hyperplasia. See

Principles of Imaging (NE-B).

MEN1-A

• Treatment of PanNETs Specic to MEN1 Patients, references added:

Faggiano A, Modica R, Lo Calzo F, et al. Lanreotide Therapy vs

Active Surveillance in MEN1-Related Pancreatic Neuroendocrine

Tumors < 2 Centimeters. J Clin Endocrinol Metab 2020;105:dgz007.

Niederle B, Selberherr A, Bartsch DK, et al. Multiple Endocrine

Neoplasia Type 1 (MEN1) and the Pancreas: Diagnosis and

Treatment of Functioning and Non-Functioning Pancreatic and

Duodenal Neuroendocrine Neoplasia within the MEN1 Syndrome -

An International Consensus Statement [published online ahead of

print September 24, 2020]. Neuroendocrinology 2020.

Multiple Endocrine Neoplasia, Type 2

MEN2-1

• Page removed: Diagnosis of or Clinical Suspicion of MEN2

(formerly MEN2-1).

• Diagnosis of or Clinical suspicion diagnosis of MEN2 (See MEN2-1).

Surveillance, middle pathway revised: Calcium annually. See

NCCN Guidelines for Medullary Thyroid Carcinoma.

Footnotes removed:

◊ For RET genetic testing recommendations, see MEN2-1.

◊ See Principles of Biochemical Testing (NE-C).

NE-A 1 of 5

• Table 1 removed from this page.

• Footnote removed: Adapted with permission from Bosman FT,

Carneiro F, Hruban RH, Theise ND. World Health Organization

Classication of Tumours of the Digestive System. IARC,

Lyon, 2010; and Travis WD, Brambilla E, Burke AP, et al. WHO

Classication of Tumours of the Lung, Pleura, Thymus and Heart.

IARC, Lyon; 2015; and Lloyd RV, Osamaru RY, Klöppel G, Rosai J.

WHO Classication of Tumours of Endocrine Organs. IARC, Lyon,

2017.

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Discussion

Continued

UPDATES

NE-A 2 of 5

• 2019 WHO Classication and Grading Criteria for

Neuroendocrine Neoplasms of the Gastrointestinal Tract and

Hepatopancreatobiliary Organs table was added to the guideline.

• Footnotes added:

Footnote a: Mitotic rates are to be expressed as the number

of mitoses/2 mm

(equaling 10 high-power elds at 40×

magnication and an ocular eld diameter of 0.5 mm) as

determined by counting in 50 elds of 0.2 mm

(ie, in a

total area of 10 mm

); the Ki-67 proliferation index value is

determined by counting at least 500 cells in the regions of

highest labeling (hot spots), which are identied at scanning

magnication; the nal grade is based on whichever of the two

proliferation indexes places the neoplasm in the higher grade

category.

Footnote b: Poorly dierentiated NECs are not formally graded

but are considered high grade by denition.

Footnote c: In most MiNENs, both the neuroendocrine and

non-neuroendocrine components are poorly dierentiated, and

the neuroendocrine component has proliferation indexes in the

same range as other NECs, but this conceptual category allows

for the possibility that one or both components may be well

dierentiated; when feasible, each component should therefore

be graded separately.

NE-A 3 of 5

• 2015 WHO Criteria for the Diagnosis of Pulmonary NET table was

added to the guideline.

NE-A 4 of 5

• Ki-67 Index, bullet added: Ki-67 immunohistochemistry should

be analyzed and/or counted in the areas of highest activity

referred to as "hot spots."

Updates in Version 1.2021 of the NCCN Guidelines for Neuroendocrine and Adrenal Tumors from Version 2.2020 include:

NE-B

• Anatomic Imaging

Bullet added: Consider MRI over CT to minimize radiation risk.

Bullet added: MRI preferred for pregnant patients.

• Functional Imaging

First bullet revised: Evaluation with somatostatin receptor

(SSR) imaging to assess receptor status and distant disease

is appropriate. This is especially important for determining

whether a patient may benet from SSR-directed therapy.

◊ First sub-bullet revised: SSR-based imaging options include

SSR-PET/CT or SSR-PET/MRI, or SSR- Octreotide SPECT/CT

(only if SSR-PET is not available).

◊ Second sub-bullet added: Appropriate SSR-PET tracers

include 68Ga-DOTATATE, 68Ga-DOTATOC, or 64Cu-

DOTATATE.

◊ Third sub-bullet added: SSR-positive if uptake in measurable

lesions is greater than liver.

Third bullet revised: SR- Octreotide SPECT/CT is much less

sensitive for dening SSR-positive disease than SSR-PET/CT,

and typically cannot be done in combination with multiphase

CT or MRI. Therefore, SSR-PET/CT or SSR-PET/MRI is preferred.

Fourth bullet revised: In selected cases where high-grade

NET or poorly dierentiated neuroendocrine carcinoma is

documented or suspected or where disease is growing rapidly,

FDG-PET/CT may be useful to identify high-grade active

disease.

• Surveillance, bullet revised: After potentially curative surgery,

surveillance is recommended for at least 10 years for most

patients. In certain cases, surveillance may be extended beyond

10 years based on risk factors such as age and aggressiveness

of disease risk of recurrence. However, data are limited on the

optimal surveillance schedule beyond 10 years.

• Transthoracic Echocardiogram (ECHO) to Assess for Carcinoid

(NET-related) Heart Disease category header was added.

Bullet added: Echocardiogram (transthoracic

echocardiography, TTE) is important for the evaluation of

carcinoid heart disease (CHD) and should include morphologic

evaluation of the valves (especially tricuspid and pulmonic) and

the right heart.

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Neuroendocrine and Adrenal Tumors

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Discussion

Continued

NE-C 1 of 3

• Bullet added: In select cases, chromogranin A may have prognostic

value but treatment decisions are not based solely on changes in

chromogranin.

• NETs of Gastrointestinal Tract, Lung, and Thymus, Testing,

removed bullet: Chromogranin A (category 3).

• PanNET added to subtypes in rst column of table.

• PanNET: PPoma

Clinical Symptoms revised: Depends on hormone secreted, Can

be cClinically silent.

Testing, bullet removed: Chromogranin A (category 3).

NE-C 2 of 3

• Pheochromocytoma/Paraganglioma, Testing, second bullet revised:

Cervical paragangliomas: consider serum or and urine dopamine

catecholamines or methoxytyramine (the metabolite of dopamine).

• Cushing Syndrome, Testing, third bullet revised: If

hypercortisolemic, test Serum ACTH (8 am cortisol) should be

done.

• Footnote c added: 24-hour urine for aldosterone, sodium and

potassium should be considered for denitive diagnosis.

• Footnote e added: Petrosal vein sampling can be considered to

differentiate adrenal from pituitary and ectopic causes.

NE-D

• This section has been signicantly revised.

NE-E

• New section added: Principles of Genetic Risk Assessment and

Counseling: Hereditary Endocrine Neoplasias.

NE-F

• "Well-Dierentiated Grade 1/2" added to table headings.

NE-F 4 of 5

• Table added for Poorly Dierentiated Neuroendocrine Carcinoma/

Large or Small Cell (Extrapulmonary) (regimens formerly listed on

PDNEC-1).

• Locoregional Unresectable/Metastatic Disease:

Option added: FOLFIRINOX.

Option added: Pembrolizumab.

UPDATES

Updates in Version 1.2021 of the NCCN Guidelines for Neuroendocrine and Adrenal Tumors from Version 2.2020 include:

NE-F 5 of 5

• References updated.

NE-G 1 of 3

• Third bullet revised: Currently Tthere are no randomized

data, but there are reports of treatment ecacy and favorable

outcomes when PRRT is used for PanNETs, for the use of PRRT

for bronchopulmonary NET, thymus NET, pheochromocytomas,

or paragangliomas, ; however, PRRT may be considered if

SSR-positive and progression on octreotide/lanreotide. and

bronchopulmonary/thymic NETs. If feasible, participation in

clinical trials of PRRT is strongly recommended for patients with

such rare groups of NET.

• Key Eligibility, second bullet revised: SSR expression of NET

as detected by SSR-PET/CT or SSR-PET/MR. (ie, 68Ga-dotatate

imaging preferred [PET/CT or PET/MRI] or SSR scintigraphy).

• Footnotes added:

Footnote a: See Principles of Imaging (NE-B).

Footnote b: PET/CT or PET/MRI of skull base to mid-thigh with

IV contrast when possible. Data are limited on the optimal timing

of scans following administration of SSAs.

NE-G 3 of 3

• References updated.

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Discussion

UPDATES

NE-H

• Indications for Hepatic Arterial Embolization, third bullet: 10% after

TARE changed to 8%.

• Embolization Modalities

TAE and TACE, third sub-bullet revised: ...Overnight observation

is typically appropriate to monitor and treat symptoms of post-

embolization syndrome such as pain and nausea and exacerbation

of hormone-related symptoms.

TARE (category 2B) may be considered particularly in the following

scenarios:

◊ Sub-bullets added:

– Lobar or segmental (less than lobular) disease distribution.

– Patients with prior Whipple surgery or biliary tract

instrumentation (lower risk of hepatobiliary infection than TAE/

TACE)

– TARE is better tolerated than TAE/TACE, but late

radioembolization-induced chronic hepatotoxicity (RECHT)

may occur in long-term survivors, and is particularly a concern

among patients undergoing bilobar radioembolization.

◊ Sub-bullets removed:

– Routine use of radioembolization (TARE) using yttrium-90

microspheres is controversial.

– Short-term side eects are milder than observed with TAE

or TACE, but late radioembolization-induced chronic liver

toxicity (RECHT) occurs in 10%–20% of long-term survivors

in retrospective series, and is particularly a concern among

patients with bilobar disease.

– TARE may be most appropriate for patients with prior biliary

interventions due to the lower risk of abscess.

Updates in Version 1.2021 of the NCCN Guidelines for Neuroendocrine and Adrenal Tumors from Version 2.2020 include:

NE-H (continued)

• Ablative Therapy (category 2B)

Bullet removed: Includes ablative techniques such as

radiofrequency, microwave, and cryotherapy. There are no

randomized clinical trials and prospective data for these

interventions are limited. However, data on the use of these

interventions are emerging.

Bullet revised: Percutaneous thermal ablation, often using

microwave energy (radiofrequency and cryoablation are also

acceptable), can be considered for oligometastatic liver disease,

generally up to four lesions each smaller than 3 cm. Feasibility

considerations include conspicuity on CT or ultrasound, a

safe percutaneous imaging-guided approach to the target

lesions, and proximity to vessels, bile ducts, or adjacent non-

target structures that may require hydro- or aero-dissection for

displacement.

References added.

ST-2

• Heading revised: American Joint Committee on Cancer (AJCC)

TNM Staging System for Well-Dierentiated Neuroendocrine

Tumors of the Duodenum and Ampulla of Vater (8th ed., 2017).

ST-12

• Table 21 heading revised: Thymus

Ampulla of Vater (high-grade

neuroendocrine carcinoma).

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Discussion

Neuroendocrine Tumors of the Gastrointestinal Tract (Well-Dierentiated

Grade 1/2)

, Lung, and Thymus

Clinical presentations:

• Jejunal, ileal, colon (See NET-1)

• Duodenal (See NET-2)

• Appendix (See NET-3)

• Rectal (See NET-4)

• Gastric (See NET-5)

• Thymus (See NET-6)

• Bronchopulmonary, NET (See NET-7)

• Locoregional advanced disease and/or distant metastases of the

GI tract (See NET-9)

• Locoregional unresectable Bronchopulmonary/Thymic NET (See NET-10)

• Distant metastatic Bronchopulmonary/Thymic NET (See NET-11)

• Carcinoid syndrome (See NET-12)

Neuroendocrine Tumors of the Pancreas (Well-Dierentiated Grade 1/2)

Clinical presentations:

• Nonfunctioning pancreatic tumors (See PanNET-1)

• Gastrinoma (See PanNET-2)

• Insulinoma (See PanNET-3)

• Glucagonoma (See PanNET-4)

• VIPoma (See PanNET-5)

• Locoregional unresectable disease and/or distant metastases (See

PanNET-7)

Neuroendocrine Tumors of Unknown Primary (Well-Dierentiated Grade 1/2)

(See NUP-1)

Well-Dierentiated, Grade 3 Neuroendocrine Tumors (See WDG3-1)

CP-1

See Principles of Pathology for Diagnosis and Reporting of Neuroendocrine Tumors (NE-A).

For well-differentiated grade 3 NET, see WDG3-1. For poorly differentiated/large or small cell carcinomas, see PDNEC-1.

Includes adrenal cortical tumors and incidentalomas.

CLINICAL PRESENTATIONS AND DIAGNOSIS

Extrapulmonary: Poorly dierentiated neuroendocrine

carcinoma/Large or small cell carcinoma other than lung/

Unknown primary (poorly dierentiated) (See PDNEC-1)

Adrenal Gland Tumors (See AGT-1)

Pheochromocytoma/Paraganglioma (See PHEO-1)

Multiple Endocrine Neoplasia, Type 1 (See MEN1-1)

• Parathyroid

• Pancreatic neuroendocrine tumors (PanNETs)

• Pituitary tumor

• Bronchial/thymic

Multiple Endocrine Neoplasia, Type 2 (See MEN2-1)

• Medullary thyroid carcinoma (Also see NCCN

Guidelines for Thyroid Carcinoma)

• Parathyroid

• Pheochromocytoma

Merkel Cell Carcinoma (See NCCN Guidelines for Merkel

Cell Carcinoma)

(NCCN

and this illustration may not be reproduced in any form without the express written permission of NCCN.

Note: All recommendations are category 2A unless otherwise indicated.

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

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NCCN Guidelines Index

Table of Contents

Discussion

NET-1

See Principles of Pathology for Diagnosis and Reporting of Neuroendocrine Tumors (NE-A).

See Principles of Imaging (NE-B).

See Principles of Biochemical Testing (NE-C).

PET/CT or PET/MRI of skull base to mid-thigh with IV contrast when possible. Data are limited on the optimal timing of scans following administration of somatostatin

analogs (SSAs).

SSR PET tracers include: 68Ga-DOTATATE, 64Cu-DOTATATE, 68Ga-DOTATOC.

See Surgical Principles for Management of Neuroendocrine Tumors (NE-D).

Should include:

• Manual palpation of the entire bowel, as synchronous tumors may be present.

• Assess for proximity to or involvement of the superior mesenteric artery and vein.

CLINICAL

LOCATION

EVALUATION

a,b,c

PRIMARY TREATMENT OF

NON-METASTATIC DISEASE

SURVEILLANCE

Jejunal/ileal/

colon

Recommended:

• Abdominal/pelvic multiphasic

CT or MRI

As appropriate:

• Somatostatin receptor (SSR)-

PET/CT or SSR-PET/MRI

b,d,e

• Colonoscopy

• Chest CT with or without contrast

• Biochemical evaluation as

clinically indicated

Locoregional

disease

Metastatic

disease

Bowel resection(s) with

regional lymphadenectomy

f,g

Metastatic Disease (NET-9)

See Surveillance

(NET-8)

(NCCN

and this illustration may not be reproduced in any form without the express written permission of NCCN.

Note: All recommendations are category 2A unless otherwise indicated.

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

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(Well-Dierentiated Grade 1/2), Lung, and Thymus

NCCN Guidelines Index

Table of Contents

Discussion

NET-2

If endoscopic resection performed, follow-up EGD as appropriate.

For non-ampullary tumors, endoscopic or local excision is

preferred. Pancreaticoduodenectomy should be considered for

ampullary tumors not amenable to endoscopic or local excision.

Invasion into muscle (see Staging, ST-2).

See Principles of Pathology for Diagnosis and Reporting of Neuroendocrine Tumors (NE-A).

See Principles of Imaging (NE-B).

See Principles of Biochemical Testing (NE-C).

PET/CT or PET/MRI of skull base to mid-thigh with IV contrast when possible. Data are

limited on the optimal timing of scans following administration of SSAs.

SSR PET tracers include: 68Ga-DOTATATE, 64Cu-DOTATATE, 68Ga-DOTATOC.

See Surgical Principles for Management of Neuroendocrine Tumors (NE-D).

CLINICAL

LOCATION

EVALUATION

a,b,c

PRIMARY TREATMENT OF

NON-METASTATIC DISEASE

SURVEILLANCE

Duodenal

Recommended:

• Abdominal/pelvic

multiphasic

CT or MRI

As appropriate:

• SSR-PET/CT or SSR-

PET/MRI

b,d,e

• EGD/endoscopic

ultrasound (EUS)

• Chest CT with or without

contrast

• Biochemical evaluation

as clinically indicated

Non-

functioning

NET

Duodenal

gastrinoma

Metastatic

disease

Metastatic Disease (NET-9)

Endoscopic resection

f,h,i

Local excision

(transduodenal)

f,i

regional lymphadenectomy

Pancreatoduodenectomy

f,i

Local excision

(transduodenal)

regional lymphadenectomy

Pancreatoduodenectomy

Noninvasive

tumors

Noninvasive

tumors

Invasive

tumors

Invasive

tumors

Routine endoscopic

surveillance

Routine endoscopic

surveillance

See Surveillance

(NET-8)

See Surveillance

(NET-8)

(NCCN

and this illustration may not be reproduced in any form without the express written permission of NCCN.

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

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(Well-Dierentiated Grade 1/2), Lung, and Thymus

NCCN Guidelines Index

Table of Contents

Discussion

NET-3

CLINICAL

LOCATION

EVALUATION

a,b,c

PRIMARY TREATMENT OF

NON-METASTATIC DISEASE

f,l

SURVEILLANCE

See Principles of Pathology for Diagnosis and Reporting of Neuroendocrine Tumors (NE-A).

See Principles of Imaging (NE-B).

PET/CT or PET/MRI of skull base to mid-thigh with IV contrast when possible. Data are limited on the optimal timing of scans following administration of SSAs.

SSR PET tracers include: 68Ga-DOTATATE, 64Cu-DOTATATE, 68Ga-DOTATOC.

See Surgical Principles for Management of Neuroendocrine Tumors (NE-D).

Some appendiceal neuroendocrine tumors will have mixed histology, including elements of adenocarcinoma. Such tumors should be managed according to colon

cancer guidelines. See NCCN Guidelines for Colon Cancer.

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

See Staging (ST-6). Patients with tumors <2 cm that do not invade beyond the mesoappendix can be considered for observation, after patient-physician discussion.

Heller D, et al. J Am Coll Surg 2019;228:839-851.

Greater than 12 lymph nodes should be retrieved.

Data are limited on survival benefit from right hemicolectomy.

Appendix

Metastatic

disease

Tumor >2 cm

Incomplete

resection or

Positive nodes/

margins

Tumor ≤2 cm

Recommended:

• Abdominal/pelvic

multiphasic CT or MRI

As appropriate:

• Consider SSR-PET/CT or

SSR-PET/MRI

b,d,e

Simple appendectomy

Consider right

hemicolectomy

f,m,n,o

No surveillance

indicated

Metastatic Disease (NET-9)

See Surveillance (NET-8)

(NCCN

and this illustration may not be reproduced in any form without the express written permission of NCCN.

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(Well-Dierentiated Grade 1/2), Lung, and Thymus

NCCN Guidelines Index

Table of Contents

Discussion

NET-4

CLINICAL

LOCATION

EVALUATION

a,b,c

PRIMARY TREATMENT

SURVEILLANCE

Rectal

Metastatic

disease

>2 cm

or node

positive

≤2 cm

T2–T4

Resection

(transanal

or endoscopic

excision, if possible)

• Low anterior

resection

• Abdominoperineal

resection (APR)

• <1 cm: No follow-up

required

• 1–≤2 cm: Endoscopy

with rectal MRI or

endorectal ultrasound

at 6 and 12 mo, then

as clinically indicated

Metastatic Disease

(NET-9)

Recommended:

• Colonoscopy

• Abdominal/Pelvic

multiphasic CT or MRI

As appropriate:

• SSR-PET/CT or

SSR-PET/MRI

b,d,e

• Chest CT with or without

contrast

See Principles of Pathology for Diagnosis and Reporting of Neuroendocrine Tumors

(NE-A).

See Principles of Imaging (NE-B).

See Principles of Biochemical Testing (NE-C).

PET/CT or PET/MRI of skull base to mid-thigh with IV contrast when possible. Data

are limited on the optimal timing of scans following administration of SSAs.

Rectal MRI

Endorectal

ultrasound

See Surveillance (NET-8)

Small (<1 cm)

completely resected

incidental tumors

All other

rectal

tumors

No additional

follow-up required

Endoscopy at 6–12

mo to assess for

residual disease

Low grade (G1)

Intermediate grade (G2)

Follow pathway

below for all other

rectal tumors

Negative margins

Indeterminate

margins

Negative

Positive or

intermediate

grade

SSR PET tracers include: 68Ga-DOTATATE, 64Cu-DOTATATE, 68Ga-

DOTATOC.

See Surgical Principles for Management of Neuroendocrine Tumors (NE-D).

For 1- to 2-cm tumors, consider examination under anesthesia (EUA) and/

or EUS with radical resection if muscularis propria invasion or node positive.

(NCCN

and this illustration may not be reproduced in any form without the express written permission of NCCN.

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NCCN Guidelines Index

Table of Contents

Discussion

NET-5

CLINICAL

LOCATION

EVALUATION

a,b,c

PRIMARY TREATMENT

/SURVEILLANCE

Gastric

• EGD

• Gastric

biopsy

• Serum

gastrin level

• Consider

Gastric

pH, as

appropriate

Hyper-

gastrinemic/

Type 2

(Zollinger-

Ellison; no

atrophic

gastritis, low

gastric pH)

Hyper-

gastrinemic/

Type 1

(atrophic

gastritis, or

high gastric

pH)

t,u

Normal

gastrin/

Type 3

• Vitamin B

level

• EUS as clinically indicated

• After baseline gastrin,

following gastrin and

CgA levels is not

recommended

Every 2–3 y or as clinically indicated:

• Endoscopic surveillance and endoscopic

resection of prominent tumors

• Abdominal multiphasic CT or

MRI

• SSR-PET/CT or

SSR-PET/MRI

b,d,e

• EUS as clinically indicated

• Other biochemical evaluation,

as clinically indicated

• Consider genetic counseling

and testing for inherited

genetic syndromes

• EUS

• Abdominal multiphasic CT or

MRI

• SSR-PET/CT or

SSR-PET/MRI

b,d,e

Consider endoscopic surveillance and

endoscopic resection of prominent tumors

and/or

Consider octreotide

or lanreotide

and

Manage gastric hypersecretion with high-

dose proton pump inhibitors

Radical resection with regional

lymphadenectomy (preferred)

Consider endoscopic or surgical

wedge resection

(if no evidence

of regional lymphadenopathy on

EUS or other imaging)

Metastatic disease (See NET-9)

Resect primary gastrinoma (See NET-2 or PanNET-2)

Primary

gastrinoma

not

resected

See

Surveillance

(NET-8)

Endoscopic

resection of

prominent

tumors

See Principles of Pathology for Diagnosis and Reporting of

Neuroendocrine Tumors (NE-A).

See Principles of Imaging (NE-B).

See Principles of Biochemical Testing (NE-C).

PET/CT or PET/MRI of skull base to mid-thigh with IV

contrast when possible. Data are limited on the optimal

timing of scans following administration of SSAs.

SSR PET tracers include: 68Ga-DOTATATE, 64Cu-

DOTATATE, 68Ga-DOTATOC.

See Surgical Principles for Management of Neuroendocrine

Tumors (NE-D).

May need multiple biopsies throughout the entire stomach.

Serum gastrin can be falsely elevated with proton pump inhibitor (PPI) use. To confirm

diagnosis, it should ideally be checked when fasting and off PPI for >1 week. However,

PPI should be continued in patients with overt clinical symptoms of gastrinoma and/or

risks of complications.

See Principles of Genetic Risk Assessment and Counseling (NE-E).

Elevated gastrin levels are usually suggestive of type 1 or type 2 tumors.

For rare, >2 cm, type 1 gastric tumors, workup should include multiphasic CT or MRI of

the abdomen. For metastatic disease, NET-11.

Type 3 gastric neuroendocrine tumors are sporadic and unifocal.

See Principles of Systemic Anti-Tumor Therapy (NE-F).

Endoscopic resection should be reserved for small (<1 cm), superficial, low-grade tumors.

(NCCN

and this illustration may not be reproduced in any form without the express written permission of NCCN.

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

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(Well-Dierentiated Grade 1/2), Lung, and Thymus

NCCN Guidelines Index

Table of Contents

Discussion

NET-6

See Principles of Pathology for Diagnosis and Reporting of Neuroendocrine Tumors

(NE-A).

See Principles of Imaging (NE-B).

See Principles of Biochemical Testing (NE-C).

PET/CT or PET/MRI of skull base to mid-thigh with IV contrast when possible. Data are

limited on the optimal timing of scans following administration of SSAs.

SSR PET tracers include: 68Ga-DOTATATE, 64Cu-DOTATATE, 68Ga-DOTATOC.

See Surgical Principles for Management of Neuroendocrine Tumors (NE-D).

See Principles of Genetic Risk Assessment and Counseling (NE-E).

CLINICAL

LOCATION

EVALUATION

a,b,c

PRIMARY TREATMENT OF NON-METASTATIC DISEASE

Thymus

Recommended:

• Chest CT and

abdominal multiphasic

CT or MRI

As appropriate:

• SSR-PET/CT or

SSR-PET/MRI

b,d,e

• Biochemical workup

for Cushing syndrome

if clinically indicated

• Other biochemical

evaluation as clinically

indicated (See NE-C)

• Consider genetic

counseling and testing

for inherited genetic

syndromes

Metastatic Disease (NET-11)

Consider observation

Consider RT

(category 3)

Consider observation

Consider RT

cytotoxic

chemo

therapy

w,z,aa

Locoregional

disease

(Stage IIIA/B)

Metastatic disease (Stage IV)

Localized disease

(Stage I–II)

Resect

Complete resection

and negative margins

Resectable

Locally

unresectable

See Principles of Systemic Anti-Tumor Therapy (NE-F).

There is a gap issue and therapeutic challenge in managing patients who

fall into this category due to a lack of data. However, the panel suggests

use of these options in select cases or as needed.

Chemoradiation is thought to have most efficacy for tumors with atypical

histology or tumors with higher mitotic and proliferative indices (eg, Ki-67).

Cytotoxic chemotherapy options include cisplatin + etoposide, or

carboplatin + etoposide.

See

Surveillance

(NET-8)

Low grade

(typical

carcinoid)

Intermediate

grade

(atypical

carcinoid)

Incomplete

resection

and/or

positive

margins

See Management of Locoregional

Advanced Disease (NET-10)

(NCCN

and this illustration may not be reproduced in any form without the express written permission of NCCN.

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(Well-Dierentiated Grade 1/2), Lung, and Thymus

NCCN Guidelines Index

Table of Contents

Discussion

NET-7

See Principles of Pathology for Diagnosis and Reporting of Neuroendocrine Tumors (NE-A).

See Principles of Imaging (NE-B).

See Principles of Biochemical Testing (NE-C).

PET/CT or PET/MRI of skull base to mid-thigh with IV contrast when possible. Data are

limited on the optimal timing of scans following administration of SSAs.

SSR PET tracers include: 68Ga-DOTATATE, 64Cu-DOTATATE, 68Ga-DOTATOC.

See Surgical Principles for Management of Neuroendocrine Tumors (NE-D).

CLINICAL

LOCATION

EVALUATION

a,b,c

PRIMARY THERAPY

f,w

Broncho-

pulmonary

Recommended:

• Chest CT with contrast

and abdominal

multiphasic CT or MRI

Consider:

• SSR-PET/CT or SSR-

PET/MRI

b,d,e

• Brain MRI, if clinically

indicated

• Bronchoscopy if

clinically indicated

• Biochemical workup for

Cushing and carcinoid

syndrome if clinically

indicated (See NE-C)

• Other biochemical

evaluation as clinically

indicated

• Consider genetic

counseling and testing

for inherited genetic

syndromes

Localized

disease

(Stage I–II)

Locoregional/

resectable

(Stage IIIA)

Locoregional/

unresectable

(Stage IIIA/B/C)

Metastatic

disease

(Stage IV)

Lobectomy or other anatomic resection

+ mediastinal node dissection or sampling

If surgery contraindicated, thermal ablation

or SBRT

Lobectomy or

other anatomic

resection

+ mediastinal

node dissection

or sampling

Metastatic Disease (NET-11)

Observation

Consider

cytotoxic

chemotherapy

(category 2B)

Low grade (typical carcinoid)

Intermediate

grade

(atypical

carcinoid)

ADJUVANT THERAPY

See

Surveillance

(NET-8)

See Principles of Genetic Risk Assessment and Counseling (NE-E).

See Principles of Systemic Anti-Tumor Therapy (NE-F).

If Cushing syndrome is suspected, assess for and treat ectopic

sources of ACTH production.

Cytotoxic chemotherapy options include cisplatin + etoposide,

carboplatin + etoposide, or temozolomide. There are limited data on the

efficacy of chemotherapy for stage III atypical bronchopulmonary NET.

See Management of

Locoregional Unresectable

Disease (NET-10)

(NCCN

and this illustration may not be reproduced in any form without the express written permission of NCCN.

Note: All recommendations are category 2A unless otherwise indicated.

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

NCCN Guidelines Version 2.2021

Neuroendocrine Tumors of the Gastrointestinal Tract

(Well-Dierentiated Grade 1/2), Lung, and Thymus

NCCN Guidelines Index

Table of Contents

Discussion

NET-8

SURVEILLANCE

c,dd,ee,

GI TRACT, LUNG, AND THYMUS

RECURRENT DISEASE MANAGEMENT OF RECURRENT DISEASE

12 wk–12 mo post-resection:

• H&P

• Consider biochemical markers as clinically

indicated (See NE-C)

• Abdominal ± pelvic multiphasic CT or MRI as

clinically indicated

• Chest CT with or without contrast for primary

lung/thymus tumors (as clinically indicated for

primary GI tumors)

>1 y post-resection to 10 y:

• Every 12–24 mo

H&P

Consider biochemical markers as clinically

indicated (See NE-C)

Abdominal ± pelvic multiphasic CT or MRI

Chest CT with or without contrast for primary

lung/thymus tumors (as clinically indicated

for primary GI tumors)

>10 y:

• Consider surveillance as clinically indicated

b,gg

Carcinoid

Syndrome

Disease recurrence

See Principles of Imaging (NE-B).

See Principles of Biochemical Testing (NE-C).

See Surgical Principles for Management of Neuroendocrine Tumors (NE-D).

Earlier, if symptoms. If initial scans are negative, the frequency of follow-up scans may decrease. For high-grade tumors, more frequent surveillance may be

appropriate.

SSR-based imaging and FDG-PET/CT scan are not recommended for routine surveillance.

See NCCN Guidelines for Survivorship.

Singh S, et al. JAMA Oncol 2018;4:1597-1604.

In select cases, resection may be considered.

See Management of Locoregional

Advanced Disease and/or Distant

Metastases (NET-9)

GI Tract

Bronchopulmonary/

Thymus

See Management of Locoregional

Unresectable Disease (NET-10)

See Management of Distant

Metastases (NET-11)

See Management of Carcinoid

Syndrome (NET-12)

(NCCN

and this illustration may not be reproduced in any form without the express written permission of NCCN.

Note: All recommendations are category 2A unless otherwise indicated.

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

NCCN Guidelines Version 2.2021

Neuroendocrine Tumors of the Gastrointestinal Tract

(Well-Dierentiated Grade 1/2), Lung, and Thymus

NCCN Guidelines Index

Table of Contents

Discussion

NET-9

MANAGEMENT OF LOCOREGIONAL ADVANCED DISEASE AND/OR DISTANT METASTASES

GASTROINTESTINAL TRACT

If complete

resection

possible

f,ii

Observe with

imaging

Octreotide

w,kk

or lanreotide

w,kk

If disease progression

Everolimus

PRRT with 177Lu-dotatate (if SSR-

positive imaging and progression on

octreotide or lanreotide) (category 1

for progressive mid-gut tumors)

w,nn

Liver-directed therapy for liver-

predominant disease

Palliative RT for symptomatic bone

metastases

Cytotoxic chemotherapy

(category

3), if no other options feasible

• Multiphasic

abdominal/pelvic

CT or MRI

• Chest CT (±

contrast) as

clinically indicated

• SSR-PET/CT or

SSR-PET/MRI

b,d,e

• Biochemical

evaluation

as clinically

indicated

Asymptomatic,

low tumor

burden

Locally

symptomatic

from primary

tumor

Clinically

significant

tumor burden

Resect primary

+ metastases

Abdominal/

pelvic

multiphasic

CT or MRI

every 12 wk–

12 mo, and

chest CT (±

contrast)

as clinically

indicated

Consider

resection of

primary tumor

Octreotide

w,kk

or lanreotide

w,kk

and/or

Alternative front-line therapy

(see options for disease progression)

Refer to surveillance

for appropriate primary

disease sites

(See NET-1 through NET-5)

If disease

progression,

octreotide

w,kk

lanreotide

w,kk

(if not already

receiving)

EVALUATION

b,c

TREATMENT

See Principles of Imaging (NE-B).

See Principles of Biochemical Testing (NE-C).

PET/CT or PET/MRI of skull base to mid-thigh with IV contrast when possible.

Data are limited on the optimal timing of scans following administration of SSAs.

SSR PET tracers include: 68Ga-DOTATATE, 64Cu-DOTATATE, 68Ga-

DOTATOC.

See Surgical Principles for Management of Neuroendocrine Tumors (NE-D).

See Principles of Systemic Anti-Tumor Therapy (NE-F).

Noncurative debulking surgery might be considered in select cases.

Resection of a small asymptomatic (relatively stable) primary in the presence

of unresectable metastatic disease is not indicated. However, taking a careful

history is recommended as surgery may be an option for asymptomatic patients

with previous, intermittent obstructions.

Treatment with octreotide or lanreotide will likely only benefit those patients

who are SSR-positive.

In select cases it may be appropriate to proceed to front-line systemic therapy

or liver-directed therapy prior to or concurrently with octreotide or lanreotide.

If disease progression, treatment with octreotide or lanreotide should

be discontinued for non-functional tumors and continued in patients with

functional tumors; those regimens may be used in combination with any of

the subsequent options. For details on the administration of octreotide or

lanreotide with 177Lu-dotatate, see NE-G.

See Principles of Peptide Receptor Radionuclide Therapy (PRRT) with

177Lu-dotatate (NE-G).

See Principles of Liver-Directed Therapy for Neuroendocrine Tumor

Metastases (NE-H).

(NCCN

and this illustration may not be reproduced in any form without the express written permission of NCCN.

Note: All recommendations are category 2A unless otherwise indicated.

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

NCCN Guidelines Version 2.2021

Neuroendocrine Tumors of the Gastrointestinal Tract

(Well-Dierentiated Grade 1/2), Lung, and Thymus

NCCN Guidelines Index

Table of Contents

Discussion

NET-10

Chemoradiation is thought to have most efficacy for tumors with atypical histology or tumors with higher mitotic and proliferative indices (eg, Ki-67).

If disease progression, treatment with octreotide or lanreotide should be discontinued for non-functional tumors and continued in patients with

functional tumors; those regimens may be used in combination with any of the subsequent options. For details on the administration of octreotide

or lanreotide with 177Lu-dotatate, see NE-G.

See Principles of Peptide Receptor Radionuclide Therapy (PRRT) with 177Lu-dotatate (NE-G).

For symptom control, consider addition of focal therapy (ie, endobronchial therapy debulking, ablation).

PRIMARY THERAPY

Bronchopulmonary/thymus

locoregional unresectable

Observation (if asymptomatic and non-

progressive)

RT ± concurrent cisplatin + etoposide or

carboplatin + etoposide

Cytotoxic chemotherapy with

cisplatin + etoposide, carboplatin +

etoposide, or temozolomide ± capecitabine

Octreotide or lanreotide (if SSR-positive and/

or hormonal symptoms)

Everolimus

Observation

(if asymptomatic)

Octreotide or lanreotide (if SSR-positive and/

or hormonal symptoms)

Everolimus

Temozolomide ± capecitabine

SUBSEQUENT

THERAPY

mm,pp

Low grade

(typical

carcinoid)

Intermediate

grade

(atypical

carcinoid)

Clinical trial (preferred)

Consider changing therapy

if progression on rst-line

therapy

Consider peptide receptor

radionuclide therapy (PRRT)

with 177Lu-dotatate (if SSR-

positive and progression on

octreotide/lanreotide)

MANAGEMENT OF LOCOREGIONAL UNRESECTABLE DISEASE

BRONCHOPULMONARY OR THYMUS

(NCCN

and this illustration may not be reproduced in any form without the express written permission of NCCN.

Note: All recommendations are category 2A unless otherwise indicated.

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

NCCN Guidelines Version 2.2021

Neuroendocrine Tumors of the Gastrointestinal Tract

(Well-Dierentiated Grade 1/2), Lung, and Thymus

NCCN Guidelines Index

Table of Contents

Discussion

NET-11

See Principles of Imaging (NE-B).

See Principles of Systemic Anti-Tumor Therapy (NE-F).

If disease progression, treatment with octreotide or lanreotide should be discontinued

for non-functional tumors and continued in patients with functional tumors; those

regimens may be used in combination with any of the subsequent options. For details on

the administration of octreotide or lanreotide with 177Lu-dotatate, see NE-G.

See Principles of Peptide Receptor Radionuclide Therapy (PRRT) with 177Lu-dotatate

(NE-G).

See Principles of Liver-Directed Therapy for Neuroendocrine Tumor Metastases (NE-H).

For symptom control, consider addition of focal therapy (ie, endobronchial

therapy debulking, ablation).

Neuroendocrine tumors are highly heterogeneous and all elements need

to be considered (eg, burden of disease, symptoms, histopathology, rate of

growth) when determining the best course of treatment.

Observation can be considered if asymptomatic or for tumors on the lower

end of the spectrum.

Can be considered for intermediate-grade/atypical tumors with Ki-67

proliferative index and mitotic index in the higher end of the defined spectrum.

MANAGEMENT OF DISTANT METASTASES

BRONCHOPULMONARY OR THYMUS

Bronchopulmonary/

Thymus

Distant metastases

Asymptomatic, low

tumor burden and

low grade (typical

carcinoid)

Observe

Octreotide or lanreotide (if SSR-positive and/

or hormonal symptoms)

Clinical trial (preferred)

Observation, in select patients

Octreotide or lanreotide (if SSR-positive and/or hormonal

symptoms)

Everolimus (category 1 for bronchopulmonary NET)

PRRT with 177Lu-dotatate (if SSR-positive and progression on

octreotide or lanreotide)

Cisplatin + etoposide

or carboplatin + etoposide

Temozolomide ± capecitabine

Liver-directed therapy for liver-predominant disease

Clinically signicant

tumor burden and

low grade (typical

carcinoid)

Evidence of disease

progression

Intermediate grade

(atypical carcinoid)

Symptomatic disease

TREATMENT

w,pp,qq

Multiple lung nodules

or tumorlets and

evidence of diuse

idiopathic pulmonary

neuroendocrine cell

hyperplasia (DIPNECH)

Chest CT with

contrast and

abdominal/pelvic

multiphasic CT or

MRI

every 3–6 mo

Consider

changing

therapy if

progression

on rst-line

therapy

w,mm

Observe

Octreotide or lanreotide (if SSR-positive and/or

chronic cough/dyspnea is not responsive to inhalers)

Chest CT (without

contrast) every

12–24 mo or as

clinically indicated

(NCCN

and this illustration may not be reproduced in any form without the express written permission of NCCN.

Note: All recommendations are category 2A unless otherwise indicated.

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

NCCN Guidelines Version 2.2021

Neuroendocrine Tumors of the Gastrointestinal Tract

(Well-Dierentiated Grade 1/2), Lung, and Thymus

NCCN Guidelines Index

Table of Contents

Discussion

NET-12

CARCINOID SYNDROME

EVALUATION SURVEILLANCE ADDITIONAL

THERAPY

TREATMENT

Octreotide

w,uu

Lanreotide

If any persistent symptoms

(ie, ushing, diarrhea),

rule out non-carcinoid

syndrome causes

and

Consider additional

therapy for symptom

control:

• Hepatic arterial

embolization or

cytoreductive surgery for

liver-predominant disease

• Telotristat for diarrhea

(250 mg, by mouth 3

times a day)

• Other systemic therapy

based on disease site

w,ww

If disease progression,

see Management

of Locoregional,

Advanced Disease and/

or Distant Metastases:

• GI Tract (NET-9

• Bronchopulmonary/

Thymus (NET-10 and

NET-11)

bSee

Principles of Imaging (NE-B).

cSee

Principles of Biochemical Testing (NE-C).

wSee

Principles of Systemic Anti-Tumor Therapy (NE-F).

mmIf

disease progression, treatment with octreotide or lanreotide should

be discontinued for non-functional tumors and continued in patients

with functional tumors; those regimens may be used in combination

with any of the subsequent options. For details on the administration

of octreotide or lanreotide with 177Lu-dotatate, see NE-G.

See Principles of Hormone Control (NE-I).

Recommended:

• Biochemical

evaluation with

24-hour urine or

plasma 5-HIAA

• Echocardiogram

• Imaging to

assess disease

progression (See

NET-10 or NET-11)

Carcinoid

syndrome

well

controlled

Carcinoid

syndrome

poorly

controlled

• Echocardiogram

every 2–3 y or

as clinically

indicated

• Abdominal/pelvic

multiphasic CT

or MRI every

12 wk–12 mo,

and chest CT

(± contrast)

as clinically

indicated

For symptom control, octreotide 150–250 mcg SC TID or octreotide LAR 20–30 mg IM

or lanreotide 120 mg SC every 4 weeks. Dose and frequency may be further increased for

symptom control as needed. Therapeutic levels of octreotide would not be expected to be

reached for 10–14 d after LAR injection. Short-acting octreotide can be added to octreotide

LAR for rapid relief of symptoms or for breakthrough symptoms. For details on the

administration of short-acting and/or long-acting octreotide with 177Lu-dotatate, see NE-G.

Evaluate for pancreatic exocrine deficiency and bile acid diarrhea.

wwSafety

and effectiveness of everolimus in the treatment of patients with carcinoid syndrome

have not been established.

(NCCN

and this illustration may not be reproduced in any form without the express written permission of NCCN.

Note: All recommendations are category 2A unless otherwise indicated.

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

NCCN Guidelines Version 2.2021

Neuroendocrine Tumors of the Pancreas

(Well-Dierentiated Grade 1/2)

NCCN Guidelines Index

Table of Contents

Discussion

PanNET-1

CLINICAL

LOCATION

EVALUATION

a,b,c

MANAGEMENT OF PRIMARY NON-METASTATIC DISEASE

h,i,j

Nonfunctioning

pancreatic

tumors

Recommended:

• Abdominal ± pelvis

multiphasic CT or MRI

As appropriate:

• SSR-PET/CT or

SSR-PET/MRI

a,d,e

• Chest CT ± contrast

• EUS

• Biochemical evaluation

as clinically indicated

(See NE-C)

• Consider genetic

counseling and testing

for inherited genetic

syndromes

See Principles of Imaging (NE-B).

See Principles of Pathology for Diagnosis and Reporting of Neuroendocrine Tumors (NE-A).

See Principles of Biochemical Testing (NE-C).

SSR PET tracers include: 68Ga-DOTATATE, 64Cu-DOTATATE, 68Ga-DOTATOC.

PET/CT or PET/MRI of skull base to mid-thigh with IV contrast when possible. Data are limited on the optimal timing of scans following administration of SSAs.

See Principles of Genetic Risk Assessment and Counseling (NE-E).

Observation can be considered for small (≤ 2 cm), low-grade, incidentally discovered, non-functional tumors. Decision based on estimated surgical risk, site of tumor,

and patient comorbidities. (Sadot E, et al. Ann Surg Oncol 2016;23:1361-70.) Follow surveillance recommendations on PanNET-6.

See Surgical Principles for Management of Neuroendocrine Tumors (NE-D).

Preoperative trivalent vaccine (ie, pneumococcus, haemophilus influenzae b, meningococcal group C), if considering surgery with possible splenectomy.

As appropriate, central pancreatectomy or spleen-preserving surgery should be considered.

Neuroendocrine tumors of the pancreas that are 1–2 cm have a small, but real risk of lymph node metastases. Therefore, lymph node resection should be considered.

Locoregional

disease

Metastatic disease

Small (≤2 cm)

Larger (>2 cm),

invasive, or

node-positive

tumors

Distal

Observation in select

cases

Enucleation ± regional

lymphadenectomy

h,k

Resection ± regional

lymphadenectomy

h,k

See

Surveillance

(PanNET-6)

Head

See Metastases (PanNET-7)

Pancreatoduodenectomy

+ regional

lymphadenectomy

Distal pancreatectomy

splenectomy + regional

lymphadenectomy

(NCCN

and this illustration may not be reproduced in any form without the express written permission of NCCN.

Note: All recommendations are category 2A unless otherwise indicated.

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

NCCN Guidelines Version 2.2021

Neuroendocrine Tumors of the Pancreas

(Well-Dierentiated Grade 1/2)

NCCN Guidelines Index

Table of Contents

Discussion

PanNET-2

CLINICAL

LOCATION

EVALUATION

a,b,c

MANAGEMENT OF PRIMARY NON-METASTATIC DISEASE

h,i,l

Gastrinoma

(usually

duodenum

or head of

pancreas)

Recommended:

• Serum gastrin

level

c,m

• Abdominal ± pelvis

multiphasic CT or

MRI

• Genetic counseling

and testing for

inherited genetic

syndromes

As appropriate:

• SSR-PET/CT or

SSR-PET/MRI

a,d,e

• Chest CT ± contrast

• EUS

• Other biochemical

evaluation as

clinically indicated

(See NE-C)

See Principles of Imaging (NE-B).

See Principles of Pathology for Diagnosis and Reporting of Neuroendocrine

Tumors (NE-A).

See Principles of Biochemical Testing (NE-C).

SSR PET tracers include: 68Ga-DOTATATE, 64Cu-DOTATATE, 68Ga-

DOTATOC.

PET/CT or PET/MRI of skull base to mid-thigh with IV contrast when possible.

Data are limited on the optimal timing of scans following administration of SSAs.

See Principles of Genetic Risk Assessment and Counseling (NE-E).

Locoregional

disease

Metastatic

disease

Distal

Observe

Exploratory surgery

including duodenotomy and

intraoperative ultrasound;

local resection/enucleation

of tumor(s) + periduodenal

node dissection

See

Surveillance

(PanNET-6)

Head

See Metastases

(PanNET-7)

Exophytic or

peripheral tumors

by imaging

Deeper or invasive

tumors and those

in proximity to the

main pancreatic duct

• Manage

gastric hyper-

secretion with

high-dose

proton pump

inhibitors

• Octreotide

or lanreotide

Duodenum

Occult

No primary tumor

or metastases on

imaging

Distal pancreatectomy

h,i

splenectomy + regional nodes

Pancreato-

duodenectomy

Enucleation

of tumor +

periduodenal

node dissection

Duodenotomy and

intraoperative ultrasound;

local resection/enucleation

of tumor(s) + periduodenal

node dissection

See Surgical Principles for Management of Neuroendocrine Tumors (NE-D).

Preoperative trivalent vaccine (ie, pneumococcus, haemophilus influenzae b,

meningococcal group C), if considering surgery with possible splenectomy.

See Principles of Hormone Control (NE-I).

Serum gastrin can be falsely elevated with proton pump inhibitor (PPI) use. To

confirm diagnosis, it should ideally be checked when fasting and off PPI for >1

week. However, PPI should be continued in patients with overt clinical symptoms

of gastrinoma and/or risks of complications.

See Principles of Systemic Anti-Tumor Therapy (NE-F).

Not adjacent to the main pancreatic duct.

(NCCN

and this illustration may not be reproduced in any form without the express written permission of NCCN.

Note: All recommendations are category 2A unless otherwise indicated.

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

NCCN Guidelines Version 2.2021

Neuroendocrine Tumors of the Pancreas

(Well-Dierentiated Grade 1/2)

NCCN Guidelines Index

Table of Contents

Discussion

PanNET-3

CLINICAL

LOCATION

EVALUATION

a,b,c

MANAGEMENT OF PRIMARY NON-METASTATIC DISEASE

h,i,l

Insulinoma

Recommended:

• Abdominal ± pelvis

multiphasic CT or MRI

• Serum insulin, pro-insulin,

and c-peptide levels

during

concurrent hypoglycemia

As appropriate:

• EUS

• Other biochemical

evaluation as clinically

indicated (See NE-C)

• SSR-PET/CT or

SSR-PET/MRI

a,d,e,p

• Chest CT ± contrast

• Consider genetic counseling

and testing for inherited

genetic syndromes

See Principles of Imaging (NE-B).

See Principles of Pathology for Diagnosis and Reporting of Neuroendocrine Tumors (NE-A).

See Principles of Biochemical Testing (NE-C).

SSR PET tracers include: 68Ga-DOTATATE, 64Cu-DOTATATE, 68Ga-DOTATOC.

PET/CT or PET/MRI of skull base to mid-thigh with IV contrast when possible. Data are

limited on the optimal timing of scans following administration of SSAs.

See Principles of Genetic Risk Assessment and Counseling (NE-E).

See Surgical Principles for Management of Neuroendocrine Tumors (NE-D.

Preoperative trivalent vaccine (ie, pneumococcus, haemophilus influenzae b, meningococcal

group C), if considering surgery with possible splenectomy.

Locoregional

disease

Metastatic disease

Distal

Tumor

enucleation

See

Surveillance

(PanNET-6)

Head

Pancreato-

duodenectomy

Distal

pancreatectomy

(spleen-

preserving

consider

minimally

invasive

resection

See Principles of Hormone Control (NE-I).

Not adjacent to the main pancreatic duct.

SSR-based imaging only if treatment with octreotide or lanreotide

is planned. Octreotide or lanreotide should only be given if tumor

demonstrates SSRs. In the absence of SSRs, octreotide or lanreotide

can profoundly worsen hypoglycemia. (See Discussion for details).

Splenectomy should be performed for larger tumors involving splenic

vessels.

See Metastases (PanNET-7)

Exophytic

peripheral

tumors by

imaging

Stabilize

glucose

levels with

diet and/or

diazoxide

and/or

everolimus

Deeper or

invasive

tumors and

those in

proximity to

the main

pancreatic

duct

Head

Distal

(NCCN

and this illustration may not be reproduced in any form without the express written permission of NCCN.

Note: All recommendations are category 2A unless otherwise indicated.

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

NCCN Guidelines Version 2.2021

Neuroendocrine Tumors of the Pancreas

(Well-Dierentiated Grade 1/2)

NCCN Guidelines Index

Table of Contents

Discussion

PanNET-4

CLINICAL

LOCATION

EVALUATION

a,b,c

MANAGEMENT OF PRIMARY NON-METASTATIC DISEASE

h,i,l

Glucagonoma

(usually tail)

Recommended:

• Glucagon and blood

glucose

• Abdominal ± pelvis

multiphasic CT or MRI

As appropriate:

• SSR-PET/CT or

SSR-PET/MRI

a,d,e

• Chest CT ± contrast

• EUS

• Biochemical evaluation

as clinically indicated

(See NE-C)

• Consider genetic

counseling and testing

for inherited genetic

syndromes

See Principles of Imaging (NE-B).

See Principles of Pathology for Diagnosis and Reporting of Neuroendocrine Tumors (NE-A).

See Principles of Biochemical Testing (NE-C).

SSR PET tracers include: 68Ga-DOTATATE, 64Cu-DOTATATE, 68Ga-DOTATOC.

PET/CT or PET/MRI of skull base to mid-thigh with IV contrast when possible. Data are limited on the optimal timing of scans following administration of SSAs.

See Principles of Genetic Risk Assessment and Counseling (NE-E).

See Surgical Principles for Management of Neuroendocrine Tumors (NE-D).

Preoperative trivalent vaccine (ie, pneumococcus, haemophilus influenzae b, meningococcal group C), if considering surgery with possible splenectomy.

See Principles of Hormone Control (NE-I).

See Principles of Systemic Anti-Tumor Therapy (NE-F).

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

Hypercoaguable state has been described. Perioperative anticoagulation can be considered.

Locoregional

disease

Metastatic

disease

Distal

See

Surveillance

(PanNET-6)

Head

(rare)

Pancreatoduodenectomy

+ peripancreatic

lymphadenectomy

h,q

Distal pancreatectomy

+ peripancreatic

lymphadenectomy

dissection +

splenectomy

h,i,q

See Metastases (PanNET-7)

• Octreotide

lanreotide

• Treat hyperglycemia

and diabetes, as

appropriate

(NCCN

and this illustration may not be reproduced in any form without the express written permission of NCCN.

Note: All recommendations are category 2A unless otherwise indicated.

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

NCCN Guidelines Version 2.2021

Neuroendocrine Tumors of the Pancreas

(Well-Dierentiated Grade 1/2)

NCCN Guidelines Index

Table of Contents

Discussion

PanNET-5

CLINICAL

LOCATION

EVALUATION

a,b,c

MANAGEMENT OF PRIMARY NON-METASTATIC DISEASE

h,i,l

VIPoma

Recommended:

• Electrolytes

• VIP levels

• Abdominal ± pelvis

multiphasic CT or MRI

As appropriate:

• SSR-PET/CT or

SSR-PET/MRI

a,d,e

• Chest CT ± contrast

• EUS

• Biochemical evaluation

as clinically indicated

(See NE-C)

• Consider genetic

counseling and testing

for inherited genetic

syndromes

See Principles of Imaging (NE-B).

See Principles of Pathology for Diagnosis and Reporting of Neuroendocrine Tumors (NE-A).

See Principles of Biochemical Testing (NE-C).

SSR PET tracers include: 68Ga-DOTATATE, 64Cu-DOTATATE, 68Ga-DOTATOC.

PET/CT or PET/MRI of skull base to mid-thigh with IV contrast when possible. Data are limited on the optimal timing of scans following administration of SSAs.

See Principles of Genetic Risk Assessment and Counseling (NE-E).

See Surgical Principles for Management of Neuroendocrine Tumors (NE-D).

Preoperative trivalent vaccine (ie, pneumococcus, haemophilus influenzae b, meningococcal group C), if considering surgery with possible splenectomy.

See Principles of Hormone Control (NE-I).

See Principles of Systemic Anti-Tumor Therapy (NE-F).

Small (<2 cm), peripheral VIPomas are rare; enucleation/local excision + peripancreatic lymph dissection may be considered.

Locoregional

disease

Metastatic

disease

Distal

See

Surveillance

(PanNET-6)

Head

Pancreatoduodenectomy

+ peripancreatic

lymphadenectomy

Distal pancreatectomy

+ peripancreatic

lymphadenectomy

dissection ±

splenectomy

h,i

See Metastases (PanNET-7)

• Octreotide

lanreotide

• Correct electrolyte

imbalance (K

, HCO

) and

dehydration

(NCCN

and this illustration may not be reproduced in any form without the express written permission of NCCN.

Note: All recommendations are category 2A unless otherwise indicated.

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

NCCN Guidelines Version 2.2021

Neuroendocrine Tumors of the Pancreas

(Well-Dierentiated Grade 1/2)

NCCN Guidelines Index

Table of Contents

Discussion

PanNET-6

SURVEILLANCE

t,u,v,w

RECURRENT DISEASE MANAGEMENT OF RECURRENT DISEASE

12 wk–12 mo post-resection:

• H&P

• Consider biochemical markers as

clinically indicated

• Abdominal multiphasic

CT or MRI

and chest CT (± contrast) as clinically

indicated

>1 y post-resection to a maximum of 10 y:

• Every 6–12 mo

H&P

Consider biochemical markers as

clinically indicated

Consider abdominal multiphasic

or MRI and chest CT (± contrast) as

clinically indicated

>10 y:

• Consider surveillance as clinically

indicated

See Principles of Imaging (NE-B).

See Principles of Biochemical Testing (NE-C).

See Surgical Principles for Management of Neuroendocrine Tumors (NE-D).

Earlier, if symptoms.

SSR-based imaging and FDG-PET/CT scan are not recommended for routine surveillance.

Surveillance recommendations also apply to cases where observation has been chosen.

See NCCN Guidelines for Survivorship.

Singh S, et al. JAMA Oncol 2018;4:1597-1604.

In select cases, resection may be considered.

See Management of Locoregional Advanced Disease

and/or Distant Metastases (PanNET-7)

Disease recurrence

(NCCN

and this illustration may not be reproduced in any form without the express written permission of NCCN.

Note: All recommendations are category 2A unless otherwise indicated.

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

NCCN Guidelines Version 2.2021

Neuroendocrine Tumors of the Pancreas

(Well-Dierentiated Grade 1/2)

NCCN Guidelines Index

Table of Contents

Discussion

PanNET-7

MANAGEMENT OF LOCOREGIONAL ADVANCED DISEASE AND/OR DISTANT METASTASES

• Abdominal ±

pelvic multiphasic

CT or MRI

and chest CT

(± contrast) as

clinically indicated

• SSR-PET/CT or

SSR-PET/MRI

a,d,e

• Biochemical

evaluation as

clinically indicated

(See NE-C)

• Consider tumor

classication/

grade (See NE-A)

• Observe with markers

and abdominal/pelvic

multiphasic

CT or MRI

every 12 wk–12 mo and

chest CT (± contrast)

as clinically indicated

• Consider octreotide

n,dd

or lanreotide

n,dd

Resect metastases + primary

See Surveillance (PanNET-6)

If complete

resection

possible

h,aa

Asymptomatic,

low tumor

burden, and

stable disease

Symptomatic

Clinically

signicant

tumor burden

Clinically

signicant

progressive

disease

TREATMENT

EVALUATION

Manage clinically

signicant symptoms

as appropriate

(PanNET-1, PanNET-2,

PanNET-3, PanNET-4,

and PanNET-5)

Consider alternative front-line therapy

(see options for disease progression)

If disease

progression,

consider

octreotide

n,dd

lanreotide

n,dd

(if not already

receiving)

If disease progression

Clinical trial

Everolimus

(category 1 for progressive

disease)

Sunitinib

(category 1 for progressive

disease)

Temozolomide + capecitabine

PRRT with 177Lu-dotatate, if SSR-positive

imaging and progression on octreotide or

lanreotide

n,

Other cytotoxic chemotherapy

Consider liver-directed therapy for liver-

predominant disease

gg,hh

Palliative RT for symptomatic bone metastases

Clinically

signicant

progressive

disease,

see below

See Principles of Imaging (NE-B).

See Principles of Biochemical Testing (NE-C).

SSR PET tracers include: 68Ga-DOTATATE, 64Cu-DOTATATE, 68Ga-DOTATOC.

PET/CT or PET/MRI of skull base to mid-thigh with IV contrast when possible. Data

are limited on the optimal timing of scans following administration of SSAs.

See Surgical Principles for Management of Neuroendocrine Tumors (NE-D).

See Principles of Systemic Anti-Tumor Therapy (NE-F).

There are limited data on management of well-differentiated G3 tumors. Treatment

options will vary based on clinical judgment, but may include those options for poorly

differentiated G3 tumors, or well-differentiated G1-2 tumors. See Discussion.

Noncurative debulking surgery might be considered in select cases.

If disease progression, treatment with octreotide or lanreotide should be

discontinued for non-functional tumors and continued in patients with functional

tumors; those regimens may be used in combination with any of the subsequent

options. For details on the administration of octreotide or lanreotide with 177Lu-

dotatate, see NE-G.

Staged or synchronous resection when possible. When performing staged

pancreatoduodenectomy and liver resection, consider hepatectomy prior to

pancreatic resection in order to reduce risk of perihepatic sepsis. De Jong MC,

et al. Ann Surg 2010;252:142-148.

For patients with insulinoma, octreotide or lanreotide should be used only if

SSR-based imaging is positive. If used, they should be used with caution in

patients with insulinoma as they may transiently worsen hypoglycemia (See

Discussion for details).

In select cases it may be appropriate to proceed to front-line systemic therapy

or liver-directed therapy prior to or concurrently with octreotide or lanreotide.

See Principles of PRRT with 177Lu-dotatate (NE-G).

After any prior biliary instrumentation, there are increased risks of infectious

complications associated with liver-directed therapies.

See Principles of Liver-Directed Therapy for Neuroendocrine Tumor

Metastases (NE-H).

(NCCN

and this illustration may not be reproduced in any form without the express written permission of NCCN.

Note: All recommendations are category 2A unless otherwise indicated.

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

NCCN Guidelines Version 2.2021

Neuroendocrine Tumors of Unknown Primary

NCCN Guidelines Index

Table of Contents

Discussion

NUP-1

INITIAL WORKUP

Tumor-directed localizing

studies:

• Chest CT with or

without contrast and

multiphasic abdominal/

pelvic CT or MRI

• SSR-PET/CT or

SSR-PET/MRI

c,d,e

• Consider FDG-PET/CT

and brain imaging (CT

or MRI) with contrast

in poorly dierentiated

carcinomas only

• Consider EGD or EUS

and/or colonoscopy

See Principles of Pathology for Diagnosis and Reporting of Neuroendocrine Tumors (NE-A).

Treat presumptively as gastroenteropancreatic (GEP) NETs if it is unknown primary.

See Principles of Imaging (NE-B).

PET/CT or PET/MRI of skull base to mid-thigh with IV contrast when possible. Data are limited on the optimal timing of scans following administration of SSAs.

SSR PET tracers include: 68Ga-DOTATATE, 64Cu-DOTATATE, 68Ga-DOTATOC.

Consider small bowel primary tumor based on symptoms and associated radiologic findings.

Indicate well- or poorly differentiated. Klimstra DS, et al. Pancreas 2010;39:707-712.

See Principles of Biochemical Testing (NE-C).

Primary not

discovered

Primary found

Well-

dierentiated

grade 1/2

g,h

Poorly

dierentiated

g,h

See Primary Treatment for poorly

dierentiated neuroendocrine

carcinoma (PDNEC-1)

See Management of

Bronchopulmonary/Thymus

Locoregional Advanced Disease

(NET-8) and/or Distant Metastases

(NET-10)

See Management of

Gastrointestinal Tract Locoregional

Advanced Disease and/or Distant

Metastases (NET-11)

See specic tumor type (CP-1)

Biopsy-proven

neuroendocrine tumors

(NETs) of unknown primary

(NCCN

and this illustration may not be reproduced in any form without the express written permission of NCCN.

Note: All recommendations are category 2A unless otherwise indicated.

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

NCCN Guidelines Version 2.2021

Well-Dierentiated, Grade 3 Neuroendocrine Tumors

NCCN Guidelines Index

Table of Contents

Discussion

WDG3-1

TUMOR TYPE

EVALUATION

Well-

dierentiated

Grade 3

neuroendocrine

tumors

Locally

advanced/

Metastatic

Locoregional

(Resectable)

Recommended:

• Multiphasic abdominal/pelvic CT or MRI

with contrast ± chest CT as clinically

indicated

• Pathology review

• SSR-PET/CT or SSR-PET/MRI

b,c

As appropriate

• FDG-PET/CT

• Biochemical evaluation as clinically

indicated (See NE-C)

• Consider tumor mutational burden

(TMB) testing

• Consider assessment of p53, Rb,

p16 by histopathologic analysis or

molecular proling if uncertain about

dierentiation

• Genetic counseling and testing for

inherited genetic syndromes (only for

duodenal or pancreatic NET)

See WDG3-2

See WDG3-3

Favorable biology (eg,

relatively low Ki-67

[<55%], slow growing,

positive SSR-based PET

imaging)

Unfavorable biology (eg,

relatively high Ki-67

[≥55%], faster growing,

negative SSR-based PET

imaging)

See WDG3-4

See Principles of Imaging (NE-B).

PET/CT or PET/MRI of skull base to mid-thigh with IV contrast when possible. Data are limited on the optimal timing of scans following administration of SSAs.

SSR PET tracers include: 68Ga-DOTATATE, 64Cu-DOTATATE, 68Ga-DOTATOC.

FDA-approved test recommended for determination of TMB.

See Principles of Genetic Risk Assessment and Counseling (NE-E).

There are limitations in terms of the data for what the appropriate cutoff should be, as well as variability/heterogeneity of Ki-67 in a given tumor and over time in serial

biopsies. The clinical course and histopathologic workup combined should dictate therapy, not solely Ki-67.

(NCCN

and this illustration may not be reproduced in any form without the express written permission of NCCN.

Note: All recommendations are category 2A unless otherwise indicated.

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

NCCN Guidelines Version 2.2021

Well-Dierentiated, Grade 3 Neuroendocrine Tumors

NCCN Guidelines Index

Table of Contents

Discussion

WDG3-2

TREATMENT SURVEILLANCE

Locoregional

disease

(resectable)

Favorable biology (eg,

relatively low Ki-67

[<55%], slow growing,

positive SSR-based

PET imaging)

Unfavorable biology (eg,

relatively high Ki-67

[≥55%], faster growing,

negative SSR-based PET

imaging)

Resection + regional lymphadenectomy if feasible

See Principles of Imaging (NE-B).

There are limitations in terms of the data for what the appropriate cutoff should be, as well as variability/heterogeneity of Ki-67 in a given tumor and over time in serial

biopsies. The clinical course and histopathologic workup combined should dictate therapy, not solely Ki-67.

May have more activity in tumors arising in pancreas.

Clinical trial (preferred)

Resection with regional

lymphadenectomy if

feasible

Neoadjuvant

chemotherapy on a case-

by-case basis (eg, Ki-67

>55%); options include:

• Temozolomide

capecitabine

• Oxaliplatin-based

therapy (FOLFOX,

CAPEOX)

• Cisplatin/etoposide or

carboplatin/etoposide

Resection

with regional

lymphadenectomy

if feasible

Every 12–24 weeks for 2

years, then every 6–12

months for up to 10 years

(depending on tumor

biology, Ki-67)

• H&P

• Abdominal/pelvic MRI with

contrast or abdominal/

pelvic multiphasic CT

• Chest CT as clinically

indicated

MANAGEMENT OF

LOCOREGIONAL DISEASE

(NCCN

and this illustration may not be reproduced in any form without the express written permission of NCCN.

Note: All recommendations are category 2A unless otherwise indicated.

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

NCCN Guidelines Version 2.2021

Well-Dierentiated, Grade 3 Neuroendocrine Tumors

NCCN Guidelines Index

Table of Contents

Discussion

WDG3-3

TREATMENT

SURVEILLANCE

Locally

advanced/

Metastatic

disease:

Favorable

biology (eg,

relatively

low Ki-67

[<55%],

positive SSR-

based PET

imaging)

Resectable

Unresectable

Asymptomatic,

low tumor

burden

Observation with short interval

follow-up scan, in selected patients

Octreotide or lanreotide (if SSR-

positive and/or hormonal symptoms)

Octreotide or lanreotide (if SSR-positive and/or hormonal

symptoms)

Clinical trial (preferred)

PRRT with 177Lu-dotatate

Everolimus

Sunitinib (pancreas only)

Pembrolizumab

for TMB-H tumors (≥10 muts/Mb)

(category 2B)

Chemotherapy (ie, temozolomide

± capecitabine,

FOLFOX, CAPEOX, cisplatin/etoposide or carboplatin/

etoposide)

Liver-directed therapy for liver-dominant disease

Clinically

signicant

tumor burden

or evidence

of disease

progression

Resection of primary + metastatic sites, if feasible

MANAGEMENT OF LOCALLY

ADVANCED/METASTATIC DISEASE:

FAVORABLE BIOLOGY

See Principles of Imaging (NE-B).

SSR PET tracers include: 68Ga-DOTATATE, 64Cu-DOTATATE, 68Ga-

DOTATOC.

There are limitations in terms of the data for what the appropriate cutoff

should be, as well as variability/heterogeneity of Ki-67 in a given tumor

and over time in serial biopsies. The clinical course and histopathologic

workup combined should dictate therapy, not solely Ki-67.

Every 12–24 weeks for 2 years,

then every 6–12 mo for up to 10

years

• H&P

• Abdominal/pelvic MRI with

contrast or abdominal/pelvic

multiphasic CT

• Chest CT as clinically indicated

Every 12–24 weeks

(depending on tumor biology)

• H&P

• Chest CT ± contrast

• Abdominal/pelvic MRI with

contrast

Chest/abdominal/pelvic

multiphasic CT

• SSR-PET/CT or SSR-PET/

MRI

or FDG PET/CT as

clinically indicated

• Biochemical markers as

clinically indicated

May have more activity in tumors arising in pancreas.

Clinical trials preferred due to a lack of data from prospective clinical trials to guide therapy.

Consider trial of SSA before PRRT. Preliminary data suggest reduced efficacy if high Ki-67

and/or FDG-PET avid. See Principles of PRRT with 177Lu-DOTATATE (NE-G).

Pembrolizumab is an option for patients with advanced tumor mutational burden-high

(TMB-H) tumors (as determined by an FDA-approved test) that have progressed following

prior treatment and have no satisfactory alternative treatment options.

See Principles of Liver-Directed Therapy for Neuroendocrine Tumor Metastases (NE-H).

(NCCN

and this illustration may not be reproduced in any form without the express written permission of NCCN.

Note: All recommendations are category 2A unless otherwise indicated.

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

NCCN Guidelines Version 2.2021

Well-Dierentiated, Grade 3 Neuroendocrine Tumors

NCCN Guidelines Index

Table of Contents

Discussion

WDG3-4

TREATMENT SURVEILLANCE

Locally advanced/Metastatic disease

Unfavorable biology (relatively high

Ki-67 [≥55%],

rapid growth rate, FDG-

avid tumors, negative SSR-based

PET imaging)

Clinical trial (preferred)

Systemic therapy, options:

• Cisplatin/etoposide

or carboplatin/etoposide

• Temozolomide ± capecitabine

• Oxaliplatin-based therapy (ie, FOLFOX or CAPEOX)

• Pembrolizumab

for TMB-H tumors (≥10 muts/Mb)

• Irinotecan-based therapy (eg. FOLFIRI, cisplatin +

irinotecan, or FOLFIRINOX)

• Nivolumab + ipilimumab (category 2B)

Consider addition of liver-directed therapy

(embolization, selective internal RT, ablation, SBRT)

Palliative RT for symptomatic bone metastases

See Principles of Imaging (NE-B).

There are limitations in terms of the data for what the appropriate cutoff should be, as well as variability/heterogeneity of Ki-67 in a given tumor and over time in serial

biopsies. The clinical course and histopathologic workup combined should dictate therapy, not solely Ki-67.

May have more activity in tumors arising in pancreas and with.

Pembrolizumab is an option for patients with advanced tumor mutational burden-high (TMB-H) tumors (as determined by an FDA-approved test) that have progressed

following prior treatment and have no satisfactory alternative treatment options.

Consider liver-directed therapy in selected cases with residual liver-predominant disease after systemic therapy. See Principles of Liver-Directed Therapy for

Neuroendocrine Tumor Metastases (NE-H).

See Principle of Biochemical Testing (NE-C).

Every 8–12 weeks (depending

on tumor biology)

• H&P

• Chest CT ± contrast

• Abdominal/pelvic MRI with

contrast or chest/abdominal/

pelvic multiphasic CT

• FDG PET/CT as clinically

indicated

• Biochemical markers as

clinically indicated

MANAGEMENT OF LOCALLY

ADVANCED/METASTATIC DISEASE:

UNFAVORABLE BIOLOGY

(NCCN

and this illustration may not be reproduced in any form without the express written permission of NCCN.

Note: All recommendations are category 2A unless otherwise indicated.

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

NCCN Guidelines Version 2.2021

Poorly Dierentiated Neuroendocrine Carcinoma/

Large or Small Cell

NCCN Guidelines Index

Table of Contents

Discussion

PDNEC-1

TUMOR TYPE EVALUATION

a,c

TREATMENT

d,e,f

SURVEILLANCE

h,i

Extrapulmonary:

• Poorly

dierentiated

neuroendocrine

carcinoma

a,b

• Large or small

cell carcinoma

(other than

lung)

• Unknown

primary (poorly

dierentiated)

Metastatic

Locoregional,

unresectable

Resectable

Therapy options depend on sites of disease.

Options may include:

• Resection + adjuvant chemotherapy

± RT

• Neoadjuvant chemotherapy

± RT +

resection

• Chemotherapy alone

• RT alone

• Denitive chemoradiation with cisplatin +

etoposide or carboplatin + etoposide

Concurrent or sequential

RT + chemotherapy

Chemotherapy

Every 12 weeks for 1 y,

then every 6 mo:

• H&P

• Appropriate imaging

studies:

Chest CT with or without

contrast and abdominal/

pelvic MRI with contrast

Chest/abdominal/pelvic

multiphasic CT

Every 6–16 weeks:

• H&P

• Appropriate imaging

studies:

Chest CT with or without

contrast and abdominal/

pelvic MRI with contrast

Chest/abdominal/pelvic

multiphasic CT

Chemotherapy

Recommended:

• Chest/abdominal/

pelvic CT

• Chest CT and

abdominal/pelvic

MRI

As appropriate:

• Brain MRI or CT

with contrast

• FDG-PET/CT

• Biochemical

evaluation as

clinically indicated

(See NE-C)

• Consider MSI,

MMR, and TMB

testing

This page is for PDNEC and not high-grade NET. Not all high-grade (Ki-67 >20%) neuroendocrine neoplasms are poorly differentiated. See WDG3-1.

See Principles of Pathology for Diagnosis and Reporting of Neuroendocrine Tumors (NE-A).

Somatostatin scintigraphy with SPECT/CT is not part of the routine evaluation of poorly differentiated neuroendocrine carcinomas, but may be considered for

morphologically well-differentiated tumors with higher proliferation index, as appropriate. See Principles of Imaging (NE-B).

Pembrolizumab can be considered for patients with mismatch repair-deficient (dMMR), microsatellite instability-high (MSI-H), or advanced tumor mutational burden-

high (TMB-H) tumors (as determined by an FDA-approved test) that have progressed following prior treatment and have no satisfactory alternative treatment options.

Combination of immune checkpoint inhibitors + chemotherapy is investigational for all patients with extrapulmonary poorly differentiated neuroendocrine carcinomas.

See Surgical Principles for Management of Neuroendocrine Tumors (NE-D).

See Principles of Systemic Anti-Tumor Therapy (NE-F).

Earlier, if symptoms.

See NCCN Guidelines for Survivorship.

If progression, consider

nivolumab + ipilimumab

(category 2B)

(NCCN

and this illustration may not be reproduced in any form without the express written permission of NCCN.

Note: All recommendations are category 2A unless otherwise indicated.

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

NCCN Guidelines Version 2.2021

Adrenal Gland Tumors

NCCN Guidelines Index

Table of Contents

Discussion

EVALUATION

a,b

Adrenal

gland

tumor on

imaging

See Principles of Pathology for Diagnosis and Reporting

of Neuroendocrine Tumors (NE-A).

See Principles of Biochemical Testing (NE-C).

If unenhanced is <+ 10 HU, then the tumor is probably

benign. If unenhanced is >+ 10 HU, then use enhanced

and washout. If >60% absolute washout in 15 minutes,

the tumor is likely to be benign; if <60%, the tumor

is possibly malignant. (Caoili E, et al. Radiology

2002;222:629-633.)

See Principles of Imaging (NE-B).

Morphologic

evaluation

See Additional Evaluation (AGT-2)

Hyperaldosteronism

Cushing syndrome

Biochemical workup (See

NE-C) for:

• Hyperaldosteronism

• Cushing syndrome

• Pheochromocytoma

• Suspected adrenocortical

carcinoma (ACC)

History of prior or

current malignancy

with risk of or

suspicion of

adrenal metastasis

No history of

prior or current

malignancy

Functional

evaluation

Pheochromocytoma

and

Adrenal protocol (CT

with and without contrast

or MRI with or without

contrast) to determine size,

heterogeneity, lipid content

(MRI), contrast washout (CT),

and margin characteristics

Suspected ACC

See Primary

Treatment (AGT-2)

See

Pheochromocytoma

Guidelines (PHEO-1)

See Primary

Treatment (AGT-4)

See Primary

Treatment (AGT-3)

CLINICAL PRESENTATION CLINICAL DIAGNOSIS

AGT-1

For benign-appearing lesions, refer to the following guidelines for the management of adrenal

incidentalomas: Zeiger MA, Thompson GB, Duh QY, et al. The American Association of Clinical

Endocrinologists and American Association of Endocrine Surgeons medical guidelines for the

management of adrenal incidentalomas. Endocrine practice: official journal of the American College

of Endocrinology and the American Association of Clinical Endocrinologists 2009;15 Suppl 1:1-20;

Fassnacht M, Arlt W, Bancos I, et al. Management of adrenal incidentalomas: European Society of

Endocrinology Clinical Practice Guideline in collaboration with the European Network for the Study

of Adrenal Tumors. Eur J Endocrinol 2016;175:G1-G34.

For benign-appearing lesions, refer to the Endocrine Society's Clinical Practice Guidelines for the

Treatment of Cushing's Syndrome (Nieman LK, et al. J Clin Endocrinol Metab 2015;100:2807-2831).

(NCCN

and this illustration may not be reproduced in any form without the express written permission of NCCN.

Note: All recommendations are category 2A unless otherwise indicated.

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

NCCN Guidelines Version 2.2021

Adrenal Gland Tumors

NCCN Guidelines Index

Table of Contents

Discussion

PRIMARY TREATMENT

Rule out pheochromocytoma

(See NE-C)

See Principles of Biochemical Testing (NE-C).

Suspect malignancies with irregular/inhomogeneous morphology, lipid-poor, do not wash-out, tumor >4 cm, or secretion of more than one hormone.

False negatives are possible; may consider proceeding directly to surgery in selected cases.

Adrenal vein sampling can be considered for distinguishing single unilateral adenomas from bilateral hyperplasia. CT imaging is not always reliable. Some NCCN

Member Institutions recommend sampling in all cases of primary aldosteronism. However, it may be reasonable to exclude adrenal vein sampling in patients <40 y.

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

Consider

image-

guided needle biopsy

if clinical suspicion of

pheochromocytoma is

low, metanephrines are

normal, and the results

will impact management

Metastasis from

other site discovered

Adrenal cortical tissue

See functional

evaluation (AGT-1)

See NCCN disease-specic

treatment guidelines

History of prior or

current malignancy

with risk of or

suspicion of

adrenal metastasis

CLINICAL DIAGNOSIS ADDITIONAL EVALUATION

Hyperaldosteronism,

suspect benign

Surgical candidate

Consider adrenal

vein sampling

for

aldosterone and cortisol

Unilateral aldosterone

production

Bilateral aldosterone

production

Not a surgical

candidate

Medical management

of hypertension and

hypokalemia with

spironolactone or

eplerenone

Adrenalectomy, minimally

invasive preferred

Open adrenalectomy

Hyperaldosteronism,

suspect malignant

AGT-2

(NCCN

and this illustration may not be reproduced in any form without the express written permission of NCCN.

Note: All recommendations are category 2A unless otherwise indicated.

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

NCCN Guidelines Version 2.2021

Adrenal Gland Tumors

NCCN Guidelines Index

Table of Contents

Discussion

PRIMARY TREATMENT

See Principles of Imaging (NE-B).

For benign-appearing lesions, refer to the Endocrine Society's Clinical Practice Guidelines for the Treatment of Cushing's Syndrome (Nieman LK, et al. J Clin

Endocrinol Metab 2015;100:2807-2831).

Some centers may use 6 cm as cutoff.

Perioperative management should include stress-dose steroids (eg, methylprednisolone or hydrocortisone).

May require removal of adjacent structures (ie, liver, kidney, pancreas, spleen, diaphragm) for complete resection.

See

Adrenocortical

Carcinoma

(AGT-5)

CLINICAL DIAGNOSIS

ADDITIONAL EVALUATION

Cushing

syndrome

Tumor >4 cm or

inhomogeneous, irregular

margins, local invasion,

or other malignant

imaging characteristics

Tumor <4 c

• FDG-PET/CT

• Chest CT with or

without contrast

• Abdominal/pelvic CT

or MRI with contrast

Metastatic disease

Apparent localized

disease, locally

resectable disease,

or regionally

advanced disease

Open

Adrenalectomy

for suspected

malignancy

k,l

Adrenalectomy (minimally

invasive preferred)

AGT-3

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NCCN Guidelines Version 2.2021

Adrenal Gland Tumors

NCCN Guidelines Index

Table of Contents

Discussion

PRIMARY TREATMENT

See Principles of Biochemical Testing (NE-C).

See Principles of Imaging (NE-B).

If size is resectable by laparoscopy, may explore with a minimally invasive approach with planned conversion for evidence of local invasion. The decision for open

versus minimally invasive surgery is based on tumor size and degree of concern regarding potential malignancy, and local surgical expertise.

CLINICAL

DIAGNOSIS

ADDITIONAL EVALUATION

Suspected

adrenocortical

carcinoma

Open adrenalectomy for

suspected carcinoma

Unresectable or suspected

metastatic disease

Resectable disease

• FDG PET/CT

• Chest CT with or

without contrast

• Abdominal/pelvic

CT or MRI with

contrast

• Biochemical

workup

AGT-4

See Adrenocortical

Carcinoma (AGT-5)

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Adrenal Gland Tumors

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Table of Contents

Discussion

TREATMENT

See Principles of Imaging (NE-B).

Staging workup, see AGT-4.

See Principles of Genetic Risk Assessment and Counseling (NE-E).

FDA-approved test recommended for determination of TMB.

May require removal of adjacent structures (ie, liver, kidney, pancreas, spleen,

diaphragm) for complete resection.

It is important to achieve negative margins and avoid breaching the tumor

capsule. There may be an increased risk for local recurrence and peritoneal

spread when done with a minimally invasive approach.

If bulky disease, or <90% is removable, surgery can be reconsidered following

response to systemic therapy.

FOLLOW-UP

Locoregional

unresectable

Metastatic

disease

• Consider observation with chest CT ± contrast and

abdominal/pelvic CT or MRI with contrast for clinically

indolent disease every 12 weeks and biomarkers (if

tumor initially functional)

• Consider resection of primary tumor and metastases if

>90% removable, particularly if functional

• Consider local therapy (ie, SBRT, thermal ablative

therapies, liver-directed therapy

)

• Consider systemic therapy preferably in clinical trial

(See Systemic Therapy for Metastatic Adrenocortical

Tumors [AGT-A])

If high risk for local recurrence:

Consider external-beam RT

(EBRT) to tumor bed

• Consider adjuvant mitotane

therapy

v,w

(category 3)

Resect tumor and

adjacent lymph nodes

(open adrenalectomy

recommended)

q,r

Localized

disease

Every 12 wk–12 mo up to 5 y

(after 5 y as clinically

indicated):

• Consider chest CT ±

contrast, and

abdominal CT or MRI with

contrast

• Consider biomarkers, if

tumor initially functional

See Principles of Liver-Directed Therapy for Neuroendocrine Tumor

Metastases (NE-H).

High-risk local recurrence features include: positive margins, Ki-67 >10%,

rupture of capsule, large size, and high grade.

Monitor mitotane blood levels. Some institutions recommend target levels

of 14–20 mcg/mL if tolerated. Steady-state levels may be reached several

months after initiation of mitotane. Life-long hydrocortisone replacement

may be required with mitotane.

Mitotane may have more benefit for control of hormone symptoms than

control of tumor.

Every 12 wk–12 mo up to 5 y

(after 5 y as clinically

indicated):

• Chest CT ± contrast and

• Abdominal/pelvic CT or

MRI with contrast or FDG-

PET/CT

AGT-5

Adrenocortical

carcinoma,

additional workup:

• Genetic

counseling

and testing for

inherited genetic

syndromes

• Consider tumor

MSI, MMR and

TMB testing

WORKUP

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Adrenal Gland Tumors

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Table of Contents

Discussion

AGT-A

SYSTEMIC THERAPY FOR LOCOREGIONAL UNRESECTABLE/METASTATIC ADRENOCORTICAL CARCINOMA

Preferred Regimens Other Recommended Regimens Useful in Certain Circumstances

• Cisplatin + etoposide

± doxorubicin ± mitotane

v,w,2

• Carboplatin + etoposide ± doxorubicin ± mitotane

v,w

• Pembrolizumab

3,4

± mitotane

v,w

• Mitotane monotherapy

v,w

• Streptozocin ± mitotane

v,w,2

Monitor mitotane blood levels. Some institutions recommend target levels of 14–20 mcg/mL if tolerated. Steady-state levels may be reached several

months after initiation of mitotane. Life-long hydrocortisone ± fludrocortisone replacement may be required with mitotane.

Mitotane may have more benefit for control of hormone symptoms than control of tumor.

See Discussion for further information regarding the phase III FIRM-ACT trial.

References

Williamson SK, Lew D, Miller GJ, et al. Phase II evaluation of cisplatin and etoposide followed by mitotane at disease progression in patients with locally advanced or

metastatic adrenocortical carcinoma: a Southwest Oncology Group Study. Cancer 2000;88:1159-1165.

Fassnacht M, Terzolo M, Allolio B, et al. Combination chemotherapy in advanced adrenocortical carcinoma. N Engl J Med. 2012;366(23):2189-2197. doi:10.1056/

NEJMoa1200966

Raj N, Zheng Y, Kelly V, et al. PD-1 blockade in advanced adrenocortical carcinoma. J Clin Oncol 2020;38:71-80.

Habra MA, Stephen B, Campbell M, et al. Phase II clinical trial of pembrolizumab efficacy and safety in advanced adrenocortical carcinoma. J Immunother Cancer

2019;7:253.

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Pheochromocytoma/Paraganglioma

NCCN Guidelines Index

Table of Contents

Discussion

PHEO-1

PRIMARY TREATMENT

EVALUATION

a,b,c

TUMOR TYPE

Pheochromocytoma/

paraganglioma

Recommended:

• Plasma free or 24-hour urine fractionated metanephrines and

normetanephrines

b,d,e

± serum or 24-hour urine catecholamines

• Adrenal protocol CT (abdomen/pelvis)

• Genetic counseling and testing for inherited genetic syndromes

As appropriate, if metastatic or multifocal disease suspected:

• Abdominal/pelvic multiphasic CT or MRI

• SSR-PET/CT or SSR-PET/MRI

e,j,k

• FDG-PET/CT (skull base to mid-thigh)

• Chest CT with or without contrast

• MIBG scan

See Primary Treatment (PHEO-2)

See Principles of Pathology for Diagnosis and Reporting of

Neuroendocrine Tumors (NE-A).

See Principles of Biochemical Testing (NE-C).

Consider medical alert ID for hormonally secreting

pheochromocytomas and paragangliomas in situ or metastatic

disease.

Review concurrent medication(s) for those that may interfere with

plasma metanephrines evaluation. Elevations that are 3 times above

the upper limit of normal are diagnostic.

For cervical paraganglioma, consider measuring serum and/or 24-

hour urine fractionated catecholamines (for dopamine).

Both catecholamines and metanephrines/normetanephrines can produce false-

positive results (see NE-C).

See Principles of Imaging (NE-B).

See Principles of Genetic Risk Assessment and Counseling (NE-E).

Data on the role of functional imaging in pheochomocytoma/paraganglioma are

evolving and the preferred method remains unclear.

PET/CT or PET/MRI of skull base to mid-thigh with IV contrast when possible.

SSR PET tracers include: 68Ga-DOTATATE, 64Cu-DOTATATE, 68Ga-DOTATOC.

MIBG scans are less sensitive than FDG-PET and 68Ga-dotatate for metastatic

and multifocal paragangliomas/pheochromocytomas. Obtain MIBG scan if

considering treatment with I131-MIBG.

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Pheochromocytoma/Paraganglioma

NCCN Guidelines Index

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Discussion

PHEO-2

Resectable

Consider medical alert ID for hormonally secreting pheochromocytomas and

paragangliomas in situ or metastatic disease.

SSR PET tracers include: 68Ga-DOTATATE, 64Cu-DOTATATE, 68Ga-DOTATOC.

Alpha 1 selective receptor blockers include terazosin, doxazosin, and prazosin, and

non-selective receptor blockers include phenoxybenzamine. Therapy for 7–14 days is

recommended prior to surgical therapy. Nonselective alpha blockade phentolamine (IV)

can be used intraoperatively.

Alpha blockade is first-line therapy for all hormonally secreting pheochromocytomas

and paragangliomas. After alpha blockade, if additional blood pressure (bp) support is

needed, the addition of dihydropyridine calcium channel blockers can be used. This is

not recommended as monotherapy unless the patient cannot tolerate alpha blockade.

Metyrosine can also be used in addition to alpha blockade to stabilize bp. Beta blockade

can be added to alpha blockade for tachycardia. B1 selective blockers or nonselective

beta blockers can be used. Combination beta/alpha blockers are not recommended.

PRIMARY TREATMENT

Locally

unresectable

Distant

metastases

Alpha

blockade

m,n

with volume

repletion and

high salt diet

for 7–14 days

or until stable

Resection (minimally invasive preferred when

safe and feasible)

Observe, if asymptomatic

Continue medical therapy for secreting tumors, and:

• RT ± cytoreductive (R2) resection, when possible,

• HSA iobenguane I 131

or other 131I-MIBG (requires prior

positive MIBG scan), or

• If SSR-positive imaging

: consider PRRT with 177Lu-dotatate,

or octreotide or lanreotide (if symptomatic)

Consider

adding:

• Dihydropyridine

calcium

channel

blockade

• Beta blockade

• Metyrosine

Observe, if asymptomatic

Continue medical therapy for secreting tumors (octreotide or

lanreotide)

and:

• Cytoreductive (R2) resection, when possible,

• Clinical trial, or

• Systemic chemotherapy (eg, CVD

or temozolomide), or

• HSA iobenguane I 131

or other 131I-MIBG (requires prior

positive MIBG scan), or

• If SSR-positive PET imaging

consider PRRT with 177Lu-

dotatate,

• Palliative RT for symptomatic metastases

Surveillance

(see PHEO-3)

HSA iobenguane I 131 is an FDA-approved option.

Data are limited on the use of PRRT with 177Lu-dotatate in this

setting. See Principles of PRRT with 177Lu-dotatate (NE-G).

CVD = cyclophosphamide, vincristine, and dacarbazine

For symptom control, octreotide 150–250 mcg SC TID or

octreotide LAR 20–30 mg IM or lanreotide 90–120 mg SC

every 4 weeks. Dose and frequency may be further increased

for symptom control as needed. Therapeutic levels of

octreotide would not be expected to be reached for 10–14 days

after LAR injection. Short-acting octreotide can be added to

octreotide LAR for rapid relief of symptoms or for breakthrough

symptoms. For details on the administration of short-acting

and/or long-acting octreotide with 177Lu-dotatate, see NE-G.

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NCCN Guidelines Index

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Discussion

PHEO-3

12 wk–12 mo post-resection:

• H&P, blood pressure, and markers

• Consider chest CT (± contrast) and abdominal/pelvic CT or MRI with contrast

>1 y post-resection up to 10 y:

• H&P, blood pressure, and markers

Years 1–3: every 6–12 mo

Years 4+ up to 10 y: annually

• Consider chest CT (± contrast) and abdominal/pelvic CT or MRI with contrast

>10 y:

• Consider surveillance as clinically indicated

See Principles of Biochemical Testing (NE-C).

PET/CT or PET/MRI of skull base to mid-thigh with IV contrast when possible.

SSR PET tracers include: 68Ga-DOTATATE, 64Cu-DOTATATE, 68Ga-DOTATOC.

See NCCN Guidelines for Survivorship.

Earlier, if symptoms; less frequently if stable disease and no new symptoms.

SURVEILLANCE

Every 12 wk–12 mo:

• H&P, blood pressure, and markers

• Consider imaging:

Chest/abdominal/pelvic CT with contrast

Chest CT (± contrast) and abdominal/pelvic MRI without contrast (if risk for hypertensive episode)

FDG-PET/CT

SSR-PET/CT

or SSR-PET/MRI

Resectable disease

(post-resection)

Locally unresectable disease

Distant metastases

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NCCN Guidelines Version 2.2021

Multiple Endocrine Neoplasia, Type 1

NCCN Guidelines Index

Table of Contents

Discussion

Clinical diagnosis of

MEN1

• Genetic

counseling

and testing for

inherited genetic

syndromes

MEN1-1

Parathyroid:

• Serum calcium

• If calcium elevated:

PTH and 25-OH vitamin D

Imaging

a,c

(neck ultrasound, parathyroid

sestamibi with SPECT scan, or 4D-CT)

See MEN1

Surveillance

(MEN1-2)

Subtotal parathyroidectomy

± cryopreservation of parathyroids

± thymectomy

Total parathyroidectomy with

autotransplantation ± cryopreservation

of parathyroids ± thymectomy

See Principles of Genetic Risk Assessment and Counseling (NE-E).

See Principles of Imaging (NE-B).

van Treijen MJC, et al. J Endocr Soc 2018;2:1067-1088.

PET/CT or PET/MRI of skull base to mid-thigh with IV contrast when possible. Data are limited on the optimal timing of scans following administration of SSAs.

SSR PET tracers include: 68Ga-DOTATATE, 64Cu-DOTATATE, 68Ga-DOTATOC.

TREATMENTCLINICAL EVALUATION

PanNET:

• Recommended

Biochemical evaluation as clinically

indicated (See NE-C)

Abdominal ± pelvic multiphasic CT or

MRI

• As appropriate

EUS

• SSR-PET/CT or SSR-PET/MRI

c,e,f

Pituitary:

• Recommended

Pituitary or sella MRI

with contrast

Biochemical evaluation as

clinically indicated (See NE-C)

Bronchial/Thymic:

• Chest CT with contrast and abdominal/

pelvic multiphasic CT or MRI

• Biochemical evaluation as clinically

indicated (See NE-C)

Consider referral to

endocrinology for further workup

See Treatment of PanNETs Specic

to MEN1 Patients (MEN1-A)

and

See appropriate sporadic PanNET

workup and treatment (PanNET-1

through PanNET-5)

See MEN1

Surveillance

(MEN1-2)

See MEN1

Surveillance

(MEN1-2)

See appropriate bronchopulmonary/

thymus workup and treatment (NET-6)

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Multiple Endocrine Neoplasia, Type 1

NCCN Guidelines Index

Table of Contents

Discussion

Parathyroid:

• Calcium annually

MEN1-2

• If calcium rises:

PTH

25-OH vitamin D

Re-image with neck ultrasound and/or parathyroid sestamibi

with SPECT scan (SPECT-CT preferred) or 4D-CT

a,h

Preference of scan will depend on institutional practice/protocol. Sestamibi may not be as sensitive since often the patient has

hyperplasia. See Principles of Imaging (NE-B).

See Principles of Imaging (NE-B).

Consider referral to an endocrinologist.

For prolonged surveillance, studies without radiation are preferred.

MEN1 SURVEILLANCE

g,h

Patients with MEN1 should be screened for all of the following tumor types:

PanNET:

• Follow previously elevated serum hormones or as symptoms

indicate

• Consider abdominal/pelvic CT or MRI

c,h

with contrast every 1–3 y

• Consider serial EUS

See appropriate sporadic PanNET workup and treatment

(PanNET-1 through PanNET-5)

See appropriate workup and treatment

for thymic (NET-6) or bronchial (NET-7)

Pituitary:

• Pituitary or sella MRI with contrast of pituitary every 3–5 y

• Prolactin, IGF-1, and other previously abnormal pituitary

hormones every 3–5 y or as symptoms indicate

Bronchial/Thymic:

• Consider chest CT or MRI

c,h

with contrast every 1–3 y

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Multiple Endocrine Neoplasia, Type 1

NCCN Guidelines Index

Table of Contents

Discussion

• In general, surgical management of patients with MEN1 is similar to those with sporadic tumors. Refer to the relevant site-specic

recommendations for PanNETs earlier in these guidelines. (See PanNET-1 through PanNET-5)

• However, one notable exception is the multi-focality of pancreaticoduodenal NETs in patients with MEN1. The role of surgery remains

controversial in patients with multifocal tumors.

• Decision to resect a pancreatic or duodenal NET in the setting of multifocal disease is complex. If surgery is performed to resect hormonally

functional tumor(s), attempts should be made to preoperatively localize the site of the functional tumor. Surgical resection can be

considered in the following scenarios:

Symptomatic functional tumors refractory to medical management

Tumor larger than 2 cm in size

Tumor with relatively rapid rate of growth over 6–12 months

• Endoscopy with EUS is recommended prior to pancreatic surgery in order to preoperatively assess and localize tumors.

• MEN1-associated metastatic PanNETs are often slower growing than metastatic sporadic tumors. Observation can be considered for non-

functioning indolent tumors.

MEN1-A

TREATMENT OF PanNETs SPECIFIC TO MEN1 PATIENTS

1-4

Yates CJ, Newey PJ, Thakker RV. Challenges and controversies in management of pancreatic neuroendocrine tumours in patients with MEN1. Lancet Diabetes

Endocrinol 2015;3:895-905.

Frost M, Lines KE, Thakker RV. Current and emerging therapies for PNETs in patients with or without MEN1. Nat Rev Endocrinol 2018;14:216-227.

Faggiano A, Modica R, Lo Calzo F, et al. Lanreotide therapy vs active surveillance in MEN1-related pancreatic neuroendocrine tumors < 2 centimeters. J Clin

Endocrinol Metab 2020;105:dgz007.

Niederle B, Selberherr A, Bartsch D, et al. Multiple Endocrine Neoplasia Type 1 (MEN1) and the Pancreas - Diagnosis and Treatment of Functioning and Non-

Functioning Pancreatic and Duodenal Neuroendocrine Neoplasia within the MEN1 Syndrome - An International Consensus Statement [published online ahead of print

September 24, 2020]. Neuroendocrinology 2020.

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Multiple Endocrine Neoplasia, Type 2

NCCN Guidelines Index

Table of Contents

Discussion

Clinical diagnosis

of MEN2

• Genetic

counseling

and testing for

inherited genetic

syndromes

MEN2-1

Medullary thyroid cancer:

• Calcitonin, CEA

• Neck ultrasound of both thyroid

and cervical lymph nodes

See NCCN Guidelines for

Medullary Thyroid Carcinoma

See Principles of Genetic Risk Assessment and Counseling (NE-E).

Preference of scan will depend on institutional practice/protocol. Sestamibi scan may not be as sensitive as other imaging options since often the patient has

hyperplasia. See Principles of Imaging (NE-B).

Evaluation of pheochromocytoma should be done before the administration of any anesthetic or invasive procedure.

More likely to be multifocal.

For synchronous bilateral pheochromocytomas, a bilateral adrenalectomy is recommended.

For the treatment of synchronous tumors, surgical resection of pheochromocytoma should take priority over thyroidectomy for medullary thyroid cancer.

Subtotal parathyroidectomy is recommended when all the parathyroid glands are abnormal. Some thyroid surgeons recommend total parathyroidectomy with

parathyroid autotransplantation, but others believe the risk of hypoparathyroidism (~6%) is too high to warrant this procedure.

TREATMENT

CLINICAL EVALUATION

Parathyroid:

• Serum calcium

• If calcium elevated:

PTH and 25-OH vitamin D

Imaging

(neck

ultrasound, parathyroid

sestamibi with SPECT

scan, or 4D-CT)

Pheochromocytoma

c,d,e

Parathyroidectomy

See NCCN Guidelines for Medullary Thyroid Carcinoma

See Pheochromocytoma Guidelines (PHEO-1)

SURVEILLANCE

NCCN Guidelines Version 2.2021

Neuroendocrine and Adrenal Tumors

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Discussion

PRINCIPLES OF PATHOLOGY FOR DIAGNOSIS AND REPORTING OF NEUROENDOCRINE TUMORS

Optional Information:

• Immunohistochemical staining for general neuroendocrine markers

• Presence of nonischemic tumor necrosis

• Presence of unusual histologic features (eg, oncocytic, clear cell,

gland forming)

• Exact distance of tumor to margin(s) if less than 0.5 cm

• Background pathology of organ (ie, PanIN, ECL cell hyperplasia)

Required Information:

• Anatomic site of tumor

• Diagnosis

• Mitotic rate and/or Ki-67

• Size of tumor

• Presence of multicentric disease

• Presence of vascular invasion

• Presence of perineural invasion

• Presence of other pathologic components

(eg, non-neuroendocrine components)

• Lymph node metastases to include the number of positive nodes

and total number of nodes examined

• Margin status (report as positive or negative)

• Assign TNM stage per the AJCC TNM system (See Staging)

NE-A

1 OF 5

Reprinted with permission from: WHO Classification of Tumours. Digestive System Tumours, 5th ed, Klimstra DS, Kloppel G, La Rosa

S, Rindi G, the WHO Classification of Tumours Editorial Board (Ed), the WHO classification of neuroendocrine neoplasms of the

Mitotic rates are to be expressed as the number of mitoses/2 mm2 (equaling 10 high-power fields at 40× magnification and an ocular field diameter of 0.5 mm) as

determined by counting in 50 fields of 0.2 mm

(ie, in a total area of 10 mm

); the Ki-67 proliferation index value is determined by counting at least 500 cells in the

regions of highest labeling (hot spots), which are identified at scanning magnification; the final grade is based on whichever of the two proliferation indexes places the

neoplasm in the higher grade category.

Poorly differentiated NECs are not formally graded but are considered high grade by definition.

In most MiNENs, both the neuroendocrine and non-neuroendocrine components are poorly differentiated, and the neuroendocrine component has proliferation indexes

in the same range as other NECs, but this conceptual category allows for the possibility that one or both components may be well differentiated; when feasible, each

component should therefore be graded separately.

Terminology Dierentiation Grade Mitotic rate

(mitoses/2 mm

)

Ki-67 index

(percent)

NET, G1 Well-dierentiated Low <2 <3

NET, G2 Well-dierentiated Intermediate 2 to 20 3 to 20

NET, G3 Well-dierentiated High >20 >20

Neuroendocrine carcinoma

(NEC), small cell type (SCNEC)

Poorly dierentiated High

>20 >20

NEC, large cell type (LCNEC) Poorly dierentiated High

>20 >20

Mixed neuroendocrine-non-

neuroendocrine neoplasm

Well or poorly

dierentiated

Variable

2019 WHO Classication and Grading Criteria for Neuroendocrine Neoplasms of the

Gastrointestinal Tract and Hepatopancreatobiliary Organs

PRINCIPLES OF PATHOLOGY FOR DIAGNOSIS AND REPORTING OF NEUROENDOCRINE TUMORS

NCCN Guidelines Version 2.2021

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Discussion

NE-A

2 OF 5

Reprinted from Travis WD, Colby TV, Corrin B, et al. (1999) WHO Histological Classification of Tumours. Histological Typing of Lung and Pleural Tumours. 3rd ed.

Berlin: Springer.

2015 WHO Criteria for the Diagnosis of Pulmonary NET

Tumor type Criteria

Typical carcinoid Carcinoid morphology and <2 mitoses/2 mm

(10 high-power elds), lacking necrosis and ≥0.5 cm

Atypical carcinoid Carcinoid morphology with 2 to 10 mitoses/2 mm

(10 high-power elds) or necrosis (often punctuate)

Large cell

neuroendocrine

carcinoma

Neuroendocrine morphology (organoid nesting, palisading, rosettes, trabeculae);

High mitotic rate ≥11/2 mm

(10 HPFs), median of 70/2 mm

;

Necrosis (often large zones);

Cytologic features of a NSCLC: large cell size, low nuclear to cytoplasmic ratio, vesicular or ne chromatin, and/or frequent

nucleoli; some tumors have ne nuclear chromatin and lack nucleoli but qualify as non-small cell lung cancer because of

large cell size and abundant cytoplasm; and

Positive immunohistochemical staining for one or more neuroendocrine markers (other than neuron-specic enolase) and/

or neuroendocrine granules by electron microscopy

Small cell

neuroendocrine

carcinoma

Small size (generally less than the diameter of three resting lymphocytes);

Scant cytoplasm;

Nuclei: nely granular nuclear chromatin, absent or faint nucleoli;

High mitotic rate: ≥11 mitoses/2 mm

(10 high-power elds), median of 80/2 mm

(10 high-power elds); and

Frequent necrosis, often in large zones

PRINCIPLES OF PATHOLOGY FOR DIAGNOSIS AND REPORTING OF NEUROENDOCRINE TUMORS

NCCN Guidelines Version 2.2021

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Discussion

NE-A

3 OF 5

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PRINCIPLES OF PATHOLOGY FOR DIAGNOSIS AND REPORTING OF NEUROENDOCRINE TUMORS

References

Functional Status

• Functioning NETs should have the same pathologic diagnosis as the non-functioning NETs at the same anatomic site, since the functional

status is based upon clinical symptoms and should not alter the pathologic diagnosis.

Immunohistochemistry and Other Ancillary Techniques

• Immunohistochemistry and other ancillary techniques may not be required to diagnose well-dierentiated NETs when sucient tumor

material is available for histologic review.

• Specic markers that may be used to establish neuroendocrine dierentiation include chromogranin A, synaptophysin, and others. In less

well-dierentiated tumors or tumors of unknown origin, it may be helpful (or required in the case of poorly dierentiated neuroendocrine

carcinomas) to utilize immunohistochemistry panels.

• Although not entirely specic, lung origin is favored by thyroid transcription factor 1 (TTF-1); intestinal origin by CDX2; and pancreatic NETs

by Isl1 and PAX8.

1,2

Classication and Grade

• Many classication schemes have been proposed for NETs.

3-11

The most recent WHO classication system is suggested for

gastroenteropancreatic (GEP) NETs and represents an attempt to unify European and American approaches.

Multiple site-specic grading

systems also exist.

• Therefore, the specic classication and grading scheme being utilized should be reported in parentheses after the diagnosis to avoid

confusion with overlapping terminology and criteria used in other systems.

• The raw data used to derive the grade should be reported.

• Regardless of the system used, it is most important to realize that the term “neuroendocrine tumor” or “neuroendocrine carcinoma” without

any further qualication as to grade is inadequate for prognostication and therapy and is inappropriate for pathology reporting.

1,12

Mitotic Rate

• Mitotic rate should be based on counting mitoses in the areas of highest mitotic density, and should be reported as the number of mitoses

per 10 high-power eld (HPF) or per 2 mm

. Ten HPF is equivalent to 2 mm

on many microscopes, although the eld size may vary

slightly.

4,5

• Note that in cases where an accurate mitotic rate is precluded by inadequate tissue, such as in small biopsy samples including ne-needle

aspiration (FNA), the Ki-67 index is the preferred method of establishing the proliferative rate.

Ki-67 Index

• Ki-67 index is reported as the percentage of positive tumor cells in the area of highest nuclear labeling. Although recommendations have

been to count 2,000 tumor cells in order to determine the Ki-67 index, this is not practical in routine clinical practice. It is therefore currently

acceptable to estimate the labeling index, despite the recognition that estimation is subject to limitations in reproducibility.

• If both mitotic rate and Ki-67 index are used and these are discordant, it is currently recommended that the higher grade be used to assign

classication.

• The pathologist should report the actual parameters used to assign grade (ie, mitotic rate, proliferation index) so clinicians have the

necessary information to make informed treatment decisions.

• Ki-67 immunohistochemistry should be analyzed and/or counted in the areas of highest activity referred to as "hot spots."

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PRINCIPLES OF PATHOLOGY FOR DIAGNOSIS AND REPORTING OF NEUROENDOCRINE TUMORS

REFERENCES

Klimstra DS, Modlin IR, Coppola D, et al. The pathologic classification of neuroendocrine tumors: a review of nomenclature, grading and staging systems. Pancreas

2010;39:707-712.

Koo J, Mertens RB, Mirocha JM, et al. Value of Islet 1 and PAX8 in identifying metastatic neuroendocrine tumors of pancreatic origin. Modern Pathology 2012; 25:893-

901.

Travis WD, Brambilla E, Burke AP, et al. WHO Classification of Tumours of the Lung, Pleura, Thymus and Heart. IARC, Lyon; 2015.

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.

Washington MK, Tang LH, Berlin J, et al. Protocol for the examination of specimens from patients with neuroendocrine tumors (carcinoid tumors) of the colon and

rectum. Arch Pathol Lab Med 2010;134:176-180.

Strosberg JR, Coppola D, Klimstra DS, et al. The NANETS consensus guidelines for the diagnosis and management of poorly differentiated (high-grade)

extrapulmonary neuroendocrine carcinomas. Pancreas 2010;39,799-800.

Boudreaux JP, Klimstra DS, Hassan MM et al. The NANETS consensus guideline for the diagnosis and management of neuroendocrine tumors: well-differentiated

neuroendocrine tumors of the jejunum, ileum, appendix, and cecum. Pancreas 2010;39,753-766.

Anthony LB, Strosberg JR, Klimstra DS et al. The NANETS consensus guidelines for the diagnosis and management of gastrointestinal neuroendocrine tumors

(NETs): well-differentiated NETs of the distal colon and rectum. Pancreas 2010;39,767-774.

Bosman F, Carneiro F, Hruban R, and Theise ND. WHO Classification of tumours of the digestive system. Lyon, France: IARC Press; 2010.

Oberg K and Castellano D. Current knowledge on diagnosis and staging of neuroendocrine tumors. Cancer Metastasis Rev 2011;30S,S3-S7.

Lloyd RV, Osamaru RY, Klöppel G, et al. WHO Classification of Tumours of Endocrine Organs. IARC, Lyon, 2017.

Klimstra DS, Modlin IR, Adsay NV, et al. Pathology reporting of neuroendocrine tumors: application of the Delphic consensus process to the development of a

minimum pathology data set. Am J Surg Pathol 2010;34:300-313.

Rindi G, Bordi C, La Rosa S, et al. Gastroenteropancreatic (neuro)endocrine neoplasms: The histology report. Digestive and Liver Disease 2011;43S;S356-S360.

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PRINCIPLES OF IMAGING

NE-B

Anatomic Imaging

• Cross-sectional imaging should include the primary site of disease.

Either CT or MRI is appropriate.

• The liver is a common metastatic site for NET, and these metastatic

lesions are often hypervascular. Therefore, multiphasic imaging

of the liver with contrast enhancement (arterial and portal venous

phase) should be performed whenever possible. Following arterial-

phase imaging of the liver, imaging of the abdomen and pelvis can be

performed in the portal-venous phase of enhancement. Oral contrast

may be helpful to delineate discrete lesions within the bowel.

• Without a known tumor or specic clinical concern, imaging of the chest

is optional for GI NET and imaging of the brain is generally not required

for well-dierentiated NET.

• For metastatic well-dierentiated NET, anatomic imaging should

generally be performed every 12 weeks–12 months based on clinical or

pathologic signs of aggressiveness.

• Consider MRI over CT to minimize radiation risk.

• MRI preferred for pregnant patients.

Functional Imaging

• Evaluation with somatostatin receptor (SSR) imaging to assess receptor

status and distant disease is appropriate. This is especially important

for determining whether a patient may benet from SSR-directed

therapy.

SSR-based imaging options include SSR-PET/CT or SSR-PET/MRI, or

octreotide SPECT/CT (only if SSR-PET is not available)

Appropriate SSR-PET tracers include 68Ga-DOTATATE, 68Ga-

DOTATOC, or 64Cu-DOTATATE.

SSR-positive if uptake in measurable lesions is greater than liver.

Data on the role of functional imaging in pheochromocytoma/paraganglioma is evolving and the preferred method remains unclear.

Castillo JC, Maib T, Zacks JS, Adams DH. Echocardiography in functional midgut neuroendocrine tumors: When and how often. Rev Endocr Metab Disord

2017;18:411-421.

• Whenever possible, SSR-PET/CT should be performed in

combination with contrast-enhanced CT or MRI (dual-phase

hepatic CT or MRI imaging preferred) to minimize the total

number of imaging studies. The contrast-enhanced CT or MRI

is vital to identify lesions that are SSR-negative as well as those

that are SSR-positive.

• Octreotide SPECT/CT is much less sensitive for dening SSR-

positive disease than SSR-PET/CT, and typically cannot be done

in combination with multiphase CT or MRI. Therefore, SSR-PET/

CT or SSR-PET/MRI is preferred.

• In selected cases where high-grade NET or poorly dierentiated

neuroendocrine carcinoma is documented or suspected or

where disease is growing rapidly, FDG-PET/CT may be useful to

identify high-grade active disease.

• As with SSR-PET/CT, combining FDG-PET with dual-phase liver

CT or MRI is preferred.

Surveillance

• After potentially curative surgery, surveillance is recommended

for at least 10 years for most patients. In certain cases,

surveillance may be extended beyond 10 years based on risk

factors such as age and risk of recurrence. However, data are

limited on the optimal surveillance schedule beyond 10 years.

Transthoracic Echocardiogram (ECHO)

to Assess for Carcinoid

(NET-related) Heart Disease

• Echocardiogram (transthoracic echocardiography, TTE) is

important for the evaluation of carcinoid heart disease (CHD)

and should include morphologic evaluation of the valves

(especially tricuspid and pulmonic) and the right heart.

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and this illustration may not be reproduced in any form without the express written permission of NCCN.

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PRINCIPLES OF BIOCHEMICAL TESTING

1-10

• Some NETs can secrete specic neuroendocrine hormones. Hormonal workup should be guided by the presence of symptoms of the excess

hormone. Screening for hormones in asymptomatic individuals is not routinely required.

• Proton pump inhibitors, other drugs, some medical conditions, and certain foods are known to cause false elevations in serum gastrin and

chromogranin A.

• If MEN2 is suspected, then patients should be evaluated for pheochromocytoma/paraganglioma prior to any procedures.

• In select cases, chromogranin A may have prognostic value but treatment decisions are not based solely on changes in chromogranin.

Location Clinical Symptoms Testing

NETs of

Gastrointestinal

Tract, Lung, and

Thymus

Primary tumors in GI tract

(ileum, appendix, rectum),

lung, or thymus

• Primary tumors in the GI tract usually

are not associated with symptoms of

hormone secretion unless extensive

metastasis.

• Symptoms of hormone secretion

may include ushing, diarrhea,

cardiac valvular brosis, and

bronchoconstriction.

• Bronchial/thymic tumors may be

associated with classic carcinoid

syndrome as well as Cushing syndrome.

• 24-hour urine or plasma 5-HIAA

Foods to avoid for 48 hours prior to

and during testing: avocados, bananas,

cantaloupe, eggplant, pineapples, plums,

tomatoes, hickory nuts/pecans, plantains,

kiwi, dates, grapefruit, honeydew, or

walnuts.

• Test for Cushing syndrome (NE-C, 2 of 3)

PanNET: PPoma Pancreas Clinically silent • Serum pancreatic polypeptide (category 3)

PanNET:

Insulinoma

Pancreas Hypoglycemia

• While hypoglycemic:

Serum insulin

Pro-insulin

C-peptide

• See Workup for insulinoma (PanNET-3)

PanNET: VIPoma Most common in pancreas,

can be extra pancreatic

Diarrhea, hypokalemia Serum VIP

PanNET:

Glucagonoma

Pancreas Flushing, diarrhea, hyperglycemia,

dermatitis, hypercoaguable state

Serum glucagon

PanNET:

Gastrinoma

Pancreas or duodenum Gastric ulcers, duodenal ulcers, diarrhea Serum gastrin

References

Basal, stimulated as indicated.

NE-C

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Location Symptoms Testing

Pheochromocytoma/

Paraganglioma

Adrenal or

extra-adrenal

sympathetic or

parasympathetic

chain

Hypertension, tachycardia,

sweating, syncope

• Plasma free or 24-hour urine fractionated metanephrines

• Cervical paragangliomas: consider serum and urine

catecholamines or methoxytyramine (the metabolite of

dopamine)

Pituitary Tumor Pituitary (part of

MEN1)

May be asymptomatic, depends

on the hormone secreted

• Serum IGF-1 (category 2B)

• Serum prolactin

• LH/FSH

• Alpha subunits

• TSH (free T4)

• Screen for Cushing syndrome

Cushing Syndrome

Adrenal, pituitary,

or ectopic (often

bronchial or

thymic)

Central weight gain, striae,

hypertension, hyperglycemia,

depression, hirsutism

• Screen for hypercortisolemia with 1 of the following tests

1 mg overnight dexamethasone suppression test

 2–3 midnight salivary cortisols

24-hour urinary free cortisol

• Conrmatory testing if positive

• Plasma ACTH

Hyperaldosteronism Adrenal Hypertension, hypokalemia • Screening: Suppressed renin/renin activity in association with

an elevated plasma aldosterone level (> 15 ng/dL)

• Conrmatory testing if positive

Suspected or

Conrmed

Adrenocortical

Carcinoma

Adrenal Symptoms of Cushing syndrome

or hyperaldosteronism (see

above)

Androgen excess symptoms

• See workup above for Cushing syndrome or

hyperaldosteronism

• Testosterone

• DHEA-S

For additional information on biochemical testing for Cushing syndrome, refer to the Endocrine Society's Clinical Practice Guidelines for the Treatment of Cushing's

Syndrome: Nieman LK, Biller BMK, Findling JW, et al. Treatment of Cushing's Syndrome: An Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab

2015;100:2807-2831.

24-hour urine for aldosterone, sodium and potassium should be considered for definitive diagnosis.

Some drugs may interfere with testing results, including: acetaminophen, labetalol, sotalol, α-methyldopa, tricyclic antidepressants, buspirone, phenoxybenzamine,

MAO inhibitors, sympathomimetics, cocaine, sulfasalazine, and levodopa. (Lenders J, Duh QY, Eisenhofer G, et al. Guidelines on pheochromocytoma and

paraganglioma. J Clin Endocrinol Metab June 2014;99:1915-1942)

Petrosal vein sampling can be considered to differentiate adrenal from pituitary and ectopic causes..

References

NE-C

2 OF 3

PRINCIPLES OF BIOCHEMICAL TESTING

1-10

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and this illustration may not be reproduced in any form without the express written permission of NCCN.

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PRINCIPLES OF BIOCHEMICAL TESTING

REFERENCES

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3 OF 3

Kaltsas G, Androulakis, II, de Herder WW, Grossman AB. Paraneoplastic syndromes secondary to neuroendocrine tumours. Endocr Relat Cancer 2010;17:R173-193.

Oberg K. Diagnostic work-up of gastroenteropancreatic neuroendocrine tumors. Clinics (Sao Paulo) 2012;67 Suppl 1:109-112.

Van Der Horst-Schrivers AN, Osinga TE, Kema IP, et al. Dopamine excess in patients with head and neck paragangliomas. Anticancer Res 2010;30:5153-5158.

Raines D, Chester M, Diebold AE, et al. A prospective evaluation of the effect of chronic proton pump inhibitor use on plasma biomarker levels in humans. Pancreas

2012;41:508-511.

Lenders JW, Duh QY, Eisenhofer G, et al. Pheochromocytoma and paraganglioma: an endocrine society clinical practice guideline. J Clin Endocrinol Metab

2014;99:1915-1942.

Cryer PE, Axelrod L, Grossman AB, et al. Evaluation and management of adult hypoglycemic disorders: an Endocrine Society Clinical Practice Guideline. J Clin

Endocrinol Metab 2009;94:709-728.

Nieman LK, Biller BM, Findling JW, et al. The diagnosis of Cushing’s syndrome: an Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab

2008;93:1526-1540.

Funder JW, Carey RM, Mantero F, et al. Case detection, diagnosis, and treatment of patients with primary aldosteronism: an endocrine society clinical practice

guideline. J Clin Endocrinol Metab 2016;101:1889-1916.

Thakker RV, Newey PJ, Walls GV, et al. Clinical practice guidelines for multiple endocrine neoplasia type 1 (MEN1). J Clin Endocrinol Metab 2012;97:2990-3011.

Modlin IM, Oberg K, Taylor A, et al. Neuroendocrine tumor biomarkers: current status and perspectives. Neuroendocrinology 2014;100:265-277.

Young WF Jr. Diagnosis and treatment of primary aldosteronism: practical clinical perspectives. J Intern Med 2019;285:126-148.

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SURGICAL PRINCIPLES FOR MANAGEMENT OF NEUROENDOCRINE TUMORS

• Standard oncologic surgery (eg, distal pancreatectomy/splenectomy

or pancreaticoduodenectomy) is appropriate for most resectable,

non-metastatic pancreatic NETs. However, there are additional

considerations for following circumstances:

Tumor enucleation should be considered primarily for insulinomas,

which are highly symptomatic (hypoglycemic) but rarely malignant.

Peripheral insulinomas should be considered for enucleation/

local resection or spleen-preserving distal pancreatectomy, when

technically feasible.

For patients with small (<2 cm) low-grade NETs, decisions on surgery

versus active surveillance need to be individualized, based on tumor

size/characteristics and patient characteristics:

◊ Tumors <1 cm have a lower malignant potential than tumors

measuring 1–2 cm.

◊ Other radiographic characteristics of small tumors (homogeneous,

well-circumscribed) may also correlate with benign behavior.

◊ Patient characteristics such as age and comorbidities are important

when determining whether surveillance is appropriate.

• Resection for larger (>2 cm) or malignant-appearing non-functional

and functional PanNETs (ie, glucagonoma, VIPoma, somatostatinoma)

should include total removal of the tumor with negative margins

(including adjacent organs) and regional lymph nodes. Tumors of the

head are generally treated with pancreatoduodenectomy (Whipple

procedure); tumors of the body and tail are treated with distal

pancreatectomy and splenectomy or spleen-preserving surgery.

Generally surgery will include splenectomy, but with benign insulinoma

spleen preservation should be considered.

• Resection of gastrointestinal NETs should include adequate regional

lymph node resection (including all palpable disease where feasible)

and thorough exploration of synchronous primary tumors (15%–30%

incidence).

NE-D

• Resection of recurrent locoregional disease, isolated distant

metastases, or a previously unresectable tumor that has

regressed should be considered for selected patients with

adequate performance status.

• Cytoreductive surgery for distant metastatic disease (typically

but not exclusively hepatic) is routinely recommended in

patients in whom >90% of disease can be safely resected by

surgery with or without ablation. This strategy is particularly

appropriate for patients with relatively indolent metastatic small

bowel NETs, and less appropriate for patients in whom rapid

progression of disease is expected after surgery. Patients who

are symptomatic from hormonal syndromes, such as carcinoid

syndrome, typically derive palliation from cytoreductive

surgery.

• Cholecystectomy is recommended when performing surgery

for advanced NETs in patients anticipated to receive long-

term octreotide therapy, as these patients are at higher risk of

developing biliary symptoms and cholecystitis.

• Liver-directed therapies (eg, liver resection, thermal ablation,

chemoembolization) for hepatic metastases from NETs

following pancreatoduodenectomy are associated with

increased risk for cholangitis and liver abscess.

• Octreotide therapy should be administered parenterally prior

to induction of anesthesia in patients with functional NETs to

prevent carcinoid crisis.

• All patients who might require splenectomy should receive

preoperative trivalent vaccine (ie, pneumococcus, haemophilus

inuenzae b, meningococcal group C).

• For MEN1-related surgical principles, see MEN1-A.

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and this illustration may not be reproduced in any form without the express written permission of NCCN.

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PRINCIPLES OF GENETIC RISK ASSESSMENT AND COUNSELING

HEREDITARY ENDOCRINE NEOPLASIAS

• The decision to oer genetic testing involves three related stages:

1) Pre-test counseling prior to ordering testing;

2) Consideration of the most appropriate testing strategy; and

3) Testing result disclosure and post-test counseling.

• It is recommended that a genetic counselor, medical geneticist, endocrinologist, oncologist, surgeon, oncology nurse, or other health

professional with expertise and experience in cancer genetics be involved at each stage whenever possible. Clinicians without direct referral

access to the appropriate expertise should be aware of the telehealth genetic counseling options available. These resources can be found

through the National Society of Genetic Counselors (NSGC) “Find a Genetic Counselor” tool (www.nsgc.org).

1) Pre-Test Counseling:

• Pre-test counseling includes the following elements:

Evaluation of patient’s knowledge, needs/concerns, and goals for familial risk assessment.

Detailed family history (including cancers/tumors and age at diagnosis, as well as clinical symptoms that can indicate an underlying

endocrine neoplasia) in rst-, second-, and third-degree family members on each side of the family.

Detailed past medical history and review of systems, including:

◊ Documentation of prior genetic testing results for patients and their family members; and

◊ Personal cancer/tumor history including age of diagnosis and treatment.

Focused physical examination (conducted by qualied clinician) when indicated.

Generation of dierential diagnosis and educating the patient of inheritance pattern, penetrance, variable expressivity, and the possibility

of genetic heterogeneity.

Discussion of possible genetic testing result outcomes, including positive (pathogenic or likely pathogenic), negative, and variants of

unknown signicance.

Discussion of the clinical implications of testing results to the patient.

Discussion of the clinical implications of testing results to potentially aected family members and their available options for pursuing risk

assessment, testing, and management.

Cost of genetic testing.

Current legislation regarding genetic discrimination and the privacy of genetic information.

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PRINCIPLES OF GENETIC RISK ASSESSMENT AND COUNSELING

HEREDITARY ENDOCRINE NEOPLASIAS

2) Considerations When Determining the Most Appropriate

Testing Strategy:

• The introduction of multigene testing for hereditary cancer/

tumor predisposition syndromes has rapidly altered the clinical

approach to genetic testing of at-risk patients and their families.

• Given the possible overlap in clinical presentation amongst

hereditary endocrine neoplasias, multigene panel testing may

be more ecient and cost-eective in many situations.

• As commercially available tests dier in the specic genes

analyzed, variant classication, and other factors (eg, methods

of DNA/RNA analysis or option to reex from a narrow to a

larger panel; provision of nancial assistance for cascade

testing of relatives), it is important to consider the indication for

testing and the expertise of the laboratory when choosing the

specic laboratory and test panel.

• The interpretation of genetic testing remains subjective and

complex. The interpretations can dier based on interlaboratory

classication rules, access to unique case-level data, and other

evidence. Additionally, variants may need to be reconsidered

and reclassied as additional data emerge in the eld.

• Genetic testing performed to identify somatic mutations arising

in malignant cells is often not designed to detect germline

variants and may thus be inadequate for evaluation of an

underlying hereditary endocrine neoplasia syndrome.

• Testing for unaected family members when no aected

member is available should be considered. Signicant

limitations of interpreting test results should be discussed.

3) Post-Test Counseling Includes the Following Elements:

• Discussion of results and implications for patient and/or family

members

• Interpretation of results in context of personal and family history

• Likely pathogenic variants are usually clinically managed similarly

to pathogenic variants, while patients with variants of unknown

signicance (VUS) and likely benign variants should be managed

based on the cancers/tumors in the family

• For patients with positive results:

Discussion of recommended medical management

Discussion of the importance of notifying family members and

oering materials/resources for information and testing at-risk

family members

For many hereditary endocrine neoplasia syndromes, testing of

children is indicated since screening interventions often start in

childhood or adolescence

Discussion of available resources such as high-risk clinics,

disease-specic support groups, and research studies

For patients of reproductive age, advise about options for prenatal

diagnosis and assisted reproduction, including pre-implantation

genetic diagnosis

Consider carrier status implications of certain autosomal recessive

disorders

• For patients with negative results:

Discussion of possible etiologies for their personal/family history

including sporadic, multifactorial, or unidentied hereditary factors

For patients with a clinical diagnosis of an endocrine neoplasia

condition (such as MEN1) and negative genetic testing, consider

following the related surveillance recommendations for patient and

rst-degree family members

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PRINCIPLES OF GENETIC RISK ASSESSMENT AND COUNSELING

HEREDITARY ENDOCRINE NEOPLASIAS

4) Criteria for Genetic Risk Evaluation for Hereditary Endocrine Neoplasia Syndromes

• Recommend evaluation in a patient with any of the following:

Adrenal cortical carcinoma (ACC)

Paraganglioma (PGL)/Pheochromocytoma (PCC)

Gastrinoma (duodenal/pancreatic or type 2 gastric NET)

Multifocal pancreatic neuroendocrine tumors.

Parathyroid adenoma or primary hyperparathyroidism before age 30, multiple parathyroid adenomas,

multigland hyperplasia (without obvious secondary causes), or recurrent primary hyperparathyroidism

Clinical suspicion for MEN2 due to the presence of medullary thyroid cancer or other combination of MEN2-

related features. See Overview of Hereditary Endocrine Neoplasia Syndromes (NE-E 4 of 7).

A mutation identied on tumor genomic testing that has clinical implications if also identied in the germline

(eg, tumor analysis shows mutation in BRCA1/2 or mismatch repair gene).

Close blood relative with a known pathogenic variant/likely pathogenic variant in a cancer susceptibility gene.

A rst-degree relative meeting one of the above criteria but not available for testing.

Recommend evaluation in a patient with clinical suspicion for MEN1 due to 2 or more of the following, or 1

AND a family history of 1 or more of the following:

◊ Primary hyperparathyroidism

◊ Duodenal/pancreatic neuroendocrine tumor

◊ Pituitary adenoma

◊ Foregut carcinoid (bronchial, thymic, or gastric)

• Consider evaluation in a patient with duodenal/pancreatic neuroendocrine tumor at any age.

Genetic testing may be a consideration for patients with other combinations of tumors or cancers in the patient and/or their family members.

Studies of unselected patients with pancreatic neuroendocrine tumors have identified germline variants in 16-17% of cases. However, these studies involved relatively

small cohorts of patients. (Raj N, et. al. JCO Precis Oncol. 2018;2018:PO.17.00267; Scarpa A, et al. Nature. 2017 Mar 2;543(7643):65-71).

NCCN Guidelines Version 2.2021

Neuroendocrine and Adrenal Tumors

(NCCN

and this illustration may not be reproduced in any form without the express written permission of NCCN.

Note: All recommendations are category 2A unless otherwise indicated.

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

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Discussion

NE-E

4 OF 7

PRINCIPLES OF GENETIC RISK ASSESSMENT AND COUNSELING

HEREDITARY ENDOCRINE NEOPLASIAS

Syndrome (Gene)

Endocrine Neoplasia Manifestations Other Manifestations Surveillance

Hereditary paraganglioma/

pheochromocytoma syndrome

(MAX, SDHA, SDHAF2, SDHB,

SDHC, SDHD, or TMEM127)

Paraganglioma

Pheochromocytoma

GIST (SDHx)

Renal cell cancer (SDHx)

See NE-E (7 of 7)

N CCN Guidelines for Kidney

Cancer (HRCC-B)

Multiple endocrine neoplasia type

1 (MEN1)

d,e

Parathyroid adenoma/hyperplasia (>95%)

Pancreatic (functioning) or duodenal

neuroendocrine tumors (20%–80%)

Gastrinoma 20%–61%

Insulinoma 7%–31%

Glucagonoma 1%–5%

VIPoma/somatostatinoma <2%

Pituitary adenomas (30%–40%)

Gastric carcinoids (7%–35%)

Bronchial/thymic carcinoids (<8%)

Adrenal adenomas (27%–36%)

Angiobromas

Collagenomas

Lipomas

Meningiomas

See MEN1-2

and MEN1-A

Multiple endocrine neoplasia type

2 (RET)

Medullary thyroid cancer (≤98%)

Pheochromocytoma (≤50%)

Parathyroid adenoma/hyperplasia (≤25%

MEN2A, rare in MEN2B)

MEN2A:

• Cutaneous lichens

amyloidosis

• Hirschsprung disease

MEN2B:

• Intestinal ganglioneuromas

• Mucosal neuromas

• Marfanoid habitus

See MEN2-1 and

NE-E (7 of 7)

N CCN Guidelines for Thyroid

Cancer (MEDU-4 and

MEDU-5)

Note: This resource is not intended to be an exhaustive list of hereditary endocrine neoplasias. Specic scenarios may warrant consideration of less

common conditions such as Carney complex, Carney triad, Currarino syndrome, or polycythemia-paraganglioma-somatostatinoma syndrome.

Overview of Hereditary Endocrine Neoplasia Syndromes

Penetrance estimates and tumor locations vary significantly by gene. For patients

with pathogenic variants in the SDHD, SDAHF2, and possibly MAX genes, tumor

risks are mostly a concern when the variant is paternally inherited.

10% of cases have de novo MEN1 mutations.

Thakker RV, Newey PJ, Walls GV, et al. Clinical practice guidelines for multiple

endocrine neoplasia type 1 (MEN1). J Clin Endocrinol Metab 2012;97:2990-3011.

50% of cases have de novo RET mutations; therefore, even if a family

history is not suggestive of a hereditary syndrome, genetic testing for

RET mutations should still be performed on the affected individual.

Wells SA Jr, Asa SL, Dralle H, et al. Revised American Thyroid

Association guidelines for the mamagement of medullary thyroid

carcinoma. Thyroid. 2015;25(6):567-610.

NCCN Guidelines Version 2.2021

Neuroendocrine and Adrenal Tumors

(NCCN

and this illustration may not be reproduced in any form without the express written permission of NCCN.

Note: All recommendations are category 2A unless otherwise indicated.

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

NCCN Guidelines Index

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Discussion

NE-E

5 OF 7

PRINCIPLES OF GENETIC RISK ASSESSMENT AND COUNSELING

HEREDITARY ENDOCRINE NEOPLASIAS

Syndrome (Gene) Endocrine Neoplasia Manifestations Other Manifestations Surveillance

Multiple endocrine neoplasia type

4 (CDKN1B)

Parathyroid adenoma/hyperplasia

Pituitary adenomas

Pancreatic or duodenal neuroendocrine tumors

Papillary thyroid cancer

Meningiomas Not available

Neurobromatosis type 1 (NF1) Pheochromocytoma (3%)

Pancreatic neuroendocrine tumors (rare)

Neurobromas

Skin lesions (CAL and freckling)

Lisch nodules

Gliomas

GIST

NCCN Guidelines for

Genetic/Familial High-

Risk Assessment: Breast,

Ovarian, and Pancreatic

AAP Health Supervision

Guidelines

Tuberous sclerosis complex

(TSC1 and TSC2)

Pituitary adenomas (rare)

Parathyroid adenoma/hyperplasia (rare)

Pancreatic neuroendocrine tumors (rare)

Skin lesions

CNS tumors/cancers

Renal angiomyolipomas

Clear cell renal cancer

Cardiac rhabdomyomas

Lymphangioleiomyomatosis

N CCN Guidelines for Kidney

Cancer (HRCC-B)

von Hippel Lindau syndrome

(VHL)

Pheochromocytoma (10%–20%)

Paraganglioma (10%–20%)

Pancreatic neuroendocrine tumors (5%–17%)

Hemangioblastomas (retinal or

CNS)

Clear cell renal cancer

Endolymphatic sac tumors

Cystadenomas

See NE-E (7 of 7)

and PanNET-6

VHLA Handbook

N CCN Guidelines for Kidney

Cancer (HRCC-B)

Overview of Hereditary Endocrine Neoplasia Syndromes

Note: This resource is not intended to be an exhaustive list of hereditary endocrine neoplasias. Specic scenarios may warrant consideration of less

common conditions such as Carney complex, Carney triad, Currarino syndrome, or polycythemia-paraganglioma-somatostatinoma syndrome.

Thakker RV, Newey PJ, Walls GV, et al. Clinical practice guidelines for multiple endocrine neoplasia type 1 (MEN1). J Clin Endocrinol Metab 2012;97:2990-3011.

MEN4 is a newly described endocrine neoplasia. Therefore, penetrance estimates and surveillance guidelines are not available. Given the clinical overlap with MEN1,

consideration can be given to following MEN1-related surveillance recommendations in patients with MEN4.

Miller, D. T., et al. (2019). Health Supervision for Children With Neurofibromatosis Type 1. Pediatrics 143(5): e20190660.

The VHL Alliance. The VHL Handbook: What you need to know about VHL. 6th ed. 2020.

NCCN Guidelines Version 2.2021

Neuroendocrine and Adrenal Tumors

(NCCN

and this illustration may not be reproduced in any form without the express written permission of NCCN.

Note: All recommendations are category 2A unless otherwise indicated.

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

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Discussion

NE-E

6 OF 7

PRINCIPLES OF GENETIC RISK ASSESSMENT AND COUNSELING

HEREDITARY ENDOCRINE NEOPLASIAS

Hereditary Cancer Predisposition Syndromes Associated with ACC

Syndrome (Gene) Other Cancer/Tumor Associations Surveillance Recommendations

Li-Fraumeni syndrome (TP53) Sarcoma, brain cancer, breast cancer,

leukemia

NCCN Guidelines for Genetic/Familial High-

Risk Assessment: Breast, Ovarian, and

Pancreatic

Lynch syndrome (MLH1, EPCAM/MSH2,

MSH6, PMS2)

Colon, endometrial, gastric, ovarian, and

other cancers

NCCN Guidelines for Genetic/Familial High-

Risk Assessment: Breast, Ovarian, and

Pancreatic

NCCN Guidelines for Genetic/Familial High-

Risk Assessment: Colorectal

Multiple endocrine neoplasia type 1

(MEN1)

Parathyroid adenoma/hyperplasia, duodenal/

pancreatic neuroendocrine tumors, pituitary

adenomas, bronchial/thymic carcinoids

See MEN1-2 and MEN1-A

Familial adenomatous polyposis (APC) Colon polyposis/cancer, duodenal/

periampullary polyposis/cancer, thyroid

cancer

NCCN Guidelines for Genetic/Familial High-

Risk Assessment: Colorectal

NCCN Guidelines Version 2.2021

Neuroendocrine and Adrenal Tumors

(NCCN

and this illustration may not be reproduced in any form without the express written permission of NCCN.

Note: All recommendations are category 2A unless otherwise indicated.

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

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Discussion

NE-E

7 OF 7

PRINCIPLES OF GENETIC RISK ASSESSMENT AND COUNSELING

HEREDITARY ENDOCRINE NEOPLASIAS

PCC/PGL-specic Screening Recommendations for Patients with Conrmed Hereditary Syndromes

h-k

Hereditary paraganglioma/pheochromocytoma (PGL/PCC) syndrome

• Surveillance starting at 6–8 years of age:

Blood pressure monitoring at all medical visits.

Annual measurement of plasma free metanephrines or 24-hour urine for fractionated metanephrines.

Cross-sectional imaging of skull base to pelvis every 2 years. Whole body MRI (if available) or other non-radiation–containing imaging

procedures. If whole body MRI not available, may consider abdominal MRI, skull base and neck MRI, and chest CT.

Multiple endocrine neoplasia type 2

• Surveillance starting by age 11 years for children in the American Thyroid Association high risk (ATA-H) and highest risk (ATA-HST)

categories and by age 16 years in children in the ATA-moderate risk (ATA-MOD) category:

Annual measurement of plasma free metanephrines or 24-hour urine for fractionated metanephrines.

Adrenal imaging with CT or MRI is indicated in patients with positive biochemical results.

von Hippel Lindau syndrome (VHL)

• Blood pressure monitoring at all medical visits starting at age 2 years.

• Annual measurement of plasma-free metanephrines (preferred) or 24-hour urine for fractionated metanephrines starting at age 5 years.

• Abdominal MRI (preferred) or CT with and without IV contrast every 2 years starting at age 15 years.

Surgical Recommendations for Patients with Conrmed Hereditary Syndromes

• Preoperative alert: Patients with a suspected or known diagnosis of a hereditary PGL/PCC syndrome should have blood and/or urine

screening for tumors prior to any surgical procedures.

• Patients with hereditary PGL/PCC, multiple endocrine neoplasia type 2, and VHL have an appreciable risk for bilateral tumors. Consideration

should be given to cortical-sparing adrenalectomy.

Redman SP, Erez A, Druker H, et al. Von Hippel Lindau and Hereditary

Pheochromocytoma/Paraganglioma Syndroms: Clinical Features,

Genetics, and Surveillance Recommendations in Childhood. Clin Cacer

Res. 2017;23(12):e68-e75.doi:10.1158/1078-0432.CCR-17-0547.

Muth A, Crona J, Gimm O, et al. Genetic testing and surveillance

guidelines in hereditary pheochromocytoma and paraganglioma. J Intern

Med. 2019;285(2):187-204. doi:10.1111/joim.12869.

Tufton N, Sahdev A, Akker SA. Radiological Surveillance Screening in

Asymptomatic Succinate Dehydrogenase Mutation Carriers. J Endocr Soc.

2017;1(7):897-907. Published 2017 Jun 6. doi:10.1210/js.2017-00230.

Neumann HPH, Young WF Jr, Eng C. Pheochromocytoma and Paraganglioma. N

Engl J Med. 2019;381(6):552-565. doi:10.1056/NEJMra1806651

SDHD, SDHAF2, and MAX patients are most at risk if the pathogenic variant was

paternally inherited. Recommend following the above recommendations if the parent

of origin is unknown. Consider screening for patients with maternally inherited

variants as case reports of tumor occurrence exist.

Available data suggests SDHAF2 patients are primarily at risk for head and neck

tumors and MAX patients are primarily at risk for adrenal tumors. Therefore,

consideration can be given to more targeted imaging in these cohorts.

Wells SA Jr, Asa SL, Dralle H, et al. Revised American Thyroid Association guidelines

for the management of medullary thyroid carcinoma. Thyroid 2015;25:567-610.

NCCN Guidelines Version 2.2021

Neuroendocrine and Adrenal Tumors

(NCCN

and this illustration may not be reproduced in any form without the express written permission of NCCN.

Note: All recommendations are category 2A unless otherwise indicated.

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

NCCN Guidelines Index

Table of Contents

Discussion

PRINCIPLES OF SYSTEMIC ANTI-TUMOR THERAPY

Locoregionally Advanced and/or Metastatic Neuroendocrine Tumors

of the Gastrointestinal Tract (Well-Dierentiated Grade 1/2), Lung, and Thymus

For symptom control, octreotide 150–250 mcg SC TID or octreotide LAR 20–30 mg IM or lanreotide 120 mg SC every 4 weeks. Dose and frequency may be further

increased for symptom control as needed. Therapeutic levels of octreotide would not be expected to be reached for 10–14 days after LAR injection. Short-acting

octreotide can be added to octreotide LAR for rapid relief of symptoms or for breakthrough symptoms.

The PROMID trial showed an antitumor effect of octreotide in advanced neuroendocrine tumors of the midgut.

The CLARINET trial showed an antitumor effect of

lanreotide in advanced, well-differentiated metastatic grade 1 and grade 2 GEP NETs.

If disease progression, treatment with octreotide or lanreotide should be continued in patients with functional tumors and may be used in combination with any of the

systemic therapy options. For details on the administration of octreotide or lanreotide with 177Lu-dotatate, see NE-G.

Safety and effectiveness of everolimus in the treatment of patients with carcinoid syndrome have not been established.

See Principles of PRRT with 177Lu-dotatate (NE-G).

• Systemic therapy may not be appropriate for every patient with locoregionally advanced or metastatic disease. Consider multidisciplinary

discussion to determine the best choice of treatment, including: observation for patients with stable disease with mild tumor burden, hepatic

regional therapy for patients with liver-predominant metastases, cytoreductive surgery, or systemic therapy, which may be appropriate

considerations.

• Currently, there are no data to support a specic sequence of regional versus systemic therapy, and no data to guide sequencing of the

following systemic therapy options.

• There is no known role for systemic treatment in the adjuvant setting for NETs.

• Doses and schedules are subject to appropriate modications depending on the circumstances.

• For management of hormone-related symptoms for GI tumors, see NET-11. For management of carcinoid syndrome, see NET-12.

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Neuroendocrine Tumors of the Gastrointestinal Tract (Well-Dierentiated Grade 1/2)

a,b,c

Preferred Regimens Other Recommended

Regimens

Useful in Certain Circumstances

Locoregional

Advanced Disease

and/or Distant

Metastases (if

progression on

octreotide or

lanreotide)

• Everolimus

d,1,2

• PRRT with 177Lu-dotatate (if SSR-

positive imaging and progression

on octreotide/lanreotide) (category

1 for progressive mid-gut tumors)

• None • Consider (listed in alphabetical order):

Cytotoxic chemotherapy, if no other options

feasible (all category 3): Anticancer agents such

as 5-uorouracil (5-FU), capecitabine, dacarbazine,

oxaliplatin, streptozocin, and temozolomide can

be used in patients with progressive metastases

for whom there are no other treatment options.

(See Discussion for details.)

References

NCCN Guidelines Version 2.2021

Neuroendocrine and Adrenal Tumors

(NCCN

and this illustration may not be reproduced in any form without the express written permission of NCCN.

Note: All recommendations are category 2A unless otherwise indicated.

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

NCCN Guidelines Index

Table of Contents

Discussion

PRINCIPLES OF SYSTEMIC ANTI-TUMOR THERAPY

Locoregionally Advanced and/or Metastatic Neuroendocrine Tumors

of the Gastrointestinal Tract (Well-Dierentiated Grade 1/2), Lung, and Thymus

If disease progression, treatment with octreotide or lanreotide should be continued in patients with functional tumors and may be used in combination with any of the

systemic therapy options. For details on the administration of octreotide or lanreotide with 177Lu-dotatate, see NE-G.

Safety and effectiveness of everolimus in the treatment of patients with carcinoid syndrome have not been established.

See Principles of PRRT with 177Lu-dotatate (NE-G).

Chemoradiation is thought to have most efficacy for tumors with atypical histology or tumors with higher mitotic and proliferative indices (eg, Ki-67). There are limited

data on the efficacy of chemoradiation for unresectable IIIA or IIIB low-grade lung neuroendocrine tumors; however, some panel members consider chemoradiation in

this situation.

Can be considered for intermediate-grade/atypical tumors with Ki-67 proliferative index and mitotic index in the higher end of the defined spectrum.

• Systemic therapy may not be appropriate for every patient with locoregionally advanced or metastatic disease. Consider multidisciplinary

discussion to determine the best choice of treatment, including: observation for patients with stable disease with mild tumor burden, hepatic

regional therapy for patients with liver-predominant metastases, cytoreductive surgery, or systemic therapy, which may be appropriate

considerations.

• Currently, there are no data to support a specic sequence of regional versus systemic therapy and no data to guide sequencing of the

following systemic therapy options.

• There is no known role for systemic treatment in the adjuvant setting for NETs.

• Doses and schedules are subject to appropriate modications depending on the circumstances.

• For management of hormone-related symptoms for GI tumors, see NET-11. For management of carcinoid syndrome, see NET-12.

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Bronchopulmonary/Thymus Neuroendocrine Tumors

Preferred Regimens Other Recommended

Regimens

Useful in Certain Circumstances

Distant Metastases

(clinically signicant

tumor burden and low

grade/progression/

intermediate

grade [atypical] or

symptomatic)

f,c

• Clinical trial

• Everolimus

d,1,2

(category 1 for

bronchopulmonary NET)

• Octreotide LAR

or lanreotide

(if SSR-positive and/or

hormonal symptoms)

• None • PRRT with 177Lu-dotatate (if SSR-positive imaging

and progression on octreotide or lanreotide)

• Temozolomide

5,6

± capecitabine

g,7-9

• Cisplatin + etoposide

g,10,11

• Carboplatin + etoposide

g,11,12

References

NCCN Guidelines Version 2.2021

Neuroendocrine and Adrenal Tumors

(NCCN

and this illustration may not be reproduced in any form without the express written permission of NCCN.

Note: All recommendations are category 2A unless otherwise indicated.

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

NCCN Guidelines Index

Table of Contents

Discussion

PRINCIPLES OF SYSTEMIC ANTI-TUMOR THERAPY

Locoregionally Advanced and/or Metastatic Pancreatic Neuroendocrine Tumors (Well-Dierentiated Grade 1/2)

For symptom control, octreotide 150–250 mcg SC TID or octreotide LAR 20–30 mg IM or lanreotide 120 mg SC every 4 weeks. Dose and frequency may be further

increased for symptom control as needed. Therapeutic levels of octreotide would not be expected to be reached for 10–14 days after LAR injection. Short-acting

octreotide can be added to octreotide LAR for rapid relief of symptoms or for breakthrough symptoms.

The PROMID trial showed an antitumor effect of octreotide in advanced neuroendocrine tumors of the midgut.

The CLARINET trial showed an antitumor effect of

lanreotide in advanced, well-differentiated metastatic grade 1 and grade 2 GEP NETs.

See Principles of PRRT with 177Lu-dotatate (NE-G).

• Systemic therapy may not be appropriate for every patient with locoregionally advanced or metastatic disease. Consider multidisciplinary

discussion to determine the best choice of treatment, including: observation for patients with stable disease with mild tumor burden, hepatic

regional therapy for patients with liver-predominant metastases, cytoreductive surgery, or systemic therapy.

• Currently, there are no data to support a specic sequence of regional versus systemic therapy and no data to guide sequencing of the

following systemic therapy options.

• There is no known role for systemic treatment in the adjuvant setting for PanNETs.

• Doses and schedules are subject to appropriate modications depending on the circumstances.

• For management of hormone-related symptoms and complications with octreotide or lanreotide, see PanNET-1 through PanNET-5.

References

NE-F

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Pancreatic Neuroendocrine Tumors (Well-Dierentiated Grade 1/2)

Preferred Regimens Other Recommended Regimens Useful in Certain

Circumstances

Locoregional

Advanced Disease

and/or

Distant Metastases

• Everolimus

(category 1 for progressive disease)

10 mg by mouth, daily

• Octreotide

a,b

LAR

lanreotide

a,5

(if

SSR-positive imaging)

• Sunitinib

(category 1 for progressive disease)

37.5 mg by mouth, daily

• Temozolomide + capecitabine

(preferred when tumor response is

needed for symptoms or debulking)

• PRRT with 177Lu-dotatate (if SSR-

positive imaging and progression on

octreotide or lanreotide)

• Cytotoxic chemotherapy options considered

in patients with bulky, symptomatic, and/or

progressive disease include:

◊ 5-FU + doxorubicin + streptozocin (FAS)

◊ Streptozocin + doxorubicin

◊ Streptozocin + 5-FU

◊ FOLFOX (leucovorin + 5-FU + oxaliplatin)

◊ CAPEOX (capecitabine + oxaliplatin)

• None

NCCN Guidelines Version 2.2021

Neuroendocrine and Adrenal Tumors

(NCCN

and this illustration may not be reproduced in any form without the express written permission of NCCN.

Note: All recommendations are category 2A unless otherwise indicated.

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

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PRINCIPLES OF SYSTEMIC ANTI-TUMOR THERAPY

Poorly Dierentiated Neuroendocrine Carcinoma/Large or Small Cell (Extrapulmonary)

References

NE-F

4 OF 5

Poorly Dierentiated Neuroendocrine Carcinoma/Large or Small Cell (Extrapulmonary)

Resectable disease:

• Cisplatin + etoposide

• Carboplatin + etoposide

• FOLFOX

• FOLFIRI

• Temozolomide ± capecitabine

Locoregional Unresectable/Metastatic Disease:

• Cisplatin + etoposide

• Carboplatin + etoposide

• Cisplatin + irinotecan

• Carboplatin + irinotecan

• FOLFOX

• FOLFIRI

• FOLFIRINOX

22,23

• Temozolomide ± capecitabine

• Nivolumab + ipilimumab (category 2B) (only for

metastatic disease with progression)

• Pembrolizumab

Chemoradiation (concurrent/sequential) for

locoregional unresectable disease

• Cisplatin + etoposide

• Carboplatin + etoposide

Pembrolizumab can be considered for patients with mismatch repair-deficient (dMMR), microsatellite instability-high (MSI-H), or advanced tumor mutational burden-

high (TMB-H) tumors (as determined by an FDA-approved test) that have progressed following prior treatment and have no satisfactory alternative treatment options.

NCCN Guidelines Version 2.2021

Neuroendocrine and Adrenal Tumors

(NCCN

and this illustration may not be reproduced in any form without the express written permission of NCCN.

Note: All recommendations are category 2A unless otherwise indicated.

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

NCCN Guidelines Index

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Discussion

NE-F

5 OF 5

PRINCIPLES OF SYSTEMIC ANTI-TUMOR THERAPY

REFERENCES

Pavel ME, Baudin E, Oberg KE, et al. Efficacy of everolimus plus octreotide

LAR in patients with advanced neuroendocrine tumor and carcinoid syndrome:

final overall survival from the randomized, placebo-controlled phase 3

RADIANT-2 study. Ann Oncol; 2017;28:1569-1575.

Pavel ME, Singh S, Strosberg JR, et al. Health-related quality of life for

everolimus versus placebo in patients with advanced, non-functional, well-

differentiated gastrointestinal or lung neuroendocrine tumours (RADIANT-4): a

multicentre, randomised, double-blind, placebo-controlled, phase 3 trial. Lancet

Oncol 2017;18:1411-1422.

Rinke A, Muller HH, Schade-Brittinger C, et al. Placebo-controlled, double-

blind, prospective, randomized study on the effect of octreotide LAR in the

control of tumor growth in patients with metastatic neuroendocrine midgut

tumors: a report from the PROMID Study Group. J Clin Oncol 2009;27:4656-

4663.

Caplin ME, Pavel M, Cwikla JB, et al. Lanreotide in metastatic enteropancreatic

neuroendocrine tumors. N Engl J Med 2014;371:224-233.

Crona J, Fanola I, Lindholm DP, et al. Effect of temozolomide in patients with

metastatic bronchial carcinoids. Neuroendocrinology. 2013;98(2):151-155.

Ekebald S, Sundin A, Janson ET, et al. Temozolomide as monotherapy is

effective in treatment of advanced malignant neuroendocrine tumors. Clin

Cancer Res 2007;13:2986-2991.

Al-Toubah T, Morse B, Strosberg J. Capecitabine and temozolomide in

advanced lung neuroendocrine neoplasms. Oncologist 2020;25(1):e48-e52.

Papaxoinis G, Kordatou Z, McCallum L, et al. Capecitabine and temozolomide

in patients with advanced pulmonary carcinoid tumours. Neuroendocrinology

2020;110(5):413-421.

Fine RL, Gulati AP, Krantz BA, et al. Capecitabine and temozolomide

(CAPTEM) for metastatic well differentiated neuroendocrine cancers: The

Pancreas Center at Columbia University experience. Cancer Chemother

Pharmacol 2013;71:663-670.

Iwasa S, Morizane C, Okusaka T, et al. Cisplatin and etoposide as first-

line chemotherapy for poorly differentiated neuroendocrine carcinoma of the

hepatobiliary tract and pancreas. Jpn J Clin Oncol 2010;40(4):313-318.

Chong CR, Wirth LJ, Nishino M, et al. Chemotherapy for locally advanced and

metastatic pulmonary carcinoid tumors. Lung Cancer 2014;86:241-246.

Rossi A, Di Maio M, Chiodini P, et al. Carboplatin- or cisplatin-based

chemotherapy in first-line treatment of small-cell lung cancer: the COCIS meta-

analysis of individual patient data. J Clin Oncol 2012;30:1692-1698.

Yao JC, Shah MH, Ito T, et al. Everolimus for advanced pancreatic

neuroendocrine tumors. N Engl J Med 2011;364:514-523.

Raymond E, Dahan L, Raoul JL, et al. Sunitinib malate for the treatment of

pancreatic neuroendocrine tumors. N Engl J Med 2011;364:501-13.

Strosberg JR, Fine RL, Choi J, et al. First-line chemotherapy with capecitabine

and temozolomide in patients with metastatic pancreatic endocrine carcinomas.

Cancer 2011;117:268-275.

Kouvaraki MA, Ajani JA, Hoff P, et al. Fluorouracil, doxorubicin, and

streptozocin in the treatment of patients with locally advanced and metastatic

pancreatic endocrine carcinomas. J Clin Oncol 2004;22:4762-71.

Moertel CG, Lefkopoulo M, Lipsitz S, Hahn RG, Klaassen D. Streptozocin-

doxorubicin, streptozocin-fluorouracil or chlorozotocin in the treatment of

advanced islet-cell carcinoma. N Engl J Med 1992;326:519-23.

Sun W, Lipsitz S, Catalano P, Mailliard JA, Haller DG. Phase II/III study of

doxorubicin with fluorouracil compared with streptozocin with fluorouracil or

dacarbazine in the treatment of advanced carcinoid tumors: Eastern Cooperative

Oncology Group Study E1281. J Clin Oncol 2005;23:4897-4904.

Kunz PL, Balise RR, Fehrenbacher L, et al. Oxaliplatin-fluoropyrimidine

chemotherapy plus bevacizumab in advanced neuroendocrine tumors: an

analysis of 2 phase II trials. Pancreas. 2016;45(10):1394-1400.

Spada F, Antonuzzo L, Marconcini R, et al. Oxaliplatin-based chemotherapy in

advanced neuroendocrine tumors: clinical outcomes and preliminary correlation

with biological factors. Neuroendocrinology. 2016;103(6):806-814.

Frizziero M, Spada F, Lamarca A, et al. Carboplatin in combination with oral or

intravenous etoposide for extra-pulmonary, poorly-differentiated neuroendocrine

carcinomas. Neuroendocrinology 2019;109:100-112.

Zhu J, Strosberg JR, Dropkin E, Strickler JH. Treatment of High-Grade

Metastatic Pancreatic Neuroendocrine Carcinoma with FOLFIRINOX. J

Gastrointest Cancer. 2015;46(2):166-169. doi:10.1007/s12029-015-9689-0

Borghesani M, Reni A, Zaninotto E, et al. Outcomes of upfront treatment

with mFOLFIRINOX regimen in G3 GEP-NENs: A monocentric retrospective

experience. Paper presented at: 18th Annual ENETS Conference for the

Diagnosis and Treatment of Neuroendocrine Tumor Disease; February 25-27,

2021; Virtual Conference.

Klein O, Kee D, Markman B, et al. Immunotherapy of ipilimumab and nivolumab

in patients with advanced neuroendocrine tumors: A subgroup analysis of the

CA209-538 Clinical Trial for Rare Cancers. Clin Cancer Res 2020;26:4454-4459.

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Neuroendocrine and Adrenal Tumors

(NCCN

and this illustration may not be reproduced in any form without the express written permission of NCCN.

Note: All recommendations are category 2A unless otherwise indicated.

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

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PRINCIPLES OF PEPTIDE RECEPTOR RADIONUCLIDE THERAPY (PRRT) WITH 177LU-DOTATATE

1-10

• Lutetium 177Lu-dotatate is a radiolabeled SSA used as PRRT.

• It is approved by the FDA for the treatment of SSR-positive gastroenteropancreatic (GEP) NETs, including foregut, midgut, and hindgut NET

in adults.

1,2

• Currently there are no randomized data, but there are reports of treatment ecacy and favorable outcomes when PRRT is used for PanNETs,

pheochromocytomas, paragangliomas, and bronchopulmonary/thymic NETs.

3-10

If feasible, participation in clinical trials of PRRT is strongly

recommended for patients with such rare groups of NET.

Key Eligibility:

• Well-dierentiated NET

• SSR expression of NET as detected by SSR-PET/CT or SSR-PET/MR.

a,b,c

• Adequate bone marrow, renal and hepatic function

Preparing Eligible Patients for 177Lu-dotatate

• Do not administer long-acting SSAs (such as lanreotide, octreotide) for 4–6 weeks prior to each 177Lu-dotatate treatment. Administer short-

acting octreotide as needed for symptom control of carcinoid syndrome; discontinue at least 24 hours prior to initiating 177Lu-dotatate.

• Counsel patients about the risks of:

Radiation exposure to themselves and others

Myelosuppression

Secondary myelodysplastic syndrome (MDS) and leukemia

Renal toxicity

Hepatic toxicity

Embryo-fetal toxicity

Infertility

Neuroendocrine hormonal crisis or carcinoid crisis: ushing, diarrhea, hypotension, bronchoconstriction or other signs and symptoms

Nausea/vomiting (related to amino acid infusion required as part of therapy)

• Discuss radiation safety precautions during and after 177Lu-dotatate.

• Verify pregnancy status in females of reproductive potential.

• Advise on use of eective contraception for up to 7 months (females) and 4 months (males) after last dose of 177Lu-dotatate.

Dose and Administration

• 177Lu-dotatate is administered intravenously (IV) via peripheral IV at a dose of 200 mCi over 30–40 minutes every 8 weeks for a total of 4

treatments.

• Amino acid solution:

Continued

See Principles of Imaging (NE-B).

PET/CT or PET/MRI of skull base to mid-thigh with IV contrast when possible. Data are limited on the optimal timing of scans following administration of SSAs.

SSR PET tracers include: 68Ga-DOTATATE, 64Cu-DOTATATE, 68Ga-DOTATOC.

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and this illustration may not be reproduced in any form without the express written permission of NCCN.

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IV infusion of amino acids is a critical part of 177Lu-dotatate therapy for nephroprotection.

Amino acids are administered 30 minutes before, concurrently with, and 3 hours after 177Lu-dotatate.

Commercial amino acid formulations infused at high rates are more emetogenic than compounded amino acids.

Solutions containing only arginine/lysine are only available through compounding pharmacies, but are much less emetogenic than

commercial amino acid solutions. Options for amino acids are as follows:

◊ Arginine 2.5%/lysine 2.5% in 1000 mL NaCl infused at 250 mL/h for 4 hours.

◊ Commercial amino acid formulation (typically containing approximately 20 amino acids) mixed in sterile water for a total volume of

approximately 2000 mL. Infusion rate can be increased to roughly 300–500 mL/h, as tolerated. Recommend starting at low rate of 50 mL/h

and increasing by 10 mL/h every 10 minutes as tolerated based on symptoms such as nausea. 177Lu-dotatate infusion should begin after

at least 250 mL of amino acids have been infused.

• Aggressive antiemetic prophylaxis is recommended with a 5-HT3 receptor antagonist with or without an NK1 receptor blocker. See NCCN

Guidelines for Antiemesis.

Post-treatment Instructions

• Detailed instructions on post-treatment radiation-risk reduction strategies should be provided per institutional radiation safety guidelines.

• Complete blood count (CBC), serum chemistry including renal and hepatic functions should be monitored.

• SSAs (octreotide or lanreotide) can be administered 4–24 hours after each 177Lu-dotatate treatment.

Timing of SSAs (Octreotide or Lanreotide) in Relation to 177Lu-dotatate

• Most patients treated with PRRT will have progressed on a rst-line SSA.

• Generally, patients with hormonally functional tumors should continue octreotide or lanreotide along with 177Lu-dotatate. It is unclear

whether patients with nonfunctional tumors benet from continuation of SSA treatment during and after 177Lu-dotatate treatment.

• There are theoretical concerns regarding the competition between SSAs and 177Lu-dotatate for SSR binding. Therefore, the following is

recommended:

Do not administer long-acting SSAs for 4–6 weeks prior to each 177Lu-dotatate treatment.

Stop short-acting SSAs 24 hours before each 177Lu-dotatate treatment.

SSAs (short- and long-acting) can be resumed 4–24 hours after each 177Lu-dotatate treatment.

References

PRINCIPLES OF PEPTIDE RECEPTOR RADIONUCLIDE THERAPY (PRRT) WITH 177LU-DOTATATE

1-10

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and this illustration may not be reproduced in any form without the express written permission of NCCN.

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PRINCIPLES OF PEPTIDE RECEPTOR RADIONUCLIDE THERAPY (PRRT) WITH 177LU-DOTATATE

REFERENCES

National Institutes of Health. Lutetium 177Lu dotatate package insert. Available at: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=72d1a024-00b7-418a-

b36e-b2cb48f2ab55. Accessed April 13, 2021.

Strosberg J, El-Haddad G, Wolin E, et al. Phase 3 trial of

177

Lu-dotatate for midgut neuroendocrine tumors. N Engl J Med 2017;376:125-135.

Brabander T, van der Zwan WA, Teunissen JJM, et al. Long-term efficacy, survival, and safety of [

177

Lu-DOTA

,Tyr

] octreotate in patients with gastroenteropancreatic

and bronchial neuroendocrine tumors. Clin Cancer Res 2017;23:4617-4624.

Baum RP, Kulkarni HR, Singh A, et al. Results and adverse events of personalized peptide receptor radionuclide therapy with 90Yttrium and 177Lutetium in 1048

patients with neuroendocrine neoplasms. Oncotarget 2018;9:16932-16950.

Sharma N, Naraev BG, Engelman EG, et al. Peptide receptor radionuclide therapy outcomes in a North American cohort with metastatic well-differentiated

neuroendocrine tumors. Pancreas 2017;46:151-156.

Katona BW, Roccardo GA, Soulen MC, et al. Efficacy of peptide receptor radionuclide therapy in a United States-based cohort of metastatic neuroendocrine tumor

patients: Single-institution retrospective analysis. Pancreas 2017;46:1121-1126.

Kong G, Grozinsky-Glasberg S, Hofman MS, et al. Efficacy of peptide receptor radionuclide therapy for functional metastatic paraganglioma and pheochromocytoma. J

Clin Endocrinol Metab 2017;102:3278-3287.

Vyakaranam AR, Crona J, Norlén O, et al. Favorable outcome in patients with pheochromocytoma and paraganglioma treated with 177Lu-DOTATATE. Cancers (Basel)

2019;11:909.

Jaiswal SK, Sarathi V, Menon SS, et al. 177Lu-DOTATATE therapy in metastatic/inoperable pheochromocytoma-paraganglioma. Endocr Connect 2020;9:864-873.

Mirvis E, Toumpanakis C, Mandair D, et al. Efficacy and tolerability of peptide receptor radionuclide therapy (PRRT) in advanced metastatic bronchial neuroendocrine

tumours (NETs). Lung Cancer 2020;150:70-75.

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(NCCN

and this illustration may not be reproduced in any form without the express written permission of NCCN.

Note: All recommendations are category 2A unless otherwise indicated.

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PRINCIPLES OF LIVER-DIRECTED THERAPY FOR NEUROENDOCRINE TUMOR METASTASES

Liver-directed therapy consists of three categories of treatment:

Surgical resection (which may include intraoperative thermal ablation of lesions); see Surgical Principles For Management of Neuroendocrine

Tumors (NE-D)

Hepatic arterial embolization, including bland transarterial embolization [TAE], chemoembolization [TACE], and radioembolization [TARE]

Percutaneous thermal ablation

Indications for Hepatic Arterial Embolization

• Embolization is recommended for well-dierentiated NETs with liver-dominant, unresectable metastases that are:

Symptomatic on an SSA or following another form of systemic therapy

Progressive on an SSA or following another form of systemic therapy

Presenting with bulky liver disease; embolization may be employed as debulking therapy without waiting for progression.

• Objective radiologic response rates vary widely in retrospective studies, but average approximately 60%, with symptom palliation in

approximately 85% of patients with hormonal syndromes.

• Relative contraindications include signicant baseline liver dysfunction (jaundice, ascites) and a liver tumor burden >70%. Prior Whipple

surgery or biliary instrumentation (sphincterotomy, stent) increases the risk of liver abscess due to biliary bacterial colonization; infectious

complications occur in about 20% of cases following TAE/TACE and 8% after TARE, even with broad-spectrum antibiotic coverage.

Embolization Modalities

• TAE and TACE

There are no completed randomized studies comparing TAE with conventional TACE and both are acceptable.

Drug-eluting embolics are associated with increased hepatobiliary toxicity in the NET population, and are not recommended.

In patients with bilobar disease, TAE/TACE is generally performed over at least two procedures, approximately one month apart. Patients

with very high liver tumor burden may require three or four embolizations to safely treat the entire liver. Short-acting octreotide should be

administered pre-embolization for patients with hormonal syndromes. Overnight observation is typically appropriate to monitor and treat

symptoms of post-embolization syndrome such as pain and nausea and exacerbation of hormone-related symptoms.

• TARE may be considered particularly in the following scenarios:

Lobar or segmental (less than lobular) disease distribution.

Patients with prior Whipple surgery or biliary tract instrumentation (lower risk of hepatobiliary infection than TAE/TACE).

1-4

TARE is better tolerated than TAE/TACE, but late radioembolization-induced chronic hepatotoxicity (RECHT) may occur in long-term

survivors, and is particularly a concern among patients undergoing bilobar radioembolization.

To date there is no evidence for or against the safety of sequencing TARE and PRRT.

5,6

Ablative Therapy (category 2B)

• Percutaneous thermal ablation, often using microwave energy (radiofrequency and cryoablation are also acceptable), can be considered

for oligometastatic liver disease, generally up to four lesions each smaller than 3 cm. Feasibility considerations include safe percutaneous

imaging-guided approach to the target lesions, and proximity to vessels, bile ducts, or adjacent non-target structures that may require

hydro- or aero-dissection for displacement.

References

NCCN Guidelines Version 2.2021

Neuroendocrine and Adrenal Tumors

(NCCN

and this illustration may not be reproduced in any form without the express written permission of NCCN.

Note: All recommendations are category 2A unless otherwise indicated.

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

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Discussion

Devulapalli KK, Fidelman N, Soulen MC, et al. 90Y radioembolization for hepatic Malignancy in patients with previous biliary intervention: Multicenter analysis of

hepatobiliary infections. Radiology 2018;288:774-781.

Patel S, Tuite CM, Mondschein JI, Soulen MC. Effectiveness of an aggressive antibiotic regimen for chemoembolization in patients with previous biliary intervention. J

Vasc Interv Radiol 2006;17:1931-1934.

Kim W, Clark TW, Baum RA, Soulen MC. Risk factors for liver abscess formation after hepatic chemoembolization. J Vasc Interv Radiol 2001;12:965-968.

Cholapranee A, van Houten D, Deitrick G, et al. Risk of liver abscess formation in patients with prior biliary intervention following yttrium-90 radioembolization.

Cardiovasc Intervent Radiol 2015;38:397-400.

Braat AJAT, Ahmadzadehfar H, Kappadath SC, et al. Radioembolization with 90Y resin microspheres of neuroendocrine liver metastases after initial peptide receptor

radionuclide therapy. Cardiovasc Intervent Radiol 2020;43:246-253.

Braat AJAT, Bruijnen RCG, van Rooij R, et al. Additional holmium-166 radioembolisation after lutetium-177-dotatate in patients with neuroendocrine tumour liver

metastases (HEPAR PLuS): a single-centre, single-arm, open-label, phase 2 study. Lancet Oncol 202;21:561-570.

PRINCIPLES OF LIVER-DIRECTED THERAPY FOR NEUROENDOCRINE TUMOR METASTASES

REFERENCES

NE-H

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Neuroendocrine and Adrenal Tumors

(NCCN

and this illustration may not be reproduced in any form without the express written permission of NCCN.

Note: All recommendations are category 2A unless otherwise indicated.

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

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PRINCIPLES OF HORMONE CONTROL

Carcinoid Syndrome

• Carcinoid syndrome (CS) primarily occurs in patients with metastatic well-dierentiated NETs originating in the distal small intestine and proximal colon

(midgut). CS can also be secondary to pulmonary NETs and rarely pancreatic NETs. Serotonin along with other vasoactive substances contributes to the

syndrome.

• Signs and symptoms include ushing, diarrhea, wheezing (rare), and CHD (in patients with highly elevated serotonin levels).

Serotonin is thought to be the most important factor in the etiology of CS diarrhea and CHD, but the etiology of ushing is less well understood.

Refractory ushing or diarrhea is dened as suboptimal symptom control in the setting of long-acting SSAs (octreotide or lanreotide) used in approved

doses.

It is important to note that diarrhea can be multifactorial: other common causes include direct side eects from SSAs, pancreatic exocrine insuciency

from SSA use resulting in steatorrhea, bile malabsorption from ileocecectomy or cholecystectomy, and short-gut symptom.

• In patients with CS, invasive procedures should only be performed in centers with experienced anesthesiologists.

Symptom Management

• CS-diarrhea and ushing

Long-acting SSA (octreotide LAR and lanreotide) are highly active for control of

both ushing and diarrhea.

Telotristat ethyl 250 mg TID is specically recommended for patients with

refractory diarrhea secondary to CS (usually with proven elevated serotonin

or 5-HIAA), in combination with long-acting SSA. Symptomatic benet can

sometimes be delayed for several weeks after initiation of the drug.

Patients who experience symptom exacerbation towards the end of each 4-week

SSA cycle can often benet from more frequent administration (ie, every 3 weeks).

Dose escalation can also sometimes benet patients with refractory symptoms.

Short-acting octreotide, given subcutaneously, administered at doses of 150–250

mcg every 8 hours as needed, can be prescribed to patients with suboptimal

control of ushing and/or diarrhea.

Serotonin antagonists such as ondansetron can improve refractory CS diarrhea in

refractory patients.

Treatments that eectively cytoreduce secretory metastatic tumors are likely to

palliate hormonal symptoms. For patients with liver-dominant disease, surgical

cytoreduction or hepatic arterial embolization are highly eective at control of

ushing and/or diarrhea. PRRT with 177Lu-dotatate has been associated with

delay in diarrhea progression.

Nonspecic antidiarrheals (ie, loperamide, diphenoxylate/atropine, tincture of

opium) and cyproheptadine can be benecial for management of refractory

diarrhea, regardless of cause.

Cyproheptadine can be considered for control of ushing for patients who cannot

tolerate SSA.

• Non CS-diarrhea

In patients who develop diarrhea/steatorrhea exacerbation while

on SSA, a trial of pancreatic enzymes for pancreatic exocrine

insuciency should be considered.

Patients with persistent diarrhea after ileocecectomy or

cholecystectomy, especially if associated with urgency, can be treated

empirically with bile acid binding drugs such as cholestyramine.

For patients with presumed short-gut syndrome, suggest referral to

appropriate gastroenterologist expert.

Nonspecic antidiarrheals (ie, loperamide, diphenoxylate/atropine,

tincture of opium) and cyproheptadine can be benecial for

management of refractory diarrhea, regardless of cause.

• CHD

CHD should be monitored by a cardiologist with expertise in

the disease as the echocardiographic diagnosis of CHD can be

challenging. Valve replacement (typically tricuspid and pulmonary) is

indicated for symptomatic patients.

NCCN Guidelines Version 2.2021

Neuroendocrine and Adrenal Tumors

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and this illustration may not be reproduced in any form without the express written permission of NCCN.

Note: All recommendations are category 2A unless otherwise indicated.

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PRINCIPLES OF HORMONE CONTROL

Pancreatic Neuroendocrine Tumors

• Medical, surgical, and interventional treatments that eectively cytoreduce secretory tumors are likely to also palliate hormonal symptoms.

The following recommendations pertain to non-cytotoxic treatments, which can reduce hormonal secretions or mitigate secretory eects.

Hormone Management

Gastrin • Manage gastric hypersecretion with high-dose proton pump inhibitors, generally given two times a day.

• Consider octreotide or lanreotide.

Insulin • Stabilize glucose levels with diet and/or diazoxide or everolimus.

• Octreotide or lanreotide can be considered but only if tumor expresses SSRs. In the absence of SSRs,

octreotide or lanreotide can profoundly worsen hypoglycemia.

VIP • Octreotide or lanreotide are the rst-line management for control of hormone symptoms.

• Correct electrolyte imbalance (K+, Mg2+, HCO3-) and dehydration.

• Corticosteroids can be eective in SSR-refractory patients.

Glucagon • Octreotide or lanreotide are the rst-line management for control of hormone symptoms.

• Treat hyperglycemia and diabetes, as appropriate.

Continued

Used with permission of the American College of Surgeons, Chicago, Illinois. The original source for this information is the AJCC Cancer Staging Manual, Eighth Edition

(2017) published by Springer International Publishing.

American Joint Committee on Cancer (AJCC)

TNM Staging System for Neuroendocrine Tumors of the Stomach (NET G1 and G2,

and rare well-dierentiated G3) (8th ed., 2017)

Table 1. Denitions for T, N, M

Stomach

T Primary Tumor

TX Primary tumor cannot be assessed

T0 No evidence of primary tumor

T1* Invades the lamina propria or submucosa and less than or equal to 1 cm in

size

T2* Invades the muscularis propria or greater than 1 cm in size

T3* Invades through the muscularis propria into subserosal tissue without

penetration of overlying serosa

T4* Invades visceral peritoneum (serosa) or other organs or adjacent structures

* Note: For any T, add (m) for multiple tumors [TX(#) or TX(m),

where X = 1–4 and # = number of primary tumors identified**];

for multiple tumors with different Ts, use the highest.

** Example: If there are two primary tumors, one of which penetrates only the subserosa, we define

the primary tumor as either T3(2) or T3(m).

N Regional Lymph Nodes

NX Regional lymph nodes cannot be assessed

N0 No regional lymph node metastasis

N1 Regional lymph node metastasis

M Distant Metastasis

M0 No distant metastasis

M1 Distant metastasis

M1a Metastasis conned to liver

M1b Metastases in at least one extrahepatic site (e.g., lung, ovary,

nonregional lymph node, peritoneum, bone)

M1c Both hepatic and extrahepatic metastases

Table 2. AJCC Prognostic Stage Groups

T N M

Stage I T1 N0 M0

Stage II T2, T3 N0 M0

Stage III T1, T2, T3 N1 M0

T4 N0, N1 M0

Stage IV Any T Any N M1

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Discussion

ST-1

Continued

Used with permission of the American College of Surgeons, Chicago, Illinois. The original source for this information is the AJCC Cancer Staging Manual, Eighth Edition

(2017) published by Springer International Publishing.

American Joint Committee on Cancer (AJCC)

TNM Staging System for Well-Dierentiated Neuroendocrine Tumors of the Duodenum and Ampulla of Vater (8th ed., 2017)

Table 3. Denitions for T, N, M

Duodenum/Ampulla

T Primary Tumor

TX Primary tumor not assessed

T1 Tumor invades the mucosa or submucosa only and is ≤1 cm (duodenal tumors);

Tumor ≤1 cm and conned within the sphincter of Oddi (ampullary tumors)

T2 Tumor invades the muscularis propria or is >1 cm (duodenal);

Tumor invades through sphincter into duodenal submucosa or muscularis propria,

or is >1 cm (ampullary)

T3 Tumor invades the pancreas or peripancreatic adipose tissue

T4 Tumor invades the visceral peritoneum (serosa) or other organs

Note: Multiple tumors should be designated as such (and the largest tumor should be used to assign

the T category):

• If the number of tumors is known, use T(#); e.g., pT3(4)N0M0.

• If the number of tumors is unavailable or too numerous, use the suffix m —T(m)—e.g., pT3(m)N0M0.

N Regional Lymph Nodes

NX Regional lymph nodes cannot be assessed

N0 No regional lymph node involvement

N1 Regional lymph node involvement

M Distant Metastasis

M0 No distant metastasis

M1 Distant metastases

M1a Metastasis conned to liver

M1b Metastases in at least one extrahepatic site (e.g., lung,

ovary, nonregional lymph node, peritoneum, bone)

M1c Both hepatic and extrahepatic metastases

Table 4. AJCC Prognostic Stage Groups

T N M

Stage I T1 N0 M0

Stage II T2 N0 M0

T3 N0 M0

Stage III T4 N0 M0

Any T N1 M0

Stage IV Any T Any N M1

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Discussion

ST-2

Continued

Used with permission of the American College of Surgeons, Chicago, Illinois. The original source for this information is the AJCC Cancer Staging Manual, Eighth Edition

(2017) published by Springer International Publishing.

American Joint Committee on Cancer (AJCC)

TNM Staging System for Neuroendocrine Tumors of the Jejunum and Ileum (small bowel [NET G1 and G2, and rare well-dierentiated G3]

arising in the jejunum and ileum.) (8th ed., 2017)

Table 5. Denitions for T, N, M

Jejunum/Ileum

T Primary Tumor

TX Primary tumor cannot be assessed

T0 No evidence of primary tumor

T1* Invades lamina propria or submucosa and less than or equal to1 cm in size

T2* Invades muscularis propria or greater than 1 cm in size

T3* Invades through the muscularis propria into subserosal tissue without

penetration of overlying serosa

T4* Invades visceral peritoneum (serosal) or other organs or adjacent structures

* Note: For any T, add (m) for multiple tumors [TX(#) or TX(m), where X = 1–4, and # = number of

primary tumors identified**]; for multiple tumors with different T, use the highest.

** Example: If there are two primary tumors, only one of which invades through the muscularis

propria into subserosal tissue without penetration of overlying serosa (jejunal or ileal), we define

the primary tumor as either T3(2) or T3(m).

N Regional Lymph Nodes

NX Regional lymph nodes cannot be assessed

N0 No regional lymph node involvement metastasis has occurred

N1 Regional lymph node metastasis less than 12 nodes

N2 Large mesenteric masses (>2 cm) and/or extensive nodal deposits (12

or greater), especially those that encase the superior mesenteric vessels

M Distant Metastasis

M0 No distant metastasis

M1 Distant metastasis

M1a Metastasis conned to liver

M1b Metastases in at least one extrahepatic site (e.g., lung,

ovary, nonregional lymph node, peritoneum, bone)

M1c Both hepatic and extrahepatic metastases

Table 6. AJCC Prognostic Stage Groups

T N M

Stage I T1 N0 M0

Stage II T2 N0 M0

T3 N0 M0

Stage III T1 N1, N2 M0

T2 N1, N2 M0

T3 N1, N2 M0

T4 N0 M0

T4 N1, N2 M0

Stage IV Any T Any N M1

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and this illustration may not be reproduced in any form without the express written permission of NCCN.

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Table of Contents

Discussion

ST-3

Continued

Used with permission of the American College of Surgeons, Chicago, Illinois. The original source for this information is the AJCC Cancer Staging Manual, Eighth Edition

(2017) published by Springer International Publishing.

American Joint Committee on Cancer (AJCC)

TNM Staging System for Neuroendocrine Tumors of the Colon and Rectum [neuroendocrine tumor G1 and G2, and rare well-dierentiated G3]

(8th ed., 2017)

Table 7. Denitions for T, N, M

Colon and Rectum

T* Primary Tumor

TX Primary tumor cannot be assessed

T0 No evidence of primary tumor

T1 Tumor invades the lamina propria or submucosa and is ≤2 cm

T1a Tumor <1 cm in greatest dimension

T1b Tumor 1–2 cm in greatest dimension

T2 Tumor invades the muscularis propria or is >2 cm with invasion of the lamina propria or

submucosa

T3 Tumor invades through the muscularis propria into subserosal tissue without

penetration of overlying serosa

T4 Tumor invades the visceral peritoneum (serosa) or other organs or adjacent structures

* Note: For any T, add “(m)” for multiple tumors [TX(#) or TX(m), where X = 1–4 and

# = number of primary tumors identified**]; for multiple tumors with different T, use the highest.

** Example: If there are two primary tumors, only one of which invades through the muscularis propria into the

subserosal tissue without penetration of the overlying serosa, we define the primary tumor as either T3(2) or T3(m).

N Regional Lymph Nodes

NX Regional lymph nodes cannot be assessed

N0 No regional lymph node metastasis has occurred

N1 Regional lymph node metastasis

M Distant Metastasis

M0 No distant metastasis

M1 Distant metastasis

M1a Metastasis conned to liver

M1b Metastases in at least one extrahepatic site (e.g., lung, ovary,

nonregional lymph node, peritoneum, bone)

M1c Both hepatic and extrahepatic metastases

Table 8. AJCC Prognostic Groups

T N M

Stage I T1 N0 M0

Stage IIA T2 N0 M0

Stage IIB T3 N0 M0

Stage IIIA T4 N0 M0

Stage IIIB T1 N1 M0

T2 N1 M0

T3 N1 M0

T4 N1 M0

Stage IV TX, T0 Any N M1

T1 Any N M1

T2 Any N M1

T3 Any N M1

T4 Any N M1

Note: For multiple synchronous

tumors, the highest T category should

be used and the multiplicity or the

number of tumors should be indicated

in parenthesis, e.g., T3(2) or T3(m).

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Discussion

ST-4

Continued

Used with permission of the American College of Surgeons, Chicago, Illinois. The original source for this information is the AJCC Cancer Staging Manual, Eighth Edition

(2017) published by Springer International Publishing.

American Joint Committee on Cancer (AJCC)

TNM Staging System for Neuroendocrine Tumors of the Pancreas [well-dierentiated neuroendocrine tumors arising in the pancreas]

(8th ed., 2017)

Table 9. Denitions for T, N, M

Pancreatic

T Primary Tumor

TX Tumor cannot be assessed

T1 Tumor limited to the pancreas,* <2 cm

T2 Tumor limited to the pancreas,* 2−4 cm

T3 Tumor limited to the pancreas,* >4 cm; or tumor invading the duodenum or

common bile duct

T4 Tumor invading adjacent organs (stomach, spleen, colon, adrenal gland) or the wall

of large vessels (celiac axis or the superior mesenteric artery)

* Limited to the pancreas means there is no invasion of adjacent organs (stomach, spleen, colon,

adrenal gland) or the wall of large vessels (celiac axis or the superior mesenteric artery).

Extension of tumor into peripancreatic adipose tissue is NOT a basis for staging.

Note: Multiple tumors should be designated as such (the largest tumor should be used to assign T category):

• If the number of tumors is known, use T(#); e.g., pT3(4) N0 M0.

• If the number of tumors is unavailable or too numerous, use the m sux, T(m); e.g., pT3(m) N0 M0.

N Regional Lymph Nodes

NX Regional lymph nodes cannot be assessed

N0 No regional lymph node involvement

N1 Regional lymph node involvement

M Distant Metastasis

M0 No distant metastasis

M1 Distant metastases

M1a Metastasis conned to liver

M1b Metastases in at least one extrahepatic site (e.g., lung, ovary, nonregional lymph

node, peritoneum, bone)

M1c Both hepatic and extrahepatic metastases

Table 10. AJCC Prognostic Stage Groups

T N M

Stage I T1 N0 M0

Stage II T2 N0 M0

T3 N0 M0

Stage III T4 N0 M0

Any T N1 M0

Stage IV Any T Any N M1

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Discussion

ST-5

Continued

American Joint Committee on Cancer (AJCC)

TNM Staging System for Neuroendocrine Tumors of the Appendix [NET G1 and G2, and rare well-dierentiated G3] (8th ed., 2017)

Table 11. Denitions for T, N, M

Appendiceal Neuroendocrine Tumors

T Primary Tumor

TX Primary tumor cannot be assessed

T0 No evidence of primary tumor

T1 Tumor 2 cm or less in greatest dimension

T2 Tumor more than 2 cm but less than or equal to 4 cm

T3 Tumor more than 4 cm or with subserosal invasion or

involvement of the mesoappendix

T4 Tumor perforates the peritoneum or directly invades other

adjacent organs or structures (excluding direct mural

extension to adjacent subserosa of adjacent bowel), e.g.,

abdominal wall and skeletal muscle

N Regional Lymph Nodes

NX Regional lymph nodes cannot be assessed

N0 No regional lymph node metastasis

N1 Regional lymph node metastasis

M Distant Metastasis

M0 No distant metastasis

M1 Distant metastasis

M1a Metastasis conned to liver

M1b Metastases in at least one extrahepatic site (e.g., lung,

ovary, nonregional lymph node, peritoneum, bone)

M1c Both hepatic and extrahepatic metastases

Used with permission of the American College of Surgeons, Chicago, Illinois. The original source for this information is the AJCC Cancer Staging Manual, Eighth Edition

(2017) published by Springer International Publishing.

Table 12. AJCC Prognostic Stage Groups

T N M

Stage I T1 N0 M0

Stage II T2 N0 M0

T3 N0 M0

Stage III T1 N1 M0

T2 N1 M0

T3 N1 M0

T4 N0 M0

T4 N1 M0

Stage IV TX, T0 Any N M1

T1 Any N M1

T2 Any N M1

T3 Any N M1

T4 Any N M1

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Discussion

ST-6

Continued

Used with permission of the American College of Surgeons, Chicago, Illinois. The original source for this information is the AJCC Cancer Staging Manual, Eighth Edition

(2017) published by Springer International Publishing.

American Joint Committee on Cancer (AJCC)

TNM Staging System for Adrenal – Neuroendocrine Tumors [Pheochromocytoma and paraganglioma] (8th ed., 2017)

Table 13. Denitions for T, N, M

Adrenal

T Primary Tumor

TX Primary tumor cannot be assessed

T1 PH <5 cm in greatest dimension, no extra-adrenal invasion

T2 PH ≥5 cm or PG-sympathetic of any size, no extra-adrenal invasion

T3 Tumor of any size with local invasion into surrounding tissues

(e.g., liver, pancreas, spleen, kidneys)

PH: within adrenal gland

PG Sympathetic: functional

PG Parasympathetic: nonfunctional, usually in the head and neck region

Note: Parasympathetic Paragaglioma are not staged because they are largely benign.

N Regional Lymph Nodes

NX Regional lymph nodes cannot be assessed

N0 No regional lymph node metastasis

N1 Regional lymph node metastasis

M Distant Metastasis

M0 No distant metastasis

M1 Distant metastasis

M1a Distant metastasis to only bone

M1b Distant metastasis to only distant lymph nodes/liver or lung

M1c Distant metastasis to bone plus multiple other sites

Table 14. AJCC Prognostic Stage Groups

Pheochromocytoma/Sympathetic Paraganglioma

T N M

Stage I T1 N0 M0

Stage II T2 N0 M0

Stage III T1 N1 M0

T2 N1 M0

T3 Any N M0

Stage IV Any T Any N M1

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Discussion

ST-7

Continued

Used with permission of the American College of Surgeons, Chicago, Illinois. The original source for this information is the AJCC Cancer Staging Manual, Eighth Edition

(2017) published by Springer International Publishing.

American Joint Committee on Cancer (AJCC)

TNM Staging System for Adrenal Cortical Carcinoma (8th ed., 2017)

Table 15. Denitions for T, N, M

Adrenal Cortical Carcinoma

T Primary Tumor

TX Primary tumor cannot be assessed

T0 No evidence of primary tumor

T1 Tumor ≤5 cm in greatest dimension, no extra-adrenal invasion

T2 Tumor >5 cm, no extra-adrenal invasion

T3 Tumor of any size with local invasion but not invading adjacent organs

T4 Tumor of any size that invades adjacent organs (kidney, diaphragm,

pancreas, spleen, or liver) or large blood vessels (renal vein or vena cava)

N Regional Lymph Nodes

NX Regional lymph nodes cannot be assessed

N0 No regional lymph node metastasis

N1 Metastasis in regional lymph node(s)

M Distant Metastasis

M0 No distant metastasis

M1 Distant metastasis

G Histologic Grade

LG Low grade (≤20 mitoses per 50 HPF)

HG High grade (>20 mitosis per 50 HPF); TP53 or CTNNB mutation

Table 16. AJCC Prognostic Stage Groups

T N M

Stage I T1 N0 M0

Stage II T2 N0 M0

Stage III T1 N1 M0

T2 N1 M0

T3 Any N M0

T4 Any N M0

Stage IV Any T Any N M1

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Discussion

ST-8

Continued

Used with permission of the American College of Surgeons, Chicago, Illinois. The original source for this information is the AJCC Cancer Staging Manual, Eighth Edition

(2017) published by Springer International Publishing.

American Joint Committee on Cancer (AJCC)

TNM Staging System for Lung (8th ed., 2017) [carcinomas of the lung, including non–small cell and small cell carcinomas, and

bronchopulmonary carcinoid tumors].

Table 17. Denitions for T, N, M

Lung

T Primary Tumor

TX Primary tumor cannot be assessed, or tumor proven by the presence of malignant cells in sputum or bronchial washings but not visualized by

imaging or bronchoscopy

T0 No evidence of primary tumor

Tis Carcinoma in situ

Squamous cell carcinoma in situ (SCIS)

Adenocarcinoma in situ (AIS): adenocarcinoma with pure lepidic pattern, ≤3 cm in greatest dimension

T1 Tumor ≤3 cm in greatest dimension, surrounded by lung or visceral pleura, without bronchoscopic evidence of invasion more proximal than

the lobar bronchus (i.e., not in the main bronchus)

T1mi Minimally invasive adenocarcinoma: adenocarcinoma (≤3 cm in greatest dimension) with a predominantly lepidic pattern and ≤5 mm invasion

in greatest dimension

T1a Tumor ≤1 cm in greatest dimension. A supercial, spreading tumor of any size whose invasive component is limited to the bronchial wall and

may extend proximal to the main bronchus also is classied as T1a, but these tumors are uncommon.

T1b Tumor >1 cm but ≤2 cm in greatest dimension

T1c Tumor >2 cm but ≤3 cm in greatest dimension

T2 Tumor >3 cm but ≤5 cm or having any of the following features:

• Involves the main bronchus regardless of distance to the carina, but without involvement of the carina

• Invades visceral pleura (PL1 or PL2)

• Associated with atelectasis or obstructive pneumonitis that extends to the hilar region, involving part or all of the lung

T2 tumors with these features are classied as T2a if ≤4 cm or if the size cannot be determined and T2b if >4 cm but ≤5 cm.

T2a Tumor >3 cm but ≤4 cm in greatest dimension

T2b Tumor >4 cm but ≤5 cm in greatest dimension

T3 Tumor >5 cm but ≤7 cm in greatest dimension or directly invading any of the following: parietal pleural (PL3), chest wall (including superior

sulcus tumors), phrenic nerve, parietal pericardium; or separate tumor nodule(s) in the same lobe as the primary

T4 Tumor >7 cm or tumor of any size invading one or more of the following: diaphragm, mediastinum, heart, great vessels, trachea, recurrent

laryngeal nerve, esophagus, vertebral body, or carina; separate tumor nodule(s) in an ipsilateral lobe dierent from that of the primary

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ST-9

Continued

American Joint Committee on Cancer (AJCC)

TNM Staging System for Lung (8th ed., 2017) [carcinomas of the lung, including non–small cell and small cell carcinomas, and

bronchopulmonary carcinoid tumors].

Table 17. Denitions for T, N, M (continued)

Lung

N Regional Lymph Nodes

NX Regional lymph nodes cannot be assessed

N0 No regional lymph node metastasis

N1 Metastasis in ipsilateral peribronchial and/or ipsilateral hilar lymph nodes

and intrapulmonary nodes, including involvement by direct extension

N2 Metastasis in ipsilateral mediastinal and/or subcarinal lymph node(s)

N3 Metastasis in contralateral mediastinal, contralateral hilar, ipsilateral or

contralateral scalene, or supraclavicular lymph node(s)

M Distant Metastasis

M0 No distant metastasis

M1 Distant metastasis

M1a Separate tumor nodule(s) in a contralateral lobe; tumor with pleural

or pericardial nodules or malignant pleural or pericardial eusion.

Most pleural (pericardial) eusions with lung cancer are a result of the

tumor. In a few patients, however, multiple microscopic examinations

of pleural (pericardial) uid are negative for tumor, and the uid

is nonbloody and not an exudate. If these elements and clinical

judgment dictate that the eusion is not related to the tumor, the

eusion should be excluded as a staging descriptor.

M1b Single extrathoracic metastasis in a single organ (including

involvement of a single nonregional node)

M1c Multiple extrathoracic metastases in a single organ or in multiple

organs

Used with permission of the American College of Surgeons, Chicago, Illinois. The original source for this information is the AJCC Cancer Staging Manual, Eighth Edition

(2017) published by Springer International Publishing.

Table 18. AJCC Prognostic Stage Groups

T N M

Occult Carcinoma TX N0 M0

Stage 0 Tis N0 M0

Stage IA1 T1mi, T1a N0 M0

Stage IA2 T1b N0 M0

Stage IA3 T1c N0 M0

Stage IB T2a N0 M0

Stage IIA T2b N0 M0

Stage IIB T1a, T1b, T1c N1 M0

T2a, T2b N1 M0

T3 N0 M0

Stage IIIA T1a, T1b, T1c N2 M0

T2a, T2b N2 M0

T3 N1 M0

T4 N0, N1 M0

Stage IIIB T1a, T1b, T1c N3 M0

T2a, T2b N3 M0

T3 N2 M0

T4 N2 M0

Stage IIIC T3 N3 M0

T4 N3 M0

Stage IVA Any T Any N M1a

Any T Any N M1b

Stage IVB Any T Any N M1c

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Discussion

ST-10

Used with permission of the American College of Surgeons, Chicago, Illinois. The original source for this information is the AJCC Cancer Staging Manual, Eighth Edition

(2017) published by Springer International Publishing.

American Joint Committee on Cancer (AJCC)

TNM Staging System for Thymus (8th ed., 2017) [including thymoma, thymic carcinoma, thymic neuroendocrine tumors, combined thymic

carcinoma]

Table 19. Denitions for T*

**, N*, M

Thymus

** Primary Tumor

TX Primary tumor cannot be assessed

T0 No evidence of primary tumor

T1 Tumor encapsulated or extending into the mediastinal fat; may involve the

mediastinal pleura

T1a Tumor with no mediastinal pleura involvement

T1b Tumor with direct invasion of mediastinal pleura

T2 Tumor with direct invasion of the pericardium (either partial or full thickness)

T3 Tumor with direct invasion into any of the following: lung, brachiocephalic vein,

superior vena cava, phrenic nerve, chest wall, or extrapericardial pulmonary artery or

veins

T4 Tumor with invasion into any of the following: aorta (ascending, arch, or descending),

arch vessels, intrapericardial pulmonary artery, myocardium, trachea, esophagus

N* Regional Lymph Nodes

NX Regional lymph nodes cannot be assessed

N0 No regional lymph node metastasis

N1 Metastasis in anterior (perithymic) lymph nodes

N2 Metastasis in deep intrathoracic or cervical lymph nodes

*Involvement must be microscopically conrmed in pathological staging, if possible.

**T categories are dened by “levels” of invasion; they reect the highest degree of invasion regardless of

how many other (lower-level) structures are invaded. T1, level 1 structures: thymus, anterior mediastinal fat,

mediastinal pleura; T2, level 2 structures: pericardium; T3, level 3 structures: lung, brachiocephalic vein,

superior vena cava, phrenic nerve, chest wall, hilar pulmonary vessels; T4, level 4 structures: aorta

(ascending, arch, or descending), arch vessels, intrapericardial pulmonary artery, myocardium, trachea, esophagus.

Table 20. AJCC Prognostic Stage Groups

T N M

Stage I T1a, b N0 M0

Stage II T2 N0 M0

Stage IIIA T3 N0 M0

Stage IIIB T4 N0 M0

Stage IVA Any T N1 M0

Any T N0, N1 M1a

Stage IVB Any T N2 M0, M1a

Any T Any N M1b

M Distant Metastasis

M0 No pleural, pericardial, or distant

metastasis

M1 Pleural, pericardial, or distant metastasis

M1a Separate pleural or pericardial nodule(s)

M1b Pulmonary intraparenchymal nodule or

distant organ metastasis

Continued

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Discussion

ST-11

Used with permission of the American College of Surgeons, Chicago, Illinois. The original source for this information is the AJCC Cancer Staging Manual, Eighth Edition

(2017) published by Springer International Publishing.

Table 21. Denitions for T, N, M

Ampulla of Vater (high-grade neuroendocrine carcinoma)

T Primary Tumor

TX Primary tumor cannot be assessed

T0 No evidence of primary tumor

Tis Carcinoma in situ

T1 Tumor limited to ampulla of Vater or sphincter of Oddi or tumor invades beyond the

sphincter of Oddi (perisphincteric invasion) and/or into the duodenal submucosa

T1a Tumor limited to ampulla of Vater or sphincter of Oddi

T1b Tumor invades beyond the sphincter of Oddi (perisphincteric invasion) and/or into the

duodenal submucosa

T2 Tumor invades into the muscularis propria of the duodenum

T3 Tumor directly invades the pancreas (up to 0.5 cm) or tumor extends more than

0.5 cm into the pancreas, or extends into peripancreatic or periduodenal tissue or

duodenal serosa without involvement of the celiac axis or superior mesenteric artery

T3a Tumor directly invades pancreas (up to 0.5 cm)

T3b Tumor extends more than 0.5 cm into the pancreas, or extends into peripancreatic

tissue or periduodenal tissue or duodenal serosa without involvement of the celiac

axis or superior mesenteric artery

T4 Tumor involves the celiac axis, superior mesenteric artery, and/or common hepatic

artery, irrespective of size

N Regional Lymph Nodes

NX Regional lymph nodes cannot be assessed

N0 No regional lymph node metastasis

N1 Metastasis to one to three regional lymph nodes

N2 Metastasis to four or more regional lymph nodes

Table 22. AJCC Prognostic Stage Groups

T N M

Stage 0 TiS N0 M0

Stage IA T1a N0 M0

Stage IB T1b, T2 N0 M0

Stage IIA T3a N0 M0

Stage IIB T3b N0 M0

Stage IIIA T1a, T1b,

T2, T3a,

T3b

N1 M0

Stage IIIB T4 Any N M0

Any T N2 M0

Stage IV Any T Any N M1

M Distant Metastasis

M0 No distant metastasis

M1 Distant metastasis

American Joint Committee on Cancer (AJCC)

TNM Staging System for Ampulla of Vater (8th ed., 2017) [applies to all primary carcinomas that arise in the ampulla or on the duodenal

papilla, including high-grade neuroendocrine carcinomas such as small cell carcinoma and large cell neuroendocrine carcinoma]

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ST-12

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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 indicated.

NCCN Categories of Preference

Preferred intervention

Interventions that are based on superior ecacy, safety, and evidence; and, when appropriate,

aordability.

Other recommended

intervention

Other interventions that may be somewhat less ecacious, more toxic, or based on less mature data;

or signicantly less aordable for similar outcomes.

Useful in certain

circumstances

Other interventions that may be used for selected patient populations (dened with recommendation).

All recommendations are considered appropriate.

CAT-1